bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lipid Dysregulation Unveil the Intricate Interplay of Lysosomal and Mitochondrial Changes in Frontotemporal Dementia with GRN Haploinsufficiency
Authors: Ondaro Jon , Zúñiga-Elizari Jose Luis , Zufiría Mónica , Garciandia-Arcelus Maddi , Zulaica Miren , Lafarga Miguel , Riancho Javier , Holt Ian James , López de Munaín Adolfo , Moreno Fermin , Gil-Bea Francisco Javier , Gereñu Gorka 
Published: January 2024

ABSTRACTThis study investigates the cellular pathology resulting from haploinsufficiency of progranulin (PGRN) in frontotemporal dementia (FTD) associated with granulin (GRN) mutations. Utilizing fibroblasts from FTD patients carrying a distinctive GRN mutation (c.709-1G>A), we observed lysosomal and lipofuscin accumulation, impaired lysosomal function, compromised autophagic flux, and mitochondrial abnormalities. Notably, recombinant human progranulin (rhPGRN) treatment restored lysosomal acidification, mitigated mitochondrial defects, and demonstrated beneficial effects. FTD-GRN fibroblasts exhibited abnormal lipid metabolism with increased lipid droplet formation, influenced by GRN haploinsufficiency and modulated by rhPGRN. Under nutrient-rich conditions, lipid droplet dynamics were shaped by autophagy and mitochondrial processes, potentially due to impaired fatty acid oxidation. These findings highlight a direct association between GRN deficiency and altered lysosomal-mitochondrial interactions, influencing lipid metabolism and contributing to FTD pathogenesis. The documented lysosomal dysfunction, impaired autophagy, mitochondrial anomalies, and altered lipid metabolism collectively suggest a complex interplay of cellular processes in the development of FTD-GRN.
Developmental emergence of first- and higher-order thalamic neuron molecular identities
Authors: Lo Giudice Quentin , Wagener Robin J. , Abe Philipp , Frangeul Laura , Jabaudon Denis 
Published: January 2024

AbstractThe thalamus is organized into nuclei that have distinct input and output connectivities with the cortex. While first-order (FO) nuclei – also called core nuclei – relay input from sensory organs on the body surface and project to primary cortical sensory areas, higher-order (HO) nuclei – matrix nuclei – instead receive their driver input from the cortex and project to secondary and associative areas within cortico-thalamo-cortical loops. Input-dependent processes have been shown to play a critical role in the emergence of FO thalamic neuron identity from a ground state HO neuron identity, yet how this identity emerges during development remains unknown. Here, using single-cell RNA sequencing of the developing embryonic thalamus, we show that FO thalamic identity emerges after HO identity and that peripheral input is critical for the maturation of excitatory, but not inhibitory FO-type neurons. Our findings reveal that subsets of HO neurons are developmentally co-opted into FO-type neurons, providing a mechanistic framework for the diversification of thalamic neuron types during development and evolution.Summary StatementSubsets of higher-order thalamic neurons are developmentally co-opted into first-order type neurons, providing a framework for the diversification of thalamic neuron types during development and evolution.
Contribution of cellular macromolecules to the diffusion of a 40 nm particle inEscherichia coli
Authors: Losa José , Heinemann Matthias 
Published: January 2024

AbstractDue to the high concentration of proteins, nucleic acids and other macromolecules, the bacterial cytoplasm is typically described as a crowded environment. However, the extent to which each of these macromolecules individually affects the mobility of macromolecular complexes, and how this depends on growth conditions, is presently unclear. In this study, we sought to quantify the crowding experienced by an exogenous 40 nm fluorescent particle in the cytoplasm ofE. coliunder different growth conditions. By performing single particle tracking measurements in cells selectively depleted of DNA and/or mRNA, we determined the contribution to crowding of mRNA, DNA and remaining cellular components, i.e., mostly proteins and ribosomes. To estimate this contribution to crowding, we quantified the difference of the particle’s diffusion coefficient in conditions with and without those macromolecules. We found that the contributions of the three classes of components were of comparable magnitude, being largest in the case of proteins and ribosomes. We further found that the contributions of mRNA and DNA to crowding were significantly larger than expected based on their volumetric fractions alone. Finally, we found that the crowding contributions change only slightly with the growth conditions. These results reveal how various cellular components partake in crowding of the cytoplasm and the consequences this has for the mobility of large macromolecular complexes.Statement of SignificanceThe mobility of a particle of interest in the cytoplasm depends on a variety of factors that include the concentration, shape and physicochemical properties of crowding obstacles. Different macromolecules in the cell are therefore expected to hinder the mobility of a given particle to different extents. However, an accurate and systematic investigation of these hindrances to mobilityin vivohas not been yet carried out. In this work, through a novel combination of experimental and computational approaches, we determine the diffusion coefficient of a 40 nm particle in the cytoplasm ofE. coliunder conditions of selective removal of some macromolecules. This allows us to quantify the hindering effect of each of the depleted macromolecules on the mobility of the said particle. For DNA, mRNA, and remaining macromolecules, we observe that this effect is of comparable magnitude, being largest in the latter case. This work sheds light on the interplay between intracellular composition and the physical properties of the cytoplasm at the 40 nm scale.
Comparison of whole-brain task-modulated functional connectivity methods for fMRI task connectomics
Authors: Masharipov Ruslan , Knyazeva Irina , Korotkov Alexander , Cherednichenko Denis , Kireev Maxim 
Published: January 2024

AbstractHigher brain functions require flexible integration of information across widely distributed brain regions depending on the task context. Resting-state functional magnetic resonance imaging (fMRI) has provided substantial insight into large-scale intrinsic brain network organisation, yet the principles of rapid context-dependent reconfiguration of that intrinsic network organisation are much less understood. A major challenge for task connectome mapping is the absence of a gold standard for deriving whole-brain task-modulated functional connectivity matrices. Here, we perform biophysically realistic simulations to control the ground-truth task-modulated functional connectivity over a wide range of experimental settings. We reveal the best-performing methods for different types of task designs and their fundamental limitations. Importantly, we demonstrate that rapid (100 ms) modulations of oscillatory neuronal synchronisation can be recovered from sluggish haemodynamic fluctuations even at typically low fMRI temporal resolution (2 s). Finally, we provide practical recommendations on task design and statistical analysis to foster task connectome mapping.
Activity-Dependent Ectopic Spiking in Parvalbumin-Expressing Interneurons of the Neocortex
Authors: Theyel Brian B. , Stevenson Rachel J. , Connors Barry W. 
Published: January 2024

ABSTRACTCanonically, action potentials of most mammalian neurons initiate at the axon initial segment and propagate bidirectionally: orthodromically along the distal axon, and retrogradely into the soma and dendrites. Under some circumstances action potentials may initiate ectopically, at sites distal to the axon initial segment, and propagate antidromically along the axon. These ‘ectopic action potentials’ (EAPs) have been observed in experimental models of seizures and chronic pain, and more rarely in nonpathological forebrain neurons. Here we report that a large majority of parvalbumin-expressing (PV+) interneurons in upper layers of mouse neocortex, from both orbitofrontal and primary somatosensory areas, fire EAPs after sufficient activation of their somata. Somatostatin-expressing interneurons also fire EAPs, though less robustly. Ectopic firing in PV+ cells occurs in varying temporal patterns and can persist for several seconds. PV+ cells evoke strong synaptic inhibition in pyramidal neurons and interneurons and play critical roles in cortical function. Our results suggest that ectopic spiking of PV+ interneurons is common, and may contribute to both normal and pathological network functions of the neocortex.SIGNIFICANCE STATEMENTA form of neuronal firing that emerges in distal axons and terminals – the ‘ectopic action potential’ (EAP) – has been detected in a few cell populations of the cerebral cortex. Previous investigations of parvalbumin-positive interneurons in neocortex had suggested only a small percentage of cells can fire EAPs. We found that a large fraction of parvalbumin-positive interneurons in the superficial layers of neocortex, including first-order and higher-order areas, can fire EAPs. These results broaden our understanding of the intrinsic firing characteristics of these critically important inhibitory interneurons.
Multiplex generation and single cell analysis of structural variants in a mammalian genome
Authors: Pinglay Sudarshan , Lalanne Jean-Benoit , Daza Riza M. , Koeppel Jonas , Li Xiaoyi , Lee David S. , Shendure Jay 
Published: January 2024

AbstractThe functional consequences of structural variants (SVs) in mammalian genomes are challenging to study. This is due to several factors, including: 1) their numerical paucity relative to other forms of standing genetic variation such as single nucleotide variants (SNVs) and short insertions or deletions (indels); 2) the fact that a single SV can involve and potentially impact the function of more than one gene and/orcisregulatory element; and 3) the relative immaturity of methods to generate and map SVs, either randomly or in targeted fashion, inin vitroorin vivomodel systems. Towards addressing these challenges, we developedGenome-Shuffle-seq, a straightforward method that enables the multiplex generation and mapping of several major forms of SVs (deletions, inversions, translocations) throughout a mammalian genome.Genome-Shuffle-seqis based on the integration of “shuffle cassettes’’ to the genome, wherein each shuffle cassette contains components that facilitate its site-specific recombination (SSR) with other integrated shuffle cassettes (via Cre-loxP), its mapping to a specific genomic location (via T7-mediatedin vitrotranscription or IVT), and its identification in single-cell RNA-seq (scRNA-seq) data (via T7-mediatedin situtranscription or IST). In this proof-of-concept, we applyGenome-Shuffle-seqto induce and map thousands of genomic SVs in mouse embryonic stem cells (mESCs) in a single experiment. Induced SVs are rapidly depleted from the cellular population over time, possibly due to Cre-mediated toxicity and/or negative selection on the rearrangements themselves. Leveraging T7 IST of barcodes whose positions are already mapped, we further demonstrate that we can efficiently genotype which SVs are present in association with each of many single cell transcriptomes in scRNA-seq data. Finally, preliminary evidence suggests our method may be a powerful means of generating extrachromosomal circular DNAs (ecDNAs). Looking forward, we anticipate thatGenome-Shuffle-seqmay be broadly useful for the systematic exploration of the functional consequences of SVs on gene expression, the chromatin landscape, and 3D nuclear architecture. We further anticipate potential uses forin vitromodeling of ecDNAs, as well as in paving the path to a minimal mammalian genome.
Chronic potentiation of metabotropic glutamate receptor 2 with a nanobody accelerates amyloidogenesis in Alzheimer’s disease
Authors: Lafon Pierre-André , Tsitokana Mireille Elodie , Alenda Ugo , Philibert Clémentine Eva , Oosterlaken Mathieu , Cimadevila Marta , Monnic Jessica , Roux Salomé , Bessié Julie , Diem Séverine , Vandermoere Franck , Prézeau Laurent , Chames Patrick , Kniazeff Julie , Claeysen Sylvie , Pin Jean-Philippe , Perrier Véronique , Liu Jianfeng , Rondard Philippe 
Published: January 2024

AbstractImmunotherapy of Alzheimer’s disease (AD) is a promising approach to reduce the accumulation of amyloid-beta (Aβ), a critical event in the onset of the disease. Targeting the group II metabotropic glutamate receptors, mGlu2 and mGlu3, could be important in controlling Aβ production, although their respective contribution remains unclear due to the lack of selective tools. Here, we show that enhancing mGlu2 receptor activity increases Aβ1-42peptide production whereas activation of mGlu3 has no effect. We show that such a difference likely results from the direct interaction of APP with mGlu3, but not with mGlu2 receptors, that prevents APP amyloidogenic cleavage and Aβ1-42peptides production. We then show that chronic treatments of the AD model 5xFAD mice with a brain-penetrating mGlu2-potentiating nanobody accelerated amyloid aggregation and exacerbated memory deficits, but had no effect in control mice. Our results confirm that a selective mGluR2 activation exacerbates AD disease development, suggesting that therapeutic benefices could be obtained with blockers of this receptor. Our study also provides the proof-of-concept that chronic administration of nanobodies targeting neuroreceptors can be envisioned to treat brain diseases.
Gut environmental factors explain variations in the gut microbiome composition and metabolism within and between healthy adults
Authors: Procházková Nicola , Laursen Martin F. , La Barbera Giorgia , Tsekitsidi Eirini , Jørgensen Malte S. , Rasmussen Morten A. , Raes Jeroen , Licht Tine R. , Dragsted Lars O. , Roager Henrik M. 
Published: January 2024

AbstractThe human gut microbiome is highly personal. However, the contribution of the gut environment to variations in the gut microbiome remains elusive. Here, we profiled the gut microbiome composition and metabolism over 9 consecutive days in 61 healthy adults and assessed gut environmental factors including segmental transit time and pH using a wireless motility capsule. Day-to-day fluctuations in gut environmental factors as well as segmental transit time and pH varied substantially between individuals. The gut environment explained more variations in gut microbiome and urine metabolome than dietary macronutrients or personal characteristics. Finally, we identified coffee-derived metabolites to be negatively correlated with small intestinal transit time and several microbial metabolites to be associated with colonic transit time including urinary proteolytic markers, faecal short-chain fatty acids, and breath methane. Our work suggests that the gut environment is key for understanding the individuality of the human gut microbiome composition and metabolism.
Progressive engagement of SST+ interneurons via Elfn1 regulates the barrel-septa response identity in the somatosensory cortex of mice
Authors: Argunşah Ali Özgür , Stachniak Tevye Jason , Yang Jenq-Wei , Cai Linbi , Kanatouris George , Karayannis Theofanis 
Published: January 2024

AbstractThe vibrissae system of rodents, akin to human hands and fingers, provides somatosensory information coming from individual whiskers for object exploration and recognition. Just as separated digits enhance somatosensation in humans, the ability of mice to sense objects through multiple whiskers in segregated streams is crucial. The segregation begins at the level of the whiskers and is maintained through their precise somatotopic organization in the Brainstem→ Thalamus→ Cortex axis, culminating in the so-called barrels and the in-between “spaces” called septa. Here, by performingin-vivosilicon probe recordings simultaneously in the barrel and septa domains in mice upon repeated 10Hz single and multi-whisker stimulation, we identify and characterize a temporal divergence in the spiking activity between these domains. Further, through genetic fate-mapping, we reveal that cortical SST+ and VIP+ inhibitory neurons show a layer-dependent differential preference in septa versus barrel domains. Utilizing a genetic manipulation that affects the temporal facilitation dynamics onto only these two inhibitory cell classes, we largely abolish the temporal response divergence between the two cortical domains. Finally, usingin-vivoviral tracing, whole-brain clearing and imaging, we show a differential barrel and septa projection pattern to cortical regions S2 and M1. We hence reveal that local temporally engaging cortical inhibition provided by SST+ neurons contribute to the functional segregation of barrel and septa domains and potentially their downstream targets.
Embryonic origins of forebrain oligodendrocytes revisited by combinatorial genetic fate mapping
Authors: Cai Yuqi , Zhao Zhirong , Shi Mingyue , Zheng Mingfang , Gong Ling , He Miao 
Published: January 2024

AbstractMultiple embryonic origins give rise to forebrain oligodendrocytes (OLs), yet controversies and uncertainty exist regarding their differential contributions. We established intersectional and subtractional strategies to genetically fate map OLs produced by medial ganglionic eminence/preoptic area (MGE/POA), lateral/caudal ganglionic eminences (LGE/CGE) and dorsal pallium. We found that, contrary to the canonical view, LGE/CGE-derived OLs make minimum contributions to the neocortex and corpus callosum, but dominate piriform cortex and anterior commissure. Additionally, MGE/POA-derived OLs, instead of being entirely eliminated, make small but sustained contribution to cortex with a distribution pattern distinctive from those derived from the dorsal origin. Our study provides a revised and more comprehensive view of cortical and white matter OL origins, and established valuable new tools and strategies for future OL studies.
Study on the impact of soil environment organic substances on the ageing of urban PE gas pipes in service
Authors: Li Manman , Bao Qing , Lei Sumin , Xing Linlin , Gai Shu 
Published: January 2024

Purpose
The service environment of urban polyethylene (PE) pipes has a crucial influence on their long-term safety and performance. Based on the application and structural performance analysis of PE pipe failure cases, this study aims to investigate the impact of organic substances in the soil on the aging behavior of PE pipes by designing organic solutions with different concentrations, which are based on the composition of organic substances in the soil environment, and periodic immersion tests.

Design/methodology/approach
Soil samples in the vicinity of the failed pipes were analyzed by gas chromatography-mass spectrometry, sensitive organic substances were screened and soaking solutions of different concentrations were designed. After the soaking test, the PE pipe samples were analyzed using differential scanning calorimetry, Fourier-transform infrared spectroscopy and other testing methods.

Findings
The performance difference between the outer surface and the middle of the cross section of PE pipes highlights the influence of the soil service environment on their aging. Different organic solutions can have varying impacts on the aging behavior of PE pipes when immersed. For instance, when exposed to amine organic solutions, PE pipes may have an increased weight and decreased material yield strength, although there is no reduction in their thermal or oxygen stability. On the contrary, when subjected to ether organic solutions, the surface of PE pipe specimens may be affected, leading to a reduction in material fracture elongation and a decrease in their thermal and oxygen stability. Furthermore, immersion in either amine or ether organic solutions may result in the production of hydroxyl and other aging groups on the surface of the material.

Originality/value
Understanding the potential impact of organic substances in the soil environment on the aging of PE pipe ensures the long-term performance and safety of urban PE pipe. This research approach will provide valuable insights into improving the durability and reliability of urban PE pipes in soil environments.
How can green suppliers boost customer loyalty? Model proposition for energy markets
Authors: Cabanelas Pablo , Mezger Andrea , López-Míguens María Jesús , Rüdiger Klaus 
Published: January 2024

Purpose
Clean and sustainable energy becomes an alternative to differentiate electricity suppliers, but it is necessary to have a better understanding of their behaviour to achieve green customer loyalty. This paper aims to deploy a behavioural model that helps explain loyalty of customers towards green electricity providers by including a series of antecedents such as trust, satisfaction, perceived environmental impact, propensity to trust and perceived risk.

Design/methodology/approach
The paper deploys a behavioural model that it is tested through structural equation modelling to a sample of 231 German electricity consumers with green contracts. The data analysis included two steps: first, the development and validation of the scales used to measure the constructs proposed in the model, and second, the model test.

Findings
Results demonstrate that trust and satisfaction directly influence loyalty, while satisfaction and the other variables included in the model have an indirect relationship with loyalty mediated by trust and satisfaction. As green characteristics of electricity are difficult to evaluate, managers should demonstrate in their communication the environmental effects of their activities while emphasising their capacity to attend to supply requirements for building long-term customer relationships.

Originality/value
The paper is focused on the understanding of those consumers who have signed a green electricity contract and the antecedents associated to their loyalty. The behavioural model helps identify how managers should apply marketing strategies to foster green consumers loyalty.
Predictors of work-related cyberaggression in a random sample of the Swedish working population
Authors: Farley Samuel , Cowen Forssell Rebecka , Holm Kristoffer , Berthelsen Hanne 
Published: January 2024

PurposeWith greater numbers of employees using computer-mediated communication, cyberaggression is becoming a more pressing problem for employees and their organizations. However, while a growing body of research illustrates its harmful effects, little is known about the factors that drive its occurrence. The authors therefore sought to identify factors that increase the risk of cyberaggression among employees.Design/methodology/approachA random sample of the Swedish working population (N = 11,556) was surveyed via Statistics Sweden (SCB), which produced a final sample of N = 2,847 (response rate = 24.6%).FindingsLogistic regression analysis showed that emotionally demanding work, availability expectations, low perceived work quality, public sector work and being in a managerial position were related to higher levels of experienced cyberaggression. In addition, exploratory analyses indicated that some of these factors were more strongly related to cyberaggression enacted by organizational insiders compared to organizational outsiders.Originality/valueTogether, the authors' findings suggest that situational factors are stronger antecedents of cyberaggression victimization than personal factors. This has implications for organizations, as practical steps can be taken to reduce cyberaggression among employees.