bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mapping grey and white matter activity in the human brain with isotropic ADC-fMRI
Authors: Spencer Arthur P C , Nguyen-Duc Jasmine , de Riedmatten Inès , Szczepankiewicz Filip , Jelescu Ileana O 
Published: October 2024

AbstractFunctional MRI (fMRI) using the blood-oxygen level dependent (BOLD) signal provides valuable insight into grey matter activity. However, uncertainty surrounds the white matter BOLD signal. Apparent diffusion coefficient (ADC) offers an alternative fMRI contrast sensitive to transient cellular deformations during neural activity, facilitating detection of both grey and white matter activity. Further, through minimising vascular contamination, ADC-fMRI has the potential to overcome the limited temporal specificity of the BOLD signal. However, the use of linear diffusion encoding introduces sensitivity to fibre directionality, while averaging over multiple directions comes at great cost to temporal resolution. In this study, we used spherical b-tensor encoding to impart diffusion sensitisation in all directions per shot, providing an ADC-fMRI contrast capable of detecting activity independently of fibre directionality. We provide evidence from two task-based experiments on a clinical scanner that isotropic ADC-fMRI is more temporally specific than BOLD-fMRI, and offers more balanced mapping of grey and white matter activity. We further demonstrate that isotropic ADC-fMRI detects white matter activity independently of fibre direction, while linear ADC-fMRI preferentially detects activity in voxels containing fibres perpendicular to the diffusion encoding direction. Thus, isotropic ADC-fMRI opens avenues for investigation into whole-brain grey and white matter functional connectivity.
Synthetic chaperone based on Hsp90-Tau interaction inhibits pathological Tau aggregation and rescues physiological Tau-Microtubule interaction
Authors: Di Lorenzo Davide , Bisi Nicolo , Kaffy Julia , Ramirez Lisa Marie , Zweckstetter Markus , Lequin Olivier , Garfagnini Irene , Luo Jinghui , Hannappel Yvonne , Ennen Inga , Dodero Veronica , Sewald Norbert , Gelmi Maria Luisa , Tonali Nicolo , Brandt Roland , Ongeri Sandrine 
Published: October 2024

AbstractThe accumulation of intracellular aggregates of Tau protein is one main hallmark of Alzheimer’s disease (AD) and is the consequence of Tau conformational changes, increased phosphorylation, and self-association to form fibrillar aggregates. This pathological process prevents the physiological interaction of Tau with microtubules to the detriment of the structural integrity of neurons. In healthy cells, aberrant protein misfolding and aggregation are counteracted by chaperone proteins whose protective capacity decreases with age. The role of the chaperone Hsp90 and the mechanism by which it can prevent Tau aggregation toxicity are controversial. The innovative strategy of mimicking Hsp90 through the design of the β-hairpin like peptidomimeticβ-Hsp90, inspired by two Hsp90/Tau interaction sequences, is presented here.β-Hsp90inhibits Tau aggregation bothin vitroandin cells, restoring Tau’s physiological interaction with microtubules.β-Hsp90, which interacts with the P1 region of Tau, is more effective than individual peptide sequences from the chaperone HSP90 and another β-hairpin mimic based on Tau sequences. Moreover,β-Hsp90dramatically reduces AD-associated Aβ1-42aggregation, offering the development of a dual inhibitor. This work paves the way for the design of new drugs targeting devastating untreated amyloid diseases, by mimicking physiological chaperones with small synthetic peptide drugs.
A stepwise, modular design of building uniform brain assembloids representing the dynamic cellular interplay between neurons and glial cells
Authors: Kim Eunjee , Kim Yunhee , Hong Soojung , Kim Inha , Lee Juhee , Yoo Jong-Yeon , Kim Jihyun , Yoo Kwangmin , Kim Joung-Hun , Choi Jungmin , Shin Kunyoo 
Published: October 2024

AbstractCurrent brain organoid technology fails to provide adequate patterning cues to induce a mature structure that represent the complexity of the human brain. Here, we developed a module-based cellular reconstitution technology to sequentially build uniform forebrain assembloids with mature cortical structures and functional connectivity. The uniformity and maturity of the newly-conceived forebrain assembloids were achieved by creating single-rosette-based organoids at the early stage, whose sizes were big and consistent with the treatment of Wnt and Hedgehog agonists, followed by spatial reconstitution with the Reelin-expressing neuronal layer and non-neuronal glial cells. The resulting single-rosette-based forebrain assembloids were highly uniform and reproducible without significant batch effects, solving major heterogeneity issues caused by difficulties in controlling the number and size of rosettes in conventional multi-rosette organoids. Furthermore, these forebrain assembloids structurally and functionally recapitulated the physiology of the human brain, including the six-layered cortical structure, functional connectivity, and dynamic cellular interplay between neurons and glial cells. Our study thus provided an innovative preclinical model to study a range of neurological disorders, understanding the pathogenesis of which requires an organoid system capable of representing the dynamic cellular interactions and the maturity of the human brain.
A low-cost, open-source 3D printer for multimaterial and high-throughput direct ink writing of soft and living materials
Authors: Weiss Jonathan D. , Mermin-Bunnell Alana , Solberg Fredrik S. , Tam Tony , Rosalia Luca , Sharir Amit , Rütsche Dominic , Sinha Soham , Choi Perry S. , Shibata Masafumi , Palagani Yellappa , Nilkant Riya , Paulvannan Kiruthika , Ma Michael , Skylar-Scott Mark A. 
Published: October 2024

AbstractDirect ink writing is a 3D printing method that is compatible with a wide range of structural, elastomeric, electronic, and living materials, and it continues to expand its uses into physics, engineering, and biology laboratories. However, the large footprint, closed hardware and software ecosystems, and expense of commercial systems often hamper widespread adoption. Here, we present a compact, simple-to-build, low-cost, multimaterial, and high-throughput direct ink writing 3D printer platform with detailed assembly files and instructions provided freely online. In contrast to existing low-cost 3D printers and bioprinters, which typically modify off-the-shelf plastic 3D printers, this system is built from scratch, offering a lower cost and full customizability. Despite its low cost, we demonstrate advanced active mixing and multimaterial multinozzle 3D (MM3D) printing methods, which previously have relied on expensive and custom motion control platforms. We finally introduce embedded multinozzle and 3D gradient nozzle designs that offer high throughput and graded 3D parts. This powerful, easy-to-build, and customizable printing platform can help stimulate a vibrant biomaker community of engineers, biologists, and educators.
mTOR signaling promotes cytokine production in T cells through 3’UTR-mediated translation control
Authors: Jurgens Anouk P. , Zwijnen Josephine , van Alphen Floris P.J. , Bradarić Antonia , Rooijers Koos , Hoogendijk Arie J. , Popović Branka , Wolkers Monika C. 
Published: October 2024

ABSTRACTT cells are key contributors to clear our body from infected and malignant cells. When T cells respond to target cells, they undergo profound translational alterations. The evolutionary and highly conserved kinase mammalian target of rapamycin (mTOR) is a central mediator of T cell differentiation, homeostasis, and T cell activation, including the production of the key pro-inflammatory cytokines TNF, IL2, and IFNγ. mTOR was shown to execute its translation activity through TOP motifs located in the 5’ Untranslated region (5’UTR) of its target genes. Here, we uncovered a distinct mechanism of mTOR signaling on cytokine production in T cells, which is under control of the 3’UTR. Even though non-classical TOP motifs are present in cytokine 3’UTRs, they do not contribute to mTOR-mediated translation regulation. Rather, AU-rich elements (AREs) are required for mTOR-mediated cytokine production. Furthermore, we discovered that the RNA binding protein DDX21 binds to 3’UTR AREs and confers the mTOR-mediated translation control. In conclusion, we here present a previously unappreciated ARE-dependent, 3’UTR-mediated mode of action that mTOR employs to regulate cytokine production.
ClassiCOL: LC-MS/MS analysis for ancient species Classification via Collagen peptide ambiguation
Authors: Engels Ian , Burnett Alexandra , Robert Prudence , Pironneau Camille , Abrams Grégory , Bouwmeester Robbin , Van der Plaetsen Peter , Di Modica Kévin , Otte Marcel , Straus Lawrence Guy , Fischer Valentin , Bray Fabrice , Mesuere Bart , De Groote Isabelle , Deforce Dieter , Daled Simon , Dhaenens Maarten 
Published: October 2024

AbstractLC-MS/MS extends on the MALDI-TOF ZooMS approach by providing fragmentation spectra for each peptide. However, ancient bone samples generate sparse datasets containing only a few collagen proteins, rendering target-decoy strategies unusable and increasing uncertainty in peptide annotation. ClassiCOL embraces and even extends this ambiguity using a novel ‘isoBLAST’ approach. The exhaustive set of potential peptide candidates created in this way is then used to retain or reject different potential paths at each taxonomic branching point down to the taxonomic level attainable with the sample information, always allowing for potential mixtures in the process. As an end point, all considered ambiguity is graphically represented with a clear prioritization of the species in the sample. Using public as well as in-house data, we demonstrate the performance of this universal postprocessing approach on different instruments and explore the possibility of identifying genetic as well as sample mixtures. Diet reconstruction from 40,000 year old cave hyena coprolites illustrates the exciting potential of this approach.TeaserClassiCOL is a postprocessing tool that allows for more accurate species classification from LC-MS/MS measurements of collagen.
STARTS: A self-adapted spatio-temporal framework for automatic E/MEG source imaging
Authors: Feng Zhao , Guan Cuntai , Sun Yu 
Published: October 2024

AbstractTo obtain accurate brain source activities, the highly ill-posed source imaging of electro- and magneto-encephalography (E/MEG) requires proficiency in incorporation of biophysiological constraints and signal-processing techniques. Here, we propose a spatio-temporal-constrainted E/MEG source imaging framework-STARTS that can reconstruct the source in a fully automatic way. Specifically, a block-diagonal covariance was adopted to reconstruct the source extents while maintain spatial homogeneity. Temporal basis functions (TBFs) of both sources and noises were estimated and updated in a data-driven fashion to alleviate the influence of noises and further improve source localization accuracy. The performance of the proposed STARTS was quantitatively assessed through a series of simulation experiments, wherein superior results were obtained in comparison with the benchmark ESI algorithms (including LORETA, EBI-Convex, & SI-STBF). Additional validations on epileptic and resting-state EEG data further indicate that the STARTS can produce neurophysiologically plausible results. Moreover, a computationally efficient version of STARTS–smooth STARTS was also introduced with an elementary spatial constraint, which exhibited comparable performance and reduced execution cost. In sum, the proposed STARTS, with its advanced spatio-temporal constraints and self-adapted update operation, provides an effective and efficient approach for E/MEG source imaging.
scChat: A Large Language Model-Powered Co-Pilot for Contextualized Single-Cell RNA Sequencing Analysis
Authors: Lu Yen-Chun , Varghese Ashley , Nahar Rahul , Chen Hao , Shao Kunming , Bao Xiaoping , Li Can 
Published: October 2024

AbstractData-driven methods, including unsupervised and supervised learning, have become essential tools for analyzing single-cell RNA sequencing (scRNA-seq) data. However, these approaches cannot incorporate research context into the analysis, limiting their ability to provide in-depth, contextual insights to researchers. We introduce scChat, a pioneering AI assistant designed for contextualized scRNA-seq analysis. Unlike existing tools that focus on standard tasks like cell annotation, scChat offers advanced capabilities, including research context-based analysis of experimental outcomes, detailed validation of research hypotheses, identification of potential explanations when hypotheses fail, and suggestions for next-step experimental design. Powered by a large language model (LLM), scChat integrates function calls for quantitative tasks, employs retrieval-augmented generation to reduce hallucination, and uses an LLM-powered search engine to seamlessly incorporate current literature into the analytical conversation.
Meru co-ordinates spindle orientation with cell polarity and cell cycle progression
Authors: McLellan Melissa M. , Aerne Birgit L. , Dhoul Jennifer J. Banerjee , Tapon Nicolas 
Published: October 2024

AbstractCorrect mitotic spindle alignment is essential for tissue architecture and plays an important role in cell fate specification through asymmetric cell division. Spindle tethering factors such asDrosophilaMud (NuMA in mammals) are recruited to the cell cortex and capture astral microtubules, pulling the spindle in the correct orientation. However, how spindle tethering complexes read the cell polarity axis and how spindle attachment is coupled to mitotic progression remains poorly understood. We explore these questions inDrosophilasensory organ precursors (SOPs), which divide asymmetrically to give rise to the epidermal mechanosensory bristles. We show that the scaffold protein Meru, which is recruited to the posterior cortex by the Frizzled/Dishevelled planar cell polarity complex, in turn recruits Mud, linking the spindle tethering and polarity machineries. Furthermore, Cyclin A/Cdk1 associates with Meru at the posterior cortex, promoting the formation of the Mud/Meru/Dsh complex via Meru and Dsh phosphorylation. Thus, Meru couples spindle orientation with cell polarity and provides a cell cycle-dependent cue for spindle tethering.
Myocarditis and neutrophil-mediated vascular leakage but not cytokine storm associated with fatal murine leptospirosis
Authors: Papadopoulos Stylianos , Hardy David , Vernel-Pauillac Frédérique , Tichit Magali , Boneca Ivo G. , Werts Catherine 
Published: October 2024

AbstractLeptospirosis is a neglected re-emerging zoonosis caused byLeptospiraspirochetes. Its pathophysiology remains mysterious, especially in the case of severe infection withL. interrogans.In the field of infectious diseases, the cause of death is rarely investigated in preclinical models. Here, for the first time, we identified unanticipated organ failures associated with death in a murine model of acute leptospirosis.Despite clinical similarities between bacterial sepsis and leptospirosis, striking differences were observed. Neither lung, liver, or kidney injury nor cytokine storm, or massive necroptosis could explain death. In contrast, severe leptospirosis was associated with high serum levels of the anti-inflammatory cytokine IL-10 and the chemokine RANTES, neutrophilia, pancreatitis and vascular damage. Unexpectedly, we demonstrated neutrophil-induced vascular permeability, making neutrophils a potential new therapeutic target. Strikingly, the main cause of death was myocarditis, an overlooked complication of human leptospirosis.These features are also found in patients, making this model a paradigm for better understanding human leptospirosis and designing novel therapeutic strategies.
A three-country analysis of the gut microbiome indicates taxon associations with diet vary by location and strain
Authors: Khatib Lora , Song Se Jin , Dilmore Amanda H , Sanders Jon G , Brennan Caitriona , Hernandez Alejandra Rios , Myers Tyler , Oles Renee , Farmer Sawyer , Cowart Charles , Birmingham Amanda , Diaz Edgar A. , Nizet Oliver , Gilbert Kat , Litwin Nicole , Das Promi , Nowinski Brent , Bryant Mackenzie , Tribelhorn Caitlin , Sanders-Bodai Karenina , Chaumont Soline , Knol Jan , Roeselers Guus , Laiola Manolo , Shetty Sudarshan A. , Veiga Patrick , Tap Julien , Derrien Muriel , Koutnikova Hana , Cotillard Aurélie , Lay Christophe , Tovar Armando R. , Torres Nimbe , Arteaga Liliana , González Antonio , McDonald Daniel , Bartko Andrew , Knight Rob 
Published: October 2024

AbstractEmerging research suggests that diet plays a vital role in shaping the composition and function of the gut microbiota. While significant efforts have been made to identify general patterns linking diet to the gut microbiome, much of this research lacks representation from low- and middle-income countries such as Mexico. Additionally, both diet and the gut microbiome have highly complex and individualized configurations, and there is growing evidence that tailoring diets to individual gut microbiota profiles may optimize the path toward improving or maintaining health and preventing disease. Using fecal metagenomic data from 1,291 individuals across three countries, we examine two bacterial genera prevalent in the human gut,PrevotellaandFaecalibacterium, which have gained significant attention due to their potential roles in human health. We find that they show significant associations with many aspects of diet, but that these associations vary in scale and direction, depending on the level of metagenomic resolution and the contextual population. These results highlight the growing importance of assembling metagenomic datasets that are standardized, comprehensive, and representative of diverse populations to increase our ability to tease apart the complex relationship between diet and the microbiome.
A combinatorial approach to ALS therapies in the PrP.TDP43-315 model of ALS; complications and tribulations
Authors: Fromholt Susan , Lopez Amanda , Xu Guilian , Lu Qing , Wymer James , Borchelt David R. 
Published: October 2024

AbstractEffective treatment for sporadic amyotrophic lateral sclerosis has been steadily advancing towards combinatorial therapies. For many years, riluzole was the only approved drug and it offered modest benefits. In 2017, edaravone was approved for ALS and became the first drug to be used in combination with riluzole. In the present study, we have attempted to build on the concepts of combinatorial therapy by testing novel drug combinations in a transgenic mouse model. Mice that express A315T mutant TDP43, using the mouse prion promoter, have been reported to develop many of the symptoms of ALS, including paralysis. Aberrant TDP43 function is a common feature in sporadic ALS, and thus TDP43 transgenic models may recapitulate disease processes that occur in humans with sporadic ALS. Although the PrP.TDP43-A315T model has been reported to develop abnormalities in gut motility that contribute to early mortality, recent studies indicated that gut motility issues could be mitigated by feeding mice with gel-based diets rather than the standard dry chow. In the present study, we have attempted to use the PrP.TDP43-A315T model to test whether we could identify a drug combination that synergized to extend life span in this model substantially. The drug combinations were built around the existing drug modalities, adding additional drugs that had indications of utility from the literature. To mitigate gut motility issues, we fed the mice gel-based diets with or without added drug combinations. Although the gel-based diets extended life expectancy in PrP.TDP43-A315T mice, most of the animals still developed gut motility abnormalities that may have contributed to early mortality. None of the drug combinations we tested extended life expectancy in this model substantially.
Assembly of branched chain amino acid (BCAA) to toxic fibrils may be related to pathogenesis of Maple syrup urine disease (MSUD)
Authors: Kanth Chandra P , Patel Monisha , Dave Raj , Singh Ankur , Joshi Aayushi , Pandey Manoj Kumar , Bhatia Dhiraj , Gour Nidhi 
Published: October 2024

AbstractInborn errors of metabolism (IEMs) are a group of diseases caused by mutations in single genes, leading to the buildup of metabolites that are typically toxic or disrupt normal cellular function. The etiological relation of metabolic disorders has been uncovered through the study of metabolite amyloids. Various metabolites that accumulate in IEMs have been reported to self-assemble into organized structures. These structures exhibit similar physicochemical properties as proteinaceous amyloid fibrils. In this context, our study illustrated the aggregation properties of Branched chain amino acid (BCAA) i.e. Isoleucine, Leucine and Valine that accumulate in Maple syrup urine disease (MSUD) to investigate their propensities to assemble into amyloid-like fibrils. The structural morphologies of BCAA were studied via. microscopic techniques like Scanning electron microscopy (SEM), optical microscopy and phase contrast microscopy. Further, characterization techniques were employed to understand the physicochemical properties of the self-assemblies and its underlying mechanism. The amyloid-like nature of these aggregates was confirmed using Thioflavin T (ThT) and Congo Red (CR) assays, indicating a possible cytotoxic effect. The MTT assay reveals BCAAs were cytotoxic and significantly decrease cell viability. Our study plays a key role in understanding the physicochemical properties of MSUD in association to amyloid disease, possibly paving the way for the development of therapeutic solutions in the future.Graphical AbstractThe self-assembly of BCAA-Ile, Leu, Val was investigated and the findings indicate that their aggregation may follow an amyloidogenic pathway.
Live-cell transcriptomics with engineered virus-like particles
Authors: Najia Mohamad Ali , Borrajo Jacob , Le Anna , Tsai FuNien , Huang Jeremy Y. , Griffith Linda G. , Daley George Q. , Blainey Paul C. 
Published: October 2024

ABSTRACTThe transcriptional state of a cell provides a multi-parameter representation of gene expression programs that reflect its identity and phenotype. However, current transcriptomic profiling technologies result in destruction of the biological sample, preventing direct analysis of transcriptional dynamics in the same living cells over time. Here, we developed a synthetic RNA export system called cellular ‘self-reporting’ to address this fundamental technological limitation. We repurposed the murine leukemia virus retroviral protein Gag to enable diverse types of immortalized and primary mammalian cells to package cellular RNA molecules in virus-like particles (VLPs) for export into the extracellular environment. We applied self-reporting to interrogate the transcriptome-wide dynamics that occur during neuronal differentiation from induced pluripotent stem cells and detected gene expression profiles from individual live cells. Leveraging this genetically encodable approach, we expanded the capabilities of self-reporting through molecular engineering of VLP components. Pseudotyping VLPs with epitope-tagged envelope proteins enabled multiplexed selective live-cell readout of transcriptional states from heterogeneous co-cultures. Furthermore, structure-guided protein engineering of Gag fusions with human RNA binding domains improved the mRNA representation in self-reporting readouts and enabled the directed export of libraries of synthetic barcode transcripts. Taken together, this work establishes self-reporting as a facile and broadly enabling technology for live-cell, transcriptome-scale profiling of dynamic processes across diverse cell types and biological applications.