bluuebunny/crossref_metadata_2025 huggingface dataset:
No Effect of Value on the Task Irrelevant Auditory Mismatch Negativity
Authors: Hutchinson Brendan T. , Jack Bradley N. , Budd Alycia , Calabro Ryan , Fogarty Danielle , Nicholls Michael E.R. , Griffiths Oren
Published: November 2024

Behavioural and neuroscientific evidence suggests visual stimuli that signal value involuntarily capture attention and are preferentially processed, even when unattended. We examined whether learned value associations for task-irrelevant auditory stimuli modulate pre-attentive processing and involuntarily capture attention. Across two experiments, the effect of learned value on the visual- and auditory-evoked mismatch negativity (MMN) and P3a event-related potential (ERP) components was measured. Participants performed a primary visual detection task while an irrelevant, unattended oddball stimulus stream was concurrently presented. Deviants within this oddball stream had been previously learned to signal one of several value outcomes: monetary reward, loss or no change. Neither the auditory nor the visual MMN was influenced by these value associations. However, stimulus value affected performance on the primary task and the magnitude of the P3a in those who could identify the stimulus-value pairings at test. Supplementary mass univariate analyses and time frequency decomposition (theta phase-locking) confirmed the presence of the MMN and the absence of any influence of stimulus value on the MMN response. Findings suggest that learned value associations do not meaningfully influence the MMN prediction signaling mechanism for task-irrelevant auditory stimuli.
Interlaboratory comparison of standardised metabolomics and lipidomics analyses in human and rodent blood using the MxP® Quant 500 kit
Authors: Zararsiz Gözde Ertürk , Lintelmann Jutta , Cecil Alexander , Kirwan Jennifer , Poschet Gernot , Gegner Hagen M. , Schuchardt Sven , Guan Xue Li , Saigusa Daisuke , Wishart David , Zheng Jiamin , Mandal Rupasri , Adams Kendra , Thompson J. Will , Snyder Michael P. , Contrepois Kevin , Chen Songjie , Ashrafi Nadia , Akyol Sumeyya , Yilmaz Ali , Graham Stewart F. , O’Connell Thomas M. , Kalecký Karel , Bottiglieri Teodoro , Limonciel Alice , Pham Hai Tuan , Koal Therese , Adamski Jerzy , Kastenmüller Gabi
Published: November 2024

Metabolomics and lipidomics are pivotal in understanding phenotypic variations beyond genomics. However, quantification and comparability of mass spectrometry (MS)-derived data are challenging. Standardised assays can enhance data comparability, enabling applications in multi-center epidemiological and clinical studies. Here we evaluated the performance and reproducibility of the MxP® Quant 500 kit across 14 laboratories. The kit allows quantification of 634 different metabolites from 26 compound classes using triple quadrupole MS. Each laboratory analysed twelve samples, including human plasma and serum, lipaemic plasma, NIST SRM 1950, and mouse and rat plasma, in triplicates. 505 out of the 634 metabolites were measurable above the limit of detection in all laboratories, while eight metabolites were undetectable in our study. Out of the 505 metabolites, 412 were observed in both human and rodent samples. Overall, the kit exhibited high reproducibility with a median coefficient of variation (CV) of 14.3 %. CVs in NIST SRM 1950 reference plasma were below 25 % and 10 % for 494 and 138 metabolites, respectively. To facilitate further inspection of reproducibility for any compound, we provide detailed results from the in-depth evaluation of reproducibility across concentration ranges using Deming regression. Interlaboratory reproducibility was similar across sample types, with some species-, matrix-, and phenotype-specific differences due to variations in concentration ranges. Comparisons with previous studies on the performance of MS-based kits (including the AbsoluteIDQ p180 and the Lipidyzer) revealed good concordance of reproducibility results and measured absolute concentrations in NIST SRM 1950 for most metabolites, making the MxP® Quant 500 kit a relevant tool to apply metabolomics and lipidomics in multi-center studies.
Hierarchical glycolytic pathways control the carbohydrate utilization regulator in human gutBacteroides
Authors: Kabonick Seth , Verma Kamalesh , Modesto Jennifer L. , Pearce Victoria H. , Winokur Kailyn M. , Groisman Eduardo A. , Townsend Guy E.
Published: November 2024

Human dietary choices control the gut microbiome. Industrialized populations consume abundant glucose and fructose, resulting in microbe-dependent intestinal disorders. Simple sugars inhibit the carbohydrate utilization regulator (Cur), a transcription factor in the prominent gut bacterial phylum,Bacteroidetes. Cur encodes products necessary for carbohydrate utilization, host immunomodulation, and intestinal colonization. Here, we demonstrate how simple sugars decrease Cur activity in the mammalian gut. Our findings in twoBacteroidesspecies show that ATP-dependent fructose-1,6-bisphosphate (FBP) synthesis is necessary for glucose or fructose to inhibit Cur, but dispensable for growth because of an essential pyrophosphate (PPi)-dependent enzyme. Furthermore, we show that ATP-dependent FBP synthesis is required to regulate Cur in the gut but does not contribute to fitness whencuris absent, indicating PPi is sufficient to drive glycolysis in these bacteria. Our findings reveal how sugar-rich diets inhibit Cur, thereby disruptingBacteroidesfitness and diminishing products that are beneficial to the host.
Brain functional network connectivity interpolation characterizes neuropsychiatric continuum and heterogeneity
Authors: Li Xinhui , Geenjaar Eloy , Fu Zening , Pearlson Godfrey D. , Calhoun Vince D.
Published: November 2024

Psychiatric disorders such as schizophrenia (SZ) and autism spectrum disorder (ASD) are challenging to characterize in part due to their heterogeneous presentation in individuals, with psychotic symptoms now thought to exist on a continuum from the general population to chronic SZ. Conventional diagnostic and neuroimaging analytical approaches rely on subjective assessment or group differences, but typically ignore progression between groups or heterogeneity within a group. Here, we propose a functional network connectivity (FNC) interpolation framework based on an unsupervised generative model, a variational autoencoder (VAE), to estimate the neuropsychiatric continuum and heterogeneity using static FNC (sFNC) and dynamic FNC (dFNC) data from controls and patients with SZ or ASD. We first demonstrate that VAEs significantly outperform a linear baseline and a semi-supervised counterpart in the interpolation task. We next utilize VAEs to perform sFNC and dFNC interpolation separately. For sFNC interpolation, we observe a high degree of correspondence between the generated sFNC and the corresponding original sFNC. We display the sFNC matrices on a two-dimensional grid to examine individual- and group-specific patterns, as well as pattern alterations. Specifically, the interpolated continua from patients to controls in both disorders show increased hyper-connectivity within the auditory, sensorimotor and visual networks, and between the subcortical and cerebellar domains, as well as hypo-connectivity between the subcortical domain and the sensory domains, and between the cerebellar domain and the sensory regions. For dFNC interpolation, we find that the generated dFNC states effectively capture representative and generalizable dynamic properties for each group. Finally, we show examples of how to leverage interpolation in the VAE latent space, following pathological, state-based, or temporal trajectories. The proposed framework offers added advantages over traditional methods, including data-driven discovery of hidden relationships, visualization of individual differences, imputation of missing values along a continuous spectrum, and estimation of the stage where an individual falls within the continuum. Further, it could potentially be applied to identify patient subgroups and predict future disorder progression.
Predictability of next elements in chimpanzee gesture sequences
Authors: Mielke Alexander , Badihi Gal , Donnellan Ed , Graham Kirsty E. , Hashimoto Chie , Mine Joseph G. , Piel Alex K. , Safryghin Alexandra , Slocombe Katie E. , Soldati Adrian , Stewart Fiona A. , Townsend Simon W. , Wilke Claudia , Zuberbühler Klaus , Zulberti Chiara , Hobaiter Catherine
Published: November 2024

Recent research has produced evidence for basic combinatorial abilities in the vocal systems of different animal species. Here, we investigate the structure of gesture sequences in Eastern chimpanzees (Pan troglodytes schweinfurthii) to detect whether gestural communication shows non-random combinations and how combinatorial rules influence predictability. Gesture, as compared to vocalization, offers greater flexibility in how signals are combined—for example overlapping in time — and as the parsing of signals into sequences is dependent on researcher decisions, we employ a multiverse approach, considering four different definitions of what constitutes a ‘sequence’ based on varying time thresholds. Our results indicate that sequences tend to be short (even with the most liberal time-window) and that transitions between some gesture types occur more frequently than expected by chance, with some transitions showing significant association across all time-windows. These transitions often involve repetition, suggesting persistence as a key aspect of chimpanzee gestural sequences. Information about previous gestures reduced uncertainty in predicting subsequent gestures. The order of gestures within sequences appears to be less critical than their cooccurrence, challenging assumptions based on the linear patterning derived from vocal communication. Our findings highlight the importance of methodological choices in sequence definition and suggest that chimpanzee gestural communication is characterised by a mix of predictability and flexibility, with implications for understanding the evolution of complex communication systems.
A Unified Approach for Identifying PET-based Neuronal Activation and Molecular Connectivity with the functional PET toolbox
Authors: Hahn Andreas , Reed Murray B. , Milz Christian , Falb Pia , Murgaš Matej , Lanzenberger Rupert
Published: November 2024

Purpose

Functional PET (fPET) enables the identification of stimulation-specific changes of various physiological processes (e.g., glucose metabolism, neurotransmitter synthesis) as well as computation of individual molecular connectivity and group-level molecular covariance. However, currently no consistent analysis approach is available for these techniques. We present a versatile, freely available toolbox designed for the analysis of fPET data, thereby filling a gap in the assessment of neuroimaging data.

Methods

The fPET toolbox supports analyses for a variety of radiotracers, scanners, experimental protocols, cognitive tasks and species. It includes general linear model (GLM)-based assessment of task-specific effects, percent signal change and absolute quantification, as well as independent component analysis (ICA) for data-driven analyses. Furthermore, it allows computation of molecular connectivity via temporal correlations of PET signals between regions and molecular covariance as between-subject covariance using static images.

Results

Toolbox performance was validated by analysis protocols established in previous work. Stimulation-induced changes in [18F]FDG metabolic demands and neurotransmitter dynamics obtained with 6-[18F]FDOPA and [11C]AMT were robustly detected across different cognitive tasks. Molecular connectivity analysis demonstrated metabolic interactions between different networks, whereas group-level covariance analysis highlighted interhemispheric relationships. These results underscore the flexibility of fPET in capturing dynamic molecular processes.

Conclusions

The toolbox offers a comprehensive, unified and user-friendly platform for analyzing fPET data across a variety of experimental settings. It provides a reproducible analysis approach, which in turn facilitates sharing of analyses pipelines and comparison across centers to advance the study of brain metabolism and neurotransmitter dynamics in health and disease.
A Comparison of Nanopore Data Types, Basecalling, and Assembly Algorithms: Whole Plant Genome Assembly and Methylation Analysis from a Single MinION Flow cell
Authors: Martin Samuel , Heavens Darren , Lan Yuxuan , Peel Ned , Irish Naomi , Horsfield Samuel , Giolai Michael , Clark Matthew D. , Leggett Richard M.
Published: November 2024

Background

Oxford Nanopore Technologies’ MinION sequencer is a compact, USB-powered device that has been available since 2014. Since the release of the earliest model, the throughput and error rate of the platform have improved dramatically and it has become possible to consider sequencing and assembly of eukaryotic organisms using a single nanopore flow cell. Here, we present MinION sequence data, assembly and methylation analysis for the Columbia (Col-0) accession of the model plantArabidopsis thaliana. Further, we demonstrate the effect that recent developments (specifically the Q20+ chemistry and basecaller improvements) have had on read accuracy and assembly quality.

Findings

DNA extracted from leaves ofA. thalianaCol-0 was sequenced on two MinION flow cells, together amounting to 115x coverage of the 135 Mb genome. Reads were assembled and polished using several bioinformatics pipelines for nanopore sequence data. We performed CpG methylation analysis directly from the nanopore data, and this correlated well with a previously published bisulfite dataset.

Conclusions

Our results suggest that a single MinION flow cell can generate sufficient data to assemble a genome of 135Mb, indicate functional elements, and unlock genomics for researchers of novel species from $600 in under 5 days. Here we release the full nanopore read sets for both flow cells, together with the nanopore-only assemblies. The data presented here is expected to be of particular interest to those in theArabidopsiscommunity, designing genome projects (with functional annotations), expanding our understanding of epigenetics across the tree of life, and for designing university or high school practicals teaching genomics and epigenomics.

Highlight

We evaluate the effect of recent nanopore chemistry and software improvements on the ability to assemble a complete genome and conduct methylation analysis using data from a single MinION flow cell.
Spatial Transcriptomic Analysis Identifies aSERPINA3-Expressing Astrocytic State Associated with the Human Neuritic Plaque Microenvironment
Authors: Karaahmet Berke , Zhang Ya , Duquesne Laurine , Sigalov Alina , Yung Christina , Kroshilina Alexandra , Bennett David A. , Taga Mariko , Klein Hans-Ulrich
Published: November 2024

Single-nucleus transcriptomic studies have revealed glial cell states associated with Alzheimer’s disease; however, these nuclei are dissociated from the complex architecture of the human neocortex. Here, we successfully performed an unbiased distance-based analytic strategy on spatially-registered transcriptomic data. Leveraging immunohistochemistry in the same tissue section, our analyses prioritizedSERPINA3and other genes, such as metallothioneins, as altered in the vicinity of neuritic amyloid plaques. Results were validated at the protein level by immunofluorescence, highlighting that a reactive SERPINA3+astrocyte subtype, Ast.5, plays a role in the plaque microenvironment.
An integrative layer-resolved atlas of the adult human meninges
Authors: Degenhard Theresa , Groh Adam M.R. , Afanasiev Elia , Luo Michael , Yaqubi Moein , Stratton Jo Anne , Petrecca Kevin
Published: November 2024

The human meninges are a dynamic tri-layered brain border that plays a key role in brain development, CSF homeostasis, immune regulation, and higher-level brain function. The meninges have also been implicated in central nervous system (CNS) pathologies such as infection, autoimmunity, and brain trauma. To understand how the meningeal microenvironment is altered under pathological conditions it is necessary to have a complete understanding of its normotypic cellular architecture and function. To date, there is no complete atlas of the normotypic adult human meninges. By surgically extracting each human meningeal layer during surgery, we generated the first layer-resolved map of all meningeal cell types via an integration of whole cell single cell RNA sequencing, multiplexed error-robust fluorescencein situhybridization (MERFISH), and protein immunolabelling. Since fibroblasts play key roles in meningeal homeostasis yet remain less well-characterised than other meningeal cell types, we deeply phenotyped these cells in all layers. We identified 10 fibroblast subpopulations with unique predicted functions that localise to distinct neuroanatomical niches. Fibroblast interaction analysis in the dura and subarachnoid space (SAS) uncovered novel interactions with vascular cell populations mediated by insulin growth factor signaling. Together, these data serve as a comprehensive resource for future investigations of meningeal function in the healthy and diseased brain.
Impaired proteasome induces mitochondrial DNA release to activate the cGAS-STING signaling pathway and cause necroptosis in mouse brain
Authors: Dwamena Abena , Asadi Yasin , Gilstrap Erin , Wang Hongmin
Published: November 2024

Impaired proteasome function is consistently associated with many neurodegenerative disorders, including Alzheimer’s disease (AD), showing neuroinflammation and neurodegeneration; however, how impaired proteasome causes neuroinflammation and neuronal death remains less understood. Here, we studied the effect of impaired proteasome on neuroinflammation and neuronal death in a knockout (KO) mouse model with reduced proteasome activity in the brain. We discovered that impaired proteasome led to the release of mitochondrial dsDNA into the cytosol, activating the cGAS-STING signaling pathway, and upregulating pro-inflammatory cytokines in the KO mouse brain relative to the control brain. Importantly, we also observed reduced brain weight, elevation of the mixed lineage kinase domain-like (MLKL) protein, phosphorylated MLKL, and receptor-interactive protein kinases (RIPK) 1 and 3 in the KO mouse brain compared to the control brain, suggesting activation of necroptosis in the KO brains. These data indicate that impaired proteasome activates the cGAS-STING pathway to induce neuroinflammation and neurodegeneration via a necroptotic manner. Our results suggest that neuroinflammation and necroptosis may be generalized factors caused by reduced proteasome activity observed in diverse neurodegenerative disorders.
Structural insights into SSNA1 self-assembly and its microtubule binding for centriole maintenance
Authors: Agostini Lorenzo , Pfister Jason , Basnet Nirakar , Ding Jienyu , Zhang Rui , Biertümpfel Christian , O’Connell Kevin F. , Mizuno Naoko
Published: November 2024

SSNA-1 is a fibrillar protein localized at the area where dynamic microtubule remodeling occurs including centrosomes. Despite the important activities of SSNA1 to microtubules such as nucleation, co-polymerization, and lattice sharing microtubule branching, the underlying molecular mechanism have remained unclear due to a lack of structural information. Here, we determined the cryo-EM structure ofC. elegansSSNA-1 at 4.55 Å resolution and evaluated its role during embryonic development inC. elegans. We found that SSNA1 forms an anti-parallel coiled-coil, and its self-assembly is facilitated by the overhangs of 16 residues at its C-terminus, which dock on the adjacent coiled-coil to form a triple-stranded helical junction. Notably, the microtubule-binding region is within the triple-stranded junction, highlighting that self-assembly of SSNA-1 facilitates effective microtubule interaction by creating hubs along a fibril. Furthermore, our genetical analysis elucidated that deletion of SSNA-1 resulted in a significant reduction in embryonic viability and the formation of multipolar spindles during cell division. Interestingly, when the ability of SSNA-1 self-assembly was impaired, embryonic viability stayed low, comparable to that of the knockout strain. Our study provides molecular insights into the self-assembly mechanisms of SSNA-1, shedding light on its role in controlling microtubule binding and cell division through the regulation of centriole stability.
Fructose-2,6-bisphosphate restores TDP-43 pathology-driven genome repair deficiency in motor neuron diseases
Authors: Chakraborty Anirban , Mitra Joy , Maloji Rao Vikas H. , Kodavati Manohar , Mandal Santi M. , Gill Satkarjeet K. , Sreenivasmurthy Sravan Gopalkrishnashetty , Vasquez Velmarini , Mankevich Mikita , Krishnan Balaji , Ghosh Gourisankar , Hegde Muralidhar L. , Hazra Tapas
Published: November 2024

TAR DNA-binding protein 43 (TDP-43) proteinopathy plays a critical role in neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia (FTD). In our recent discovery, we identified that TDP-43 plays an essential role in DNA double-strand break (DSB) repair via the non-homologous end joining (NHEJ) pathway. Here, we found persistent DNA damage in the brains of ALS/FTD patients, primarily in the transcribed regions of the genome. We further investigated the underlying mechanism and found that polynucleotide kinase 3’-phosphatase (PNKP) activity was severely impaired in the nuclear extracts of both patient brains and TDP-43-depleted cells. PNKP is a key player in DSB repair within the transcribed genome, where its 3’-P termini processing activity is crucial for preventing persistent DNA damage and neuronal death. The inactivation of PNKP in ALS/FTD was due to reduced levels of its interacting partner, phosphofructo-2-kinase fructose 2,6 bisphosphatase (PFKFB3), and its biosynthetic product, fructose-2,6-bisphosphate (F2,6BP), an allosteric modulator of glycolysis. Recent work from our group has shown that F2,6BP acts as a positive modulator of PNKP activityin vivo. Notably, exogenous supplementation with F2,6BP restored PNKP activity in nuclear extracts from ALS/FTD brain samples and patient-derived induced pluripotent stem (iPS) cells harboring pathological mutations. Furthermore, we demonstrate that supplementation of F2,6BP restores genome integrity and partially rescues motor phenotype in aDrosophilamodel of ALS. Our findings underscore the possibility of exploring the therapeutic potential of F2,6BP or its analogs in TDP-43 pathology-associated motor neuron diseases.
Genome content in the non-model ciliateChilodonella uncinata: insights into nuclear architecture, gene-sized chromosomes among the total DNA in their somatic macronuclei during their development
Authors: Ahsan Ragib , Maurer-Alcalá Xyrus X. , Katz Laura A.
Published: November 2024

Ciliates are a model lineage for studies of genome architecture given their unusual genome structures. All ciliates have both somatic macronuclei (MAC) and germline micronuclei (MIC), both of which develop from a zygotic nucleus following sex (i.e., conjugation). Nuclear developmental stages are not as well explored among non-model ciliate genera, includingChilodonella uncinata(Class-Phyllopharyngea), the focus of our work. Here, we characterize nuclear architecture and genome dynamics inC. uncinataby combining DAPI (4′,6-diamidino-2-phenylindole) staining and fluorescencein situhybridization (FISH) techniques with confocal microscopy. We developed a telomere probe for staining alongside DAPI, which allows for the identification of fragmented somatic chromosomes among the total DNA in the nuclei. We quantify both total DNA and telomere-bound signals to explore changes in DNA content and chromosome maturation acrossChilodonella’s nuclear life cycle. Specifically, we find that MAC developmental stages in the ciliateC. uncinataare different than the data reported from other ciliate species. These data provide insights into nuclear dynamics during nuclear development and enrich our understanding of genome evolution in non-model ciliates.
Characterization ofFLOWERING LOCUS Trelated genes and their putative gene regulatory network in semi-winterBrassica napuscultivar Zhongshaung11
Authors: Wang Juanjuan , Zhou Hao-Ran , Wang Jing , Turck Franziska
Published: November 2024

Flowering time is a crucial phenological trait with a direct influence on biomass and seed yield of crop plants. In many plant species,FLOWERING LOCUS T(FT)-like genes promote transition to flowering by integrating environmental signals, in particular photoperiod, and internal cues.

-Brassica napuscontains eightFT-like genes, of which four are orthologs ofFT, one functional and two pseudogenes belong to an Brassicacae linage II-specific and one gene to a Brassica C-genome-specific orthogroup.

- All six extantFT-like genes induce early flowering inftmutant background if expressed at the shoot apex, but only three orthologs are fully functional as mobile florigens.

- BnaFT.C6 was not fully functional al mobile florigen. A change of the last amino-acid from threonine to cysteine contributes to the reduced function and is private to a subset of semi-winter accessions

- Both distal enhancers ofFTwere found at all four syntenic genes inB. napus; however, homeologsBnaFT.A7andBnaFT.C6showed rearrangements of DNA-motifs binding NF-Y/CO and NF-Y transcription activator complexes between the proximal promoter and the downstream enhancer Block E.

- Homeologs with rearranged motifs could not be trans-activated byB. napusCO in transient reporter assays

- AllFTorthologs were dependent on long day photoperiod and vernalization. Homeologs with rearranged and canonical motif arrangement showed higher transcript levels in vegetative and paraclade leaves, respectively

- Diurnal transcriptome data of leaves fromB. napusplants grown in SD and LD photoperiod indicate that a large group of NF-Y encoding genes show a peak of expression in the critical phase between ZT12 and ZT16, exclusively in LD.

In sum,B. napusphotoperiod dependent regulation ofFT-like genes is a case study for the consequence of gene duplications, indicating gene retraction through loss-of-function, homeolog retention partially explained by differences transcriptional regulation and possibly variation between cultivated varieties due to changes in protein function.
Interictal spikes during spatial working memory carry helpful or distracting representations of space and have opposing impacts on performance
Authors: Yi Justin D. , Pasdarnavab Maryam , Kueck Laura , Tarcsay Gergely , Ewell Laura A.
Published: November 2024

In temporal lobe epilepsy, interictal spikes (IS) – hypersynchronous bursts of network activity – occur at high rates in between seizures. We sought to understand the influence of IS on working memory by recording hippocampal local field potentials from epileptic mice while they performed a delayed alternation task. We found that IS disrupted performance when they were spatially non-restricted and occurred during running. In contrast, when IS were clustered at reward locations, animals performed well. A machine learning decoding approach revealed that IS at reward sites were larger than IS elsewhere on the maze, and could be classified as occurring at specific reward locations – suggesting they carry informative content for the memory task. Finally, a spiking model revealed that spatially clustered IS preserved hippocampal replay, while spatially dispersed IS disrupted replay by causing over-generalization. Together, these results show that IS can have opposing outcomes on memory.
Curcumin attenuates microglia-mediated chronic neuropathic pain through CDK5 /p35 signaling pathway
Authors: Tong Fei , Zhao li , Yang Yue , Zhang ZhuoYue , Liu Lu , Wu YaXuan , Di XuanYi , Zhang ZiWen , Xu XiaoXia , Zhang YuanLi , Shen Yue , Yu liang , Zhang lei , Yao YongXing , Zhang HongHai
Published: November 2024

Curcumin is a phenolic compound derived from turmeric, one of the main ingredients of curry powder, which is widely used for its antioxidant, anti-inflammatory and immunomodulatory effects. Curcumin has been reported to help relieve pain, such as neuropathic pain caused by injury or disease, but the specific mechanism of its antinociceptive effect on pathological pain is unclear. Cyclin-dependent kinase 5 (Cdk5) is a key control point for the release of neurotransmitters from presynaptic vesicles. Cdk5 and its activator p35 couple to regulate key signaling cascades, thereby participating in the pain process. In this study, we established a NP model by chronic constriction injury (CCI) of the bilateral sciatic nerve in rats and evaluated behavioral hyperalgesia using mechanical and hot and cold tests. Protein expression and distribution were evaluated using western blotting and immunofluorescence. The results showed that Iba-1 and Cdk5/p35 were co-localized in the dorsal horn and dorsal root ganglia, respectively. After CCI, the expression of Cdk5 and p35 was upregulated in the dorsal horn and dorsal root ganglia, while intraperitoneal injection of curcumin significantly reversed the activation of Cdk5/p35 protein and alleviated the hyperalgesia in rats. In addition, the injection of curcumin reduced the co-localization expression of Iba-1 and Cdk5/p35, indicating that curcumin inhibited the activation of Cdk5/p35 protein in the dorsal horn and dorsal root ganglia, thereby affecting the activation of microglia, thereby having a destructive effect on the neuronal cell plasticity and synaptic structure remodeling in the development of NP. Our study provides new evidence that Cdk5/p35 in the dorsal horn and dorsal root ganglia is related to the occurrence of NP, introduces microglia as the basis for the long-term maintenance of NP, and provides insights into the molecular mechanisms involved in the analgesic effect of curcumin.

Graphical Abstract
Pathological microcircuits initiate epileptiform events in patient hippocampal slices
Authors: Elliott Matthew A.T. , Andrews John P. , van der Molen Tjitse , Geng Jinghui , Spaeth Alex , Voituik Kateryna , Core Cordero , Gillespie Thomas , Sinervo Ari , Parks David F. , Robbins Ash , Solís Daniel , Chang Edward F. , Nowakowski Tomasz Jan , Teodorescu Mircea , Haussler David , Sharf Tal
Published: November 2024

How seizures begin at the level of microscopic neural circuits remains unknown. High-density CMOS microelectrode arrays provide a new avenue for investigating neuronal network activity, with unprecedented spatial and temporal resolution. We use high-density CMOS-based microelectrode arrays to probe the network activity of human hippocampal brain slices from six patients with mesial temporal lobe epilepsy in the presence of hyperactivity promoting media. Two slices from the dentate gyrus exhibited epileptiform activity in the presence of low magnesium media with kainic acid. Both slices displayed an electrophysiological phenotype consistent with a reciprocally connected circuit, suggesting a recurrent feedback loop is a key driver of epileptiform onset. Larger prospective studies are needed, but these findings have the potential to elucidate the network signals underlying the initiation of seizure behavior.
Evolutionary consequences of domestication on the selective effects of new amino acid changing mutations in canids
Authors: Amorim Carlos Eduardo G. , Di Chenlu , Lin Meixi , Marsden Clare , Del Carpio Christina A. , Mah Jonathan C. , Robinson Jacqueline , Kim Bernard Y. , Mooney Jazlyn A. , Cornejo Omar E. , Lohmueller Kirk E.
Published: November 2024

The domestication of wild canids led to dogs no longer living in the wild but instead residing alongside humans. Extreme changes in behavior and diet associated with domestication may have led to the relaxation of the selective pressure on traits that may be less important in the domesticated context. Thus, here we hypothesize that strongly deleterious mutations may have become less deleterious in domesticated populations. We test this hypothesis by estimating the distribution of fitness effects (DFE) for new amino acid changing mutations using whole-genome sequence data from 24 gray wolves and 61 breed dogs. We find that the DFE is strikingly similar across canids, with 26-28% of new amino acid changing mutations being neutral/nearly neutral (|s|< 1e-5), and 41-48% under strong purifying selection (|s|> 1e-2). Our results are robust to different model assumptions suggesting that the DFE is stable across short evolutionary timescales, even in the face of putative drastic changes in the selective pressure caused by artificial selection during domestication and breed formation. On par with previous works describing DFE evolution, our data indicate that the DFE of amino acid changing mutations depends more strongly on genome structure and organismal characteristics, and less so on shifting selective pressures or environmental factors. Given the constant DFE and previous data showing that genetic variants that differentiate wolf and dog populations are enriched in regulatory elements, we speculate that domestication may have had a larger impact on regulatory variation than on amino acid changing mutations.

Significance Statement

Domestication of dogs to live alongside humans resulted in a dramatic shift in the pressures of natural selection. Thus, comparing dogs and wolves offers a unique opportunity to assess how these shifts in selective pressures have impacted the fitness effects of individual mutations. In this project, we use patterns of genetic variation in dogs and wolves to estimate the distribution of fitness effects (DFE), or the proportions of amino acid changing mutations with varying fitness effects throughout the genome. Overall, we find that the DFE for amino acid changing mutations is similar between dogs and wolves. Even genes thought to be most affected by domestication show a similar DFE, suggesting that the DFE has remained stable over evolutionary time.
Peripheral CGRP engages brain-wide electrical network activity of migraine
Authors: Johnson Micah , Eberle Maureen , Hultman Ian , Zhang Xinyu , Filali Yassine , Hing Benjamin , Jimenez Alli , Matkovich Molly , Mitchell Sara , Adegboyo Anjayooluwa , Velamuri Radha , Miller Julia , Chan Kung-Sik , Srivastava Sanvesh , Hultman Rainbo
Published: November 2024

Migraine is a disorder consisting of severe, recurrent headaches and debilitating sensory symptoms which often include affective symptoms or comorbidities such as depression, anxiety, and irritability. As such, migraine is a complex nervous system disorder that involves integration of many modalities across the brain. This makes migraine a complex systems neuroscience problem represented by the confluence of sensory, pain, cognitive, autonomic, and affect-related circuits. Thus, it is essential to understand how neuronal activity across various brain regions implicated in migraine is coordinated during migraine pathophysiology. Using a calcitonin gene-related peptide (CGRP) mouse model of migraine, we probed neural oscillatory activity in the anterior cingulate cortex, amygdala (BLA and CeA), thalamus (Po, VPM, and MDthal), and parabrachial nucleus following peripheral administration of CGRP. We identified three frequency bands in which directional signals occur in this network and found that power in these frequencies across the network was lower than vehicle within 10 minutes of peripheral CGRP exposure, which was sustained for (∼40-50 min). Coherence, on the other hand, was mostly disrupted in CeA brain region pairings, and took on a shorter timecourse. Sumatriptan partially blunted or reversed these CGRP-induced network responses, especially with regard to amygdala power and coherence pairings. Early life stress, which has been shown to increase the likelihood of migraine in adulthood in humans, exacerbated CGRP-induced migraine-related behavioral phenotypes and induced corresponding network changes in LFP power in the CeA and Po and coherence in Po-related pairings. Clustering based on a changepoint analysis of coherence identified individual mice hypersusceptible to migraine. Overall, our findings demonstrate coordinated brain-wide network activity by which migraine is mediated in the brain in response to peripheral CGRP.
High plasticity increases phenotype-environment mismatch leading to sub-optimal performance in underutilized crop species
Authors: Alagarasan Ganesh , Arnold Pieter A. , Ramireddy Eswarayya
Published: November 2024

As climate change threatens agricultural yields, crop diversification, including the reintroduction of underutilized species, has emerged as a proposed solution for resilience. But what determines the extent of environmental change that underutilized crop species can cope with upon their reintroduction? One critical factor is maladaptive plasticity, a theoretical concept suggesting that populations may respond negatively to rapid environmental shifts, at least in the short term. To test this empirically, we conducted a repeated-measures study using historically underutilizedAmaranthusspecies as a model. Upon reintroduction, we observed higher plasticity in vegetative and reproductive traits than in life-history traits. This suggests that while these species adapt to immediate environmental changes through adjustments in growth and reproduction, limited plasticity in life-history traits may constrain long-term adaptation. Our study aimed to (1) identify the environmental factors driving these plastic responses, (2) determine whether these responses are maladaptive, and (3) assess if maladaptive plasticity also occurs within native environments. Using machine learning models, we found that temperature was a primary driver of plastic responses. Generalized Additive Model (GAM) reaction norm analysis further revealed these temperature-induced responses to be maladaptive, suggesting a mismatch betweenAmaranthus’ traits and the new environment. Applying transfer learning to predict responses in native settings, we found similar maladaptive responses to temperature, indicating that maladaptive plasticity may not be limited to non-native environments, thereby complicating climate adaptation efforts. This study underscore the need for detailed trait plasticity assessments before crop reintroduction for agricultural resilience.
Ribosome abundance, not paralogue composition, is essential for germline development
Authors: Grobicki Katarina Z A , Gebert Daniel , Sun Carol , Teixeira Felipe Karam
Published: November 2024

Ribosomes catalyse all protein synthesis, and mutations altering their levels and function underlie many developmental diseases and cancer. Historically considered to be invariant machines, ribosomes differ in composition between tissues and developmental stages, incorporating a diversity of ribosomal proteins (RP) encoded by duplicated paralogous genes. Here, we useDrosophilato systematically investigate the origins and functions of non-canonical RP paralogues. We show that new paralogues mainly originated through retroposition, and that only a few new copies retain coding capacity over time. Although transcriptionally active non-canonical RP paralogues often present tissue-specific expression, we show that the majority of those are not required for either viability or fertility inDrosophila melanogaster. The only exception, RpS5b, which is required for oogenesis, is functionally interchangeable with its canonical paralogue, indicating that theRpS5b-/-phenotype results from insufficient ribosomes rather than the absence of an RpS5b-specific, functionally-specialised ribosome. Altogether our results provide evidence that, instead of new functions, RP gene duplications provide a means to regulate ribosome levels during development.
A multi-tissue developmental gene expression atlas towards understanding the biological basis of phenotypes in sheep
Authors: Zhao Bingru , Luo Hanpeng , Fu Xuefeng , Zhang Guoming , Clark Emily L. , Wang Feng , Dalrymple Brian Paul , Oddy V. Hutton , Vercoe Philip E. , Wu Cuiling , Liu George E. , Li Cong-jun , Xiang Ruidong , Tian Kechuan , Zhang Yanli , Fang Lingzhao
Published: November 2024

Sheep (Ovis aries) represents one of the most important livestock species for animal protein and wool production worldwide. However, little is known about the genetic and biological basis of ovine phenotypes, particularly for those of high economic value and environmental impact. Here, by generating and integrating 1,413 RNA-seq samples from 51 distinct tissues across 14 developmental time points, representing early prenatal, late prenatal, neonate, lamb, juvenile, adult, and elderly stages, we built a high-resolution developmental Gene Expression Atlas (dGEA) in sheep. We observed dynamic patterns of gene expression and regulatory networks across tissues and developmental stages. When harnessing this resource for interpreting genomic associations of 48 monogenetic and 12 complex traits in sheep, we found that genes upregulated at prenatal developmental stages played more important roles in shaping these phenotypes than those upregulated at postnatal stages. For instance, genetic associations of crimp number, mean staple length (MSL), and individual birth weight were significantly enriched in the prenatal rather than postnatal skin and immune tissues. By comprehensively integrating fine-mapping results and the sheep dGEA, we identified several key genes associated with complex traits in sheep, such as SOX9 (associated with MSL), GNRHR (associated with litter size at birth), and PRKDC (associated with live weight). These results provide novel insights into the gene regulatory and developmental architecture underlying ovine phenotypes. The dGEA (https://sheepdgea.njau.edu.cn/) will serve as an invaluable resource for sheep developmental biology, genetics, genomics, and selective breeding.
Biofilm Formation and Niche Adaptation Play Fundamental Role in Shaping Long-Distance Transported Dust Microbial Community
Authors: Lang-Yona Naama , Levy Barazany Hilit , Salti Talal , Ben Navi Rahamim , Rahamin Ben-Navi Liat , Kolodkin-Gal Ilana
Published: November 2024

The long-distance transport of microorganisms via dust events is expected to become more prominent and intensified. At the same time, the survival mechanisms of air/dust-borne bacteria and their possible contribution to global processes remain poorly understood. In this study, we characterizedBacillusspecies from transitional season dust storms, previously identified as a significant component of the bioactive community of the dust microbiome. Our results demonstrated substantial growth and biofilm formation diversification, potentially linked to niche adaptation and surface-associated biofilm formation within heterogeneous dust particles. Most dust isolates form biofilms while exhibiting different preferences for media composition. Sterile dust induced biofilm formation, growth, matrix gene expression ofB. subtilis, and robust biofilms in key related dust isolates. Overall, our results highlight the significance of biofilm formation as an adaptive mechanism in the distinct habitat of dust storms, with niche adaptation potentially playing a role in microenvironments within the dust particle. These results hold significant potential for implications on terrestrial and aquatic ecology and health, suggesting a pivotal process by which bacteria survive and evolve in this understudied habitat.
Recurrent Inhibitory Dynamics in the Entorhinal Cortex Support Pattern Separation
Authors: Zheng Yicong , Antony James , Ranganath Charan , O’Reilly Randall C.
Published: November 2024

The entorhinal cortex (EC) provides the major input to the hippocampus (HPC). Numerous computational models on the EC propose that its grid cells serve as a spatial metric, supporting path integration and efficient generalization. However, little is known about how these cells could contribute to episodic memory, which emphasizes episode-specific representations that align with pattern separation. Taking into consideration anatomical specifications of EC inputs to the HPC and computational principles underlying the EC-HPC memory system, we argue that EC layer IIa (EC2a) supports pattern separation and EC layer IIb/III (EC2b/3) supports generalization. Utilizing recurrent inhibition and the nature of single EC2a neurons binding converging inputs from the neocortex (i.e., conjunctive coding), we built a biologically-based neural network model of the EC-HPC system for episodic memory. By examining how EC2a transformed its cortical inputs and output them to the trisynaptic pathway (EC2a - Dentate Gyrus - CA3 - CA1), we found that instead of systematically generalizing across similar inputs, recurrent inhibition and conjunctive coding in EC2a neurons support strong pattern separation and increase mnemonic discrimination. Furthermore, lesioning EC2a neurons in the model resembled memory impairments found in people with Alzheimer’s Disease, suggesting an intertwined relationship between memory and the majority of pure grid cells in the EC. On the other hand, the topographically organized monosynaptic pathway (EC2b/3 - CA1) is computationally more suitable for efficient factorization and generalization. This model provides novel anatomically-based predictions regarding the computational roles of EC cells in pattern separation and generalization, which together form a critical computational framework for both episodic memory and spatial navigation.
Modeling of blood flow dynamics in the rat somatosensory cortex
Authors: Battini Stéphanie , Cantarutti Nicola , Kotsalos Christos , Roussel Yann , Cattabiani Alessandro , Arnaudon Alexis , Favreau Cyrille , Antonel Stefano , Markram Henry , Keller Daniel
Published: November 2024

The cerebral microvasculature forms a dense network of interconnected blood vessels where flow is modulated partly by astrocytes. Increased neuronal activity stimulates astrocytes to release vasoactive substances at the endfeet, altering the diameters of connected vessels. Our study simulated the coupling between blood flow variations and vessel diameter changes driven by astrocytic activity in the rat somatosensory cortex. We developed a framework with three key components: coupling between vasculature and synthesized astrocytic morphologies, a fluid dynamics model to compute flow in each vascular segment, and a stochastic process replicating the effect of astrocytic endfeet on vessel radii. The model was validated against experimental flow values from literature across cortical depths. We found that local vasodilation from astrocyte activity increased blood flow, especially in capillaries, exhibiting a layer-specific response in deeper cortical layers. Additionally, the highest blood flow variability occurred in capillaries, emphasizing their role in cerebral perfusion regulation. We discovered that astrocytic activity impacts blood flow dynamics in a localized, clustered manner, with most vascular segments influenced by two to three neighboring endfeet. These insights enhance our understanding of neurovascular coupling and guide future research on blood flow-related diseases.