bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating the temporal effects of ovarian failure on single muscle fibre contractility using a chemically-induced ovarian failure model in mice
Authors: Mashouri Parastoo , Saboune Jinan , Pyle W. Glen , Power Geoffrey A.
Published: July 2024

We investigated the effects of chemically-induced ovarian failure on single muscle fibre contractility of the soleus and extensor digitorum longus (EDL) muscles throughout ovarian failure, thereby mimicking the menopausal transition into late-stage menopause: [(D60;peri-menopause), (D120;onset of menopause), (D134;early-onset menopause), (D176;late-stage menopause)]. We used 4-vinylcyclohexene diepoxide (VCD) to induce ovarian failure in sexually-mature female mice. At D120 and D176, mice with VCD-induced ovarian failure produced higher force as compared with controls (p<0.05). On D134, however, VCD had lower force production compared with controls (p<0.05). The cross-sectional area of the soleus fibres from the VCD group was larger at D120 compared with controls (p<0.05), but not at any other time point (p>0.05). As well, at D120-D176, the proportion of Type II fibres relative to Type I increased for the soleus, but not the EDL. No differences in rate of force redevelopment (Ktr) was observed for the soleus (p>0.05), while calcium sensitivity increased by late-stage menopause (p<0.05). There were no differences in force, cross-sectional area, stiffness, Ktr, or calcium sensitivity between groups for the EDL (p>0.05). Muscle contractility across the peri-menopausal transition into late-stage menopause is both muscle and phase-dependent, emphasizing the complexity of changing hormones throughout the lifespan on muscle contractile function.
RAF2Net: Automated grading of Renal cell Carcinoma utilizing Attention-enhanced deep learning models through Feature Fusion
Authors: Kundu Shreyan , Roy Nirban , Talukdar Rahul , Das Semanti , Mukhopadhyay Souradeep , Basu Mallik Biswadip
Published: July 2024

It is anticipated that the number of instances of kidney cancer will continue to rise globally, which motivates changes to the current diagnostic framework in order to address emerging issues. Renal cell carcinoma (RCC) accounts for 80–85% of all renal tumors and is the most common kind of kidney cancer. Based on kidney histopathology images, this study presented a completely automated, robust, and computationally efficient Renal Cell Carcinoma Grading Network (RAF2Net). Our suggested model incorporates 3 different Mobilenet backbones with intelligent feature fusion. Moreover, the attention blocks help us give more importance to the important pixels, which are majorly responsible for classification. For comparison purposes, Similar tests were conducted using transfer learning methods with pre-trained ImageNet weights and deep learning models created from scratch. To show the efficacy of the suggested method, we have computed evaluation parameters like Accuracy, Precision, F score, Recall, Confusion Matrix, and TSNE. Based on the provided KMC dataset, the experimental result demonstrates that the proposed RAF2Net outperforms the nine most recent classification methods regarding prediction Accuracy, Recall, Precision, and F score with a value greater than 92%.
Leveraging multivariate information for community detection in functional brain networks
Authors: Puxeddu Maria Grazia , Pope Maria , Varley Thomas F. , Faskowitz Joshua , Sporns Olaf
Published: July 2024

Embedded in neuroscience is the concept that brain functioning is underpinned by specialized systems whose integration enables cognition and behavior. Modeling the brain as a network of interconnected brain regions, allowed us to capitalize on network science tools and identify these segregated systems (modules, or communities) by optimizing the weights of pairwise connections within them. However, just knowing how strongly two brain areas are connected does not paint the whole picture. Brain dynamics is also engendered by interactions involving more areas at the same time, namely, higher-order interactions. In this paper, we propose a community detection algorithm that accounts for higher-order interactions and finds modules of brain regions whose brain activity is maximally redundant. Compared to modules identified with methods based on bivariate interactions, our redundancy-dominated modules are more symmetrical between the hemispheres, they overlap with canonical systems at the level of the sensory cortex, but describe a new organization of the transmodal cortex. By detecting redundant modules across spatial scales, we identified a sweet spot of maximum balance between segregation and integration of information as that scale where redundancy within modules and synergy between modules peaked. Moreover, we defined a local index that distinguishes brain regions in segregators and integrators based on how much they participate in the redundancy of their modules versus the redundancy of the whole system. Finally, we applied the algorithm to a lifespan dataset and tracked how redundant subsystems change across time. The results of this paper serve as educated guesses on how the brain organizes itself into modules accounting for higher-order interactions of its fundamental units, and pave the way for further investigation that could link them to cognition, behavior, and disease.
Transient Non-local Interactions Dominate the Dynamics of Measles Virus NTAIL
Authors: Otteson Lillian , Nagy Gabor , Kunkel John , Kodis Gerdenis , Zheng Wenwei , Bignon Christophe , Longhi Sonia , Grubmüller Helmut , Vaiana Andrea C. , Vaiana Sara M.
Published: July 2024

The RNA genome of measles virus is encapsidated by the nucleoprotein within a helical nucleocapsid that serves as template for both transcription and replication. The intrinsically disordered domain of the nucleoprotein (NTAIL), partly protruding outward from the nucleocapsid, is essential for binding the polymerase complex responsible for viral transcription and replication. As for many IDPs, binding of NTAILoccurs through a short molecular recognition element (MoRE) that folds upon binding, with the majority of NTAILremaining disordered. Though NTAILregions far from the MoRE influence the binding affinity, interactions between them and the MoRE have not been investigated in depth. Using an integrated approach, relying on photo-induced electron transfer (PET) experiments between tryptophan and cysteine pairs placed at different positions in the protein under varying salt and pH conditions, combined with simulations and analytical models, we identified transient interactions between two disordered regions distant in sequence, which dominate NTAILdynamics, and regulate the conformational preferences of both the MoRE and the entire NTAILdomain. Co-evolutionary analysis corroborates our findings, and suggests an important functional role for the same intramolecular interactions. We propose mechanisms by which these non-local interactions may regulate binding to the phosphoprotein, polymerase recruitment, and ultimately viral transcription and replication. Our findings may be extended to other IDPs, where non-local intra-protein interactions affect the conformational preferences of intermolecular binding sites.
A potent and selective reaction hijacking inhibitor ofPlasmodium falciparumtyrosine tRNA synthetase exhibits single dose oral efficacyin vivo
Authors: Xie Stanley C. , Tai Chia-Wei , Morton Craig J. , Ma Liting , Huang Shih-Chung , Wittlin Sergio , Du Yawei , Hu Yongbo , Dogovski Con , Salimimarand Mina , Griffin Robert , England Dylan , de la Cruz Elisa , Deni Ioanna , Yeo Tomas , Burkhard Anna Y. , Striepen Josefine , Schindler Kyra A. , Crespo Benigno , Gamo Francisco J. , Khandokar Yogesh , Hutton Craig A. , Rabie Tayla , Birkholtz Lyn-Marié , Famodimu Mufuliat T. , Delves Michael J. , Bolsher Judith , Koolen Karin M. J. , van der Laak Rianne , Aguiar Anna C. C. , Pereira Dhelio B. , Guido Rafael V. C. , Creek Darren J. , Fidock David A. , Dick Lawrence R. , Brand Stephen L. , Gould Alexandra E. , Langston Steven , Griffin Michael D.W. , Tilley Leann
Published: July 2024

ThePlasmodium falciparumcytoplasmic tyrosine tRNA synthetase (PfTyrRS) is an attractive drug target that is susceptible to reaction-hijacking by AMP-mimicking nucleoside sulfamates. We previously identified an exemplar pyrazolopyrimidine ribose sulfamate, ML901, as a potent pro-inhibitor ofPfTyrRS. Here we examined the stage specificity of action of ML901, showing very good activity against the schizont stage, but lower trophozoite stage activity. We explored a series of ML901 analogues and identified ML471, which exhibits improved potency against trophozoites and enhanced selectivity against a human cell line. Additionally, it has no inhibitory activity against human ubiquitin-activating enzyme (UAE)in vitro. ML471 exhibits low nanomolar activity against asexual blood stageP. falciparumand potent activity against liver stage parasites, gametocytes and transmissible gametes. It is fast-acting and exhibits a longin vivohalf-life. ML471 is well-tolerated and shows single dose oral efficacy in the SCID mouse model ofP. falciparummalaria. We confirm that ML471 is a pro-inhibitor that is converted into a tight binding Tyr-ML471 conjugate by thePfTyrRS enzyme. A crystal structure of thePfTyrRS/ Tyr-ML471 complex offers insights into improved potency, while molecular docking into UAE provides a rationale for improved selectivity.
Enhanced anti-tumor effects through continuous administration of engineered CAR-macrophages derived from pluripotent stem cell-derived myeloid cell lines
Authors: Atsumi Yuya , Niwa Akira , Kumaki Tatsuro , Yagyu Shigeki , Nakazawa Yozo , Saito Megumu K.
Published: July 2024

Even after chimeric antigen receptor (CAR)-based immunotherapy has dramatically changed therapeutic approaches for malignancies, balancing therapeutic efficacy with labor and financial cost remains a major problem for immunotherapy. Current study developed a cost-effective and enhanced approach to chimeric antigen receptor (CAR)-macrophage therapy for cancer and demonstrated its therapeutic effects by repeated administration of anti-HER2 CAR macrophages generated from human pluripotent stem cell (PSC)-derived immortalized myeloid cell lines (ML). These ML-derived CAR macrophages (CAR-ML-MPs) exhibit potent antigen-specific killing activity against HER2-expressing tumor cells by phagocytosisin vitroand effectively inhibit tumor progressionin vivo, which is enhanced by repeated administration. CAR-ML-MPs provide a promising off-the-shelf cellular resource for tumor adoptive cell immunotherapy, solving the cost and time problems associated with conventional CAR-based immunotherapy.
Boosting the Predictive Power of Protein Representations with a Corpus of Text Annotations
Authors: Duan Haonan , Skreta Marta , Cotta Leonardo , Rajaonson Ella Miray , Dhawan Nikita , Aspuru-Guzik Alán , Maddison Chris J.
Published: July 2024

Protein language models are trained to predict amino acid sequences from vast protein databases, while learning to represent proteins as feature vectors. These vector representations have enabled impressive applications, from predicting mutation effects to protein folding. One of the reasons offered for the success of these models is that conserved sequence motifs tend to be important for protein fitness. Yet, the relationship between sequence conservation and fitness can be confounded by the evolutionary and environmental context. Should we therefore look to other data sources that may contain more direct functional information? In this work, we conduct a comprehensive study examining the effects of training protein models to predict nineteen types of text annotations from UniProt. Our results show that finetuning protein models on a subset of these annotations enhances the models’ predictive capabilities on a variety of function prediction tasks. Notably, our model outperforms the search algorithm BLAST, which none of the pre-trained protein models accomplished in our evaluation. Our results suggest that a much wider array of data modalities, such as text annotations, may be tapped to improve protein language models. We host our model checkpoints onhttps://huggingface.co/h4duan.
Highly ordered clustering of TNFα and BAFF ligand-receptor-adaptor complexes bound to lipid membranes
Authors: Lim Chan Seok , Lee Jisun , Kim Ji Won , Lee Jie-Oh
Published: July 2024

We report the cryo-EM structures of clusters of TNF receptor family proteins, TNFR1 and BAFFR. The receptor-ligand complexes were anchored to a flat lipid layer to mimic the membrane-bound state. We observed that the TNFα-TNFR1 complex forms highly ordered binary, bent, trigonal, and linear quadruple clusters of trimers on the lipid membrane. A non-competitive antagonist of TNFR1 disrupted these clusters without interfering with ligand binding. Moreover, we found that the BAFF-BAFFR complex forms pentagonal, double-pentagonal, or half-spherical clusters of trimers. Mutations in BAFF that inhibit BAFFR receptor activation prevented ordered clustering without disrupting receptor binding. TRAF3 induced a structural shift in the BAFF-BAFFR cluster, resulting in a flat hexagonal cluster. Our data demonstrated that precisely structured clustering is essential for the activation of these receptors. The lipid monolayer method will aid in studying the clusters of other transmembrane proteins and facilitate the discovery of therapeutic agents that regulate their clustering.
Metabolic profiling using benchtop NMR identifies the metabolomic signature of persistent CAR-T cells
Authors: Song Suk-Heung , Ryan Herb , Hoefflin Jens , Kyung Taeyoon , Mace Joshua , Raman Jai , Eshghi Shawdee
Published: July 2024

Analytical technologies for engineered biological systems hold great promise in addressing various challenges in modern pharmaceuticals and biomedical therapies. These endeavors often follow a design-build-test-learn approach, utilizing biological data from genetic circuits, signal pathways, metabolites, and proteins to optimize biological systems. Deciphering large and intricate datasets can prove to be a formidable task. Principal component analysis (PCA) tool is an invaluable method for reducing dataset complexity and enhancing interpretability while minimizing information loss, simultaneously. PCA tool achieves this by creating new, uncorrelated variables that capture the maximum variance in the data. Herein chimeric antigen receptors (CARs) T cells metabolomic study presents a slightly inverse problem, where PCA is applied to model sparse extracellular metabolites data from CAR-T cells, resulting in a two-component model. Using an benchtop NMR spectrometer only six metabolites could be annotated, nevertheless, the PCA model could identify differences in the metabolites of CAR-T cells based on the design of CARs, specifically the combinations of the intracellular domain (ICDs). It’s noteworthy that the behavior and fate of CAR-T cells are distinctly influenced by the type of ICDs used upon antigen recognition.
Size evolution of gigantic genomes suggests stochastic outcomes of transposable element/host silencing interactions
Authors: Wang Jie , Zhang Guangpu , Sun Cheng , Chang Liming , Wang Yingyong , Yang Xin , Chen Guiying , Itgen Michael W. , Haley Ava , Tang Jiaxing , Mueller Rachel Lockridge
Published: July 2024

Size evolution among gigantic genomes involves gain and loss of many gigabases of transposable elements (TEs), sequences that parasitize host genomes. Animals suppress TEs using piRNA and KRAB-ZFP pathways. TEs and hosts coevolve in an arms race, where suppression strength reflects TE fitness costs. In enormous genomes, additional TE costs become miniscule. How, then, do TEs and host suppression invoke further addition of massive DNA amounts? We analyzed TE proliferation histories, deletion rates, and community diversities in six salamander genomes (21.3 - 49.9 Gb), alongside gonadal expression of TEs and suppression pathways. TE activity is higher in testes than ovaries, attributable to lower KRAB-ZFP suppression. Unexpectedly, genome size/expansion is uncorrelated with TE deletion rate, proliferation history, expression, and host suppression. Also, TE community diversity increases with genome size, contrasting theoretical predictions. TE/host antagonism in gigantic genomes likely produces stochastic TE accumulation, determined by noisy intermolecular interactions in huge genomes/cells.
Relevance of the synergy of surveillance and populational networks in understanding the Usutu virus outbreak within common blackbirds (Turdus merula) in Metropolitan France, 2018
Authors: Bouchez-Zacria Malika , Calenge Clément , Villers Alexandre , Lecollinet Sylvie , Gonzalez Gaelle , Quintard Benoit , Leclerc Antoine , Baurier Florence , Paty Marie-Claire , Faure Éva , Eraud Cyril , Decors Anouk
Published: July 2024

Usutu virus (USUV) was first isolated in Africa in 1959 and has since spread to and through Europe with a typical enzootic mosquito-bird cycle. In France, it was first detected in birds in 2015, but during summer 2018 the spread of USUV was particularly significant throughout the country, killing mainly common blackbirds (Turdus merula) and to a lesser extent great grey owls (Strix nebulosa), among other captive and non-captive wild bird species. Previous studies of USUV in France have focused on reconstructing pathways of introduction, but not on structural aspects of virus spread within the country. Data (RT-PCR of geolocated dead birds) on this 2018 outbreak were collected through both an event-based wildlife network named SAGIR and the health surveillance of the French-speaking Association of Zoo Veterinarians (AFVPZ). In addition, common blackbird populations could be monitored through another network (REZOP). Statistical analysis (spatial, temporal, spatiotemporal and environmental determinants) of the SAGIR and AFVPZ network data helped to highlight the early appearance of separate large clusters of USUV cases in mid-July 2018, the subsequent diffusion into smaller and secondary clusters at the end of August 2018, and a meanwhile enlargement of the first clusters with an increase in the number of cases. High human density (top 10.5% densest areas in France) and wetland concentration (top 19.3% most likely wetland areas) were significant factors in USUV case locations. Using generalised additive mixed models on REZOP data, we also highlighted the decline in common blackbird population trends in areas with medium and even more with high USUV pressure (areas defined based on SAGIR-AFVPZ data) following the 2018 outbreak (respectively −7.4% [−11.4; −3.9]95%and −15.7% [−16.2; −9.1]95%). A large area (radius ∼150 km) in the centre and centre-west of France, and smaller areas in the south-east, north and north-east of France (each with a radius ∼ 50 km) were particularly affected. We conclude on the importance to work with synergistic networks to assess infection spread in wild bird species, as well as the negative impact of an emerging arbovirus. The responsiveness of such a network system could be improved by automating alerts.
Assessing the effectiveness of multi-session online emotion recognition training in autistic adults
Authors: Reed Zoe E , Bastiani Oliver , Eastwood Andy , Penton-Voak Ian S , Jarrold Christopher , Munafò Marcus R , Attwood Angela S
Published: July 2024

Purpose

Difficulties with emotion recognition can occur in neurodevelopmental conditions, including in autistic individuals. Providing interventions to support this would therefore be beneficial, particularly in terms of downstream effects on wellbeing, social relationships and education.

Methods

In this online experimental study, we examined the effect of a recently developed facial emotion recognition training task versus a sham/control task in an adult population identifying as autistic over four sessions in a 2-week period, with a fifth follow-up session (N=184).

Results

Our main analyses showed that facial emotion recognition accuracy was greater in Session 4 in the active group, with an estimated improvement of 14% (equivalent to approximately 7 additional correct responses), compared to 2% (equivalent to approximately 1 additional correct responses) in the sham group. Additional analyses suggested training effects were generalisable to facial stimuli that participants had not been trained on and were still present, although attenuated, two weeks later. We also observed some self-reported improvements in social interactions post-training.

Conclusion

Overall, this study demonstrated improved emotion recognition in an adult autistic sample with this training task. Future work is needed to investigate the effect of this emotion recognition training on emotion recognition accuracy in autistic children, where support could be most beneficial.
Designing and validating a Hereditary Spastic Paraplegia-specific Quality of Life Rating Scale (HSPQoL)
Authors: Siow Sue Faye , Fleming Jane , Barlow-Stewart Kristine , Kumar Kishore R , Sue Carolyn M
Published: July 2024

Background

Patients with Hereditary Spastic Paraplegia (HSP) report reduced quality of life (QoL) compared to the general population. Generic QoL measures do not address disease-specific aspects such as spasticity, access to specialty HSP clinics, and bladder symptoms. We designed and validated an HSP-specific QoL scale (HSPQoL), intended for use in standard clinical settings and clinical trials.

Methods

HSP-specific items were added to the RAND 36-Item Short Form Health Survey (SF-36) to form HSPQoL. Following literature review/expert input, 23 items were presented to a panel of HSP clinicians, patients, and patient representatives (n=12) using a modified Delphi process. Items were ranked for clarity and relevance (inclusion criteria: 80% consensus). Interviews with patients (n=5) assessed suitability, comprehension, clarity, and response options to additional items. Patients completed the HSPQoL and EQ5D-5L for evaluation of construct validity (correlation, exploratory factor analysis) and test-retest reliability.

Results

Following the modified Delphi process, 21/23 items met the inclusion criteria. Based on cognitive interview results, items were modified (n=4), removed (n=7), or added (n=3). Sixty-one participants completed the HSPQoL and EQ5D-5L. The HSPQoL was repeated with 19 patients: 15/17 additional items moderately to strongly correlated with pre-existing SF-36 subscores (Spearman correlation 0.319-0.771, p<0.05). Exploratory factor analyses showed high percentage of variance in the first component (>45%). HSPQoL demonstrated good internal consistency (Cronbach alpha 0.94), test-retest reliability (ICC 0.957), and convergent validity with EQ5D-5L (r=0.725).

Conclusions

Demonstrated validity and reliability of the HSPQoL confirms consideration of its use for assessing specific QoL in individuals with HSP.
Functional Movement Disorder Is Associated with Abnormal Interoceptive Brain Activity: A Task-based Functional MRI Study
Authors: Spagnolo Primavera A , Parker Jacob A , Hallett Mark , Horovitz Silvina
Published: July 2024

Background

Aberrant interoceptive processing has been hypothesized to contribute to the pathophysiology of functional neurological disorder, although findings have been inconsistent. Here, we utilized functional magnetic resonance imaging (fMRI) to examine neural correlates of interoceptive attention – the conscious focus and awareness of bodily sensations – in functional movement disorder (FMD).

Methods

We used voxelwise analyses to compare blood oxygenation level-dependent responses between 13 adults with hyperkinetic FMD and 13 healthy controls (HCs) during a task requiring attention to different bodily sensations and to an exteroceptive stimulus. Additionally, we examined between-group differences in self-reported measures of interoception and evaluated their relationship with neural activity.

Results

Interoceptive conditions (heartbeat, stomach and ‘body’, indicating sensations from the body part or limb affected in FMD participants) activated a network involving the precuneus, the posterior cingulate cortex (PCC) and caudate nucleus (CN) bilaterally, and the right anterior insula (aINS) (p<0.05 , corrected). Group differences in brain activity were mainly driven by processing of disease-related interoceptive signals, which in the FMD group was associated with a broader neural activation than monitoring gastric interoception, while no group differences were detected during cardiac interoception. Differences based on interoceptive focus (body vsheartbeat and stomach) between FMD subjects and HCs were found in PCC, CN, angular gyrus, thalamus, and in the mid-insula (p<0.05, corrected).

Conclusions

This is, to our knowledge, the first study showing that FMD is associated with abnormal interoceptive processing in regions involved in monitoring body state, attentional focus, and homeostatic inference.
Amortized template-matching of molecular conformations from cryo-electron microscopy images using simulation-based inference
Authors: Dingeldein Lars , Silva-Sánchez David , Evans Luke , D’Imprima Edoardo , Grigorieff Nikolaus , Covino Roberto , Cossio Pilar
Published: July 2024

Abstract

Biomolecules undergo conformational changes to perform their function. Cryo-electron microscopy (cryo-EM) can capture snapshots of biomolecules in various conformations. However, these images are noisy and display the molecule in unknown orientations, making it difficult to separate conformational differences from differences due to noise or projection directions. Here, we introduce cryo-EM simulation-based inference (cryoSBI) to infer the conformations of biomolecules and the uncertainties associated with the inference from individual cryo-EM images. CryoSBI builds on simulation-based inference, a combination of physics-based simulations and probabilistic deep learning, allowing us to use Bayesian inference even when likelihoods are too expensive to calculate. We begin with an ensemble of conformations, which can be templates from molecular simulations or modelling, and use them as structural hypotheses. We train a neural network approximating the Bayesian posterior using simulated images from these templates, and then use it to accurately infer the conformations of biomolecules from experimental images. Training is only done once, and after that, it takes just a few milliseconds to make inference on an image, making cryoSBI suitable for arbitrarily large datasets. CryoSBI eliminates the need to estimate particle pose and imaging parameters, significantly enhancing the computational speed in comparison to explicit likelihood methods. We illustrate and benchmark cryoSBI on synthetic data and showcase its promise on experimental single-particle cryo-EM data.
Improved constructs for bait RNA display in a bacterial three-hybrid assay
Authors: Nguyen Linh D. , LeBlanc Hannah , Berry Katherine E.
Published: July 2024

We have previously developed a transcription-based bacterial three-hybrid (B3H) assay as a genetic approach to probe RNA-protein interactions inside ofE. colicells. This system offers a straightforward path to identify and assess the consequences of mutations in RBPs with molecular phenotypes of interest. One limiting factor in detecting RNA-protein interactions in the B3H assay is RNA misfolding arising from incorrect base-pair interactions with neighboring RNA sequences in a hybrid RNA. To support correct folding of hybrid bait RNAs, we have explored the use of a highly stable stem (“GC clamp”) to isolate regions of a hybrid RNA as discrete folding units. In this work, we introduce new bait RNA constructs to 1) insulate the folding of individual components of the hybrid RNA with GC clamps and 2) express bait RNAs that do not encode their own intrinsic terminator. We find that short GC clamps (5 or 7 bp long) are more effective than a longer 13bp GC clamp in the B3H assay. These new constructs increase the number of Hfq-sRNA and -5′UTR interactions that are detectable in the B3H system and improve the signal-to-noise ratio of many of these interactions. We therefore recommend the use of constructs containing short GC clamps for the expression of future B3H bait RNAs. With these new constructs, a broader range of RNA-protein interactions are detectable in the B3H assay, expanding the utility and impact of this genetic tool as a platform to search for and interrogate mechanisms of additional RNA-protein interactions.
The Biochemical Effects of Carotenoids in Orange Carrots on the Colonic Proteome in a Mouse Model of Diet-induced Obesity
Authors: Balbuena Emilio , Milhem Fadia , Kiremitci Buse Zeren , Williams Taufika Islam , Collins Leonard , Shu Qingbo , Eroglu Abdulkerim
Published: July 2024

Carotenoids are naturally occurring pigments in plants and are responsible for the orange, yellow, and red color of fruits and vegetables. Carrots are one of the primary dietary sources of carotenoids. The biological activities of carotenoids in higher organisms are well documented in most tissues but not the large intestine. The gastrointestinal barrier acts as a line of defense against the systemic invasion of pathogenic bacteria, especially at the colonic level. Proteins involved in tight junction assembly between epithelial cells and mucus secretion from goblet cells are essential for maintaining intestinal barrier homeostasis. A high-fat diet can cause gut impairment by inducing barrier permeability, leading to low-grade chronic inflammation via metabolic endotoxemia. Our hypothesis for this study is that the dietary intake of carotenoid-rich foods can alleviate obesity-associated gut inflammation and strengthen the intestinal barrier function. Male C57BL/6J mice were randomized to one of four experimental diets for 20 weeks (n = 20 animals/group): Low-fat diet (LFD, 10% calories from fat), high-fat diet (HFD, 45% calories from fat), HFD with white carrot powder (HFD + WC), or HFD with orange carrot powder (HFD + OC). Colon tissues were harvested to analyze the biochemical effects of carotenoids in carrots. The distal sections were subjected to isobaric labeling-based quantitative proteomics in which tryptic peptides were labeled with tandem mass tags, followed by fractionation and LC-MS/MS analysis in an Orbitrap Eclipse Tribrid instrument. High-performance liquid chromatography results revealed that the HFD+WC pellets were carotenoid-deficient, and the HFD+OC pellets contained high concentrations of provitamin A carotenoids, specifically α-carotene and β-carotene. As a result of the quantitative proteomics, a total of 4410 differentially expressed proteins were identified. Intestinal barrier-associated proteins were highly upregulated in the HFD+OC group, particularly mucin-2 (MUC-2). Upon closer investigation into mucosal activity, other proteins related to MUC-2 functionality and tight junction management were upregulated by the HFD+OC dietary intervention. Collectively, our findings suggest that carotenoid-rich foods can prevent high-fat diet-induced intestinal barrier disruption by promoting colonic mucus synthesis and secretion in mammalian organisms. Data are available via ProteomeXchange with identifier PXD054150.
Comparative analysis of 43 distinct RNA modifications by nanopore tRNA sequencing
Authors: White Laura K. , Dobson Kezia , del Pozo Samantha , Bilodeaux Jill M. , Andersen Shelby E. , Baldwin Amber , Barrington Chloe , Körtel Nadine , Martinez-Seidel Federico , Strugar Saylor M. , Watt Kristin E.N. , Mukherjee Neelanjan , Hesselberth Jay R.
Published: July 2024

Transfer RNAs are the fundamental adapter molecules of protein synthesis and the most abundant and heterogeneous class of noncoding RNA molecules in cells. The study of tRNA repertoires remains challenging, complicated by the presence of dozens of post transcriptional modifications. Nanopore sequencing is an emerging technology with promise for both tRNA sequencing and the detection of RNA modifications; however, such studies have been limited by the throughput and accuracy of direct RNA sequencing methods. Moreover, detection of the complete set of tRNA modifications by nanopore sequencing remains challenging. Here we show that recent updates to nanopore direct RNA sequencing chemistry (RNA004) combined with our own optimizations to tRNA sequencing protocols and analysis workflows enable high throughput coverage of tRNA molecules and characterization of nanopore signals produced by 43 distinct RNA modifications. We share best practices and protocols for nanopore sequencing of tRNA and further report successful detection of low abundance mitochondrial and viral tRNAs, providing proof of concept for use of nanopore sequencing to study tRNA populations in the context of infection and organelle biology. This work provides a roadmap to guide future efforts towardsde novodetection of RNA modifications across multiple organisms using nanopore sequencing.
WITHDRAWN: Experimental verification on “Telomere DNA and ribosomal DNA co-regulation model for cell senescence”
Authors: Huang Bilu , Wu Zhengzhi
Published: July 2024

Withdrawal Statement

This manuscript has been withdrawn as it was submitted and made public without the full consent of all the authors. Therefore, this work should not be cited as reference for the project. If you have any questions, please contact the corresponding author.
Different timescales of neural activities introduce different representations of task-relevant information
Authors: Kurikawa Tomoki
Published: July 2024

Recent findings indicate significant variations in neuronal activity timescales across and within cortical areas, yet their impact on cognitive processing remains inadequately understood. This study explores the role of neurons with different timescales in information processing within the neural system, particularly during the execution of context-dependent working memory tasks. Especially, we hypothesized that neurons with varying timescales contribute distinctively to task performance by forming diverse representations of task-relevant information. To test this, the model was trained to perform a context-dependent working memory task with a machine-learning technique. Results revealed that slow timescale neurons maintained stable representations of contextual information throughout the trial, whereas fast timescale neurons responded transiently to immediate stimuli. This differentiation in neuronal function suggests a fundamental role for timescale diversity in supporting the neural system’s ability to integrate and process information dynamically. Our findings contribute to understanding how neural timescale diversity underpins cognitive flexibility and task-specific information processing, highlighting implications for both theoretical neuroscience and practical applications in designing artificial neural networks.
Evolutionary plasticity and functional repurposing of the essential metabolic enzyme MoeA
Authors: Megrian Daniela , Martinez Mariano , Alzari Pedro M , Wehenkel Anne Marie
Published: July 2024

MoeA, or gephyrin in higher eukaryotes, is crucial for molybdenum cofactor biosynthesis required in redox reactions. Gephyrin is a moonlighting protein also involved in postsynaptic receptor clustering, a feature thought to be a recent evolutionary trait. We showed previously that a repurposed copy of MoeA (Glp) is involved in bacterial cell division. To investigate how MoeA acquired multifunctionality, we used phylogenetic inference and protein structure analyses to understand the diversity and evolutionary history of MoeA. Glp-expressing Bacteria have at least two copies of the gene, and our analysis suggests that Glp has lost its enzymatic role. In Archaea we identified an ancestral duplication where one of the paralogs might bind tungsten instead of molybdenum. In eukaryotes, the acquisition of the moonlighting activity of gephyrin comprised three major events: first, MoeA was obtained from Bacteria by early eukaryotes, second, MogA was fused to the N-terminus of MoeA in the ancestor of opisthokonts, and finally, it acquired the function of anchoring GlyR receptors in neurons. Our results support the functional versatility and adaptive nature of the MoeA scaffold, which has been repurposed independently both in eukaryotes and bacteria to carry out analogous functions in network organization at the cell membrane.
Graph-structured populations elucidate the role of deleterious mutations in long-term evolution
Authors: Sharma Nikhil , Das Suman G. , Krug Joachim , Traulsen Arne
Published: July 2024

Birth-death models have long been employed to understand the interplay of genetic drift and natural selection. While well-mixed populations remain unaffected by the choice of replacement rules, the evolutionary outcomes in spatially structured populations are strongly impacted by this choice. Moving parent individuals to vacant sites gives rise to new update rules, leading to new fixation categories for spatial graphs. We discover a new category of graphs, amplifiers of fixation, where a structure has a higher probability of fixation for mutants than the well-mixed population, regardless of their fitness value. Under death-Birth updating with parents moving to vacant sites, the star graph is an amplifier of fixation. For very large population sizes, the probability to fix deleterious mutants on the star graph converges to a non-zero value, in contrast to the result from well-mixed populations where the probability goes to zero. Additionally, most random graphs are amplifiers of fixation for death-Birth updating, with parent individuals replacing dead individuals. Conversely, most random graphs are suppressors of fixation− graphs with lower fixation probability for mutants regardless of their fitnesses− for Birth-death updating with offspring replacing dead individuals. When subjected to long-term evolution, amplifiers of fixation, despite being more efficient at fixing beneficial mutants, attain lower fitness than the well-mixed population, whereas suppressors attain higher fitness despite their inferior ability to fix beneficial mutants. These surprising findings can be explained by their deleterious mutant regime. Therefore, the deleterious mutant regime can be as crucial as the beneficial mutant regime for adaptive evolution.
QCM: real-time quantitative quality control of single-molecule localization microscopy acquisitions
Authors: Mailfert Sébastien , Djendli Meriem , Fabre Roxane , Marguet Didier , Bertaux Nicolas
Published: July 2024

Single molecule localization microscopy (SMLM) has revolutionized the understanding of cellular organization by reconstructing informative images with quantifiable spatial distributions of molecules far beyond the optical diffraction limit. Much effort has been devoted to optimizing localization accuracy. Among them, assessing the quality of SMLM data in real-time, rather than after lengthy post-acquisition analysis, represent a computational challenge.

Here, we overcome this difficulty by implementing an innovative mathematical approach to drastically reduce the computational analysis of particle localization. We have therefore designed the Quality Control Map (QCM) workflow to process data at a much higher rate than that limited by the frequency required by current cameras. Moreover, QCM requires no parameters other than the PSF radius characteristic of the optical system and only a GPU card to reach its computational speed. Thus, QCM is robust and adaptable to any type of input data. Finally, the QCM off-line mode can be used to evaluate synthetic or previously acquired data, and as a tool for teaching the basic concepts of the SMLM approach.

Teaser

QCM, a parameter-free algorithm, calculates indicators for instant feedback on single-molecule localization precision experiments
Mapping fitness landscapes to interpret sex allocation in hermaphrodites
Authors: Chen Kai-Hsiu , Pannell John R.
Published: July 2024

Sex allocation theory successfully predicts sex-ratio variation among organisms with separate sexes, but it has been much less successful in explaining variation in sex allocation in hermaphrodites because the assumption of a direct tradeoff between male and female functions is often violated. Here, we show that sex-allocation theory can be applied to hermaphrodites simply by mapping components of seasonal reproductive success onto a fitness landscape defined by potentially independent measures of allocation to male and female functions on orthogonal axes. Taking this approach allowed us to interpret the complex variation in the reproductive strategy of a long-lived perennial herb (Pulsatilla alpina) that produces both male and bisexual flowers and that shifts between male and female allocation among seasons. We find that components of reproductive success forP. alpinamap onto a rugged landscape with peaks that reflect an interactive effect of male and female allocations on self-fertilization and total reproductive success and that correspond to the observed sex-allocation strategies adopted by the species in nature. This simple approach should be widely applicable to problems in the study of hermaphroditic reproduction in other plants and animals.

Significance Statement

Sex allocation theory has helped to explain sex-ratio variation in numerous dioecious species, but it has been difficult to apply to hermaphrodites, in which male-female tradeoffs are often obscure. Here, we show that by mapping fitness estimates for plants with complex allocation patterns on a two-dimensional landscape defined by both male and female allocations, we sidestep the tradeoff assumption. Our analysis reveals fitness peaks that correspond precisely to the strategic allocation decisions adopted by the species in nature. Our simple but novel approach provides a rescue-line for a powerful body of theory that has been criticized for being too difficult to apply to the messy world of hermaphrodites, both in plants and animals.
Genome admixture among four hare species in Iberia: focus on the broom hare (Lepus castroviejoi)
Authors: Souto João , Marques João P. , Farelo Liliana , Costa José , Queirós João , Pietri Christian , Ballesteros Fernando , Alves Paulo C. , Boursot Pierre , Melo-Ferreira José
Published: July 2024

Pleistocene climatic fluctuations have often driven range shifts and hybridization among related species, leaving present-day genomic footprints. In the Iberian Peninsula,Lepus timidus, after its post-deglaciation retreat, has left extensive mitochondrial DNA traces in three other hare species, but the genomic correlates and underlying biogeographic scenarios are still incompletely understood. This study focuses onLepus castroviejoi, endemic to the Cantabrian region, using its non-Iberian sister species,L. corsicanus, for comparison. By analyzing coalescent patterns from 10 genomes, we estimate that these species remained isolated since their divergence, around 50,000 years ago, consistent with their current allopatry. Further analyses with 25 additional genomes indicate that small fractions of theL. castroviejoigenome originate fromL. granatensis,L. timidus, andL. europaeus(0.72%, 0.08%, and 0.04%, respectively). Introgression dating based on tract lengths suggestsL. granatensiswas already admixed withL. timiduswhen it hybridized withL. castroviejoi, which could explain thegranatensis-timidusancestry tract junctions detected inL. castroviejoi. Genomic segments with such junctions contain genes enriched for cell signaling and olfactory receptor activity, possibly facilitating genetic exchange. This research demonstrates how genomic ancestry inferences can reveal complex multiway admixture histories and illuminate past biogeographic events.
Flexible hippocampal representation of abstract boundaries supports memory-guided choice
Authors: Esposito Mariachiara , Abdul Lubna , Ghouse Ameer , Rodriguez Aramendía Marta , Kaplan Raphael
Published: July 2024

Hippocampal cognitive maps encode the relative locations of spatial cues in an environment and adapt their representation when boundaries geometrically change. Hippocampal cognitive maps can represent abstract knowledge, yet it’s unclear whether the hippocampus is sensitive to changes to the extreme coordinates, boundaries, of abstract spaces. We created a memory-guided choice task to test whether the human hippocampus and medial prefrontal cortex(mPFC) flexibly learn abstract boundary representations in distinct two-dimensional(2D) knowledge spaces. Participants built up a 2D map-like representation of abstract boundaries, where the hippocampus and mPFC represented a decision cue’s Euclidean distance to the closest boundary. Notably, mPFC distance representations selectively reflected individual performance improvements during the task. Testing for neural sensitivity to boundary-defined contextual changes, only the hippocampus flexibly represented abstract boundaries, which related to choice behavior. These findings suggest that abstract knowledge retrieval within dynamically changing contexts is facilitated by generalized mPFC and flexible hippocampal boundary representations.
Paralemmin-1 controls the nanoarchitecture of the neuronal submembrane cytoskeleton
Authors: Macarrón-Palacios Victor , Hubrich Jasmine , do Rego Barros Fernandes Lima Maria Augusta , Metzendorf Nicole G. , Kneilmann Simon , Trapp Marleen , Acuna Claudio , Patrizi Annarita , D’Este Elisa , Kilimann Manfred W.
Published: July 2024

The Membrane-associated Periodic Skeleton (MPS) is a specialized submembrane cytoskeleton of neuronal cells, characterized by a highly ordered 190 nm periodic lattice, with emerging functions in mechanical resilience, inter- and intracellular signaling, and action potential transmission. Here, we identify Paralemmin-1 (Palm1) as a new component and regulator of the MPS. Palm1 binds to the N-terminal region of βII-spectrin, a core MPS component, and is periodically organized along the axon in hippocampal neurons. Applying the 3D imaging power of MINFLUX, we locate Palm1 in close proximity (<20 nm) to the actin-capping protein and MPS component adducin. Functionally, Palm1 overexpression enhances the degree of periodicity of several MPS proteins (βII-spectrin, adducin, and ankyrinB) without altering their local concentrations, while the knock-out severely compromises the MPS structure and modifies electrophysiological properties of neurons. Both the MPS-binding and remodelling activities of Palm1 are abolished by mutating a single amino acid (W54A) in the conserved Paralemmin sequence motif. Our findings identify Palm1 as the first protein specifically dedicated to organizing the MPS, and will advance the understanding of the regulation of MPS assembly and remodelling, as well as of the Paralemmin protein family.
Contrasting topologies of synchronous and asynchronous functional brain networks
Authors: McIntyre Clayton C. , Bahrami Mohsen , Shappell Heather M. , Lyday Robert G. , Fish Jeremie , Bollt Erik M. , Laurienti Paul J.
Published: July 2024

We generated asynchronous functional networks (aFNs) using a novel method called optimal causation entropy (oCSE) and compared aFN topology to the correlation-based synchronous functional networks (sFNs) which are commonly used in network neuroscience studies. Functional magnetic resonance imaging (fMRI) time series from 212 participants of the National Consortium on Alcohol and NeuroDevelopment in Adolescence (NCANDA) study were used to generate aFNs and sFNs. As a demonstration of how aFNs and sFNs can be used in tandem, we used multivariate mixed effects models to determine whether age interacted with node efficiency to influence connection probabilities in the two networks.

After adjusting for differences in network density, aFNs had higher global efficiency but lower local efficiency than the sFNs. In the aFNs, nodes with the highest outgoing global efficiency tended to be in the brainstem and orbitofrontal cortex. aFN nodes with the highest incoming global efficiency tended to be members of the Default Mode Network (DMN) in sFNs. Age interacted with node global efficiency in aFNs and node local efficiency in sFNs to influence connection probability. We conclude that the sFN and aFN both offer information about functional brain connectivity which the other type of network does not.