bluuebunny/crossref_metadata_2025 huggingface dataset:
STANCE: a unified statistical model to detect cell-type-specific spatially variable genes in spatial transcriptomics
Authors: Su Haohao , Wu Yuesong , Chen Bin , Cui Yuehua
Published: September 2024

A significant challenge in analyzing spatial transcriptomics data is the effective and efficient detection of spatially variable genes (SVGs), whose expression exhibits non-random spatial patterns in tissues. Many SVGs show spatial variation in expression that is highly correlated with cell type categories or compositions, leading to the concept of cell type-specific spatially variable genes (ctSVGs). Existing statistical methods for detecting ctSVGs treat cell type-specific spatial effects as fixed effects when modeling, resulting in a critical issue: the testing results are not invariant to the rotation of spatial coordinates. Additionally, an SVG may display random spatial patterns within a cell type, and a ctSVG may exhibit random spatial patterns from a general perspective, indicating that an SVG does not necessarily have to be a ctSVG, and vice versa. This poses challenges in real analysis when detecting SVGs or ctSVGs. To address these problems, we propose STANCE, a unified statistical model developed to detect both SVG and ctSVGs in spatial transcriptomics. By integrating gene expression, spatial location, and cell type composition through a linear mixed-effect model, STANCE enables the identification of both SVGs and ctSVGs in an initial stage, followed by a second stage test dedicated to ctSVG detection. Its design ensures robustness in complex scenarios and the results are spatial rotation invariant. We demonstrated the performance of STANCE through comprehensive simulations and analyses of three public datasets. The downstream analyses based on ctSVGs detected by STANCE suggest promising future applications of the model in spatial transcriptomics and various areas of genome biology. A software implementation of STANCE is available athttps://github.com/Cui-STT-Lab/STANCE.
TMX1, a disulfide oxidoreductase, is necessary for T cell function through regulation of CD3ζ
Authors: Chai Timothy , Loh Kyle M. , Weissman Irving L.
Published: September 2024

T cell-targeted therapies are commonly used to manage T cell hyperactivity in autoimmune disorders, graft-versus-host diseases (GVHD), and transplant rejections. However, many patients experience significant side effects or inadequate responses to current treatments, highlighting the urgent need for alternative strategies. In this study, we searched for regulators of T cells through proximity labeling with APEX2 to detect proteins interacting with CD8α, a coreceptor of the T-cell receptor (TCR). This screen revealed TMX1, an ER resident transmembrane disulfide oxidoreductase, is essential for T cell cytotoxicity and NFAT, NFκB, and AP1 signaling but not cell proliferation. TMX1 deletion decreases surface TCR expression and destabilizes CD3ζ, a subunit of TCR complex; however, overexpression of CD3ζ rescues the phenotype, suggesting that TMX1 is not required for CD3ζ function. Mechanistically, TMX1 was found to directly engage the CxxC motif of CD3δ, which has been reported to be essential for proper TCR assembly and function. We hypothesize that the loss of TMX1 interaction with CD3δ leads to impaired TCR assembly and subsequent CD3ζ destabilization. These findings identify TMX1 as a novel regulator of T-cell receptor assembly and a potential target for immunosuppressive therapy.
Magnetic Resonance Imaging Data Phenotypes for the Parkinson’s Progression Markers Initiative
Authors: Avants Brian B , Fonville Leon , Hampton Olivia , Reardon Alexandra , Stenger Andrew , Wang Xue , Tustison Nicholas J , Stone James R , Cook Philip A , Marebwa Barbara , Chahine Lana M , Poston Kathleen L , Marek Kenneth , Becerra Lino , Gunn Roger ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: September 2024

The Parkinson’s Progression Markers Initiative (PPMI) delivers multiple modality MRI (M3RI) and biomarker data for a comprehensive longitudinal study of Parkinson’s Disease (PD). These provide quantitative indices of deep brain and cortical structure (T1-weighted MRI), microstructural integrity of brain tissue (diffusion-weighted imaging) and resting brain function (resting state functional MRI). Integrating and uniformly analyzing M3RI alongside non-imaging biological and clinical data is challenging due to the distinct nature of each modality. This study systematically organizes these complex data into a structured format, provides a PD-focused evaluation of the methodologies and evidence for technical robustness of the approach. The cohort encompasses 841 idiopathic PD, 309 genetic PD, 1364 presymptomatic PD and 240 control subjects at baseline with followup at a mean of 1.83 years.
A decade of shifting cholera burden in Africa and its implications for control: a statistical mapping analysis
Authors: Perez-Saez Javier , Zheng Qulu , Kaminsky Joshua , Zou Kaiyue , Demby Maya N. , Alam Christina , Landau Daniel , DePencier Rachel , Langa Jose Paulo M. , Chilengi Roma , Okitayemba Placide Welo , Bwire Godfrey , Esso Linda , Ngomba Armelle Viviane , Mbarga Nicole Fouda , Okunga Emmanuel Wandera , Yennan Sebastian , Kapaya Fred , Ohize Stephen Ogirima , Seriki Adive Joseph , Hegde Sonia T. , Sikder Mustafa , Lessler Justin , Datta Abhirup , Azman Andrew S. , Lee Elizabeth C.
Published: September 2024

Background

The World Health Organization declared a global cholera emergency in 2023 due to an increase in cholera outbreaks, with most cholera-associated deaths reported in Africa. Characterizing large-scale burden patterns can help with monitoring progress in cholera control and targeting interventions.

Methods

We modeled the mean annual incidence of suspected cholera for 2011-2015 and 2016-2020 on a 20 km by 20 km grid across Africa using a global cholera database and spatial statistical models. We then examined how 2011-2020 incidence is associated with post-2020 cholera occurrence and investigated the potential reach of prospective interventions when prioritized by past incidence.

Findings

Across 43 African countries mean annual incidence rates remained steady at 11 cases per 100,000 population through both periods. Cholera incidence shifted from Western to Eastern Africa, and we estimated 125,701 cases annually (95% CrI: 124,737-126,717) in 2016-2020. There were 296 million (95% CrI: 282-312 million) people living in high-incidence second-level administrative (ADM2) units (≥ 10 cases per 100,000 per year) in 2020, of which 135 million experienced low incidence (<1 per 100,000) in 2011-2015. ADM2 units with sustained high incidence in Central and Eastern Africa from 2011-2020 were more likely to report cholera in 2022-2023, but cases were also reported in sustained low ADM2 units. Targeting the 100 million highest burden populations had potential to reach up to 63% of 2016-2020 mean annual cases but only 37% when targeting according to past 2011-2015 incidence.

Interpretation

By revealing the changing spatial epidemiology of cholera in Africa, these 10-year subnational estimates may be used to project OCV demand, characterize the potential of targeting interventions based on past burden, and track progress towards disease control goals.
Understanding Embolus Transport And Source To Destination Mapping Of Thromboemboli In Hemodynamics Driven By Left Ventricular Assist Device
Authors: Majee Sreeparna , Sahni Akshita , Pal Jay D. , McIntyre Erin E. , Mukherjee Debanjan
Published: September 2024

Left Ventricular Assist Devices (LVADs) are a key treatment option for patients with advanced heart failure, but they carry a significant risk of thromboembolic complications. While improved LVAD design, and systemic anticoagulation regimen, have helped mitigate thromboembolic risks, ischemic stroke due to adverse thromboembolic events remains a major concern with current LVAD therapies. Improved understanding of embolic events, and embolus movement to the brain, is critical to develop techniques to minimize risks of occlusive embolic events such as a stroke after LVAD implantation. Here, we address this need, and devise a quantitativein silicoframework to characterize thromboembolus transport and distrbution in hemodynamics driven by an operating LVAD. We conduct systematic numerical experiments to quantify the source-to-destination transport patterns of thromboemboli as a function of: LVAD outflow graft anastomosis, LVAD operating pulse modulation, thromboembolus sizes, and origin locations of emboli. Additionally, we demonstrate how the resulting embolus distribution patterns compare and correlate with descriptors based solely on hemodynamic patterns such as helicity, vorticity, and wall shear stress. Using the concepts of size-dependent embolus-hemodynamics interactions, and two jet flow model for hemodynamics under LVAD operation as established in our prior works, we gain valuable insights on departure of thromboembolus distribution from flow distribution, and establish that ourin silicomodel can generate deep insights into embolus dynamics which is not otherwise available from standard of care imaging and clinical data.
Established Sulfopeptide Tandem Mass Spectrometry Behavior and Sulfotransferase Assays Refute Tyrosine Sulfation as a Histone Mark
Authors: Youssef Menatallah M. , Szot Carson W. , Ayad Miriam F. , Hussein Lobna A. , Abdel-Ghany Maha F. , Bailey Ryan C. , Mostafa Ahmed M. , Hakansson Kristina
Published: September 2024

Tyrosylprotein sulfotransferases (TPST1 and TPST2) are only known to exist in the Golgi1. Thus, Yu et al.’s findings that histone H3 sulfation occurs in the cytosol are surprising. Cytosolic sulfotransferase SULT1B1, which sulfates phenolic small molecules, was proposed to catalyze H3Y99 sulfation with 3′-phosphoadenosine 5′-phosphosulfate (PAPS) as SO3donor. Bottom-up liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based proteomic analyses were key to this conclusion. Such experiments appear to have been mainly performed following standard protocols, including reduction (reagent unknown), alkylation with iodoacetamide (IAA), and proteolytic digestion prior to nanoflow LC (nanoLC) separation of proteolytic peptides and data-dependent higher energy collision dissociation (HCD) to generate sequence-informative peptide fragments. However, the published HCD MS/MS spectra do not match established sulfopeptide fragmentation behavior. We present reannotation of these spectra and additional experiments that found a lack of evidence to support H3Y99 sulfation.
Hippocampal representations of alternative possibilities are flexibly generated to meet cognitive demands
Authors: Comrie Alison E. , Monroe Emily J. , Kahn Ari E. , Denovellis Eric L. , Joshi Abhilasha , Guidera Jennifer A. , Krausz Timothy A. , Berke Joshua D. , Daw Nathaniel D. , Frank Loren M.
Published: September 2024

The cognitive ability to go beyond the present to consider alternative possibilities, including potential futures and counterfactual pasts, can support adaptive decision making. Complex and changing real-world environments, however, have many possible alternatives. Whether and how the brain can select among them to represent alternatives that meet current cognitive needs remains unknown. We therefore examined neural representations of alternative spatial locations in the rat hippocampus during navigation in a complex patch foraging environment with changing reward probabilities. We found representations of multiple alternatives along paths ahead and behind the animal, including in distant alternative patches. Critically, these representations were modulated in distinct patterns across successive trials: alternative paths were represented proportionate to their evolving relative value and predicted subsequent decisions, whereas distant alternatives were prevalent during value updating. These results demonstrate that the brain modulates the generation of alternative possibilities in patterns that meet changing cognitive needs for adaptive behavior.
Effects of age on resting-state cortical networks
Authors: Gohil Chetan , Kohl Oliver , Pitt Jemma , van Es Mats W.J. , Quinn Andrew J , Vidaurre Diego , Turner Martin R , Nobre Anna C. , Woolrich Mark W
Published: September 2024

Magnetoencephalography recordings of functional brain activity reveal large-scale cortical networks that are associated with cognition. The correlation of individualised networks with age and cognitive performance (age effects and cognitive performance effects respectively) was studied using a large cross-sectional healthy cohort (N=612, 18-88 years old) and accounting for a comprehensive set of confounds. Age effects were found in time-averaged functional networks in five canonical frequency bands (delta, theta, alpha, beta, gamma) that are consistent with the posterior-anterior shift with age observed in functional magnetic resonance imaging. Evidence from cognitive performance effects in time-averaged networks suggested the importance of maintaining alpha-band activity for cognitive health. A more detailed description of the functional activity was obtained by adopting an established machine learning approach (the Hidden Markov Model). Ten transient large-scale cortical networks with fast dynamics (~100 ms) were identified, which provided insight into age and cognitive performance effects that were not observed in the time-averaged analyses. The time spent in most networks increased with age, whereas the time spent in frontal networks decreased. The cognitive performance effects for the transient networks suggested that age effects in the frontal networks are compensatory. Thus, our study suggests both the maintenance of functional activity (lesser age effects) and the recruitment of compensatory functional activity can co-occur to produce good cognitive performance in older individuals. The time-averaged and transient functional networks have been made publicly available as a resource.
High-speed 3D Imaging with 25-Camera Multifocus Microscope
Authors: Hirata Miyasaki Eduardo , Bajor Antone A. , Pettersson Gustav M. , Senftleben Maximilian L. , Fouke Kaitlyn E. , Graham Thomas G.W. , John Demis D. , Morgan Jennifer R. , Haspel Gal , Abrahamsson Sara
Published: September 2024

We here report an aberration-corrected 25-plane camera array Multifocus microscope (M25) for high-speed, high-resolution wide-field optical microscopy in three spatial dimensions (3D). We demonstrate live imaging of 25-plane 3D volumes of up to 180×180×50um at >100 volumes per second. 3D data is recorded simultaneously by an array of 25 small, sensitive, synchronized machine-vision cameras. M25 employs aberration-corrected Multifocus microscopy—an optical method where diffractive Fourier optics are used for multiplexing and refocusing light— with a simplified design for chromatic dispersion correction where a corrective diffractive gratings is placed on each camera in the array. This elegant architecture for chromatic correction will be applicable in a broad range of diffractive imaging applications. M25 is a powerful optical tool for high-speed 3D microscopy in that it allows both non-invasive, label-free bright-field and highly sensitive fluorescence microscopy. We showcase M25 capabilities in 3D particle tracking, bright-field, and fluorescence imaging inD. melanogaster, and locomotion and neural activity studies inC. elegans.
Structural Basis for Antibody Neutralization of Pertussis Toxin
Authors: Goldsmith Jory A. , Nguyen Annalee W. , Wilen Rebecca E. , Wijagkanalan Wassana , McLellan Jason S. , Maynard Jennifer A.
Published: September 2024

SUMMARY/ABSTRACT

Pertussis toxin (PT) is a key protective antigen in vaccine- and natural immunity-mediated protection fromBordetella pertussisinfection. Despite its importance, no PT-neutralizing epitopes have been characterized structurally. To define neutralizing epitopes and identify key structural elements to preserve during PT antigen design, we determined a 3.6 Å cryo-electron microscopy structure of genetically detoxified PT (PTg) bound to hu11E6 and hu1B7, two potently neutralizing anti-PT antibodies with complementary mechanisms: disruption of toxin adhesion to cells and intracellular activities, respectively. Hu11E6 bound the paralogous S2 and S3 subunits of PTg via a conserved epitope, but surprisingly did not span the sialic acid binding site implicated in toxin adhesion. High-throughput glycan array analysis showed that hu11E6 specifically prevents PTg binding to sialylated N-glycans, while a T cell activation assay showed that hu11E6 blocks PTg mitogenic activities to define the neutralizing mechanism. Hu1B7 bound a quaternary epitope spanning the S1 and S5 subunits, although functional studies of hu1B7 variants suggested that S5 binding is not involved in its PT neutralization mechanism. These results are the first to structurally define neutralizing epitopes on PT, improving our molecular understanding of immune protection fromB. pertussisand providing key information for the future development of PT immunogens.

SIGNIFICANCE

Antibodies neutralizing pertussis toxin (PT) prevent the severe clinical symptoms associated with infection byBordetella pertussis. However, the molecular basis of effective PT-targeted immunity is poorly understood. To gain insight into PT-inhibitory mechanisms, we determined the cryo-electron microscopy structure of genetically detoxified PT (PTg) with two potently neutralizing antibodies to precisely define their epitopes. Carbohydrate-binding studies show that the hu11E6-binding surface on PT interacts with N-linked glycans and that blocking these interactions prevents PT’s T cell mitogenic activities. Hu1B7 binds an epitope near the S1 active site that includes S5 contacts but these do not appear important for neutralization. This work identifies PT-neutralizing epitopes and supports inclusion of the hu1B7 and hu11E6 epitopes in next-generation vaccines and PT-based immunogens.
Temporal integration in human auditory cortex is predominantly yoked to absolute time, not structure duration
Authors: Norman-Haignere Sam V , Keshishian Menoua K. , Devinsky Orrin , Doyle Werner , McKhann Guy M. , Schevon Catherine A. , Flinker Adeen , Mesgarani Nima
Published: September 2024

Sound structures such as phonemes and words have highly variable durations. Thus, there is a fundamental difference between integrating across absolute time (e.g., 100 ms) vs. sound structure (e.g., phonemes). Auditory and cognitive models have traditionally cast neural integration in terms of time and structure, respectively, but the extent to which cortical computations reflect time or structure remains unknown. To answer this question, we rescaled the duration of all speech structures using time stretching/compression and measured integration windows in the human auditory cortex using a new experimental/computational method applied to spatiotemporally precise intracranial recordings. We observed significantly longer integration windows for stretched speech, but this lengthening was very small (∼5%) relative to the change in structure durations, even in non-primary regions strongly implicated in speech-specific processing. These findings demonstrate that time-yoked computations dominate throughout the human auditory cortex, placing important constraints on neurocomputational models of structure processing.
Elucidation of the glycan structure of the b-type flagellin ofPseudomonas aeruginosaPAO1
Authors: Hensbergen Paul J. , van Huijkelom Loes , van Angeren Jordy , de Ru Arnoud H. , Claushuis Bart , van Veelen Peter A. , Smits Wiep Klaas , Corver Jeroen
Published: September 2024

Flagella are essential for motility and pathogenicity in many bacteria. The main component of the flagellar filament, flagellin, often undergoes post-translational modifications, with glycosylation being a common occurrence. InPseudomonas aeruginosaPAO1, the b-type flagellin isO-glycosylated with a structure that includes a rhamnose, a phospho-group and a previous unknown moiety. This structure resembles the well-characterized glycan (Type A) inClostridioides difficilestrain 630, which features anN-acetylglucosamine linked to anN-methylthreonine via a phosphodiester bond.

This study aimed to characterize the b-type glycan structure inPseudomonas aeruginosaPAO1 using a set of mass spectrometry experiments. For this purpose, we used wildtypeP. aeruginosaPAO1 and several gene mutants from the b-type glycan biosynthetic cluster. Moreover, we compared the mass spectrometry characteristics of the b-type glycan with those ofin vitromodified Type A-peptides fromC. difficilestrain 630Δerm.

Our results demonstrate that the thus far unknown moiety of the b-type glycan inP. aeruginosaconsists of anN,N-dimethylthreonine. These data allowed us to refine our model of the flagellin glycan biosynthetic pathway in bothP. aeruginosaPAO1 andC. difficilestrain 630.
Comparative proteomic analysis of the composition of decellularized extracellular matrix (dECM) and dECM-based inks as compared to the native tissue
Authors: Irastorza Ainhoa , Vázquez-Aristizabal Paula , Guerrero Pedro , de la Caba Koro , Izeta Ander
Published: September 2024

Regenerative medicine and tissue engineering approaches based on the use of 3D-bioprinted decellularized extracellular matrix (dECM) present the advantage of a relatively biomolecule-rich matrix, which directs cell growth and differentiation in a tissue-specific manner. However, little is known about the composition changes that occur with standard processing of dECM-based inks. To characterize this process, six porcine tissues/tissue layers (artery, breast, dermis, epidermis, muscle and nerve) were independently decellularized via chemical, mechanical and enzymatic processes and the resulting dECMs formulated into biocompatible inks, to serve as source biomaterials for 3D printing. A comparative liquid chromatography–tandem mass spectrometry (LC–MS/MS)-based proteomic analysis was carried out for native tissue, decellularized and formulated ECMs, and the resulting complexity of the matrisome analyzed. A core matrisome was found to overlap in all decellularized tissues, as well as tissue-specific components that correlated with predicted functional (gene ontology-based) definitions. The proportion of collagens (mostly the α1 chains of collagen type I and III) increased in the final processing step (inks) as compared to the native ECM and dECM stages. Overall, a median of 55 matrisomal proteins (range 45-126) was detected in the dECM-derived inks. This complexity is far superior in terms of mimicking the composition of native tissue to non-dECM-based inks. Our results support the use of dECM-based inks and biomaterials in mimicking native tissue ECM complexity.
OPLS-based Multiclass Classification and Data-Driven Inter-Class Relationship Discovery
Authors: Forsgren Edvin , Björkblom Benny , Trygg Johan , Jonsson Pär
Published: September 2024

Multiclass datasets and large-scale studies are increasingly common in omics sci-ences, drug discovery, and clinical research due to advancements in analytical platforms. Efficiently handling these datasets and discerning subtle differences across multiple classes remains a significant challenge.

In metabolomics, two-class OPLS-DA (Orthogonal Projection to Latent Structures Discriminant Analysis) models are widely used due to their strong discrimination capa-bilities and ability to provide interpretable information on class differences. However, these models face challenges in multiclass settings. A common solution is to transform the multiclass comparison into multiple two-class comparisons, which, while more ef-fective than a global multiclass OPLS-DA model, unfortunately results in a manual, time-consuming model-building process with complicated interpretation.

Here, we introduce an extension of OPLS-DA for data-driven multiclass classifi-cation: Orthogonal Partial Least Squares-Hierarchical Discriminant Analysis (OPLS-HDA). OPLS-HDA integrates Hierarchical Cluster Analysis (HCA) with the OPLS-DA framework to create a decision tree, addressing multiclass classification challenges and providing intuitive visualization of inter-class relationships. To avoid overfitting and ensure reliable predictions, we use cross-validation during model building. Benchmark results show that OPLS-HDA performs competitively across diverse datasets compared to eight established methods.

This method represents a significant advancement, offering a powerful tool to dissect complex multiclass datasets. With its versatility, interpretability, and ease of use, OPLS-HDA is an efficient approach to multiclass data analysis applicable across various fields.
Low intensity pulsed ultrasound activates excitatory synaptic networks in cultured hippocampal neurons
Authors: Li Fenfang , Lin Jia Wei , Jiang Hao , Yong Yu , Augustine George J.
Published: September 2024

Ultrasound can non-invasively penetrate deep into brain for neuromodulation and has demonstrated good potential for clinical application. Excitation or inhibition of neurons by ultrasound has been reported, but the underlying mechanisms are largely unknown. So far most in vitro studies have focused on the activation of individual neurons by ultrasound with calcium imaging. As the focal region of ultrasound is typically millimeter or submillimeter size, it is important to investigate yet so far unclear how the mechanical effects of ultrasound would influence on the synaptic circuit activity of neurons.

Methods

Low-intensity pulsed ultrasound (LIPUS) (25 MHz, 5% duty cycle, 5 Hz pulse repetition frequency, 0.4 – 1.6 W/cm2) was used to stimulate cultured hippocampal neurons. Action potentials and excitatory postsynaptic currents were recorded in individual cells with the whole-cell patch-clamp technique. We also simultaneously imaged intracellular calcium, along with neuronal electrical signals, to resolve neuronal network dynamics during LIPUS.

Results

Excitatory postsynaptic currents (EPSCs) were evoked by LIPUS in high-density neuronal cultures. Both the frequency and amplitude of EPSCs increased, indicating enhanced glutamatergic synaptic transmission. The probability of evoking responses, as well as the total charge of EPSCs evoked by ultrasound, increased with ultrasound intensity. Mechanistic analysis reveals that extracellular calcium influx, action potential (AP) firing and synaptic transmission are necessary for the responses to ultrasound in the high-density culture. In contrast, EPSCs were not enhanced in cultures with low densities of neurons. Simultaneous calcium imaging of neuronal network activity indicated that recurrent excitatory network activity is recruited during ultrasound stimulation in high-density cultures.

Conclusion

Ultrasound can activate recurrent neuronal network activity, caused by excitatory synaptic transmission, over tens to hundreds of seconds. Our study provides insights into the mechanisms involved in the response of the brain to ultrasound and illuminates the potential to use ultrasound to regulate synaptic function in neurological disorders that involve synaptic dysfunction, such as Parkinson’s disease and Alzheimer’s disease.

Graphical Abstract
Galvanin is an electric-field sensor for directed cell migration
Authors: Belliveau Nathan M. , Footer Matthew J. , Platenkamp Amy , Kim Heonsu , Eustis Tara E. , Theriot Julie A.
Published: September 2024

Directed cell migration is critical for the rapid response of immune cells, such as neutrophils, following tissue injury or infection. Endogenous electric fields, generated by the disruption of the transepithelial potential across the skin, help to guide the movement of immune and skin cells toward the wound site. However, the mechanisms by which cells sense these physical cues remain largely unknown. Through a CRISPR-based screen, we identified Galvanin, a previously uncharacterized single-pass transmembrane protein that is required for human neutrophils to change their direction of migration in response to an applied electric field. Our results indicate that Galvanin rapidly relocalizes to the anodal side of a cell on exposure to an electric field, and that the net charge on its extracellular domain is necessary and sufficient to drive this relocalization. The spatial pattern of neutrophil protrusion and retraction changes immediately upon Galvanin relocalization, suggesting that it acts as a direct sensor of the electric field that then transduces spatial information about a cell’s electrical environment to the migratory apparatus. The apparent mechanism of cell steering by sensor relocalization represents a new paradigm for directed cell migration.
A toolbox for ablating excitatory and inhibitory synapses
Authors: Bareghamyan Aida , Deng Changfeng , Daoudi Sarah , Yadav Shubash C. , Lu Xiaocen , Zhang Wei , Campbell Robert E. , Kramer Richard H. , Chenoweth David M. , Arnold Don B.
Published: September 2024

Recombinant optogenetic and chemogenetic proteins are potent tools for manipulating neuronal activity and controlling neural circuit function. However, there are few analogous tools for manipulating the structure of neural circuits. Here, we introduce three rationally designed genetically encoded tools that use E3 ligase-dependent mechanisms to trigger the degradation of synaptic scaffolding proteins, leading to functional ablation of synapses. First, we developed a constitutive excitatory synapse ablator, PFE3, analogous to the inhibitory synapse ablator GFE3. PFE3 targets the RING domain of the E3 ligase Mdm2 and the proteasome-interacting region of Protocadherin 10 to the scaffolding protein PSD-95, leading to efficient ablation of excitatory synapses. In addition, we developed a light-inducible version of GFE3, paGFE3, using a novel photoactivatable complex based on the photocleavable protein PhoCl2c. paGFE3 degrades Gephyrin and ablates inhibitory synapses in response to 400 nm light. Finally, we developed a chemically inducible version of GFE3, chGFE3, which degrades inhibitory synapses when combined with the bio-orthogonal dimerizer HaloTag ligand-trimethoprim. Each tool is specific, reversible, and capable of breaking neural circuits at precise locations.
Amyloid-β-induced Alteration of Fast and Localized Calcium Elevations in Cultured Astrocytes
Authors: Nakata Kaito , Sakamoto Joe , Otomo Kohei , Sato Masanao , Ishii Hirokazu , Tsutsumi Motosuke , Enoki Ryosuke , Nemoto Tomomi
Published: September 2024

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that causes cognitive decline. Uncovering the mechanisms of neurodegeneration in the early stages is essential to establish a treatment for AD. Recent research has proposed the hypothesis that amyloid-β (Aβ) oligomers elicit an excessive glutamate release from astrocytes toward synapses through intracellular free Ca2+([Ca2+]i) elevations in astrocytes, finally resulting in neuronal dendritic spine loss. Under physiological conditions, astrocytic [Ca2+]ielevations range spatially from microdomains to network-wide propagation and temporally from milliseconds to tens of seconds. Astrocytic localized and fast [Ca2+]ielevations might correlate with glutamate release; however, the Aβ-induced alteration of localized, fast astrocytic [Ca2+]ielevations remains unexplored.

In this study, we quantitatively investigated the Aβ dimers-induced changes in the spatial and temporal patterns of [Ca2+]iin a primary culture of astrocytes by two-photon excitation spinning-disk confocal microscopy. The frequency of fast [Ca2+]ielevations occurring locally in astrocytes (≤0.5 s, ≤35 µm2) and [Ca2+]ievent occupancy relative to cell area significantly increased after exposure to Aβ dimers.

The effect of Aβ dimers appeared dose-dependently above 500 nM, and these Aβ dimers-induced [Ca2+]ielevations were primarily mediated by a metabotropic purinergic receptor (P2Y1 receptor) and Ca2+release from the endoplasmic reticulum. Our findings suggest that the Aβ dimers-induced alterations and hyperactivation of astrocytic [Ca2+]iis a candidate cellular mechanism in the early stages of AD.
Human untargeted metabolomics in the gut microbiome era: ethanol vs methanol
Authors: Zuffa Simone , Charron-Lamoureux Vincent , Brennan Caitriona , Ambre Madison , Knight Rob , Dorrestein Pieter C.
Published: September 2024

Untargeted metabolomics is frequently performed on human fecal samples in conjunction with sequencing to unravel gut microbiome functionality. As sample collection efforts rapidly expand, with individuals often collecting specimens at home, metabolomics experiments should adapt to accommodate the safety and needs of bulk off-site collections. Here, we show that a 95% ethanol, safe to be shipped and handled, extraction pipeline recovers comparable amounts of metabolites as a validated 50% methanol extraction, preserving metabolic profiles differences between subjects. Additionally, the fecal metabolome remains relatively stable when stored in 95% ethanol for up to a week at room temperature. Finally, we suggest a metabolomics data analysis workflow using robust centered log ratio transformation, which removes variance introduced by different sample weights, allowing for reliable and integration-ready untargeted metabolomics experiments in gut microbiome studies.
Surface delivery quantification reveals distinct trafficking efficiencies among clustered protocadherin isoforms
Authors: May Elizabeth J. , Gaudet Rachelle
Published: September 2024

Proteins that transmit molecules and signals across the plasma membrane are crucial in cell biology because they enable cells to sense and respond to their surroundings. A major challenge for studying cell-surface proteins is that often they do not fold or traffic properly to the plasma membrane when produced in heterologous cells. We developed a strategy for quantifying surface localization from fluorescence microscopy images of surface-stained cells. Using clustered protocadherins, a protein family important for cell-cell recognition during neuronal development, as a model system, we found that surface delivery levels vary among clustered protocadherin isoforms and between wildtype and engineered variants. Quantifying these differences provides evidence that challenges the generally accepted hypothesis thatcisdimerization controls surface delivery of clustered protocadherins. This work establishes a generalizable framework for screening proteins and variants of interest for proper cell surface localization.

Significance

Surface proteins allow cells to interact with their environments, and their activities are often regulated by their delivery to and removal from the plasma membrane. We developed a strategy to quantitatively compare surface delivery of proteins based on established epitope tag-based surface staining methods. Using natural and engineered variants of clustered protocadherins, cell-surface proteins essential for neuron development, we show that such quantitative comparisons of surface trafficking facilitate the interpretation of mutational effects and can shed light on key regulatory mechanisms. We find that surface trafficking levels differ between variants and that, contrary to what was previously thought, a domain that inhibits surface delivery in some clustered protocadherins may do so independently of its protein-protein interaction interface.
Mother-child dyadic interactions shape children’s social brain and theory of mind
Authors: Li Lei , Xiao Jinming , Zhao Weixing , Zheng Qingyu , Huang Xinyue , Shan Xiaolong , Ming Yating , Wang Peng , Wu Zhen , Chen Huafu , Menon Vinod , Duan Xujun
Published: September 2024

Social cognition develops through a complex interplay between neural maturation and environmental factors, yet the neurobehavioral mechanisms underlying this process remain unclear. Using a naturalistic fMRI paradigm, we investigated the effects of age and parental caregiving on social brain development and Theory of Mind (ToM) in 50 mother-child dyads. The functional maturity of social brain networks was positively associated with age, while mother-child neural synchronization during movie viewing was related to dyadic relationship quality. Crucially, parenting and child factors interactively shaped social cognition outcomes, mediated by ToM abilities. Our findings demonstrate the dynamic interplay of neurocognitive development and interpersonal synchrony in early childhood social cognition, and provide novel evidence for Bandura’s theory of social learning and reciprocal determinism. This integrative approach, bridging brain, behavior, and parenting environment, advances our understanding of the complex mechanisms shaping social cognition. The insights gained can inform personalized interventions promoting social competence, emphasizing the critical importance of nurturing parental relationships in facilitating healthy social development.
Why do we have so many excitatory neurons?
Authors: Wang Qingyang , Cardona Albert , Zlatic Marta , Vogelstein Joshua T. , Priebe Carey E.
Published: September 2024

Approximately four in five neurons are excitatory. This is true across functional regions and species. Why do we have so many excitatory neurons? Little is known. Here we provide a normative answer to this question. We designed a task-agnostic, learning-independent and experiment-testable measurement of functional complexity, which quantifies the network’s ability to solve complex problems. Using the larvalDrosophilawhole-brain electron microscopy connectome, we discovered the optimal Excitatory-Inhibitory (E-I) ratio that maximizes the functional complexity: 75-81% percentage of neurons are excitatory. This number is consistent with the true distribution observed via scRNA-seq. We found that the abundance of excitatory neurons confers an advantage in functional complexity, but only when inhibitory neurons are highly connected. In contrast, when the E-I identities are sampled uniformly (not dependent on connectivity), the optimal E-I ratio falls around equal population size, and its overall achieved functional complexity is sub-optimal. Our functional complexity measurement offers a normative explanation for the over-abundance of excitatory neurons in the brain. We anticipate that this approach will further uncover the functional significance of various neural network structures.
New approach to finding invisible states in
e+e−
annihilation and application to BESIII data
Authors: Farrar Glennys R. , Li Qi-Ming , Yuan Chang-Zheng
Published: September 2024

We compare precision e+e−→μ+μ− cross section measurements by BESIII in the Ecm=3.8–4.6  GeV range, to predictions based on measured Rhad data. The consistency is poor (p-value <0.012). Allowing for resonance contributions not seen in Rhad gives an excellent fit. The 4.6σ state required at 4421 MeV suggests that a substantial portion of ψ(4415) decays are not identified, while the 3.2σ structure at 4211 MeV, if confirmed, points to a new, very narrow resonance. This analysis shows the power of precision e+e−→μ+μ− measurements to uncover or probe otherwise difficult to access states.

Published by the American Physical Society
2024
Gravitational-Wave Data Analysis with High-Precision Numerical Relativity Simulations of Boson Star Mergers
Authors: Evstafyeva Tamara , Sperhake Ulrich , Romero-Shaw Isobel M. , Agathos Michalis
Published: September 2024

Gravitational-wave signals detected to date are commonly interpreted under the paradigm that they originate from pairs of black holes or neutron stars. Here, we explore the alternative scenario of boson-star signals being present in the data stream. We perform accurate and long (∼20 orbits) numerical simulations of boson-star binaries and inject the resulting strain into LIGO noise. Our Bayesian inference reveals that some boson-star signals are degenerate with current approximants, albeit with biased parameters, while others exhibit smoking-gun signatures leaving behind conspicuous residuals.

Published by the American Physical Society
2024
Measurement of Angular Coefficients of
B¯→D*ℓν¯ℓ
: Implications for
|Vcb|
and Tests of Lepton Flavor Universality
Authors: Prim M. T. , Bernlochner F. , Metzner F. , Aihara H. , Asner D. M. , Aushev T. , Ayad R. , Babu V. , Banerjee Sw. , Behera P. , Belous K. , Bennett J. , Bessner M. , Bhardwaj V. , Bhuyan B. , Bilka T. , Biswas D. , Bodrov D. , Bondar A. , Borah J. , Bračko M. , Branchini P. , Browder T. E. , Budano A. , Campajola M. , Cao L. , Červenkov D. , Chang P. , Cheon B. G. , Choi S.-K. , Choi Y. , Choudhury S. , Cochran J. , Das S. , Dash N. , De Nardo G. , De Pietro G. , Dhamija R. , Di Capua F. , Doležal Z. , Dong T. V. , Dubey S. , Ecker P. , Epifanov D. , Ferber T. , Ferlewicz D. , Fulsom B. G. , Garg R. , Gaur V. , Giri A. , Goldenzweig P. , Gu T. , Gudkova K. , Hadjivasiliou C. , Hara T. , Hayashii H. , Hazra S. , Hedges M. T. , Herrmann D. , Hernández Villanueva M. , Hou W.-S. , Hsu C.-L. , Inami K. , Inguglia G. , Ipsita N. , Ishikawa A. , Itoh R. , Iwasaki M. , Jacobs W. W. , Kiesling C. , Kim C. H. , Kim D. Y. , Kim K.-H. , Kodyš P. , Konno T. , Korobov A. , Korpar S. , Kovalenko E. , Križan P. , Krokovny P. , Kuhr T. , Kumar M. , Kumar R. , Kwon Y.-J. , Lam T. , Lee S. C. , Lewis P. , Li L. K. , Li Gioi L. , Libby J. , Liventsev D. , Ma Y. , Matsuda T. , Matvienko D. , Maurya S. K. , Meier F. , Merola M. , Miyabayashi K. , Mizuk R. , Mohanty G. B. , Nakamura I. , Nakao M. , Narwal D. , Natkaniec Z. , Natochii A. , Nayak L. , Nishida S. , Ono H. , Oskin P. , Pakhlov P. , Pakhlova G. , Park S.-H. , Passeri A. , Patra S. , Pedlar T. K. , Pestotnik R. , Piilonen L. E. , Podobnik T. , Prencipe E. , Röhrken M. , Rout N. , Russo G. , Sandilya S. , Santelj L. , Savinov V. , Schmolz P. , Schnell G. , Schwanda C. , Seino Y. , Senyo K. , Shan W. , Shiu J.-G. , Singh J. B. , Solovieva E. , Starič M. , Stottler Z. S. , Sumihama M. , Takizawa M. , Tanida K. , Tenchini F. , Tiwary R. , Trabelsi K. , Unno Y. , Uno S. , Urquijo P. , Usov Y. , Vahsen S. E. , Varvell K. E. , Vossen A. , Wang M.-Z. , Wang X. L. , Won E. , Yabsley B. D. , Yan W. , Yang S. B. , Yin J. H. , Yuan L. , Zhang Z. P. , Zhilich V. , Zhukova V. ,   Belle Collaboration
Published: September 2024

We measure the complete set of angular coefficients Ji for exclusive B¯→D*ℓν¯ℓ decays (ℓ=e, μ). Our analysis uses the full 711  fb−1 Belle dataset with hadronic tag-side reconstruction. The results allow us to extract the form factors describing the

B

¯

→

D

*

transition and the Cabibbo-Kobayashi-Maskawa matrix element |Vcb|. Using recent lattice QCD calculations for the hadronic form factors, we find |Vcb|=(40.7±0.7)×10−3 using the Boyd-Grinstein-Lebed parametrization, compatible with determinations from inclusive semileptonic decays. We search for lepton flavor universality violation as a function of the hadronic recoil parameter w and investigate the differences of the electron and muon angular distributions. We find no deviation from standard model expectations.

Published by the American Physical Society
2024
Crystal structure and supramolecular features of a host–guest inclusion complex based on A1/A2-hetero-difunctionalized pillar[5]arene
Authors: Vinodh Mickey , Al-Azemi Talal F.
Published: September 2024

A host–guest supramolecular inclusion complex was obtained from the co-crystallization of A1/A2-bromobutoxy-hydroxy difunctionalized pillar[5]arene (PilButBrOH) with adiponitrile (ADN), C47H53.18Br0.82O10·C6H8N2. The adiponitrile guest is stabilized within the electron-rich cavity of the pillar[5]arene host via multiple C—H...O and C—H...π interactions. Both functional groups on the macrocyclic rim are engaged in supramolecular interactions with an adjacent inclusion complex via hydrogen-bonding (O—H...N or C—H...Br) interactions, resulting in the formation of a supramolecular dimer in the crystal structure.
Student perspectives on designing and implementing an interprofessional education module in chronic disease management at primary care level in Vietnam
Authors: Nguyen Huyen Thi Thanh , Nguyen Tam Minh , Tsakitzidis Giannoula , Valcke Martin , Nguyen Lo , Nguyen Anh Thi Kim , Ha Nhan Chan , Le Chi Van , Hoang Tien Anh , Vo Toan Duc , Nguyen Tu Minh , Le Anh Ho Thi Quynh , Nguyen Huy Vu Quoc , Wens Johan
Published: September 2024

Purpose

This study explored students' perspectives on designing and implementing the new clinical interprofessional education (IPE) module for chronic disease management at the primary care level in the Vietnamese context.

Design/methodology/approach

Students from seven different university-level healthcare programmes participated in a cross-sectional survey Course Experience Questionnaire-based study. Additionally, two open-ended questions were presented to gather qualitative data, mapping student perspectives. Statistical analyses and thematic analyses were performed.

Findings

The results show that students agree with quality statements about IPE design features, such as good teaching, clear goals and standards, appropriate workload, appropriate assessment and a blended learning approach. Answers to the open-ended comments pointed out the strengths of the IPE module in providing opportunities for interprofessional learning, improving interprofessional collaboration competencies, real-life interprofessional collaboration practice and continuous feedback from tutors. Students also reported weaknesses in the IPE module, including a lack of feedback on the care plan and logistics of the IPE module.

Originality/value

Students positively recognise key design features of the IPE module, combining classroom activities with standardised patient simulations, clinical practice and home visits. Chronic disease management at the primary care level is a suitable context for training students to work interprofessionally. The strengths and weaknesses identified by students could help in the redesign and future implementation of the IPE module in the Vietnamese context. They could inspire practices in Southeast Asian medical education and beyond.
The role of upscale restaurants in destination image formation: a semiotic perspective on gastronomy tourism
Authors: Marine-Roig Estela , Daries Natalia , Cristobal-Fransi Eduard , Sánchez-García Javier
Published: September 2024

Purpose

High-end gastronomic tourism is currently trending and significantly impacts a destination’s image. This research aims to demonstrate the importance of high-level local gastronomy in forming the destination image from a semiotic perspective.

Design/methodology/approach

To achieve this objective, the three phases of the upscale dining experience – pre-visit, in situ and post-visit – are examined from a descriptive (informative use), appraisive (valuative use) and prescriptive (incitive use) semiotic perspective. This conceptual model includes six constructs: restaurant image, consumer need for status, consumer expectations, consumer satisfaction, restaurant loyalty and destination loyalty. The study is based on a survey of high-end restaurant customers (N = 421).

Findings

The research findings highlight that the characteristics of upscale dining establishments influence customer expectations, while customer satisfaction plays a crucial role in fostering loyalty towards both the restaurant and the destination. Additionally, the study reveals that individuals' social status or reputation moderates their expectations and satisfaction levels.

Originality/value

Although studies relate gastronomic image to global destination image, this relationship from a semiotic perspective has not been demonstrated through surveys. This proposed three-phase model based on the Peircean semiotic triad and Morris semiotic trichotomies not only addresses a gap in the existing literature but also offers valuable insights for destination managers and restaurant owners.