bluuebunny/crossref_metadata_2025 huggingface dataset:
The Ramp protocol: Uncovering individual differences in walking to an auditory beat using TeensyStep
Authors: Zagala Agnès , Foster Nicholas E.V. , van Vugt Floris T. , Dal Maso Fabien , Dalla Bella Simone
Published: March 2024

Intentionally walking to the beat of an auditory stimulus seems effortless for most humans. However, studies have revealed significant individual differences in the spontaneous tendency to synchronize. Some individuals tend to adapt their walking pace to the beat, while others show little or no adjustment. To fill this gap we introduce the Ramp protocol, which measures spontaneous adaptation to a change in an auditory rhythmic stimulus in a gait task. First, participants walk at their preferred cadence without stimulation. After several steps, a metronome is presented, timed to match the participant’s heel-strike. Then, the metronome tempo progressively departs from the participant’s cadence by either accelerating or decelerating. The implementation of the Ramp protocol required real-time detection of heel-strike and auditory stimuli aligned with participants’ preferred cadence. To achieve this, we developed the TeensyStep device, which we validated compared to a gold standard for step detection. We also demonstrated the sensitivity of the Ramp protocol to individual differences in the spontaneous response to a tempo-changing rhythmic stimulus by introducing a new measure: the Response Score. This new method and quantification of spontaneous response to rhythmic stimuli holds promise for highlighting and distinguishing different profiles of adaptation in a gait task.
An engineered human cardiac tissue model reveals contributions of systemic lupus erythematosus autoantibodies to myocardial injury
Authors: Fleischer Sharon , Nash Trevor R. , Tamargo Manuel A. , Lock Roberta I. , Venturini Gabriela , Morsink Margaretha , Li Vanessa , Lamberti Morgan J. , Graney Pamela L. , Liberman Martin , Kim Youngbin , Zhuang Richard Z. , Whitehead Jaron , Friedman Richard A. , Soni Rajesh K. , Seidman Jonathan G. , Seidman Christine E. , Geraldino-Pardilla Laura , Winchester Robert , Vunjak-Novakovic Gordana
Published: March 2024

Systemic lupus erythematosus (SLE) is a highly heterogenous autoimmune disease that affects multiple organs, including the heart. The mechanisms by which myocardial injury develops in SLE, however, remain poorly understood. Here we engineered human cardiac tissues and cultured them with IgG fractions containing autoantibodies from SLE patients with and without myocardial involvement. We observed unique binding patterns of IgG from two patient subgroups: (i) patients with severe myocardial inflammation exhibited enhanced binding to apoptotic cells within cardiac tissues subjected to stress, and (ii) patients with systolic dysfunction exhibited enhanced binding to the surfaces of viable cardiomyocytes. Functional assays and RNA sequencing (RNA-seq) revealed that IgGs from patients with systolic dysfunction exerted direct effects on engineered tissues in the absence of immune cells, altering tissue cellular composition, respiration and calcium handling. Autoantibody target characterization by phage immunoprecipitation sequencing (PhIP-seq) confirmed distinctive IgG profiles between patient subgroups. By coupling IgG profiling with cell surface protein analyses, we identified four pathogenic autoantibody candidates that may directly alter the function of cells within the myocardium. Taken together, these observations provide insights into the cellular processes of myocardial injury in SLE that have the potential to improve patient risk stratification and inform the development of novel therapeutic strategies.
Differential predictive value of resident memory CD8+T cell subpopulations in non-small-cell lung cancer patients treated by immunotherapy
Authors: Paolini Léa , Tran Thi , Corgnac Stéphanie , Villemin Jean-Philippe , Wislez Marie , Arrondeau Jennifer , Johannes Ludger , Ulmer Jonathan , Vieillard Louis-Victorien , Pineau Joséphine , Gey Alain , Quiniou Valentin , Barennes Pierre , Pham Hang Phuong , Gruel Nadège , Hasan Milena , Libri Valentina , Mella Sébastien , De Percin Sixtine , Boudou-Rouquette Pascaline , Cremer Isabelle , Blons Hélène , Leroy Karen , Laurent-Puig Pierre , De Saint Basile Hortense , Gibault Laure , Ravel Patrice , Chouaib Fathia Mami- , Goldwasser François , Fabre Elizabeth , Damotte Diane , Tartour Eric
Published: March 2024

A high density of resident memory T cells (TRM) in tumors correlates with improved clinical outcomes in immunotherapy-treated patients. However, in preclinical models, only some subpopulations of TRMare associated with cancer vaccine efficacy.

We identified two main TRMsubpopulations in tumor-infiltrating lymphocytes derived from non-small cell lung cancer (NSCLC) patients: one co-expressing CD103 and CD49a (DP), and the other expressing only CD49a (MP); both exhibiting additional TRMsurface markers like CD69. DP TRMexhibited greater functionality compared to MP TRM. Analysis of T-cell receptor (TCR) repertoire and of the stemness marker TCF-1 revealed shared TCRs between populations, with the MP subset appearing more progenitor-like phenotype. In two NSCLC patient cohorts, only DP TRMpredicted PD-1 blockade response. Multivariate analysis, including various biomarkers (CD8, TCF1+CD8+T cells, and PD-L1) associated with responses to anti-PD(L)1, showed that only intra-tumoral infiltration by DP TRMremained significant. This study highlights the non-equivalence of TRMpopulations and emphasizes the importance of distinguishing between them to better define their role in antitumor immunity and as a biomarker of response to immunotherapy.
High-resolution perfusion imaging in rodents using pCASL at 9.4 T
Authors: Pires Monteiro Sara , Hirschler Lydiane , Barbier Emmanuel L. , Figueiredo Patricia , Shemesh Noam
Published: March 2024

Adequate perfusion is critical for maintaining normal brain function and aberrations thereof are hallmarks of many diseases. Pseudo-Continuous Arterial Spin Labeling (pCASL) MRI enables noninvasive perfusion mapping without contrast agent injection and with higher signal-to-noise ratio (SNR) than alternative methods. Despite its great potential, pCASL remains challenging, unstable, and relatively low-resolution in rodents – especially in mice – thereby limiting the investigation of perfusion properties in many transgenic or other relevant rodent models of disease. Here, we address this gap by developing a novel experimental setup for high-resolution pCASL imaging in mice and combining it with the enhanced SNR of cryogenic probes. We show that our new experimental setup allows for optimal positioning of the carotids within the cryogenic coil, rendering labelling reproducible. With the proposed methodology, we managed to increase the spatial resolution of pCASL perfusion images by a factor of 15 in mice; a factor of 6 in rats is gained compared to the state of the art just by virtue of the cryogenic coil. We also show that the improved pCASL perfusion imaging allows much better delineation of specific brain areas, both in healthy animals as well as in rat and mouse models of stroke. Our results bode well for future high-definition pCASL perfusion imaging in rodents.

Data availability

Data will be freely made available upon request.
Microsaccadic suppression of peripheral perceptual detection performance as a function of foveated visual image appearance
Authors: Greilich Julia , Hafed Ziad M.
Published: March 2024

Microsaccades are known to be associated with a deficit in perceptual detection performance for brief probe flashes presented in their temporal vicinity. However, it is still not clear how such a deficit might depend on the visual environment across which microsaccades are generated. Here, and motivated by studies demonstrating an interaction between visual background image appearance and perceptual suppression strength associated with large saccades, we probed peripheral perceptual detection performance of human subjects while they generated microsaccades over three different visual backgrounds. Subjects fixated near the center of a low spatial frequency grating, a high spatial frequency grating, or a small white fixation spot over an otherwise gray background. When a computer process detected a microsaccade, it presented a brief peripheral probe flash at one of four locations (over a uniform gray background), and at different times. After collecting full psychometric curves, we found that both perceptual detection thresholds and slopes of psychometric curves were impaired for peripheral flashes in the immediate temporal vicinity of microsaccades, and they recovered with later flash times. Importantly, the threshold elevations, but not the psychometric slope reductions, were stronger for the white fixation spot than for either of the two gratings. Thus, like with larger saccades, microsaccadic suppression strength can show a certain degree of image-dependence. However, unlike with larger saccades, stronger microsaccadic suppression did not occur with low spatial frequency textures. This observation might reflect the different spatio-temporal retinal transients associated with the small microsaccades in our study versus larger saccades.
WITHDRAWN: DiDBiT-TMT: A novel method to quantify changes in the proteomic landscape induced by neural plasticity
Authors: Gamaleldin Mariam , Yu Nam-Kyung , Diedrich Jolene K , Ma Yuanhui , Wienand Anne , McClatchy Daniel B. , Nykjaer Anders , Nabavi Sadegh , Yates John R.
Published: March 2024

Withdrawal Statement

The authors have withdrawn this manuscript because during the peer review process in the journal, it was discovered that one of the processed proteomic data groups (the chemical LTP group) was mistakenly processed from the raw data for the norepinephrine group, resulting in an apparent complete overlap between the two conditions.

For a correct analysis, please refer to the currently published peer-reviewed publication through the following DOI:https://doi.org/10.1021/acs.jproteome.4c00180

Therefore, the authors do not wish this preprint to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Inter-modality source coupling: a fully-automated whole-brain data-driven structure-function fingerprint shows replicable links to reading in a large-scale (N∼8K) analysis
Authors: Kotoski Aline , Liu Jingyu , Morris Robin , Calhoun Vince
Published: March 2024

Objective

Both structural and functional brain changes have been individually associated with developing cognitive processes such as reading. However, there is limited research about the combined influence of resting-state functional and structural magnetic resonance imaging (rs-fMRI and sMRI) features in reading development, which could provide insights into the interplay between brain structure and function in shaping cognitive growth. We propose a method called inter-modality source coupling (IMSC) to study the coupling between the rs-fMRI and sMRI and its relationship to reading ability in school-age children.

Methods

This approach is applied to baseline data from four thousand participants (9-11 years) and replicated in a second group. Our analysis focused on the relationship of IMSC to overall reading score.

Results

Our findings indicate that higher reading ability was linked with increased function-structure coupling among higher-level cortical regions, particularly those links between the inferior parietal lobule and inferior frontal areas, and conversely, lower reading ability was associated with enhanced function-structure coupling among the fusiform and lingual gyrus. Our study found evidence of spatial correspondence between the data indicating an interplay between brain structure and function in our participants.

Conclusion

Our approach revealed a linked pattern of whole brain structure to the corresponding functional connectivity pattern that correlated with reading ability. This novel IMSC analysis method provides a new approach to study the multimodal relationship between brain function and structure.

Significance

These findings have interesting implications for understanding the multimodal complexity underlying the development of the neural basis for reading ability in school-aged children.
Protein language models are biased by unequal sequence sampling across the tree of life
Authors: Ding Frances , Steinhardt Jacob
Published: March 2024

Protein language models (pLMs) trained on large protein sequence databases have been used to understand disease and design novel proteins. In design tasks, the likelihood of a protein sequence under a pLM is often used as a proxy for protein fitness, so it is critical to understand what signals likelihoods capture. In this work we find that pLM likelihoods unintentionally encode a species bias: likelihoods of protein sequences from certain species are systematically higher, independent of the protein in question. We quantify this bias and show that it arises in large part because of unequal species representation in popular protein sequence databases. We further show that the bias can be detrimental for some protein design applications, such as enhancing thermostability. These results highlight the importance of understanding and curating pLM training data to mitigate biases and improve protein design capabilities in under-explored parts of sequence space.
CLCluster: a redundancy-reduction contrastive learning-based clustering method of cancer subtype based on multi-omics data
Authors: Wang Hong , Zhang Yi , Li Wen , Wang Zhenlong , Wei Zhen , Yang Mengyuan
Published: March 2024

Alternative splicing (AS) enables the regulated generation of multiple mRNA and protein products from a single gene. Cancer cells have general, cancer type-specific, and subtype-specific alterations in the splicing process that can have predictive value and contribute to cancer diagnosis, prognosis, and treatment. Currently, multi-omics data have been used to identify the molecular subtype of cancer. However, alternative splicing is rarely used to identify the cancer subtypes. Here, we propose a redundancy-reduction contrastive learning-based method (CLCluster) based on copy number variation, DNA methylation, gene expression, miRNA expression, and alternative splicing for cancer subtype clustering of 33 cancer types. Experimental results demonstrate the superior performance of the proposed CLCluster model in identifying cancer subtypes over the currently available state-of-the-art clustering methods. Moreover, ablation experiments demonstrate the advantages of alternative splicing data for cancer subtyping tasks. We performed multiple analyses for cancer subtype-related AS events, including open reading frame annotation, and RNA binding protein-associated alternative splicing regulation. From our analysis, we identified 2,930 AS events that were associated with patient survival, and ORF analysis showed that 417 of them could cause in-frame and 420 could cause frameshift. we also identified 1,752 RBP-AS regulatory pairs that could be associated with patient survival. Accurate classification of the cancer type using CLCluster, and effective annotation of cancer subtype related AS events can effectively facilitate the identification of patient’s therapeutically targetable AS events.
Are ChatGPT and Copilot Reliable for Health Education on Statistical Testing?
Authors: Rovetta Alessandro , Mansournia Mohammad Ali
Published: March 2024

The introduction of Artificial Intelligence (AI) has revolutionized daily life and scientific research, with applications ranging from writing scientific articles to clinical assistance. However, the effectiveness of AI models like ChatGPT 3.5 by Open AI and Bing Copilot GPT-4 by Microsoft in explaining complex concepts such as statistical testing is a cause for concern. This study investigates the ability of these AI models to explain fundamental statistical concepts, such as P-values, confidence intervals, and surprisals, crucial to properly inform conclusions in scientific research and public health. Our results highlight significant misconceptions in both AI models’ understanding and teaching of inferential statistics. These deficiencies include the mixing of incompatible statistical approaches, the nullism fallacy, the dichotomization of (statistical) significance, the incorrect interpretation of statistical measures and concepts, and an overestimation of the role of p-values and confidence intervals. Additionally, both models lack knowledge of recent alternative statistical methods like S-values and S-intervals, showing biases similar to those present in traditional statistical approaches. Given the importance of accurate statistical understanding in various sectors and the widespread integration of AI in decision-making processes, urgent intervention by OpenAI and Microsoft is necessary to update their platform databases. It is essential to align AI knowledge with the latest developments in scientific research to ensure the reliability of generated results. Collaboration with organizations such as the American Statistical Association is recommended to facilitate this process. In conclusion, this scenario underscores the need for immediate corrective action by the developing companies of such platforms. Indeed, only through continuous updates and improvements can we ensure that AI can contribute positively to scientific and technological progress.
Directional swimming patterns in jellyfish aggregations
Authors: Malul Dror , Berman Hadar , Solodoch Aviv , Tal Omri , Barak Noga , Mizrahi Gur , Berenshtein Igal , Toledo Yaron , Lotan Tamar , Sher Daniel , Shavit Uri , Lehahn Yoav
Published: March 2024

Having a profound influence on marine and coastal environments worldwide, jellyfish hold significant scientific, economic, and public interest. The predictability of outbreaks and dispersion of jellyfish is limited by a fundamental gap in our understanding of their movement. Although there is evidence that jellyfish may actively affect their position, the role of active swimming in controlling jellyfish movement, and the characteristics of jellyfish swimming behavior, are not well understood. Consequently, jellyfish are often regarded as passively drifting or randomly moving organisms, both conceptually and in process studies. Here we show that the movement of jellyfish is controlled by distinctly directional swimming patterns, which are oriented against the direction of surface gravity waves. Taking a Lagrangian viewpoint from drone videos that allows the tracking of multiple adjacent jellyfish, and focusing the scyphozoan jellyfishRhopilema nomadicaas a model organism, we show that the behavior of individual jellyfish translates into a synchronized directional swimming of the aggregation as a whole. Numerical simulations show that this counter-wave swimming behavior results in biased correlated random-walk movement patterns that reduce the risk of stranding, thus providing jellyfish with an adaptive advantage critical to their survival. Our results emphasize the importance of active swimming in regulating jellyfish movement, and open the way for a more accurate representation in model studies, thus improving the predictability of jellyfish outbreaks and their dispersion, and contributing to our ability to mitigate their possible impact on coastal infrastructure and populations.
Chk2 sustains PLK1 activity in mitosis to ensure proper chromosome segregation
Authors: Black Elizabeth M. , Ramírez Parrado Carlos Andrés , Trier Isabelle , Li Wenxue , Joo Yoon Ki , Pichurin Jennifer , Liu Yansheng , Kabeche Lilian
Published: March 2024

Polo-like kinase 1 (PLK1) protects against genome instability by ensuring timely and accurate mitotic cell division. PLK1 activity is tightly regulated throughout the cell cycle. Although the pathways that initially activate PLK1 in G2 are well-characterized, the factors that directly regulate PLK1 in mitosis remain poorly understood. Here, we identify that human PLK1 activity is sustained by the DNA damage response kinase Checkpoint kinase 2 (Chk2) in mitosis. Chk2 directly phosphorylates PLK1 T210, a residue on its T-loop whose phosphorylation is essential for full PLK1 kinase activity. Loss of Chk2-dependent PLK1 activity causes increased mitotic errors, including chromosome misalignment, chromosome missegregation, and cytokinetic defects. Moreover, Chk2 deficiency increases sensitivity to PLK1 inhibitors, suggesting that Chk2 status may be an informative biomarker for PLK1 inhibitor efficacy. This work demonstrates that Chk2 sustains mitotic PLK1 activity and protects genome stability through discrete functions in interphase DNA damage repair and mitotic chromosome segregation.
Non-endothelial expression of Endomucin in the mouse and human choroid
Authors: Brookins Elysse , Serrano Sophia E. , Yacu George S. , Finer Gal , Thomson Benjamin R
Published: March 2024

Endomucin (EMCN) is a 261 AA transmembrane glycoprotein that is highly expressed by venous and capillary endothelial cells where it plays a role in VEGF-mediated angiogenesis and regulation of immune cell recruitment. However, it is better known as a histological marker, where it has become widespread due to the commercial availability of high-quality antibodies that work under a wide range of conditions and in many tissues. The specificity of EMCN staining has been well-validated in retinal vessels, but while it has been used extensively as a marker in other tissues of the eye, including the choroid, the pattern of expression has not been described in detail. Here, in addition to endothelial expression in the choriocapillaris and deeper vascular layers, we characterize a population of EMCN-positive perivascular cells in the mouse choroid that did not co-localize with cells expressing other endothelial markers such as PECAM1 or PODXL. To confirm that these cells represented a new population of EMCN-expressing stromal cells, we then performed single cell RNA sequencing in choroids from adult wild-type mice. Analysis of this new dataset confirmed that, in addition to endothelial cells,EmcnmRNA expression was present in choroidal pericytes and a subset of fibroblasts, but not vascular smooth muscle cells. BesidesEmcn, no known endothelial gene expression was detected in these cell populations, confirming that they did not represent endothelial-stromal doublets, a common technical artifact in single cell RNA seq datasets. Instead, choroidalEmcn-expressing fibroblasts exhibited high levels of chemokine and interferon signaling genes, whileEmcn-negative fibroblasts were enriched in genes encoding extracellular matrix proteins.Emcnexpressing fibroblasts were also detected in published datasets from mouse brain and human choroid, suggesting that stromalEmcnexpression was not unique to the choroid and was evolutionarily conserved. Together, these findings highlight unique fibroblast and pericyte populations in the choroid and provide new context for the role of EMCN in angiogenesis and immune cell recruitment.
Evolutionary sequence and structural basis for the distinct conformational landscapes of Tyr and Ser/Thr kinases
Authors: Gizzio Joan , Thakur Abhishek , Haldane Allan , Post Carol Beth , Levy Ronald M.
Published: March 2024

Protein kinases are molecular machines with rich sequence variation that distinguishes the two main evolutionary branches – tyrosine kinases (TKs) from serine/threonine kinases (STKs). Using a sequence co-variation Potts statistical energy model we previously concluded that TK catalytic domains are more likely than STKs to adopt an inactive conformation with the activation loop in an autoinhibitory “folded” conformation, due to intrinsic sequence effects. Here we investigated the structural basis for this phenomenon by integrating the sequence-based model with structure-based molecular dynamics (MD) to determine the effects of mutations on the free energy difference between active and inactive conformations, using a novel thermodynamic cycle involving many (n=108) protein-mutation free energy perturbation (FEP) simulations in the active and inactive conformations. The sequence and structure-based results are consistent and support the hypothesis that the inactive conformation “DFG-out Activation Loop Folded”, is a functional regulatory state that has been stabilized in TKs relative to STKs over the course of their evolution via the accumulation of residue substitutions in the activation loop and catalytic loop that facilitate distinct substrate binding modesin transand additional modes of regulationin cisfor TKs.
Adaptive generalization in pollinators: hawkmoths increase fitness to long-tubed flowers, but secondary pollinators remain important
Authors: Wenzell Katherine E. , Zhang Johnathan Y. , Skogen Krissa A. , Fant Jeremie B.
Published: March 2024

Selection on floral traits by animal pollinators is important in the evolution of flowering plants, yet whether floral divergence requires specialized pollination remains uncertain. Longer floral tubes, a trait associated with long-tongued pollinators, can also exclude other pollinators from accessing rewards, a potential mechanism for specialization. Across most of its range,Castilleja sessilifloradisplays much longer corollas than mostCastillejaspecies, though tube length varies geographically and correlates partially with hawkmoth visitation. To assess if long corolla tubes reflect adaptation to hawkmoth pollinators, we performed a day/night pollinator exclusion experiment in nine natural populations that varied in corolla length across the range ofC. sessilifloraand short-tubed members of the parapatricC. purpureacomplex. We compared the fitness contributions of nocturnal and diurnal visitors, revealing that long-tubed populations visited predominantly by hawkmoths experienced greater fruit set at night, in contrast with short-tubed populations or those visited mainly by diurnal pollinators. Next, leveraging a range-wide multi-year dataset of pollinator visitation to these species, we identify that hawkmoth visitation is associated with increased fitness in long-tubed populations overall, and that long tubes are associated with less diverse visitor assemblages. Thus, long corollas represent an adaptation to hawkmoth pollination at the exclusion of diverse pollinators. Nonetheless, while hawkmoths were scarce in the northern range, secondary diurnal pollinators contributed to fruit set across the range, providing reproductive assurance despite possible trait mismatch. This study illustrates adaptive generalization in pollination modes and that floral divergence may proceed along a continuum of generalized and specialized pollinator interactions.
Nurture Early for Optimal Nutrition (NEON) Pilot Randomised Controlled Trial: Qualitative study of community facilitators and attendees’ perspective on intervention delivery
Authors: Manikam Logan , Patil Priyanka , Bello Ummi , Chakraborty Subarna , Fujita Sumire , Dwardzweska Joanna , Oyebode Oyinlola , Llewellyn Clare H. , Webb-Martin Kelley , Irish Carol , Archibong Mfon , Gilmour Jenny , Kalungi Phoebe , Batura Neha , Conway Rana , Lakhanpaul Monica , Heys Michelle
Published: March 2024

Background

Appropriate and healthy feeding practices can enhance a child’s health, prevent obesity, and reduce chronic metabolic disease risks. Given the ethnic variations in feeding practices and metabolic risk, interventions must be community specific. Culturally tailored, grassroots interventions targeting infant feeding can induce behavioural changes, mitigating chronic metabolic disease risks in later life.

Aim

The aim of this study was to explore participant feedback and inform intervention delivery methods within marginalised communities.

Methods

A pilot three-arm cluster randomised controlled trial was conducted in London’s Tower Hamlets and Newham boroughs, involving community participatory learning and action groups. The study recruited 186 South Asian (Indian, Bangladeshi, Pakistani, and Sri Lankan) mothers or carers of 0-2-year-old children. Attendees were invited to either face-to-face or online intervention arms, facilitated by trained multilingual community facilitators, offering culturally informed discussions on child nutrition and care practices. Qualitative feedback was collected from attendees and facilitators, with thematic analysis identifying key themes, underscoring intervention fidelity and acceptance.

Results

Of the initial attendees, 42 (from the remaining 153 at the study’s conclusion) and 9 community facilitators offered feedback on the intervention’s delivery and suggestions for enhancing community-based interventions’ success. Key findings highlighted the need for a more flexible approach to boost participation and the significance of providing accessible, translated documents and resources.

Conclusion

Parenting interventions, particularly for new mothers, should adopt a hybrid design. This would provide attendees with the flexibility to select the delivery method, session timings, and the option to participate at any stage of the intervention.
Brain State-dependent Repetitive Transcranial Magnetic Stimulation for Motor Stroke Rehabilitation: A Proof of Concept Randomized Controlled Trial
Authors: Mahmoud Wala , Baur David , Zrenner Brigitte , Brancaccio Arianna , Belardinelli Paolo , Ramos-Murguialday Ander , Zrenner Christoph , Ziemann Ulf
Published: March 2024

Background

In healthy subjects, repetitive transcranial magnetic stimulation (rTMS) targeting the primary motor cortex (M1) demonstrated plasticity effects contingent on electroencephalography (EEG)-derived excitability states, defined by the phase of the ongoing sensorimotor μ-oscillation. The therapeutic potential of brain state-dependent rTMS in the rehabilitation of upper limb motor impairment post-stroke remains unexplored.

Objective

Proof-of-concept trial to assess the efficacy of rTMS, synchronized to the sensorimotor µ-oscillation, in improving motor function and reducing upper-limb spasticity in stroke patients.

Methods

We conducted a parallel group, randomized double-blind controlled trial in 30 chronic stroke patients. The experimental intervention group received EEG-triggered rTMS of the ipsilesional M1 (1,200 pulses; 0.33 Hz; 90% of the resting motor threshold (RMT)), while the control group received low-frequency rTMS of the contralesional motor cortex (1,200 pulses; 1 Hz, 115% RMT), i.e., an established treatment protocol. Both groups received 12 rTMS sessions (20 min, 3x per week, 4 weeks) followed by 50 min of physiotherapy. The primary outcome measure was the change in upper-extremity Fugl-Meyer assessment (FMA-UE) scores between baseline, immediately post-treatment and 3 months’ follow-up.

Results

Both groups showed significant FMA-UE improvement and spasticity reduction (clinical and objective measures). There were no significant differences between the groups in any of the outcome measures.

Conclusions

The application of brain state-dependent rTMS for rehabilitation in chronic stroke patients is feasible. This pilot study demonstrated that the brain oscillation-synchronized rTMS protocol produced beneficial effects on motor disability and spasticity that were comparable to those observed with an established therapeutic rTMS protocol.
High fat and low carbohydrate supplies are linked to decreased epilepsy disease burden globally
Authors: Ni Duan , Senior Alistair , Raubenheimer David , Simpson Stephen J. , Nanan Ralph
Published: March 2024

Objectives

Epilepsy is one of the major neural disorders globally. Ketogenic diets with high fat, low carbohydrate and moderate to low protein contents are well-established as interventions for epilepsy, particularly the intricate ones, exemplifying that modifying dietary compositions might have profound effects on established epilepsy. However, most of the diet-related epilepsy interventions have focused on dividual nutrients or specific diets with set nutrient compositions. An important unanswered question is whether specific macronutrient exposure through diets and food environments are linked to epilepsy and could potentially extend to primary preventive qualities.

Methods

Macronutrient supply, gross domestic product (GDP), and epilepsy disease burden data were collated from more than 150 countries spanning from 1990 to 2018. Nutritional geometry generalized additive mixed models (GAMMs) were carried out for analysis.

Results

GAMM modelling unravelled the interactive effects of nutrient supplies and socioeconomic status on epilepsy disease burden. Carbohydrate supply was associated with increased epilepsy while fat supply had the opposite effect. A high fat low carbohydrate supplies dietary environment, similar to ketogenic diets, was linked to the lowest epilepsy disease burden. These associations were conserved across sexes and were not confounded by the total energy supply.

Conclusions

A high fat low carbohydrate supplies dietary environment is associated with decreased epilepsy disease burden, hinting a plausible primary preventive role. This might expand the clinical application of ketogenic diets and inform future nutrient-based epilepsy treatment and/or prevention.
Dorsal hippocampus represents locations to avoid as well as locations to approach during approach-avoidance conflict
Authors: Calvin Olivia L. , Erickson Matthew T. , Walters Cody J. , David Redish A.
Published: March 2024

Worrying about perceived threats is a hallmark of multiple psychological disorders including anxiety. This concern about future events is particularly important when an individual is faced with an approach-avoidance conflict. Potential goals to approach are known to be represented in the dorsal hippocampus during theta sweeps. Similarly, important non-local information is represented during hippocampal high synchrony events (HSEs), which are correlated with sharp-wave ripples (SWRs). It is likely that potential future threats may be similarly represented. We examined how threats and rewards were represented within the hippocampus during approach-avoidance conflicts in rats faced with a predator-like robot guarding a food reward. We found representations of the pseudo-predator during HSEs when hesitating in the nest, and during theta prior to retreating as the rats approached the pseudo-predator. After the first attack, we observed new place fields appearing at the location of the robot (not the location the rat was when attacked). The anxiolytic diazepam reduced anxiety-like behavior and altered hippocampal local field potentials, including reducing SWRs, suggesting that one potential mechanism of diazepam’s actions may be through altered representations of imagined threat. These results suggest that hippocampal representation of potential threats could be an important mechanism that underlies worry and a potential target for anxiolytics.
Gliding motility of the diatom Craspedostauros australis correlates with the intracellular movement of raphid-specific myosins
Authors: Davutoglu Metin Gabriel , Geyer Veikko F. , Niese Lukas , Soltwedel Johannes R. , Zoccoler Marcelo L. , Haase Robert , Kroeger Nils , Diez Stefan , Poulsen Nicole
Published: March 2024

Raphid diatoms are one of the few eukaryotes capable of gliding motility, which is remarkably fast and allows for quasi-instantaneous directional reversals. Besides other mechanistic models, it has been suggested that an actomyosin system provides the force for diatom gliding. However, in vivo data on the dynamics of actin and myosin in diatoms are lacking. In this study we demonstrate that the raphe-associated actin bundles required for diatom movement do not exhibit a directional turnover of subunits and thus their dynamics do not contribute directly to force generation. By phylogenomic analysis we identified four raphid diatom-specific myosins in Craspedostauros australis (CaMyoA-D) and investigated their in vivo localization and dynamics through GFP-tagging. Only CaMyoB-D but not CaMyoA exhibited coordinated movement during gliding, consistent with a role in force generation. The characterization of raphid diatom-specific myosins lays the foundation for unraveling the molecular mechanisms that underlie the gliding motility of diatoms.
A cellular assay system revealed the deamidase-mediated regulation of the Arg-mediated N-end rule protein degradation pathway
Authors: Yoshida Shusei , Ohta Ren , Miyabe Mami , Tamura Taku
Published: March 2024

Regulated protein production and degradation are essential for maintaining proteostasis in eukaryotic cells. The N-end rule, or N-degron pathway, is a protein degradation machinery in which the N-terminal amino acid is the mark of the protein degradation via the proteasome. The N-end rule is a conserved protein disposal machinery in eukaryotic cells. However, the precise cellular mechanisms and their physiological roles are not fully understood. Herein, we report the development of an Arg-mediated N-end rule assay system using artificial substrates expressed in cultured cell lines. We demonstrated that the N-end rule degradation is significantly influenced by the expression levels of N-terminal amino acid-modifying enzymes, including NTAN1, NTAQ1, and ATE1. In the N-terminal Asn protein pathway, an increase in NTAN1 or ATE1 expression promotes its disposal via the N-end rule degradation pathway. Interestingly, overexpression of NTAQ1 decreased the degradation of the protein bearing Gln at the N-terminus. Computational prediction of NTAQ1 and ATE1 complex formation suggests that the outer loop region of NTAQ1 is involved in its interaction with ATE1 and that the NTAQ1 overexpression may negatively affect this interaction. Our findings suggest that the degradation activity of the Arg/N-end rule pathway is positively or negatively regulated by deamidase expression levels and propose a higher degree of control of protein degradation by the Arg/N-end rule within cells.
YmoA functions as a molecular stress sensor inYersinia
Authors: Héchard Tifaine , Lu Lu , Edgren Tomas , Chi Celestine , Wang Helen
Published: March 2024

Pathogenic bacteria sense and respond to environmental fluctuations, a capability essential for establishing successful infections. The YmoA/Hha protein family are conserved transcription regulators in Enterobacteriaceae, playing a critical role in these responses. Specifically, YmoA inYersiniaadjusts the expression of virulence-associated traits upon temperature shift. Still, the molecular mechanisms transducing environmental signal through YmoA remain elusive. Our study employed nuclear magnetic resonance spectroscopy, biological assays and RNA-seq analysis to elucidate these mechanisms. We demonstrated that YmoA underwent structural fluctuations and conformational dynamics in response to temperature and osmolarity changes, correlating with changes in plasmid copy number, bacterial fitness and virulence function. Notably, chemical shift analysis identified key roles of a few specific residues and of the C-terminus region in sensing both temperature and salt-driven switch. These findings demonstrate that YmoA acts as a central stress sensor inYersinia, fine-tuning virulence gene expression and balancing metabolic trade-offs.
Exploring the therapeutic potential of defective interfering particles in reducing the replication of SARS-CoV-2
Authors: Locke Macauley , Grebennikov Dmitry , Sazonov Igor , Lopez-Garcia Martin , Loguinova Marina , Meyerhan Andreas , Bocharov Gennady , Molina-Paris Carmen
Published: March 2024

SARS-CoV-2 still presents a global threat to human health due to the continued emergence of new strains and waning immunity amongst vaccinated populations. Therefore, it is still relevant to investigate potential therapeutics, such as therapeutic interfering particles (TIPs). Mathematical and computational modelling are valuable tools to study viral infection dynamics for predictive analysis. Here, we expand on the previous work by Grebennikov et al. (2021) on SARS-CoV-2 intra-cellular replication dynamics to include defective interfering particles (DIPs) as potential therapeutic agents. We formulate a deterministic model that describes the replication of wild-type (WT) SARS-CoV-2 virus in the presence of DIPs. Sensitivity analysis of parameters to several model outputs is employed to inform us on those parameters to be carefully calibrated from experimental data. We then study the effects of co-infection on WT replication and how DIP dose perturbs the release of WT viral particles. Furthermore, we provide a stochastic formulation of the model that is compared to the deterministic one. These models could be further developed into population-level models or used to guide the development and dose of TIPs.
Stochastic Voronoi Tessellations as Models for Cellular Neighborhoods in Simple Multicellular Organisms
Authors: Srinivasan Anand , Höhn Steph S.M.H. , Goldstein Raymond E.
Published: March 2024

Recent work on distinct multicellular organisms has revealed a hitherto unknown type of biological noise; rather than a regular arrangement, cellular neighborhood volumes, obtained by Voronoi tessellations of the cell locations, are broadly distributed and consistent with gamma distributions. We propose an explanation for those observations in the case of the algaVolvox, whose somatic cells are embedded in an extracellular matrix (ECM) they export. Both a solvable one-dimensional model of ECM growth derived from bursty transcriptional activity and a two-dimensional “Voronoi liquid” model are shown to provide one-parameter families that smoothly interpolate between the empirically-observed near-maximum-entropy gamma distributions and the crystalline limit of Gaussian distributions governed by the central limit theorem. These results highlight a universal consequence of intrinsic biological noise on the architecture of certain tissues.
Multiple levels of transcriptional regulation control glycolate metabolism inParacoccus denitrificans
Authors: Schada von Borzyskowski Lennart , Hermann Lucas , Kremer Katharina , Barthel Sebastian , Pommerenke Bianca , Glatter Timo , Paczia Nicole , Bremer Erhard , Erb Tobias J.
Published: March 2024

The hydroxyacid glycolate is a highly abundant carbon source in the environment. Glycolate is produced by unicellular photosynthetic organisms and excreted at petagram scales to the environment, where it serves as growth substrate for heterotrophic bacteria. In microbial metabolism, glycolate is first oxidized to glyoxylate by the enzyme glycolate oxidase. The recently described β-hydroxyaspartate cycle (BHAC) subsequently mediates the carbon-neutral assimilation of glyoxylate into central metabolism in ubiquitous Alpha- and Gammaproteobacteria. While the reaction sequence of the BHAC was elucidated inParacoccus denitrificans, little is known about the regulation of glycolate and glyoxylate assimilation in this relevant alphaproteobacterial model organism. Here, we show that regulation of glycolate metabolism inP. denitrificansis surprisingly complex, involving two regulators, the IclR-type transcription factor BhcR that acts as an activator for the BHAC gene cluster, as well as the GntR-type transcriptional regulator GlcR, a previously unidentified repressor that controls the production of glycolate oxidase. Furthermore, an additional layer of regulation is exerted at the global level, which involves the transcriptional regulator CceR that controls the switch between glycolysis and gluconeogenesis inP. denitrificans. Together, these regulators control glycolate metabolism inP. denitrificans, allowing the organism to assimilate glycolate together with other carbon substrates in a simultaneous fashion, rather than sequentially. Our results show that the metabolic network of Alphaproteobacteria shows a high degree of flexibility to react to the availability of multiple substrates in the environment.
Disentangling the potential factors definingBacillus subtilisabundance in natural soils
Authors: Xu Xinming , Pioppi Adele , Kiesewalter Heiko T. , Strube Mikael Lenz , Kovács Ákos T.
Published: March 2024

Bacillus subtilisis ubiquitously and broadly distributed in various environments but mostly isolated from soil. Given that species ofB. subtilisare known as key plant growth-promoting rhizobacteria in agriculture, we here aimed to describe the natural distribution of this species and uncover how biotic and abiotic factors affect its distribution. When comparing different soils, we discovered thatB. subtilisis most abundant in grasslands, but can rarely be isolated from forest soil, even if the sample sites for the two types of soil are situated in proximity. Differential analysis revealed that spore-forming bacteria exhibited enrichments in the grassland, suggesting niche overlap or synergistic interactions leading to the proliferation of certainBacillusspecies in grassland environments. Network analysis further revealed thatBacillusand otherBacillotaestablished a densely interconnected hub module in the grassland soil samples, characterized by positive associations indicating co-occurrence, a pattern not observed in the forest soil. Speculating that this difference was driven by abiotic factors, we next combined amplicon sequencing with physio-chemical analysis of soil samples, and found multiple chemical variables, mainly pH, to affect microbial composition. Our study pinpoints the factors that influenceB. subtilisabundance in natural soils and, therefore, offers insights for designingB. subtilis-based biocontrol products in agricultural settings.
The Dsc ubiquitin ligase complex identifies transmembrane degrons to degrade orphaned proteins at the Golgi
Authors: Weyer Yannick , Schwabl Sinead Iduna , Tang Xuechen , Widerin Michael A. , Niedrist Veronika , Tettamanti Maria G. , Weys Sabine , Sarg Bettina , Kremser Leopold , Liedl Klaus R. , Schmidt Oliver , Teis David
Published: March 2024

The Golgi apparatus is essential for protein sorting, yet its quality control mechanisms are poorly understood. Here we show that the Dsc ubiquitin ligase complex, particularly the rhomboid pseudo-protease subunit, Dsc2, assesses the hydrophobic length of α-helical transmembrane domains (TMDs) at the Golgi. Thereby the Dsc complex interacts with orphaned ER and Golgi proteins that have shorter TMDs and ubiquitinates them for targeted degradation. Some Dsc substrates will be K63 polyubiquitinated for ESCRT dependent vacuolar degradation or K48 polyubiquitinated forendosome andGolgiassociated proteasomaldegradation (EGAD). Other Dsc substrates are exclusively extracted by Cdc48 for EGAD. The accumulation of Dsc substrates entails a specific increase in glycerophospholipids with shorter and asymmetric fatty acyl chains. Hence, the Dsc complex mediates the selective degradation of orphaned proteins at the sorting center of cells, which prevents their spreading across other organelles and thus preserves cellular membrane protein and lipid composition.
Protection from plague via single dose administration of antibody to neutralize the type I interferon response
Authors: Marks KD , Anderson DM
Published: March 2024

Yersinia pestisis a gram-negative bacterium and the causative agent for the plague.Yersinia spp. use effector proteins of the type III secretion system (T3SS) to skew the host immune response toward a bacterial advantage during infection. Previous work established that mice which lack the type I IFN receptor (IFNAR), exhibit resistance to pulmonary infection byY. pestis. In this work, we addressed the efficacy of a single dose administration of neutralizing antibody to IFNAR (MAR1) as a preventive treatment for plague. We show that single dose administration of MAR1 provides protection from mortality due to secondary septicemic plague where it appears to reduce the production of serum TNFα during the disease phase. We further demonstrate that the T3SS effector protein YopJ is necessary for MAR1-induced protection, however IFNAR-dependent serum TNFα was observed independent of YopJ. We further define tissue-specific anti-bacterial roles of IFNAR that are blocked by YopJ activity indicating that YopJ and IFNAR work in parallel to promote disease. The combined data suggest that therapeutic targeting of IFNAR signaling may reduce the hyper-inflammatory response associated with plague.