bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic control of axon regeneration and functional recovery bylet-7miRNA and Insulin signalling (IIs) pathways
Authors: Ravivarma Sruthy , Behera Sibaram , Roy Dipanjan , Ghosh-Roy Anindya 
Published: August 2024

AbstractThe capability of neurons to regenerate after injury becomes poor in adulthood. Previous studies indicated that loss of eitherlet-7miRNA or components of Insulin signalling (IIs) can overcome the age-related decline in axon regeneration inC. elegans. In this study, we wanted to understand the relationship between these two pathways in axon regeneration. We found that the simultaneous removal oflet-7and the gene for insulin receptordaf-2synergistically increased the functional recovery involving posterior touch sensation following axotomy of PLM neuron in adulthood. Conversely, the loss oflet-7could bypass the regeneration block due to the loss of DAF-16, a transcriptional target of DAF-2. Similarly, the loss ofdaf-2could bypass the requirement of LIN-41, a transcriptional co-factor of thelet-7pathway. Our analysis revealed that these two pathways synergistically control targeting of the regenerating axon to the ventral nerve cord, which leads to functional recovery. The computational analysis of the gene expression data revealed a large number of genes, their interacting modules, and hub genes underlet-7andIIspathway are exclusive in nature. Our study highlights a potential to promote neurite regeneration by harnessing the independent gene expression program involving thelet-7and Insulin signalling pathways.
Computational model for synthesizing auditory brainstem responses to assess neuronal alterations in aging and autistic animal models
Authors: Li Ben-Zheng , Poleg Shani , Ridenour Matthew , Tollin Daniel , Lei Tim , Klug Achim 
Published: August 2024

AbstractThe auditory brainstem response (ABR) is a widely used objective electrophysiology measure for non-invasively assessing auditory function and neural activities in the auditory brainstem, but its ability to reflect detailed neuronal processes is limited due to the averaging nature of the electroencephalogram recordings. This study addresses this limitation by developing a computational model of the auditory brainstem which is capable of synthesizing ABR traces based on a large, population scale neural extrapolation of a spiking neuronal network of auditory brainstem neural circuitry. The model was able to recapitulate alterations in ABR waveform morphology that have been shown to be present in two medical conditions: animal models of autism and aging. Moreover, in both of these conditions, these ABR alterations are caused by known distinct changes in auditory brainstem physiology, and the model could recapitulate these changes. In the autism model, the simulation revealed myelin deficits and hyperexcitability, which caused a decreased wave III amplitude and a prolonged wave III-V interval, consistent with experimentally recorded ABRs in Fmr1-KO mice. In the aging model, the model recapitulated ABRs recorded in aged gerbils and indicated a reduction in activity in the medial nucleus of the trapezoid body (MNTB), a finding validated by confocal imaging data. These results demonstrate not only the model’s accuracy but also its capability of linking features of ABR morphologies to underlying neuronal properties and suggesting follow-up physiological experiments.Significance StatementThis study presents a novel computational model of the auditory brainstem, capable of synthesizing auditory brainstem response (ABR) traces by simulating large-scale neuronal activities. Addressing limitations of traditional ABR measurements, the model links ABR waveform features to underlying neuronal properties. Validated using empirical ABRs from animal models of autism and aging, the model accurately reproduced observed ABR alterations, revealing influences of myelin deficits and hyperexcitability in Fragile X syndrome, and degraded inhibitory activity in aging. These findings, supported by experimental data, demonstrate the model’s potential for predicting changes in auditory brainstem physiology and guiding further physiological investigations, thus advancing our understanding of auditory neural processes.
Transocular detection of premotor Parkinson’s disease via retinal capillary neurovascular coupling through functional OCT angiography
Authors: Liu Kaiyuan , Wang Ruixue , Huang Longqian , Zhang Huiying , Gao Mengqin , Sun Bin , Tan Yizhou , Ye Juan , Ding Zhihua , Gu Ying , Zhang Shaomin , Li Peng 
Published: August 2024

AbstractEarly detection of Parkinson’s disease (PD) is essential for timely initiating neuroprotective interventions before significant loss of dopaminergic (DAergic) neurons, but faces challenges in accurately and noninvasively detecting subtle neuronal changes in the midbrain. Here, we propose a transocular functional imaging method termed fOCTA-rNVC, which detects premotor PD by measuring alterations in retinal neurovascular coupling (rNVC) at the capillary level using specialized functional OCT angiography (fOCTA). Our findings demonstrate that capillary rNVC is significantly attenuated and delayed due to concurrent retinal dopaminergic degeneration in premotor PD mice. Notably, this PD-related rNVC attenuation can be temporarily reversed in acute levodopa challenge. Utilizing the functional characteristics of capillary rNVC in PD, we achieved an impressive accuracy of ∼100% in detecting premotor PD mice even with only ∼14.1% loss of midbrain DAergic neurons, at which stage prompt treatment offered superior outcomes. In contrast, no significant changes were observed in retinal thickness or vasculature in the premotor PD mice. These findings suggest that fOCTA-rNVC is a promising noninvasive solution for accurately detecting premotor PD and guiding early interventions.
Sound preferences in mice are sex-dependent
Authors: Sehrawat Kamini , Nelken Israel 
Published: August 2024

AbstractWe investigated the impact of early exposure to sound and to silence on sound preferences later in life in mice. We exposed young mice during the critical periods to excerpts of music (first movement of Beethoven’s symphony no. 9), non-music sounds, or to silence. We tested the sound preference behavior a few weeks later. Music exposure affected mouse behavior in a sex- dependent manner: male mice largely preferred the environment to which they were exposed, while female mice showed a weak reduction in their seemingly inborn aversion to sound. The neural activity in auditory cortex was suppressed in exposed compared to naive mice, regardless of exposure type. Remarkably, a robust negative correlation was found between neural response and behavior in female, but not in male, mice.
Get to know your neighbors with a SNAQTM: A framework for single cell spatial neighborhood analysis in immunohistochemical images
Authors: Silver Aryeh , Chakraborty Avirup , Pittu Avinash , Feier Diana , Anica Miruna , West Illeana , Sarkisian Matthew R. , Deleyrolle Loic P. 
Published: August 2024

AbstractMotivationAnalyzing the local microenvironment of tumor cells can provide significant insights into their complex interactions with their cellular surroundings, including immune cells. By quantifying the prevalence and distances of certain immune cells in the vicinity of tumor cells through a neighborhood analysis, patterns may emerge that indicate specific associations between cell populations. Such analyses can reveal important aspects of tumor-immune dynamics, which may inform therapeutic strategies. This method enables an in-depth exploration of spatial interactions among different cell types, which is crucial for research in oncology, immunology, and developmental biology.ResultsWe introduce an R Markdown script called SNAQTM(Single-cell SpatialNeighborhoodAnalysis andQuantification), which conducts a neighborhood analysis on immunofluorescent images without the need for extensive coding knowledge. As a demonstration, SNAQTMwas used to analyze images of pancreatic ductal adenocarcinoma. Samples stained for DAPI, PanCK, CD68, and PD-L1 were segmented and classified using QuPath. The resulting CSV files were exported into RStudio for further analysis and visualization using SNAQTM. Visualizations include plots revealing the cellular composition of neighborhoods around multiple cell types within a customizable radius. Additionally, the analysis includes measuring the distances between cells of certain types relative to others across multiple regions of interest.Availability and implementationThe R Markdown files that comprise the SNAQTMalgorithm and the input data from this paper are freely available on the web athttps://github.com/AryehSilver1/SNAQ.Visual AbstractCreated with BioRender.com.
Standardising a microbiome pipeline for body fluid identification from complex crime scene stains
Authors: Swayambhu Meghna , Gysi Mario , Haas Cordula , Schuh Larissa , Walser Larissa , Javanmard Fardin , Flury Tamara , Ahannach Sarah , Lebeer Sarah , Hanssen Eirik , Snipen Lars , Bokulich Nicholas , Kümmerli Rolf , Arora Natasha 
Published: August 2024

AbstractBackgroundRecent advances in next-generation sequencing have opened up new possibilities for utilizing the human microbiome in various fields, including forensics. Researchers have capitalized on the site-specific microbial communities found in different parts of the body to identify body fluids from biological evidence. Despite promising results, microbiome-based methods have not yet been fully integrated into forensic practice due to the lack of standardized protocols and systematic testing of methods on forensically relevant samples. Our study addresses critical decisions in establishing these protocols, focusing on bioinformatics choices and the use of machine learning to present microbiome results in court for forensically relevant and challenging samples.ResultsWe propose using Operational Taxonomic Units (OTUs) for read data processing and creating heterogeneous training datasets for training a random forest classifier. Our classifier incorporates six forensically relevant classes: saliva, semen, hand skin, penile skin, urine, and vaginal/menstrual fluid. Across these classes, our classifier achieved a high weighted average F1 score of 0.89. Systematic testing on mixed-source samples and underwear revealed reliable detection of at least one component of the mixture and the identification of vaginal fluid from underwear substrates. Additionally, when investigating the sexually shared microbiome (sexome) of heterosexual couples, our classifier shows promising results for the inference of sexual activity.ConclusionIn our study, we recommend the use of a novel random forest classifier trained on a heterogenous dataset for obtaining predictions from samples mimicking forensic evidence. We also highlight the potential of the sexome for assessing the nature of sexual activities in forensic investigations, while delineating areas that warrant further research. Furthermore, we underscore key considerations when presenting machine learning results for classifying mixed-source samples.
A familial, telomere-to-telomere reference for humande novomutation and recombination from a four-generation pedigree
Authors: Porubsky David , Dashnow Harriet , Sasani Thomas A. , Logsdon Glennis A. , Hallast Pille , Noyes Michelle D. , Kronenberg Zev N. , Mokveld Tom , Koundinya Nidhi , Nolan Cillian , Steely Cody J. , Guarracino Andrea , Dolzhenko Egor , Harvey William T. , Rowell William J. , Grigorev Kirill , Nicholas Thomas J. , Oshima Keisuke K. , Lin Jiadong , Ebert Peter , Watkins W. Scott , Leung Tiffany Y. , Hanlon Vincent C.T. , McGee Sean , Pedersen Brent S. , Goldberg Michael E. , Happ Hannah C. , Jeong Hyeonsoo , Munson Katherine M. , Hoekzema Kendra , Chan Daniel D. , Wang Yanni , Knuth Jordan , Garcia Gage H. , Fanslow Cairbre , Lambert Christine , Lee Charles , Smith Joshua D. , Levy Shawn , Mason Christopher E. , Garrison Erik , Lansdorp Peter M. , Neklason Deborah W. , Jorde Lynn B. , Quinlan Aaron R. , Eberle Michael A. , Eichler Evan E. 
Published: August 2024

ABSTRACTUsing five complementary short- and long-read sequencing technologies, we phased and assembled >95% of each diploid human genome in a four-generation, 28-member family (CEPH 1463) allowing us to systematically assessde novomutations (DNMs) and recombination. From this family, we estimate an average of 192 DNMs per generation, including 75.5de novosingle-nucleotide variants (SNVs), 7.4 non-tandem repeat indels, 79.6de novoindels or structural variants (SVs) originating from tandem repeats, 7.7 centromericde novoSVs and SNVs, and 12.4de novoY chromosome events per generation. STRs and VNTRs are the most mutable with 32 loci exhibiting recurrent mutation through the generations. We accurately assemble 288 centromeres and six Y chromosomes across the generations, documentingde novoSVs, and demonstrate that the DNM rate varies by an order of magnitude depending on repeat content, length, and sequence identity. We show a strong paternal bias (75-81%) for all forms of germline DNM, yet we estimate that 17% ofde novoSNVs are postzygotic in origin with no paternal bias. We place all this variation in the context of a high-resolution recombination map (∼3.5 kbp breakpoint resolution). We observe a strong maternal recombination bias (1.36 maternal:paternal ratio) with a consistent reduction in the number of crossovers with increasing paternal (r=0.85) and maternal (r=0.65) age. However, we observe no correlation between meiotic crossover locations andde novoSVs, arguing against non-allelic homologous recombination as a predominant mechanism. The use of multiple orthogonal technologies, near-telomere-to-telomere phased genome assemblies, and a multi-generation family to assess transmission has created the most comprehensive, publicly available “truth set” of all classes of genomic variants. The resource can be used to test and benchmark new algorithms and technologies to understand the most fundamental processes underlying human genetic variation.
Discovery of the first-efficacious A2AR negative allosteric modulators for high adenosine cancer immunotherapies
Authors: Boujut Margot , Héritier Margaux , Gouiller Aurélie , Süess Camille , Scapozza Alessandro , Smedt Thibaut De , Guibert Maxime , Tardy Sébastien , Hamed Hesham , Pejoski David , Scapozza Leonardo 
Published: August 2024

AbstractInhibition of adenosine 2A receptor (A2AR) is recognized as a promising immunotherapeutic strategy but is challenged by the ubiquity of A2AR function in the immune system. To develop a safe yet efficacious immunotherapy, the discovery of a novel negative allosteric modulator (NAM) was preferred. Leveraging an in-house, sensitive, high-throughput screening cellular assay, novel A2AR NAM scaffolds were identified followed by an extensive structure-activity relationship (SAR) study, leading to the discovery of potent 2-amino-3,5-dicyanopyridine derivatives. Allosteric mode of action of active compounds was confirmed by shift assay, non-linearity of the Schild plot analysis, biophysical measurements, and retained satisfactory potencies in high-adenosine concentrations. Further correlation of A2AR engagement and downstream signaling was done in a human blood translational assay, clearly showcasing the potential of A2AR allosteric modulation as a novel approach for efficient and safer cancer immunotherapies.
Arsenic impairsDrosophilaneural stem cell mitotic progression and sleep behavior in a tauopathy model
Authors: Adebambo Temitope H. , Flores Ma. Fernanda Medina , Zhang Shirley L. , Lerit Dorothy A. 
Published: August 2024

AbstractDespite established exposure limits, arsenic remains the most significant environmental risk factor detrimental to human health and is associated with carcinogenesis and neurotoxicity. Arsenic compromises neurodevelopment, and it is associated with peripheral neuropathy in adults. Exposure to heavy metals, such as arsenic, may also increase the risk of neurodegenerative disorders. Nevertheless, the molecular mechanisms underlying arsenic- induced neurotoxicity remain poorly understood. Elucidating how arsenic contributes to neurotoxicity may mitigate some of the risks associated with chronic sublethal exposure and inform future interventions. In this study, we examine the effects of arsenic exposure onDrosophilalarval neurodevelopment and adult neurologic function. Consistent with prior work, we identify significant developmental delays and heightened mortality in response to arsenic. Within the developing larval brain, we identify a dose-dependent increase in brain volume. This aberrant brain growth is coupled with impaired mitotic progression of the neural stem cells (NSCs), progenitors of the neurons and glia of the central nervous system. Live imaging of cycling NSCs reveals significant delays in cell cycle progression upon arsenic treatment, leading to genomic instability. In adults, chronic arsenic exposure reduces neurologic function, such as locomotion. Finally, we show arsenic selectively impairs circadian rhythms in a humanized tauopathy model. These findings inform mechanisms of arsenic neurotoxicity and reveal sex- specific and genetic vulnerabilities to sublethal exposure.
CellClear: Enhancing Single-cell RNA Data Quality via Biologically-Informed Ambient RNA Correction
Authors: Huang Wanxiang , Hu LongFei , Qian Zhengzong , Fan Jue 
Published: August 2024

AbstractAmbient RNA, caused by the pool of mRNA molecules released from lysed or dead cells in samples, poses persistent challenges to single-cell RNA sequencing data analysis, and leads to potential problems such as inaccurate classification of cell types and downstream functional analyses. Here we propose CellClear to estimate and remove the ambient RNA expression programs in single-cell RNA sequencing data. CellClear demonstrates significant increase in the accuracy of ambient gene expression correction comparing with state-of-art methods, without distorting native information of individual cell types.
Neural Processing of Taste-Related Signals in the Mediodorsal Thalamus of Mice
Authors: Odegaard Katherine E. , Bouaichi Cecilia G. , Owanga Greg , Vincis Roberto 
Published: August 2024

AbstractOur consummatory decisions depend on the taste of food and the reward experienced while eating, which are processed through neural computations in interconnected brain areas. Although many gustatory regions of rodents have been explored, the mediodorsal nucleus of the thalamus (MD) remains understudied. The MD, a multimodal brain area connected with gustatory centers, is often studied for its role in processing associative and cognitive information and has been shown to represent intraorally-delivered chemosensory stimuli after strong retronasal odor-taste associations. Key questions remain about whether MD neurons can process taste quality independently of odor-taste associations and how they represent extraoral signals predicting rewarding and aversive gustatory outcomes. Here, using C57 male and female mice we present electrophysiological evidence demonstrating how MD neurons represent and encode 1) the identity and concentrations of basic taste qualities during active licking, and 2) auditory signals anticipating rewarding and aversive taste outcomes. Our data reveal that MD neurons can reliably and dynamically encode taste identity in a broadly tuned manner and taste concentrations with spiking activity positively and negatively correlated with stimulus intensity. Our data also show that MD can represent information related to predictive cues and their associated outcomes, regardless of whether the cue predicts a rewarding or aversive outcome. In summary, our findings suggest that the mediodorsal thalamus is integral to the taste pathway, as it can encode sensory-discriminative dimensions of tastants and participate in processing associative information essential for ingestive behaviors.
Genome-Wide Association Study and transcriptome analysis reveals a complex gene network that regulates opsin gene expression and cell fate determination inDrosophilaR7 photoreceptor cells
Authors: Aldrich John C. , Vanderlinden Lauren A. , Jacobsen Thomas L. , Wood Cheyret , Saba Laura M. , Britt Steven G. 
Published: August 2024

AbstractBackgroundAn animal’s ability to discriminate between differing wavelengths of light (i.e., color vision) is mediated, in part, by a subset of photoreceptor cells that express opsins with distinct absorption spectra. InDrosophilaR7 photoreceptors, expression of the rhodopsin molecules, Rh3 or Rh4, is determined by a stochastic process mediated by the transcription factorspineless. The goal of this study was to identify additional factors that regulate R7 cell fate and opsin choice using a Genome Wide Association Study (GWAS) paired with transcriptome analysis via RNA-Seq.ResultsWe examined Rh3 and Rh4 expression in a subset of fully-sequenced inbred strains from theDrosophilaGenetic Reference Panel and performed a GWAS to identify 42 naturally-occurring polymorphisms—in proximity to 28 candidate genes—that significantly influence R7 opsin expression. Network analysis revealed multiple potential interactions between the associated candidate genes,spinelessand its partners. GWAS candidates were further validated in a secondary RNAi screen which identified 12 lines that significantly reduce the proportion of Rh3 expressing R7 photoreceptors. Finally, using RNA-Seq, we demonstrated that all but four of the GWAS candidates are expressed in the pupal retina at a critical developmental time point and that five are among the 917 differentially expressed genes insevenlessmutants, which lack R7 cells.ConclusionsCollectively, these results suggest that the relatively simple, binary cell fate decision underlying R7 opsin expression is modulated by a larger, more complex network of regulatory factors. Of particular interest are a subset of candidate genes with previously characterized neuronal functions including neurogenesis, neurodegeneration, photoreceptor development, axon growth and guidance, synaptogenesis, and synaptic function.
Th1 polarization inBordetella pertussisvaccine responses is maintained through a positive feedback loop
Authors: Willemsen Lisa , Lee Jiyeun , Shinde Pramod , Soldevila Ferran , Aoki Minori , Orfield Shelby , Kojima Mari , da Silva Antunes Ricardo , Sette Alessandro , Peters Bjoern 
Published: August 2024

AbstractOutbreaks ofBordetella pertussis(BP), the causative agent of whooping cough, continue despite broad vaccination coverage and have been increasing since vaccination switched from whole-BP (wP) to acellular BP (aP) vaccines. wP vaccination has been associated with more durable protective immunity and an induced Th1 polarized memory T cell response. Here, a multi-omics approach was applied to profile the immune response of 30 wP and 31 aP-primed individuals and identify correlates of T cell polarization before and after Tdap booster vaccination. We found that transcriptional changes indicating an interferon response on day 1 post-booster along with elevated plasma concentrations of IFN-γ and interferon-induced chemokines that peaked at day 1-3 post-booster correlated best with the Th1 polarization of the vaccine-induced memory T cell response on day 28. Our studies suggest that wP-primed individuals maintain their Th1 polarization through this early memory interferon response. This suggests that stimulating the interferon pathway during vaccination could be an effective strategy to elicit a predominant Th1 response in aP-primed individuals that protects better against infection.