bluuebunny/crossref_metadata_2025_split huggingface dataset:
Structures of aberrant spliceosome intermediates on their way to disassembly
Authors: Soni Komal , Horvath Attila , Dybkov Olexandr , Schwan Merlin , Trakansuebkul Sasanan , Flemming Dirk , Wild Klemens , Urlaub Henning , Fischer Tamás , Sinning Irmgard 
Published: September 2024

AbstractIntron removal during pre-mRNA splicing is of extraordinary complexity and its disruption causes a vast number of genetic diseases in humans1. While key steps of the canonical spliceosome cycle have been revealed by combined structure-function analyses2,3, structural information on an aberrant spliceosome committed to premature disassembly is not available. Here, we report two cryo-EM structures of post-Bactspliceosome intermediates fromS. pombeprimed for disassembly. We identify the DEAH-box helicase – G patch protein pair (Gih35-Gpl1, homologous to human DHX35-GPATCH1) and show how it maintains catalytic dormancy. In both structures, Gpl1 recognizes a remodeled active site introduced by an over-stabilization of the U5 loop I interaction with the 5’ exon leading to a single nucleotide insertion at the 5’splice site. Remodeling is communicated to the spliceosome surface and the Ntr1 complex that mediates disassembly is recruited. Our data pave the way for a targeted analysis of splicing quality control.
Altered polyadenylation site usage in SERPINA1 3’UTR in response to cellular stress affects A1AT protein expression
Authors: Jiamutai FNU , Hatfield Abigail , Herbert Austin , Majumdar Debarati , Shankar Vijay , Lackey Lela 
Published: September 2024

AbstractAlternative polyadenylation results in different 3’ isoforms of messenger RNA (mRNA) transcripts. Alternative polyadenylation in the 3’ untranslated region (3’UTR) can alter RNA localization, stability and translational efficiency. TheSERPINA1mRNA has two distinct 3’ UTR isoforms, both of which express the protease inhibitor α-1-antitrypsin (A1AT). A1AT is an acute phase protein that is expressed and secreted from liver hepatocytes and upregulated during inflammation. Low levels of A1AT in the lung contributes to chronic obstructive pulmonary disease, while misfolding of A1AT in the liver contributes to liver cirrhosis. We analyzed the dynamics of alternative polyadenylation during cellular stress by treating the liver cell line HepG2 with the cytokine interleukin 6 (IL-6), ethanol or peroxide.SERPINA1is transcriptionally upregulated after IL-6 treatment and has altered polyadenylation, resulting in an increase in long 3’UTR isoforms. We find that the long 3’UTR represses endogenous A1AT protein expression even with high levels ofSERPINA1mRNA.SERPINA1expression and 3’ end processing were not affected by ethanol or peroxide. IL-6-induced changes in transcriptome-wide transcriptional regulation suggest changes to the endoplasmic reticulum and in secretory protein processing. Our data suggest that inflammation influences polyA site choice forSERPINA1transcripts, resulting in reduced A1AT protein expression.
Motor learning leverages coordinated low-frequency cortico-basal ganglia activity to optimize motor preparation in humans with Parkinson’s Disease
Authors: Presbrey Kara N. , Wozny Thomas A. , Louie Kenneth H. , Little Simon , Starr Philip A. , Abbasi-Asl Reza , Wang Doris D. 
Published: September 2024

ABSTRACTLearning dexterous motor sequences is crucial to autonomy and quality of life but can be altered in Parkinson’s Disease (PD). Learning involves optimizing pre-movement planning (preplanning) of multiple sequence elements to reduce computational overhead during active movement. However, it is unclear which brain regions mediate preplanning or how this process evolves with learning. Recording cortico-basal ganglia field potentials during a multi-day typing task in four individuals with PD, we found evidence for network-wide multi-element preplanning that improved with learning, facilitated by functional connectivity. In both cortex and basal ganglia, pre-movement gamma (γ, 30–250 Hz) activity, historically linked to population spiking, distinguished between future action sequences and became increasingly predictive with learning. For motor cortex γ, this increase was tied to learning-related cross-frequency coupling led by cortically-driven network delta (δ, 0.5–4 Hz) synchrony. More generally, coordinated network δ supported a complex pattern of learning-driven cross-frequency couplings within and between cortex and basal ganglia, including striatal lead of cortical beta (β, 12–30 Hz) activity, reflecting the specialized roles of these brain regions in motor preparation. In contrast, impaired learning was characterized by practice-driven decreases in γ’s predictive value, limited cross-frequency coupling and absent network δ synchrony, with network dynamics possibly altered by pathologically high inter-basal ganglia δ synchrony. These results suggest that cortically-led δ phase coordination optimized cortico-basal ganglia multi-element preplanning through enhanced recruitment of higher-frequency neural activity. Neurostimulation that enhances cortico-basal ganglia δ synchrony may thus hold potential for improving skilled fine motor control in PD.
Modelling coordinated nocturnal rhythms in ungulates
Authors: Ukrow Johann , Gübert Jennifer , Hahn-Klimroth Max , Dierkes Paul Wilhelm , Schneider Gaby 
Published: September 2024

AbstractStudying animal behavior is an important aspect of ethology and behavioral biology and a prerequisite to improving animal management in zoos. As the nocturnal behavior of many ungulate species is, in contrast to the behavior during daylight, poorly studied, a better understanding of nocturnal behavior is necessary to improve animal welfare.We analyse the nocturnal behavior of ungulates recorded in a large number of German and Dutch zoos. These animals show a switching between standing and lying phases, which can be associated with a certain degree of regularity. Interestingly, this regularity is not always captured in the simple length distributions of behavioral phases but shows in the autocorrelation and in the coordination of standing and lying across animals. Particularly, this phenomenon often occurs in younger animals.We provide an explanation to this phenomenon by proposing a stochastic model that can describe these processes. For individual behavior, regular standing cycles are assumed to be potentially interrupted by short lying phases, such that a regular background rhythm appears in the autocorrelation but not necessarily in the raw length distribution of the activity phases. For coordinated behavior, crosscorrelation functions allow to analyse the degree to which pairs of animals that are sharing the same stable box show a synchronization of their standing-lying rhythms.In the data set, our analyses suggest that indeed, baseline regularity does not seem to be reduced in younger animals. Instead, younger animals showed increased probabilities for interruption of standing phases by short lying phases. In addition, the coordination of the standing-lying rhythm between animals in the same box ranged up to 100% and decreased with the distance between boxes. We also found systematic delays between the standing activity of young and adult animals.Author summaryIn this paper, we investigate rhythms observed in the nocturnal behavior of a large number of ungulates housed in zoos. Motivated by the observation that younger individuals, in particular, exhibit irregular standing-lying cycles, we propose and analyze a mathematical model to describe the basic rhythms of the observed animals and quantify the regularity of their standing-lying behavior.Our model enables us to measure both the regularity and synchronization of behavior among individuals. The results suggest that even individuals initially perceived as highly irregular actually follow a strict base rhythm during the night, but single standing phases may be interrupted. Moreover, we observe that animals stalled together typically synchronize their behavior, particularly in the case of a dam and her calf.
Egocentric anchoring-and-adjustment of social knowledge in the hippocampal formation
Authors: Rodríguez Aramendía Marta , Esposito Mariachiara , Kaplan Raphael 
Published: September 2024

AbstractRecent work suggests the hippocampal formation(HF) assimilates relational social knowledge similar to how it transforms egocentric spatial cues into map-like representations. Yet whether hippocampal map-like representations of social knowledge still represent lingering egocentric biases is unclear. We test if a prominent egocentric bias involving an implicit reliance on self-knowledge when rating others, anchoring-and-adjustment, is present when the relative attributes of different social entities are assimilated by the HF. Participants provided likelihood ratings of partaking in everyday activities for themselves, fictitious individuals, and familiar social groups. Adapting a functional neuroimaging task from Kaplan and Friston, participants then learned a stranger’s preference for an activity relative to one of the fictitious individuals and inferred how the stranger’s preference related to the groups’ preferences. Egocentric anchoring-and-adjustment was present when participants rated the other entities. Isolating the neural representation of egocentric anchoring-and-adjustment when flexibly comparing different social entities, the HF and dorsomedial prefrontal cortex(dmPFC) represented group-self rating discrepancy. Furthermore, the HF also reflected how well group preferences were remembered, where memory for group preferences correlates with task performance. We found the HF selectively represented group identity over other learned entities, confirming that the HF was primarily engaged by social comparisons in a more ample frame of reference. Taken together, these results imply that self-knowledge influences how the HF assimilates map-like knowledge about others.
A systems model of alternating theta sweeps via firing rate adaptation
Authors: Ji Zilong , Chu Tianhao , Wu Si , Burgess Neil 
Published: September 2024

AbstractPlace and grid cells provide a neural system for self-location and tend to fire in sequences within each cycle of the hippocampal theta rhythm when rodents run on a linear track. These sequences correspond to the decoded location of the animal sweeping forward from its current location (“theta sweeps”). However recent findings in open-field environments show alternating left-right theta sweeps, and propose a circuit for their generation. Here, we present a computational model of this circuit, comprising head direction cells, conjunctive grid x direction cells, and pure grid cells, based on continuous attractor dynamics, firing rate adaptation, and modulated by the medial-septal theta rhythm. Due to firing rate adaptation, the head-direction ring attractor exhibits left-right sweeps coding for internal direction, providing an input to the grid cell attractor network shifted along the internal direction, via an intermediate layer of conjunctive grid x direction cells, producing left-right sweeps of position by grid cells. Our model explains the empirical findings, including the alignment of internal position and direction sweeps and the dependence of sweep length on grid spacing. It makes predictions for thetamodulated head-direction cells, including specific relationships between theta phase precession during turning, theta skipping, anticipatory firing and directional tuning width. These predictions are verified in experimental data from anteroventral thalamus. The model also makes several predictions for the relationships between position and direction sweeps, running speed and dorsal-ventral location within the entorhinal cortex. Overall, a simple intrinsic mechanism explains the complex theta dynamics of the spatial circuit, with testable predictions.
Cav3.1 is a leucine sensor in POMC neurons mediating appetite suppression and weight loss
Authors: Tsang Anthony H. , Heeley Nicholas , Alcaino Constanza , Hwang Eunsang , Lam Brian Y. , Rahman Taufiq , Darwish Tamana , Nuzzaci Danae , Kay Richard G. , Sarkar Amar , Wang Ruiyan , Basha Nihal , Punnoose Austin , Kirwan Peter , Ma Marcella , Yeo Giles S. , Merkle Florian T , Gribble Fiona M. , Reimann Frank , William Kevin , Blouet Clémence 
Published: September 2024

SummaryHypothalamic leucine sensing promotes satiety and weight loss but an understanding of how leucine regulates neuronal activity is lacking. Here we show thatCacna1g, encoding the T-type voltage-gated calcium channel Cav3.1, is enriched in hypothalamic leucine-sensing neurons and mediates leucine sensing. Pharmacological inhibition of Cav3.1 blunts leucine-induced activation of POMC neurons as well as the anorectic response to leucine in vivo. In addition, genetic deletion ofCacna1gin POMC neurons abolishes the appetite- and weight-suppressive effects of high-protein feeding. Mechanistically, we show that leucine binds to the voltage-sensing segment of Cav3.1, thereby reducing its threshold for voltage-dependent activation. Last, pharmacological activation of hypothalamic Cav3.1 promotes weight loss in diet-induced obese mice and potentiates the weight loss response to GLP-1 receptor agonism. These results reveal that Cav3.1 is a neuronal leucine sensor and a relevant weight loss target.
Computational metabolic modeling unveils gut microbiome’s role in metabolic shifts during murine cancer cachexia
Authors: Kuehnast Torben , Pototschnig Isabella , Träger Manuela , Diener Christian , Habisch Hansjörg , Vogel Andrea , Wink Lisa , Mahnert Alexander , Madl Tobias , Weichhart Thomas , Schweiger Martina , Moissl-Eichinger Christine 
Published: September 2024

AbstractCancer cachexia is a multifactorial syndrome characterized by involuntary weight loss, muscle wasting, systemic inflammation, and metabolic alterations, affecting up to 87% of pancreatic and gastric cancer patients. Unlike simple starvation, cachexia is driven by metabolic disruption involving both host physiology and the gut microbiome. While microbiome changes in cachexia have been documented, a coherent understanding of how these changes translate into functional metabolic shifts remains elusive.In this study, we combined in vivo fecal and plasma metabolomic analyses with a novel computational microbiome simulation pipeline to identify cachexia-associated microbial metabolites. Using the murine MCA207 tumor line and its cachectic derivative CHX207, we differentiated microbiome changes driven by cachexia from those induced by tumor growth. Our computational tool, McMurGut, a murine-tailored extension of MICOM, enabled simulation of microbial metabolic interactions specific to the mouse microbiome, covering 91% of identified genera.We identified significant abundance changes in 35 microbial genera and corresponding shifts in metabolite production, including reductions in short-chain fatty acids (SCFAs) like acetate and butyrate, alongside increased production of galactose, formate, and propionate. Notably, decreases in SCFA production, particularly by genera such asFaecalibaculumandDubosiella, correlated with exacerbated cachectic symptoms. Additionally, the elevated production of formate and galactose, primarily byBacteroidesandLactobacillus, suggested altered fermentation pathways in cachexia, potentially linked to increased mucus degradation.Validation of our computational predictions via NMR metabolomics highlighted key congruencies between predicted and experimentally observed metabolites, supporting the role of microbiome-driven metabolic shifts in cachexia pathology. These findings provide crucial insights into the microbiome’s involvement in cachexia and suggest future avenues for therapeutic interventions aimed at modulating microbial taxa and their metabolic outputs to improve patient outcomes.
Opponent visuospatial coding structures responses during memory recall and visual perception in medial parietal cortex
Authors: Scrivener Catriona L. , Silson Edward H. 
Published: September 2024

AbstractThe mechanisms linking perceptual and memory representations in the brain are not yet fully understood. In early visual cortex, perception and memory are known to share similar neural representations, but how they interact beyond early visual cortex is less clear. Recent work identified that scene-perception and scene-memory areas on the lateral and ventral surfaces of the brain are linked via a shared but opponent visuospatial coding scheme, suggesting that shared visuospatial coding might provide a framework for perceptual-memory interactions. Here, we test whether the pattern in visuospatial coding within category-selective memory areas of medial parietal cortex structures responses during memory recall and visual perception. Using functional magnetic resonance imaging, we observe signatures of visuospatial coding in the form of population receptive fields (pRFs) with both positive and negative response profiles within medial parietal cortex. Crucially, the more dissimilar the timeseries of a pair of positive/negative pRFs within a region, the more dissimilar their responses during both memory recall and visual perception - tasks that place very different demands on these regions: internally oriented memory recall versus externally oriented visual perception. These data extend recent work to suggest that the interplay between pRFs with opponent visuospatial coding may play a vital role in integrating information across different representational spaces.
On the coupling between membrane bending and stretching in lipid vesicles
Authors: Wennerström Håkan , Sparr Emma , Stenhammar Joakim 
Published: September 2024

AbstractThe formation of a lipid vesicle from a lamellar phase involves a cost in bending energy of 100–1000 times the thermal energy for values of the membrane bending rigidityκtypical for phospholipid bilayers. The bending rigidity of a bilayer is however a strongly decreasing function of its thicknessh, and the bilayer can thus reduce its bending energy by stretching (and thus thinning) the bilayer. In this paper, we construct a simple model to describe this mechanism for the coupling between bending and stretching and analyse its effect on the bending energy and thermal fluctuations of spherical lipid vesicles. We show that the bilayer thinning becomes significant for small vesicles, and for a vesicle with radiusR0∼ 15 nm there is a sizeable thinning of the bilayer compared to the planar state. We furthermore demonstrate how this thinning is associated with a significant decrease in free energy due to the thermally excited bending modes. We argue that this previously unexplored effect can explain the experimentally observed lower limit of achievable vesicle sizes, which eventually become unstable due to the thinning of the bilayer. We also sketch how this effect provides a potential generic mechanism for the strong curvature dependence of protein adsorption to lipid membranes.
In silico analysis reveals differential targeting of enterovirus species by commonly used PCR assays
Authors: Trinh Van N. , Mulakken Nisha , Nelson Kara L. , Be Nicholas , Kantor Rose S. 
Published: September 2024

AbstractQuantitative polymerase chain reaction (qPCR) assays are sensitive molecular tools commonly used to quantify pathogens in environmental samples. These assays have become a staple of wastewater-based surveillance and often form the basis of quantitative microbial risk assessments. However, PCR assays may fail to capture all of their intended targets due to signature erosion over time. Here, we performed anin silicoanalysis of four human enterovirus PCR assays to assess signature erosion against the NCBI virus database. The predicted number of genomes hit by each assay rose alongside total genomes in the database through 2010 but the proportion of predicted hits began to level off with the emergence of the clinically important enterovirus D-68. We found that although all assays captured a majority of enterovirus species, only one recently developed assay adequately captured enterovirus D species. Some assays also appeared more likely to capture non-human enteroviruses than others, an important consideration for data interpretation. We conclude that broad-spectrum virus assays applied to environmental samples should be regularly checked against expanding sequence databases and provide methods to do so.
BRD4 expression in microglia supports recruitment of T cells into the CNS and exacerbates EAE
Authors: Dey Anup , Butcher Matthew , Gegonne Anne , Singer Dinah S. , Zhu Jinfang , Ozato Keiko 
Published: September 2024

AbstractIn EAE, a mouse model of multiple sclerosis, immunization with MOG autoantigen results in the generation of Th1/Th17 T cells in the periphery. MOG-specific T cells then invade into the central nervous system (CNS), resulting in neuronal demyelination. Microglia, innate immune cells in the CNS are known to regulate various neuronal diseases. However, the role of microglia in EAE has remained elusive. BRD4 is a BET protein expressed in microglia, whether BRD4 in microglia contributes to EAE has not been determined. We show that EAE pathology was markedly reduced with microglia-specific Brd4 conditional knockout (cKO). In these mice, microglia- T cell interactions were greatly reduced, leading to the lack of T cell reactivation. Microglia specific transcriptome data showed downregulation of genes required for interaction with and reactivation of T cells in Brd4 cKO samples. In summary, BRD4 plays a critical role in regulating microglia function in normal and EAE CNS.SummaryThis study demonstrates that in a EAE model, microglia-specific Brd4 conditional knockout mice were defective in expressing genes required for microglia- T cells interaction and those involved in neuroinflammation, and demyelination resulting in fewer CNS T cell invasion and display marked reduction in EAE pathology.
Superiority Illusion in Older Adults: Volume and Functional Connectivity of the Precuneus
Authors: Shidei Yuki , Matsuyoshi Daisuke , Isato Ayako , Sugihara Genichi , Takahashi Hidehiko , Yamada Makiko 
Published: September 2024

AbstractAimPositive thinking, which has been known to extend the lifespan, tends to increase with age. One specific form of positive thinking, the superiority illusion (SI), involves the belief that one is better than others. Despite its potential benefits in aging, the neural basis of the SI in elderly populations remains underexplored.MethodsThis study combined a behavioral task, voxel-based morphometry (VBM), and resting-state functional connectivity (rsFC) analyses to investigate the neural substrates of the SI in a cohort of 100 participants, including young (N = 33), middle-aged (N = 33), and older adults (N = 34).ResultsOur findings indicated that higher SI scores in older adults were correlated with greater gray matter volume in the right precuneus and stronger rsFC between the right precuneus and the left lateral occipital cortex. However, these correlations were not evident in younger and middle-aged groups.ConclusionsOur findings underscore the importance of the right precuneus and its connectivity in the manifestation of the SI, particularly in older adults, highlighting its potential role in adaptive aging processes.