bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of a constant magnetic field on morphology and motility of cell with cytoskeleton-associated magnetic nanoparticles
Authors: Karavashkova Olga , Maltseva Alexandra , Minin Artem S , Demin Alexander , Tin Pavel , Aitova Aleria , Tsvelaya Valeria , Latypova Anastasiia Alfredovna , Zubarev Ilya
Published: May 2024

1.

Cell motility, shape supporting, and intracellular signaling are followed by changes in cell morphology and cytoskeleton. The cell reaction and the reorganization of the cytoskeleton occurs in a single volume of the cytoplasm and affects all components of the cytoskeleton: intermediate filaments, microtubules and microfilaments. A promising way to manipulate cells is magnetic nanoparticles that control cellular physiology. This approach is called magnetogenetics and has found application in various fields of cell and molecular biology. Using a magnetic field, it is possible to non-invasively regulate biochemical processes, migration and changes in the morphology of cells with magnetic nanoparticles. Our work opens up new possibilities for spatial manipulation of individual cytoskeletal components in vitro and operates biochemical pathways associated with individual cytoskeletal components.
Parallel feedback processing for voluntary control: knowledge of spinal feedback in motor cortex
Authors: Guang Hui , Nashed Joseph Y. , Pruszynski J. Andrew , Kalidindi Hari Teja , Crevecoeur Frederic , Cross Kevin P. , Blohm Gunnar , Scott Stephen H.
Published: May 2024

How hierarchical feedback pathways coordinate goal-directed motor corrections remains unknown. We show that systematic increases in spinal reflex responses to applied loads lead to a reciprocal reduction in the neural response in primary motor cortex. We use a neural network model to highlight how knowledge on lower-level feedback processing (i.e. spinal reflexes) can be embedded into a network to generate goal-directed corrections through parallel feedback pathways.
Temporal prediction captures key differences between spiking excitatory and inhibitory V1 neurons
Authors: Taylor Luke , Zenke Friedemann , King Andrew J. , Harper Nicol S.
Published: May 2024

Neurons in primary visual cortex (V1) respond to natural scenes with a sparse and irregular spike code that is carefully balanced by an interplay between excitatory and inhibitory neurons. These neuron classes differ in their spike statistics, tuning preferences, connectivity statistics and temporal dynamics. To date, no single computational principle has been able to account for these properties. We developed a recurrently connected spiking network of excitatory and inhibitory units trained for efficient temporal prediction of natural movie clips. We found that the model exhibited simple and complex cell-like tuning, V1-like spike statistics, and, notably, also captured key differences between excitatory and inhibitory V1 neurons. This suggests that these properties collectively serve to facilitate efficient prediction of the sensory future.
Compartmentalized Cytoplasmic Flows Direct Protein Transport to the Cell’s Leading Edge
Authors: Galbraith Catherine G. , English Brian P. , Boehm Ulrike , Galbraith James A.
Published: May 2024

Inside the cell, proteins essential for signaling, morphogenesis, and migration navigate complex pathways, typically via vesicular trafficking or microtubule-driven mechanisms1–3. However, the process by which soluble cytoskeletal monomers maneuver through the cytoplasm’s ever-changing environment to reach their destinations without using these pathways remains unknown.4–6Here, we show that actin cytoskeletal treadmilling leads to the formation of a semi-permeable actin-myosin barrier, creating a specialized compartment separated from the rest of the cell body that directs proteins toward the cell edge by advection, diffusion facilitated by fluid flow. Contraction at this barrier generates a molecularly non-specific fluid flow that transports actin, actin-binding proteins, adhesion proteins, and even inert proteins forward. The local curvature of the barrier specifically targets these proteins toward protruding edges of the leading edge, sites of new filament growth, effectively coordinating protein distribution with cellular dynamics. Outside this compartment, diffusion remains the primary mode of protein transport, contrasting sharply with the directed advection within. This discovery reveals a novel protein transport mechanism that redefines the front of the cell as a pseudo-organelle, actively orchestrating protein mobilization for cellular front activities such as protrusion and adhesion. By elucidating a new model of protein dynamics at the cellular front, this work contributes a critical piece to the puzzle of how cells adapt their internal structures for targeted and rapid response to extracellular cues. The findings challenge the current understanding of intracellular transport, suggesting that cells possess highly specialized and previously unrecognized organizational strategies for managing protein distribution efficiently, providing a new framework for understanding the cellular architecture’s role in rapid response and adaptation to environmental changes.
Molecular and clinical characterization of a founder mutation causing G6PC3 deficiency
Authors: Zhen Xin , Betti Michael J , Kars Meltem Ece , Patterson Andrew , Medina-Torres Edgar Alejandro , Mendoza Selma Cecilia Scheffler , Sánchez Diana Andrea Herrera , Lopez-Herrera Gabriela , Svyryd Yevgeniya , Mutchinick Osvaldo M. , Gamazon Eric , Rathmell Jeffrey C , Itan Yuval , Markle Janet , Romanillos Patricia O’Farrill , Lugo-Reyes Saul Oswaldo , Martinez-Barricarte Ruben
Published: May 2024

Background

G6PC3 deficiency is a rare genetic disorder that causes syndromic congenital neutropenia. It is driven by the intracellular accumulation of a metabolite named 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) that inhibits glycolysis. Patients display heterogeneous extra-hematological manifestations, contributing to delayed diagnosis.

Objective

TheG6PC3c.210delC variant has been identified in patients of Mexican origin. We set out to study the origin and functional consequence of this mutation. Furthermore, we sought to characterize the clinical phenotypes caused by it.

Methods

Using whole-genome sequencing data, we conducted haplotype analysis to estimate the age of this allele and traced its ancestral origin. We examined how this mutation affected G6PC3 protein expression and performed extracellular flux assays on patient-derived cells to characterize how this mutation impacts glycolysis. Finally, we compared the clinical presentations of patients with the c.210delC mutation relative to other G6PC3 deficient patients published to date.

Results

Based on the length of haplotypes shared amongst ten carriers of theG6PC3c.210delC mutation, we estimated that this variant originated in a common ancestor of indigenous American origin. The mutation causes a frameshift that introduces a premature stop codon, leading to a complete loss of G6PC3 protein expression. When treated with 1,5-anhydroglucitol (1,5-AG), the precursor to 1,5-AG6P, patient-derived cells exhibited markedly reduced engagement of glycolysis. Clinically, c.210delC carriers display all the clinical features of syndromic severe congenital neutropenia type 4 observed in prior reports of G6PC3 deficiency.

Conclusion

TheG6PC3c.210delC is a loss-of-function mutation that arose from a founder effect in the indigenous Mexican population. These findings may facilitate the diagnosis of additional patients in this geographical area. Moreover, thein vitro1,5-AG-dependent functional assay used in our study could be employed to assess the pathogenicity of additionalG6PC3variants.
Small molecule biomarkers predictive of Chagas disease progression
Authors: Liu Zongyuan , Vucetich Steffany , DeToy Kelly , Saucedo Gustavo Durán , Verastegui Manuela , Carballo-Jimenez Paula , Mercado-Saavedra Brandon N. , Tinajeros Freddy , Málaga-Machaca Edith S. , Marcus Rachel , Gilman Robert H. , Bowman Natalie M. , McCall Laura-Isobel
Published: May 2024

Chagas disease (CD) is a neglected tropical disease caused by the parasitic protozoanTrypanosoma cruzi. However, only 20% to 30% of infected individuals will progress to severe symptomatic cardiac manifestations. Current treatments are benznidazole and nifurtimox, which are poorly tolerated regimens. Developing a biomarker to determine the likelihood of patient progression would be helpful for doctors to optimize patient treatment strategies. Such a biomarker would also benefit drug discovery efforts and clinical trials. In this study, we combined untargeted and targeted metabolomics to compare serum samples fromT. cruzi-infected individuals who progressed to severe cardiac disease, versus infected individuals who remained at the same disease stage (non-progressors). We identified four unannotated biomarker candidates, which were validated in an independent cohort using both untargeted and targeted analysis techniques. Overall, our findings demonstrate that serum small molecules can predict CD progression, offering potential for clinical monitoring.
Outcomes and Risk Factors for Postoperative Vasoplegia Following Implant of Continuous-Flow Left Ventricular Assist Devices
Authors: Wright Jonathan C. , Wilbur Jameson G. , Modi Sujal , Abdel-Rasoul Mahmoud , Whitson Bryan A. , Ganapathi Asvin M. , Smith Sakima
Published: May 2024

Refractory postoperative vasoplegia following cardiac surgery and left ventricular assist device (LVAD) implantation predicts poor outcomes. We aimed to investigate outcomes and predictors of postoperative vasoplegia. We retrospectively reviewed a single-center cohort of 190 patients who received LVADs from January 2015 through March 2022 at The Ohio State Wexner Medical Center. Primary outcomes included duration of ICU stay, development of right heart failure (RHF), and mortality. Secondary outcomes included pre-implant medications and post-implant blood products. Vasoplegia was defined as physician documentation of vasoplegia with patients requiring ≥1 intravenous vasopressors within 48-hours following LVAD implantation to maintain a mean arterial pressure >65 mmHg for >24 hours. Overall, 55 (29%) patients developed vasoplegia following LVAD implantation. Our sample was stratified into two cohorts: patients with vasoplegia and without vasoplegia. Baseline characteristics, LVAD indication, creatinine clearance, and comorbidities did not vary significantly between cohorts. Patients without vasoplegia were more likely to have prior implantable cardiac defibrillators (p = 0.02) and were more commonly prescribed pre-operative inotropes (p = 0.03). Blood-product administration within the first 48-hours postoperatively did not differ. While patients with vasoplegia required a longer ICU stay post-op (5 vs 7 days, p = 0.03), there were no significant differences in development of RHF (39% vs 44%), 30-day (7% vs 13%), 1-year (31% vs 29%), and 2-year mortality (39% vs 33%) in patients without and with vasoplegia, respectively. Overall, our vasoplegia rates were consistent with previous literature (29%) and vasoplegia did not confer inferior outcomes for mortality or developing RHF.
Cell-matrix force transmission regulates the loss of naïve pluripotency in mouse embryonic stem cells
Authors: Viswanadha Srivatsava , Gómez-González Manuel , Labouesse Celine , Venturini Valeria , Trepat Xavier , Chalut Kevin , Kechagia Zanetta , Roca-Cusachs Pere
Published: May 2024

The first step in the differentiation of mouse embryonic stem cells (mESCs) is the loss of naïve pluripotency. This step involves a major reshaping of cells from a rounded to a spread, adhesive phenotype. Whereas such reshaping is typically associated with increased force transmission to the extracellular matrix (ECM), the magnitude and role of cell-matrix forces in the loss of naïve pluripotency is unknown. Here, we show that cell-matrix forces increase during, and are required for, the loss of naïve pluripotency in mESCs. Using traction force microscopy, we show that mESCs progressively increase cell-traction forces and mechanotransduction markers as naïve pluripotency dissolves. Modulation of force transmission through myosin inhibition, substrate stiffness, or spatial differences within mESC colonies regulates the process. Increased force is triggered by GSK3-mediated signalling, and the effect of force is regulated in part by its transmission to the cell nucleus. Our work unveils a major role of cell-ECM forces in pluripotency dissolution, adding an important aspect to the interplay between biochemical and biophysical cues that drive this process.
Novel cell states arise in embryonic cells devoid of key reprogramming factors
Authors: Youlten Scott E. , Miao Liyun , Hoppe Caroline , Boswell Curtis W. , Musaev Damir , Abdelmessih Mario , Krishnaswamy Smita , Tornini Valerie A. , Giraldez Antonio J.
Published: May 2024

The capacity for embryonic cells to differentiate relies on a large-scale reprogramming of the oocyte and sperm nucleus into a transient totipotent state. In zebrafish, this reprogramming step is achieved by the pioneer factors Nanog, Pou5f3, and Sox19b (NPS). Yet, it remains unclear whether cells lacking this reprogramming step are directed towards wild type states or towards novel developmental canals in the Waddington landscape of embryonic development. Here we investigate the developmental fate of embryonic cells mutant for NPS by analyzing their single-cell gene expression profiles. We find that cells lacking the first developmental reprogramming steps can acquire distinct cell states. These states are manifested by gene expression modules that result from a failure of nuclear reprogramming, the persistence of the maternal program, and the activation of somatic compensatory programs. As a result, most mutant cells follow new developmental canals and acquire new mixed cell states in development. In contrast, a group of mutant cells acquire primordial germ cell-like states, suggesting that NPS-dependent reprogramming is dispensable for these cell states. Together, these results demonstrate that developmental reprogramming after fertilization is required to differentiate most canonical developmental programs, and loss of the transient totipotent state canalizes embryonic cells into new developmental statesin vivo.
A computational model for angular velocity integration in a locust heading circuit
Authors: Pabst Kathrin , Gkanias Evripidis , Webb Barbara , Homberg Uwe , Endres Dominik
Published: May 2024

Accurate navigation often requires the maintenance of a robust internal estimate of heading relative to external surroundings. We propose a novel model for angular velocity integration to update the representation of heading in the central complex of the desert locust. In contrast to similar models proposed for the fruit fly, this circuit model uses a single 360° heading direction representation and is updated by neuromodulatory angular velocity inputs. Our computational model was implemented using steady-state firing rate neurons with dynamical synapses. The circuit connectivity was constrained by biological data and remaining degrees of freedom were optimised with a machine learning approach to yield physiologically plausible neuron activities. We demonstrate that the integration of heading and angular velocity in this circuit is robust to noise. The heading signal can be effectively used as input to an existing insect goal-directed steering circuit, adapted for outbound locomotion in a steady direction that resembles locust migration. Our study supports the possibility that similar computations for orientation may be implemented differently in the neural hardware of the fruit fly and the locust.
Compositional restrictions in the flanking regions give potential specificity and strength boost to binding in short linear motifs
Authors: Acs Veronika , Hatos Andras , Tantos Agnes , Kalmar Lajos
Published: May 2024

Short linear motif (SLiM)-mediated protein–protein interactions play important roles in several biological processes where transient binding is needed. They usually reside in intrinsically disordered regions (IDRs), which makes them accessible for interaction. Although information about the possible necessity of the flanking regions surrounding the motifs is increasingly available, it is still unclear if there are any generic amino acid attributes that need to be functionally preserved in these segments. Here, we describe the currently known ligand-binding SLiMs and their flanking regions with biologically relevant residue features and analyse them based on their simplified characteristics. Our bioinformatics analysis reveals several important properties in the widely diverse motif environment that presumably need to be preserved for proper motif function, but remained hidden so far. Our results will facilitate the understanding of the evolution of SLiMs, while also hold potential for expanding and increasing the precision of current motif prediction methods.

Author summary

Protein–protein interactions between short linear motifs and their binding domains play key roles in several molecular processes. Mutations in these binding sites have been linked to severe diseases, therefore, the interest in the motif research field has been dramatically increasing. Based on the accumulated knowledge, it became evident that not only the short motif sequences themselves, but their surrounding flanking regions also play crucial roles in motif structure and function. Since most of the motifs tend to be located within highly variable disordered protein regions, searching for functionally important physico-chemical properties in their proximity could facilitate novel discoveries in this field. Here we show that the investigation of the motif flanking regions based on different amino acid attributes can provide further information on motif function. Based on our bioinformatics approach we have found so far hidden features that are generally present within certain motif categories, thus could be used as additional information in motif searching methods as well.
Impact of U2-type introns on splice site prediction inArabidopsis thalianausing deep learning
Authors: Kabanga Espoir , Yun Soeun , Van Messem Arnout , De Neve Wesley
Published: May 2024

In this study, we investigate the impact of introns on the effectiveness of splice site prediction using deep learning models, focusing onArabidopsis thaliana. We specifically utilize U2-type introns due to their ubiquity in plant genomes and the rich datasets available. We formulate two hypotheses: first, that short introns would lead to a higher effectiveness of splice site prediction than long introns due to reduced spatial complexity; and second, that sequences containing multiple introns would improve prediction effectiveness by providing a richer context for splicing events. Our findings indicate that (1) models trained on datasets with shorter introns consistently outperform those trained on datasets with longer introns, highlighting the importance of intron length in splice site prediction, and (2) models trained with datasets containing multiple introns per sequence demonstrate superior effectiveness over those trained with datasets containing a single intron per sequence. Furthermore, our findings not only align with the two hypotheses we put forward but also confirm existing observations from wet lab experiments regarding the impact of length of an intron and the number of introns present in a sequence on splice site prediction effectiveness, suggesting that our computational insights come with biological relevance.

Author summary

In this study, we explore how intron characteristics affect the effectiveness of splice site predictions inArabidopsis thalianausing deep learning. In particular, focusing on U2-type introns due to their prevalence in plant genomes and their relevance for large-scale data analysis, we demonstrate that both the length of these introns and the number of introns present in a sequence substantially influence prediction outcomes. Our findings highlight that deep learning models trained on data with shorter introns or multiple introns per sequence produce better predictions, aligning with observations from wet lab experiments regarding the impact of intron length and the number of introns per sequences on splice site prediction effectiveness.
The histone variant H2A.Z is required for efficient transcription-coupled NER and to maintain genome integrity in UV challenged yeast cells
Authors: Gaillard Hélène , Ciudad Toni , Aguilera A. , Wellinger Ralf E.
Published: May 2024

The genome of living cells is constantly challenged by DNA lesions that interfere with cellular processes such as transcription and replication. A manifold of mechanisms act in concert to ensure adequate DNA repair, gene expression, and genome stability. Bulky DNA lesions, such as those induced by UV light or the DNA-damaging agent 4-nitroquinoline oxide, act as transcriptional and replicational roadblock and thus represent a major threat to cell metabolism. When located on the transcribed strand of active genes, these lesions are handled by transcription-coupled nucleotide excision repair (TC-NER), a yet incompletely understood NER sub-pathway. Here, using a genetic screen in the yeastSaccharomyces cerevisiae, we identified histone variant H2A.Z as an important component to safeguard transcription and DNA integrity following UV irradiation. In the absence of H2A.Z, repair by TC-NER is severely impaired and RNA polymerase II clearance reduced, leading to an increase in double-strand breaks. Thus, H2A.Z enables proficient TC-NER and plays a major role in the maintenance of genome stability upon UV irradiation.

Author summary

The genome of living organisms is constantly challenged by intrinsic and extrinsic DNA damaging agents. The resulting DNA lesions must be readily repaired to maintain genome integrity. This is particularly important for bulky DNA lesions, such as those produced by UV light, as they will block the progress of elongating RNA polymerases on transcribed genes. These DNA lesions are repaired by a specific pathway called transcription-coupled nucleotide excision repair (TC-NER), the dysfunction of which is associated with severe human diseases. In this work, we used budding yeast as a eukaryotic model organism to perform a genetic screen for new TC-NER factors. We discovered that theHTZ1gene, encoding the histone variant H2A.Z, is required for efficient DNA repair by TC-NER. Our molecular and genetic analyses showed that in the absence of H2A.Z, RNA polymerases persist on damaged DNA, causing interference with DNA replication and genome instability. Our findings further highlight the importance of chromatin plasticity for the maintenance of genome integrity.
Hijacking a dedicated entorhinal-hippocampal extinction circuit to remove traumatic memory
Authors: Lin Ze-Jie , Gu Xue , Gong Wan-Kun , Wang Mo , Wu Yan-Jiao , Wang Qi , Wu Xin-Rong , Zhao Xin-Yu , Zhu Michael X. , Wang Lu-Yang , Liu Quanying , Yuan Ti-Fei , Li Wei-Guang , Xu Tian-Le
Published: May 2024

Effective psychotherapy of post-traumatic stress disorder (PTSD) remains challenging due to the fragile nature of fear extinction, for which ventral hippocampal CA1 (vCA1) region is considered as a central hub. However, neither the core pathway nor the cellular mechanisms involved in implementing extinction are known. Here, we unveil a direct pathway, where layer 2a fan cells in the lateral entorhinal cortex (LEC) target parvalbumin-expressing interneurons (PV-INs) in the vCA1 region to propel low gamma-band synchronization of the LEC-vCA1 activity during extinction learning. Bidirectional manipulations of either hippocampal PV-INs or LEC fan cells suffice fear extinction. Gamma entrainment of vCA1 by deep brain stimulation (DBS) or noninvasive transcranial alternating current stimulation (tACS) of LEC persistently enhances the PV-IN activity in vCA1, thereby promoting fear extinction. These results demonstrate that the LEC-vCA1 pathway forms a top-down motif to empower low gamma-band oscillations that facilitate fear extinction. Finally, application of low gamma DBS and tACS to a mouse model with persistent PTSD shows potent efficacy, suggesting that the dedicated LEC-vCA1 pathway can be hijacked for therapy to remove traumatic memory trace.

Graphical Abstract
Investigating the impact of X-rays on decay: X-ray computed tomography as a non-invasive visualisation technique for sediment-based decay experiments
Authors: Cavicchini Iacopo , Wilson Paul F. , Giles Sam , Atterby Jake , Jones Andy S. , Williams Mark A. , Clements Thomas
Published: May 2024

Decay experiments are ever increasing in complexity to better understand taphonomic processes. However, adding new variables, such as sediment, can create methodological biases, such as artificial anatomical character loss during exhumation. Non-invasive in situ imaging techniques such as X-ray computed tomography (XCT scanning) could mitigate this, but the consequences of exposing carcasses to X-rays are not fully understood, and evidence regarding the impact of X-rays on internal microbial faunas that drive decay is conflicting. Here, we test whether XCT scanning impacts the decay ofDanio reriocarcasses within a substrate. Our control experiments show that quartz sand sediment physically stabilises the carcass throughout decay and the sequence of anatomical character loss remains constant, however, both the onset and rate of decay of soft tissues are initially accelerated. Our XCT data show that exposure to X-rays does not cause a deviation from the normal sequence of decay, validating XCT as a non-destructive visualisation method for decay experiments. Furthermore, when accompanied with traditional exhumation and dissection, XCT provides decay data with higher accuracy of character analysis than traditional methods, and allows novel quantitative techniques to monitor physical changes in the decaying carcass (e.g., total volume, build-up of gases, collapse of the body cavity etc.). We also underline limitations with the technique, but our experiment acts as an important ‘stepping stone’ for progression toward non-invasive designs of decay experiments.
Drosophilamales require the longitudinal stretch receptors to tremulate their abdomen and produce substrate-borne signals during courtship
Authors: Lee Jonathan K. M. , Yen Eugenie C. , Fabre Caroline C. G.
Published: May 2024

Substrate-borne cues are important species-specific signals that are widely used during courtship of many animals, from arthropods to vertebrates. They allow mating partners to communicate with, recognise and choose one another. Animals often produce substrate-borne signals by vibrating a body part, such as the abdomen. DuringDrosophilacourtship, species-specific substrate-borne vibrations are generated by the male’s regular up-and-down abdominal tremulations and these must be precisely controlled to produce an effective and specific signal. The vibrations immobilise the female, therefore facilitating copulation. It is not known how the male’s nervous system regulates this abdominal tremulation. Here, we demonstrate a role for the dorsal abdominal longitudinal stretch receptors (LSR), which include the dorsal bipolar dendritic (dbd) neurons. These neurons are a set of conserved proprioceptors found throughout Insecta. We show that impairing the function of dbd neurons through general inhibition results in males exhibiting high level of arhythmic abdominal movements (referred to as bobbing) and decreased level of tremulation. Strikingly, this causes a failure in the females’ response during courtship. We show that depleting the mechanosensitive ion channel TRPA1 (but not Piezo) in the dbd neurons leads to a similar increase in bobbing movements. Thus, we identify neurons and a key molecular player necessary for males to perform this important mode of communication.
The nucleating agent crystallophore induces instant protein crystallization
Authors: Sauter Claude , Housset Dominique , Orlans Julien , de Wijn Raphaël , Rollet Kévin , Rose Samuel , Basu Shibom , Bénas Philippe , Perez Javier , de Sanctis Daniele , Maury Olivier , Girard Eric
Published: May 2024

The rapid preparation of homogeneous suspensions of micro- or nano-crystals is a crucial step in serial crystallography. We show how additives, such as the crystallophore (TbXo4) that acts as a molecular glue by promoting protein-protein interactions, can facilitate sample preparation for both serial synchrotron crystallography (SSX) and micro electron diffraction (3D ED). This lanthanide complex was used here for its nucleating properties to crystallize hen egg white lysozyme. SAXS monitoring indicates that crystals formed in a few minutes in low salt conditions that would not lead to spontaneous nucleation. Resulting micro- and nano-crystals were successfully used to determine the structure of the lysozyme-TbXo4 complex by SSX and 3D ED, illustrating the diffraction quality of the produced crystals and the usefulness of such compounds in the sample preparation pipeline for serial crystallography.
The interplay of spontaneous pupil-size fluctuations and EEG power in near-threshold detection
Authors: Ruuskanen Veera , Boehler C. Nico , Mathôt Sebastiaan
Published: May 2024

Detection of near-threshold stimuli depends on the properties of the stimulus and the state of the observer. In visual detection tasks, improved sensitivity is associated with larger pre-stimulus pupil size. However, it is still unclear whether this association is due to optical effects (more light entering the eye), correlations with arousal, correlations with cortical excitability (as reflected in alpha power), or a mix of these. To better understand this, we investigated the relative contributions of pupil size and power in the alpha, beta, and theta frequency bands on near-threshold detection. We found that larger pre-stimulus pupil size is associated with improved sensitivity and a more liberal criterion (the likelihood of reporting that a stimulus was detected). Importantly, the relationship between pupil size and sensitivity was not mediated by any of the measured neural variables; the relationship with criterion however was mediated by power in the beta band (12-30 Hz). Pupil size was positively correlated with power in the alpha and beta bands. Additionally, we show that pre-stimulus theta suppression (4 - 8 Hz) is associated with improved sensitivity and a more liberal criterion. Taken together, our results show an independent effect of pupil size on detection sensitivity that is not driven by cortical excitability, but may be driven by optical effects, arousal, or a mix of both.
An algorithm for identifying task-specific brain subnetworks using the visuomotor system as an example
Authors: Ellison Ryan , Matar Mona , Gokoglu Suleyman A. , Prabhu Raj K. , Hooper Scott L.
Published: May 2024

We describe an algorithm that identifies a subnetwork of brain regions involved in producing a task-specific behavior, here visuomotor behavior, from an anatomically defined primate brain connectome. The algorithm first finds the brain regions connected to an output region (here, primary motor cortex, M1) by one connection. It then identifies all regions, termed “layer 2” regions, connected to these “layer 1” regions by one connection. This process continues until the layer containing the input region (here, primary visual cortex, V1) is reached. The algorithm then finds, subject to a user-set maximum step number, all paths linking the input and output regions. The brain regions in these paths constitute the initial subnetwork identification that performs the task. Regions known not to be task-involved (for example, regions in the ventral stream of visual information vs. the dorsal stream, which helps generate visuomotor behavior) are then removed. Structural subnetwork analysis showed that the intraparietal sulcus of the parietal cortex (PCIP) was most, and the secondary visual (V2) and superior parietal (PCS) cortices second-most, central to local network activity. Changing PCIP, V2 and PCS activity was thus most likely to alter activity of the entire subnetwork. Model sufficiency was tested by instantiating each brain region’s inherent activity with multiple versions of a simple two-dimensional (2D) model that can produce oscillatory activity and synaptically interconnecting the regions to produce a macroscopic visuomotor model. The model reproduced the experimental local field potential (LFP) activity of the brain regions identified as part of the visuomotor subnetwork.
Mitochondrial dysfunction heightens the integrated stress response to drive ALS pathogenesis
Authors: Landry Curran , Costanzo James , Mitne-Neto Miguel , Zatz Mayana , Schaffer Ashleigh , Hatzoglou Maria , Muotri Alysson , Miranda Helen Cristina
Published: May 2024

Vesicle-associated membrane protein-associated protein-B (VAPB) is an ER membrane bound protein. VAPB P56S causes a dominant, familial form of amyotrophic lateral sclerosis (ALS), however, the mechanism through which this mutation causes motor neuron (MN) disease remains unknown. Using inducible wild type (WT) and VAPB P56S expressing iPSC-derived MNs we show that VAPB P56S, but not WT, protein decreased neuronal firing and mitochondrial-ER contact (MERC) with an associated age-dependent decrease in mitochondrial membrane potential (MMP); all typical characteristics of MN-disease. We further show that VAPB P56S expressing iPSC-derived MNs have enhanced age-dependent sensitivity to ER stress. We identified elevated expression of the master regulator of the Integrated Stress Response (ISR) marker ATF4 and decreased protein synthesis in the VAPB P56S iPSC-derived MNs. Chemical inhibition of ISR with the compound, ISRIB, rescued all MN disease phenotype in VAPB P56S MNs. Thus, our results not only support ISR inhibition as a potential therapeutic target for ALS patients, but also provides evidence to pathogenesis.
Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex: Implications for renal dysfunction
Authors: Ihara Jittoku , Huang Yibin , Takami Yoichi , Nozato Yoichi , Takahashi Toshimasa , Kakino Akemi , Wang Cheng , Wang Ziwei , Guo Yu , Liu Weidong , Yin Nanxiang , Ohara Ryoichi , Fujimoto Taku , Yoshida Shino , Hongyo Kazuhiro , Koriyama Hiroshi , Akasaka Hiroshi , Takeshita Hikari , Sakai Shinsuke , Inoue Kazunori , Isaka Yoshitaka , Rakugi Hiromi , Sawamura Tatsuya , Yamamoto Koichi
Published: May 2024

Chronic kidney disease (CKD) and atherosclerotic heart disease, frequently associated with dyslipidemia and hypertension, represent significant health concerns. We investigated the interplay among these conditions, focusing on the role of oxidized low-density lipoprotein (oxLDL) and angiotensin II (Ang II) in renal injury via G protein αq subunit (Gq) signaling. We hypothesized that oxLDL enhances Ang II-induced Gq signaling via the AT1 (Ang II type 1 receptor)-LOX1 (lectin-like oxLDL receptor) complex. Based on CHO and renal cell model experiments, oxLDL alone did not activate Gq signaling. However, when combined with Ang II, it significantly potentiated Gq-mediated inositol phosphate 1 production and calcium influx in cells expressing both LOX-1 and AT1 but not in AT1-expressing cells. This suggests a critical synergistic interaction between oxLDL and Ang II in the AT1-LOX1 complex. Conformational studies using AT1 biosensors have indicated a unique receptor conformational change due to the oxLDL-Ang II combination. In vivo, wild-type mice fed a high-fat diet with Ang II infusion presented exacerbated renal dysfunction, whereas LOX-1 knockout mice did not, underscoring the pathophysiological relevance of the AT1-LOX1 interaction in renal damage. These findings highlight a novel mechanism of renal dysfunction in CKD driven by dyslipidemia and hypertension and suggest the therapeutic potential of AT1-LOX1 receptor complex in patients with these comorbidities.
SAUSI: an integrative assay for measuring social aversion and motivation
Authors: Grammer Jordan , Valles Rene , Bowles Alexis , Zelikowsky Moriel
Published: May 2024

Social aversion is a key feature of numerous mental health disorders such as Social Anxiety and Autism Spectrum Disorders. Nevertheless, the biobehavioral mechanisms underlying social aversion remain poorly understood. Progress in understanding the etiology of social aversion has been hindered by the lack of comprehensive tools to assess social aversion in model systems. Here, we created a new behavioral task – Selective Access to Unrestricted Social Interaction (SAUSI), which integrates elements of social motivation, hesitancy, decision-making, and free interaction to enable the wholistic assessment of social aversion in mice. Using this novel assay, we found that social isolation-induced social aversion in mice is largely driven by increases in social fear and social motivation. Deep learning analyses revealed a unique behavioral footprint underlying the socially aversive state produced by isolation, demonstrating the compatibility of modern computational approaches with SAUSI. Social aversion was further assessed using traditional assays – including the 3-chamber sociability assay and the resident intruder assay – which were sufficient to reveal fragments of a social aversion phenotype, including changes to either social motivation or social interaction, but which failed to provide a wholistic assessment of social aversion. Critically, these assays were not sufficient to reveal key components of social aversion, including social freezing and social hesitancy behaviors. Lastly, we demonstrated that SAUSI is generalizable, as it can be used to assess social aversion induced by non-social stressors, such as foot shock. Our findings debut a novel task for the behavioral toolbox – one which overcomes limitations of previous assays, allowing for both social choice as well as free interaction, and offers a new approach for assessing social aversion in rodents.
Pericytes mediate neurovascular remodeling in chronic arterial hypertension
Authors: Morton Lorena , Garza Alejandra P. , Debska-Vielhaber Grazyna , Villafuerte Luis E. , Henneicke Solveig , Arndt Philipp , Meuth Sven G. , Schreiber Stefanie , Dunay Ildiko R.
Published: May 2024

Chronic arterial hypertension restructures the vascular architecture of the brain, leading to a series of pathological responses that culminate in cerebral small vessel disease. Pericytes respond dynamically to vascular challenges; however, how they manifest under the continuous strain of hypertension has not been elucidated. Therefore, in this study, we characterized pericyte behavior alongside hypertensive states in the spontaneously hypertensive stroke-prone rat (SHRSP) model, emphasizing their phenotypic and metabolic transformation. Our results reveal an early transition in PDGFRß+pericytes toward increased NG2 and CD13 co-expressing subtypes, signaling enhanced pericyte reactivity in an effort to stabilize vascular structures and an inflammatory engagement within the vascular niche in response to hypertensive stress. Gene expression profiling of microvessels revealed altered expression within crucial pathways i.e., angiogenesis, blood-brain barrier integrity, hypoxia and inflammation. Furthermore, we detected that circulating extracellular vesicles from SHRSP alter pericyte mitochondrial membrane potential, highlighting their ability to transmit pathogenic signals that exacerbate vascular remodeling. Detailed metabolic analysis revealed a significant shift toward glycolytic metabolism in pericytes already in initial hypertension, alongside a dysregulation of ATP production pathways. These findings emphasize the transformative influence of hypertension on cerebral pericytes and the extensive consequences on cerebral vascular health.
Hyperactive mTORC1/4EBP1 Signaling Dysregulates Proteostasis and Accelerates Cardiac Aging
Authors: Zarzycka Weronika , Kobak Kamil A , King Catherine J , Peelor Frederick F , Miller Benjamin F , Chiao Ying Ann
Published: May 2024

The mechanistic target of rapamycin complex 1 (mTORC1) has a major impact on aging by regulation of proteostasis. It is well established that mTORC1 signaling is hyperactivated with aging and age-related diseases. Previous studies have shown that partial inhibition of mTOR signaling by rapamycin reverses the age-related decline in cardiac function and structure in old mice. However, the downstream signaling pathways involved in this protection against cardiac aging have not been established. TORC1 phosphorylates 4E-binding protein 1 (4EBP1) to promote the initiation of cap-dependent translation. The aim of this project is to examine the role of the mTORC1/4EBP1 axis in age-related cardiac dysfunction. We utilized a whole-body 4EBP1 KO mouse model, which mimics a hyperactive 4EBP1/eIF4E axis, to investigate the effects of hyperactive mTORC1/4EBP1 axis in cardiac aging. Echocardiographic measurements revealed that young 4EBP1 KO mice have no difference in cardiac function at baseline compared to WT mice. Interestingly, middle-aged (14–15-month-old) 4EBP1 KO mice show impaired diastolic function and myocardial performance compared to age-matched WT mice and their diastolic function and myocardial performance are at similar levels as 24-month-old WT mice, suggesting that 4EBP1 KO mice experience accelerated cardiac aging. Old 4EBP1 KO mice show further declines in systolic and diastolic function compared to middle-aged 4EBP1 KO mice and have worse systolic and diastolic function than age-matched old WT mice. Gene expression levels of heart failure markers are not different between 4EBP1 KO and WT mice at these advanced ages. However, ribosomal biogenesis and overall protein ubiquitination are significantly increased in 4EBP1 KO mice when compared to WT, which suggests dysregulated proteostasis. Together, these results show that a hyperactive 4EBP1/eIF4E axis accelerates cardiac aging, potentially by dysregulating proteostasis.
A Genome-Wide Association Study Reveals Novel Genetic Markers Associated with Human African Trypanosomiasis
Authors: Mulindwa Julius , Kimuda Magambo Phillip , Noyes Harry , Ilboudo Hamidou , Koffi Mathurin , Ahouty Bernadin , Nyangiri Oscar , Cooper Anneli , Clucas Caroline , Nambala Peter , Musaya Janelisa , Ngoyi Dieudonne ́ Mumba , Karume Kevin , Fataki Olivier , Simo Gustave , Ofon Elvis , Enyaru John , Nerima Barbara , Tait Andy , Marcello Lucio , Chisi John , Kabore Jacques , Kabore Justin Windingoudi , Kamoto Kelita , Simuunza Martin , Alibu Vincent P. , Jamonneau Vincent , Camera Marianne , Camara Mamadou , Bucheton Bruno , Hertz-Fowler Christiane , Macleod Annette , Matovu Enock ,   TrypanoGEN Research Group as members of The H3Africa Consortium
Published: May 2024

Trypanosoma brucei gambienseandTrypanosoma brucei rhodesiensecause human African trypanosomiasis (HAT), a neglected tropical disease that constitutes an important public health issue in sub-Saharan Africa. In the absence of a vaccine, only chemotherapy and vector control has been used to combat the disease. Environmental factors, such as exposure to infected tsetse files, and genetic factors such as variants in theAPOL1gene have been shown to contribute to the risk of developing HAT. However, the known factors only explain a small part of the risk of developing trypanosomiasis. We have undertaken a genome wide association study (GWAS) using 3813 samples fromT. b. gambienseandT.b. rhodesienseHAT foci in Guinea, Côte d’Ivoire, Cameroon, DRC, Malawi and Uganda. 2141 samples were genotyped on the H3Africa SNP chip followed by a genotyping a validation cohort of an additional 1,627 samples at candidate loci. After the primary and validation studies we identified a novel locus nearSMOC2with genome-wide significance. We also identified suggestive associations nearNXN, NTNG1andNCKAP5that have stronger associations with disease susceptibility than theAPOL1loci that has been previously identified by hypothesis driven approaches. These genes offer new entry points for future studies of the underlying genetic mechanisms of HAT.
Subcortical alterations in newly diagnosed epilepsy and associated changes in brain connectivity and cognition
Authors: de Bézenac Christophe E , Leek Nicola , Adan Guleed , Mohanraj Rajiv , Biswas Shubhabrata , Marson Anthony G , Keller Simon S
Published: May 2024

Objectives

Patients with chronic focal epilepsy commonly exhibit subcortical atrophy, particularly of the thalamus. The timing of these alterations remains uncertain, though preliminary evidence suggests that observable changes may already be present at diagnosis. It is also not yet known how these morphological changes are linked to the coherence of white matter pathways throughout the brain, or to neuropsychological function often compromised before anti-seizure medication treatment. This study investigates localised atrophy in subcortical regions using surface shape analysis in individuals with newly diagnosed focal epilepsy (NDfE) and assesses their implications on brain connectivity and cognitive function.

Methods

We collected structural (T1w) and diffusion weighted MRI, as well as neuropsychological data from 104 patients with NDfE and 45 healthy controls (HC) matched for age, sex and education. A vertex-based shape analysis was performed on subcortical structures to compare patients with NDfE and HC, adjusting for age, sex and intracranial volume. The mean deformation of significance areas (pcor < 0.05) was used to identify white matter pathways associated with overall shape alterations in patients relative to controls using correlational tractography. Additionally, the relationship between significant subcortical shape values and neuropsychological outcomes was evaluated using a generalised canonical correlation approach.

Results

Shape analysis revealed bilateral focal inward deformation (a proxy for localised atrophy) in anterior areas of the right and left thalamus and right pallidum in patients with NDfE compared to HC (FWE corrected). No structures showed areas of outward deformation in patients. The connectometry analysis revealed that fractional anisotropy (FA) was positively correlated with thalamic and pallidal shape deformation, i.e., reduced FA was associated with inward deformation in tracts proximal to and or connecting with the thalamus including the fornix, frontal, parahippocampal and corticothalamic pathways. Thalamic and pallidal shape changes were also related to with increased depression and anxiety, and reduced memory and cognitive function.

Discussion

These findings suggest that atrophy of the thalamus, which has previously been associated with the generation and maintenance of focal seizures, may present at epilepsy diagnosis and relate to alterations in both white matter connectivity and cognitive performance. We suggest that at least some alterations in brain structure and consequent impact on cognitive and affective processes are the result of early epileptogenic processes rather than exclusively due to the chronicity of longstanding epilepsy, recurrent seizures, and treatment with anti-seizure medication.