bluuebunny/crossref_metadata_2025 huggingface dataset:
Comprehensive bioinformatics analysis of FXR1 across pan-cancer: Unraveling its diagnostic, prognostic, and immunological significance
Authors: Xiao Keyuan , Ullah Ihsan , Yang Fan , Wang Jiao , Hou Chunxia , Liu Yuqiang , Li Xinghua
Published: December 2023

Fragile X-related protein 1 (FXR1) is an RNA-binding protein that belongs to the fragile X-related (FXR) family. Studies have shown that FXR1 plays an important role in cancer cell proliferation, invasion and migration and is differentially expressed in cancers. This study aimed to gain a comprehensive and systematic understanding of the analysis of FXR1’s role in cancers. This would lead to a better understanding of how it contributes to the development and progression of various malignancies. this study conducted through The Cancer Genome Atlas (TCGA), GTEx, cBioPortal, TISIDB, GEPIA2 and HPA databases to investigated FXR1’s role in cancers. For data analysis, various software platforms and web platforms were used, such as R, Cytoscape, hiplot plateform. A significant difference in FXR1 expression was observed across molecular and immune subtypes and across types of cancer. FXR1 expression correlates with disease-specific survival (DSS), and overall survival (OS) in several cancer pathways, further in progression-free interval (PFI) in most cancers. Additionally, FXR1 showed a correlation with genetic markers of immunomodulators in different cancer types. Our study provides insights into the role of FXR1 in promoting, inhibiting, and treating diverse cancers. FXR1 has the potential to serve as a diagnostic and prognostic biomarker for cancer, with therapeutic value in immune-based, targeted, or cytotoxic treatments. Further clinical validation and exploration of FXR1 in cancer treatment is necessary.
Ionic conductances driving tonic firing in Purkinje neurons of larval zebrafish
Authors: Jadhav Meha P. , Verma Shivangi , Thirumalai Vatsala
Published: December 2023

Purkinje neurons are critical for the functioning of the cerebellum, which is among the oldest and most conserved regions of the vertebrate brain. In mammals and in larval zebrafish, Purkinje neurons can generate tonic firing even when isolated from the network. Here we investigated the ionic basis of tonic firing in Purkinje neurons of larval zebrafish using voltage clamp for isolation of membrane currents along with pharmacology. We discovered that these neurons express L-type and P/Q-type high voltage-gated calcium currents, T-type low voltage-gated calcium currents and SK and BK-type calcium dependent potassium currents. Among these, L-type calcium currents and SK-type calcium-dependent potassium currents were indispensable for tonic firing, while blocking T-type, P/Q-type and BK currents had little effect. We observed that action potentials were broadened when either L-type or SK channels were blocked. Based on these results, we propose that calcium entry via L-type calcium channels activates SK potassium channels leading to faster action potential repolarization, in turn aiding the removal of inactivation of sodium channels. This allows larval zebrafish Purkinje neurons to continue to fire tonically for sustained periods. In mammals also, tonic firing in Purkinje neurons is driven by calcium channels coupling to calcium-dependent potassium channels, yet the specific types of channels involved are different. We therefore suggest that coupling of calcium channels and calcium-dependent potassium channels could be a conserved mechanism for sustaining long bouts of high frequency firing.

Key points

Tonic firing is an intrinsic property of Purkinje neurons in mammals and fish.

These neurons express multiple types of voltage-gated conductances including L-type, T-type, and P/Q-type calcium currents and SK- and BK-type calcium-dependent potassium currents.

Blocking L-type calcium channels and SK-type calcium dependent potassium channels resulted in spike broadening and reduced tonic firing.

L-type calcium currents were activated during the repolarisation of the spike.

Based on this we conclude that calcium entry via L-type channels activates SK-channels causing faster repolarization of the spike and therefore sustained tonic firing.
LncPNdeep: A long non-coding RNA classifier based on Large Language Model with peptide and nucleotide embedding
Authors: Dai Zongrui , Deng Feiyang
Published: December 2023

Long non-coding RNA plays an important role in various gene transcription and peptide interactions. Classifying lncRNAs from coding RNA is a crucial step in bioinformatics analysis which seriously affects the post-analysis for transcriptome annotation. Although several machine learning-based methods were developed to classify lncRNAs, these methods were mainly focused on nucleotide features without considering the information from the peptide sequence. To integrate both nucleotide and peptide information in lncRNA classification, one efficient deep learning is desired. In this study, we developed one concatenated deep neural network named LncPNdeep to combine this information. LncPNdeep incorporates both peptide and nucleotide embedding from masked language modeling (MLM), being able to discover complex associations between sequence information and lncRNA classification. LncPNdeep achieves state-of-the-art performance in the human transcript database compared with other existing methods (Accuracy=97.1%). It also exhibits superior generalization ability in cross-species comparison, maintaining consistent accuracy and F1 scores compared to other methods. The combination of nucleotide and peptide information makes LncPNdeep able to facilitate the identification of novel lncRNA and gain high accuracy for classification. Our code is available athttps://github.com/yatoka233/LncPNdeep
Dopaminergic-related Anatomical Pattern of Dorsal Striatum in Schizophrenia
Authors: Xie Chao , Xiang Shitong , Zheng Yueyuan , Shen Chun , Peng Xuerui , Li Yuzhu , Cheng Wei , Chang Xiao , Cheng Jingliang , Cui Long-Biao , Huang Chu-Chung , Kuang Nanyu , Li Chunbo , Lin Ching-Po , Luo Cheng , Tang Yingying , Wang Jijun , Wu Xinran , Yao Dezhong , Zhang Jie , Zhang Tianhong , Heinz Andreas , Robbins Trevor W. , Howes Oliver D. , Schumann Gunter , Jia Tianye , Feng Jianfeng
Published: December 2023

Striatal dopaminergic overactivity was hypothesized as the core pathophysiology of schizophrenia. However, morphological alterations of striatum in schizophrenia remains exclusive, largely because brain regional heterogeneity limited traditional group-mean based approach. Leveraging third-party brain maps of neurotransmitter and cognition behaviours, we developed a pattern-based representation feature score (ReFS) to investigate structural spatial pattern variation in schizophrenia. Structural ReFS of subcortical regions, particularly the striatum, were linked to schizophrenia diagnosis, symptom severity, and genetic susceptibility. Dopaminergic-ReFS of striatum was increased in schizophrenia patients and reliably reproduced across 13 datasets. The pattern-based ReFS effectively captured the shared genetic pathways underlying both schizophrenia and striatum. The results provide convergent, multimodal suggest the central role of striatal spatial patterns in schizophrenia psychopathologies and and open new avenues to develop individualized treatments for psychotic disorders.
Common and rare variant analyses implicate late-infancy cerebellar development and immune genes in ADHD
Authors: Zhong Yuanxin , Baum Larry W. , Tubbs Justin D. , Ye Rui , Chen Lu Hua , Wu Tian , Hung Se-Fong , Tang Chun-Pan , Ho Ting-Pong , Moyzis Robert , Swanson James , Lee Chi-Chiu , Sham Pak C. , Leung Patrick W. L.
Published: December 2023

Background

Attention-deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder with a significant genetic component, characterized by persistent symptoms of inattention, hyperactivity, and/or impulsivity. The latest genome-wide association study (GWAS) meta-analysis of ADHD identified 27 whole-genome significant risk loci in the European population. However, genetic risk factors for ADHD are less well-characterized in the Asian population, especially for rare variants.

Methods

Here, we present an analysis of common and rare variant contributions to ADHD in a Hong Kong sample comprising 279 cases and 432 controls, who were genotyped using the Illumina Infinium Global Screening Array.

Results

We identified 41 potential genomic risk loci with a suggestive association (p< 1e−4), pointing to 111 candidate risk genes, which were enriched for genes differentially expressed during late infancy brain development. Furthermore, tissue enrichment analysis implicated the involvement of the cerebellum.POC1B, a gene previously found in a genome-wide significant locus of ADHD in the European population, was replicated in the current study, potentially implicating a trans-ancestral effect in ADHD. In addition, an accumulation of ADHD common-variant risks found in European ancestry samples was found to be significantly associated with ADHD in the current study. At the polygenic level, we also discovered a strong genetic correlation with resting-state functional MRI connectivity of the cerebellum involved in the attention/central executive and subcortical-cerebellum networks, which is consistent with the neural pathophysiology for ADHD. In rare variant analyses, we discovered that ADHD cases carried an elevated load of rare damaging variants inTEP1,MTMR10,DBH,TBCC,andANO1. ADHD genetic risk was associated with immune processes, demonstrated in both common and rare variant analyses.

Conclusions

These findings re-validate the abnormal development of the neural system in ADHD and extend the existing neuro-dysfunction hypothesis to a multi-system perspective.
Parkinson’s disease-derived α-Synuclein assemblies combined with chronic-type inflammatory cues promote a neurotoxic microglial phenotype
Authors: Yildirim Cansu , Fenyi Alexis , Besnault Pierre , Gomez Lina , Sepulveda-Diaz Julia E. , Michel Patrick P. , Melki Ronald , Hunot Stéphane
Published: December 2023

Parkinson’s disease (PD) is a common age-related neurodegenerative disorder characterized by the aggregation of α-synuclein (αSYN) building up intraneuronal inclusions termed Lewy pathology. Mounting evidence suggests that neuron-released αSYN aggregates could be central to microglial activation, which in turn mounts and orchestrates neuroinflammatory processes potentially harmful to neurons. Therefore, understanding the mechanisms that drive microglial cell activation, polarization and function in PD might have important therapeutic implications. Here, using primary microglia, we investigated the inflammatory potential of pure αSYN fibrils derived from PD patients. We further explored and characterized microglial cell responses to a chronic-type inflammatory stimulation combining PD patient-derived αSYN fibrils (FPD), Tumor necrosis factor-α (TNFα) and prostaglandin E2(PGE2) (TPFPD). We showed that FPDhold stronger inflammatory potency than pure αSYN fibrils generatedde novo. When combined with TNFα and PGE2, FPDpolarizes microglia toward a particular functional phenotype departing from FPD-treated cells and featuring lower inflammatory cytokine and higher glutamate release. Whereas metabolomic studies showed that TPFPD-exposed microglia were closely related to classically activated M1 proinflammatory cells, notably with similar tricarboxylic acid cycle disruption, transcriptomic analysis revealed that TPFPD-activated microglia assume a unique molecular signature highlighting upregulation of genes involved in glutathione and iron metabolisms. In particular, TPFPD-specific upregulation ofSlc7a11(which encodes the cystine-glutamate antiporter xCT) was consistent with the increased glutamate response and cytotoxic activity of these cells toward midbrain dopaminergic neuronsin vitro. Together, these data further extend the structure-pathological relationship of αSYN fibrillar polymorphs to their innate immune properties and demonstrate that PD-derived αSYN fibrils, TNFα and PGE2act in concert to drive microglial cell activation toward a specific and highly neurotoxic chronic-type inflammatory phenotype characterized by robust glutamate release and iron retention.
Histone deacetylases regulate organ-specific growth in a horned beetle
Authors: Hu Yonggang , Crabtree Jordan R. , Macagno Anna L. M. , Moczek Armin P.
Published: December 2023

Background

Nutrient availability is among the most widespread means by which environmental variability affects developmental outcomes. Because almost all cells within an individual organism share the same genome, structure-specific growth responses must result from changes in gene regulation. Earlier work suggested thathistone deacetylases(HDACs) may serve as epigenetic regulators linking nutritional conditions to trait-specific development. Here we expand on this work by assessing the function of diverseHDACsin the structure-specific growth of both sex-shared and sex-specific traits including evolutionarily novel structures in the horned dung beetleOnthophagus taurus.

Results

We identified fiveHDACmembers whose down-regulation yielded highly variable mortality depending on whichHDACmember was targeted. We then show thatHDAC1,3, and4operate in both a gene- and trait-specific manner in the regulation of nutrition-responsiveness of appendage size and shape. Specifically,HDAC 1, 3,or4knockdown diminished wing size similarly while leg development was differentially affected by RNAi targetingHDAC3andHDAC4. In addition, depletion ofHDAC3transcript resulted in a more rounded shape of genitalia at the pupal stage and decreased the length of adult aedeagus across all body sizes. Most importantly, we find thatHDAC3and4pattern the morphology and regulate the scaling of evolutionarily novel head and thoracic horns as a function of nutritional variation.

Conclusion

Collectively, our results suggest that both functional overlap and division of labor amongHDACmembers contribute to morphological diversification of both conventional and recently evolved appendages. More generally, our work raises the possibility thatHDAC-mediated scaling relationships and their evolution may underpin morphological diversification within and across insect species broadly.
Do nocturnal pollinators carry a more conspecific pollen load than diurnal ones?
Authors: Razanajatovo Mialy , Schurr Frank M. , Muhthassim Nadia , Troesch Sandra , Knop Eva
Published: December 2023

Plant-pollinator interactions are key for the reproduction of wild plants and for food security. However, the role nocturnal pollinators play in wild plant communities is not yet clear. Specifically, it has rarely been studied whether nocturnal pollinators are comparable to diurnal ones in the pollination services they deliver in plant communities. We tested whether nocturnal pollinators have the potential to provide higher pollination services than diurnal ones by carrying a more conspecific pollen load. We compared pollen loads carried by nocturnal and diurnal pollinators captured over 24-hour cycles in co-flowering plant communities in European ruderal meadows. Pollen load was less diverse at night, and the proportion of conspecific pollen carried by nocturnal pollinators was similar to or higher than that of diurnal ones. Thus, nocturnal pollinators do not only carry pollen but can remove and deposit conspecific pollen with a comparable or even superior performance to diurnal ones. Therefore, nocturnal pollinators can be more efficient pollination vectors than diurnal ones, which might compensate their lower pollen load.
Exploring Discrete Space-Time Models for Information Transfer: Analogies from Mycelial Networks to the Cosmic Web
Authors: Wood Tommy , Sorakivi Tuomas , Ayres Phil , Adamatzky Andrew
Published: December 2023

Fungal mycelium networks are large scale biological networks along which nutrients, metabolites flow. Recently, we discovered a rich spectrum of electrical activity in mycelium networks, including action-potential spikes and trains of spikes. Reasoning by analogy with animals and plants, where travelling patterns of electrical activity perform integrative and communicative mechanisms, we speculated that waves of electrical activity transfer information in mycelium networks. Using a new discrete space-time model with emergent radial spanning-tree topology, hypothetically comparable mycelial morphology and physically comparable information transfer, we provide physical arguments for the use of such a model, and by considering growing mycelium network by analogy with growing network of matter in the cosmic web, we develop mathematical models and theoretical concepts to characterise the parameters of the information transfer.
Deciphering the Biosynthetic Potential of Microbial Genomes Using a BGC Language Processing Neural Network Model
Authors: Lai Qilong , Yao Shuai , Zha Yuguo , Zhang Haobo , Ye Ying , Zhang Yonghui , Bai Hong , Ning Kang
Published: December 2023

Microbial secondary metabolites are usually synthesized by colocalized genes termed biosynthetic gene clusters (BGCs). A large portion of BGCs remain undiscovered in microbial genomes and metagenomes, representing a pressing challenge in unlocking the full potential of natural product diversity. In this work, we propose BGC-Prophet, a language model based on the transformer encoder that captures the distant location-dependent relationships among biosynthetic genes, allows accurately and efficiently identifies known BGCs and extrapolates novel BGCs among the microbial universe. BGC-Prophet is the first ultrahigh-throughput (UHT) method that is several orders of magnitude faster than existing tools such as DeepBGC, enabling pan-phylogenetic screening and whole-metagenome screening of BGCs. By analyzing 85,203 genomes and 9,428 metagenomes, new insights have been obtained about the diversity of BGCs on genomes from the majority of bacterial and archaeal lineages. The profound enrichment of BGCs in microbes after important geological events have been revealed: Both the Great Oxidation and Cambrian Explosion events led to a surge in BGC diversity and abundance, particularly in polyketides. These findings suggest that it is a general but constantly evolving approach for microbes to produce secondary metabolites for their adaptation in the changing environment. Taken together, BGC-Prophet enables accurate and fast detection of BGCs on a large scale, holds great promise for expanding BGC knowledge, and sheds light on the evolutionary patterns of BGCs for possible applications in synthetic biology.

Highlights

BGC-Prophet shows superior performance to existing tools in terms of accuracy and speed.

BGC-Prophet is the first ultrahigh-throughput (UHT) method that enables pan-phylogenetic screening and whole-metagenome screening of BGCs.

BGC-Prophet builds the comprehensive profile of BGCs on 85,203 genomes and 9,428 metagenomes from the majority of bacterial and archaeal lineages.

BGC-Prophet reveals the profound enrichment pattern of BGCs after important geological events.
Learning spatio-temporal V1 cells from diverse LGN inputs
Authors: Ruslim Marko A. , Burkitt Anthony N. , Lian Yanbo
Published: December 2023

Since the Nobel-winning discovery of simple cells and complex cells in cat’s primary visual cortex (V1) by Hubel and Wiesel, many experimental studies of the visual system of the brain have been conducted. Experimental data of V1 cells from animal recordings show spatio-temporal properties, namely that they display both spatial and temporal response properties. For spatial properties, each V1 cell responds to a specific feature (such as bars, blobs, etc.) in the visual space, which is called the receptive field of this cell. The receptive fields of different V1 cells are typically different in size, orientation, spatial frequencies, etc. Furthermore, V1 cells also display temporal properties, namely that the receptive fields of V1 cells can change over time, and there is a great variety of ways in which they change over time. For example, the population of V1 cells show a great diversity from monophasic response to biphasic response, and some V1 cells are selective to a preferred direction. However, given many computational learning models that explain how spatial properties of V1 cells can be learnt, how temporal properties emerge is still not well understood. In this paper, we use a simple learning model based on sparse coding to show that spatio-temporal V1 cells, such as biphasic and direction selective cell, can emerge via synaptic plasticity when diverse spatio-temporal LGN cells are used as upstream input to V1 cells. This work suggests that temporal along with spatial properties of V1 cells may simply come from a learning process that aims to encode upstream input with spatio-temporal properties, which greatly enhances our understanding of V1 cells.
Maternofetal transfer of human NMDAR antibodies leads to cortical network defect in the adult
Authors: Altahini Saleh , Doering Jan , Kuchling Joseph , Backhaus Hendrik , Kreye Jakob , Guimaraes-Backhaus Roberta , Finke Carsten , Prüss Harald , Stroh Albrecht
Published: December 2023

IgG antibodies that bind to the N-methyl-D-aspartate receptors (NMDAR-Ab) can be detected in up to 1 % of healthy individuals. This suggests that a considerable subgroup of pregnant women is at risk of transferring NMDAR-antibodies to the fetus. We ask whether a transientin uteroexposure to human NMDAR-Ab can lead to neural network defects in adulthood. In mouse model of maternofetally transferred human NMDAR-Ab, at P51, corresponding to early adulthood in humans, we conducted two-photon calcium imaging in awake behaving mice. We found that microcircuits in NMDAR-Ab exposed mice exhibited a lower spontaneous activity and increased bursty firing. Upon visual stimulation, neurons in NMDAR-Ab exposed mice had a higher orientation selectivity. In NMDAR-Ab exposed mice, a large fraction of neurons active upon visual stimulation did not fire spontaneously, andvice versa. This dissociation is in sharp contrast to the operational principles in healthy networks, in which the majority of all neurons were co-active. These findings suggest that transientin uteroexposure to NMDAR-Ab shifts cortical microcircuits to a maladaptive state persisting into adulthood, characterized by a dissociation between spontaneous and visually evoked activity. Such dissociation has long been hypothesized to play a role in the development of psychosis.
Imprecise perception of hand position during early motor adaptation
Authors: Will Matthias , Stenner Max-Philipp
Published: December 2023

Localizing one’s body parts is important for movement control and motor learning. Recent studies have shown that the precision with which people localize their hand places constraints on motor adaptation. While these studies have assumed that hand localization remains equally precise across learning, we show that precision decreases rapidly during early motor learning. In three experiments, healthy young participants (n=92) repeatedly adapted to a 45° visuomotor rotation for a cycle of two to four reaches, followed by a cycle of two to four reaches with veridical feedback. Participants either used an aiming strategy that fully compensated for the rotation (experiment 1), or always aimed directly at the target, so that adaptation was implicit (experiment 2). We omitted visual feedback for the last reach of each cycle, after which participants localized their unseen hand. We observed an increase in the variability of angular localization errors when subjects used a strategy to counter the visuomotor rotation (experiment 1). This decrease in precision was less pronounced in the absence of re-aiming (experiment 2), and when subjects knew that they would have to localize their hand on the upcoming trial, and could thus fully allocate attention to hand position (experiment 3). We propose that attention to vision during strategic re-aiming decreases the precision of perceived hand position. We discuss how these dynamics in precision during early motor learning could impact on motor control, and shape the interplay between implicit and strategy-based motor adaptation.

NEW & NOTEWORTHY

Recent studies indicate that the precision with which people localize their hand limits implicit visuomotor learning. We found that localization precision is not static, but decreases early during learning. This decrease is pronounced when people apply a re-aiming strategy to compensate for a visuomotor perturbation, and diminishes when the hand is fully attended. We propose that these attention-dependent dynamics in position sense during learning may influence how implicit and strategy-based motor adaption interact.
Time-of-day effects of cancer drugs revealed by high-throughput deep phenotyping
Authors: Ector Carolin , Schmal Christoph , Didier Jeff , De Landtsheer Sébastien , Finger Anna-Marie , Müller-Marquardt Francesca , Schulte Johannes , Sauter Thomas , Keilholz Ulrich , Herzel Hanspeter , Kramer Achim , Granada Adrián E.
Published: December 2023

The circadian clock, a fundamental biological regulator, governs essential cellular processes in health and disease. Circadian-based therapeutic strategies are increasingly gaining recognition as promising avenues. Aligning drug administration with the circadian rhythm can enhance treatment efficacy and minimize side effects. Yet, uncovering the optimal treatment timings remains challenging, limiting their widespread adoption. In this work, we introduce a novel high-throughput approach integrating live-imaging and data analysis techniques to deep-phenotype cancer cell models, evaluating their circadian rhythms, growth, and drug responses. We devised a streamlined process for profiling drug sensitivities across different times of the day, identifying optimal treatment windows and responsive cell types and drug combinations. Finally, we implement multiple computational tools to uncover cellular and genetic factors shaping time-of-day drug sensitivity. Our versatile approach is adaptable to various biological models, facilitating its broad application and relevance. Ultimately, this research leverages circadian rhythms to optimize anti-cancer drug treatments, promising improved outcomes and transformative treatment strategies.
CIA: a Cluster Independent Annotation method to investigate cell identities in scRNA-seq data
Authors: Ferrari Ivan , Battistella Mattia , Vincenti Francesca , Gobbini Andrea , Marini Federico , Notarbartolo Samuele , Costanza Jole , Biffo Stefano , Grifantini Renata , Abrignani Sergio , Galeota Eugenia
Published: December 2023

Single-cell RNA sequencing (scRNA-seq) has revolutionized our understanding of the transcriptional landscape of complex tissues, enabling the discovery of novel cell types and biological functions. However, the identification and classification of cells from scRNA-seq datasets remain significant challenges. To address this, we developed a new computational tool called CIA (Cluster Independent Annotation), which accurately identifies cell types across different datasets without requiring a fully annotated reference dataset or complex machine learning processes. Based on predefined cell type signatures, CIA provides a highly user-friendly and practical solution to functional annotation of single cells. Our results demonstrate that CIA outperforms other state-of-the-art approaches, while also having significantly lower computational running time. Overall, CIA simplifies the process of obtaining reproducible signature-based cell assignments that can be easily interpreted through graphical summaries providing researchers with a powerful tool to explore the complex transcriptional landscape of single cells.

The CIA framework is implemented in both the Python and R programming languages, making it applicable to all main single-cell analysis frameworks, and it is available under the MIT license with its documentation at the following links:

Python package:https://pypi.org/project/cia-python/

Python tutorial:https://cia-python.readthedocs.io/en/latest/tutorial/Cluster_Independent_Annotation.html

R package and tutorial:https://github.com/ingmbioinfo/CIA_R
Cortical responses to looming sources are explained away by the auditory periphery
Authors: Benghanem Sarah , Guha Rudradeep , Pruvost-Robieux Estelle , Lévi-Strauss Julie , Joucla Coralie , Cariou Alain , Gavaret Martine , Aucouturier Jean-Julien
Published: December 2023

A wealth of behavioral evidence indicate that sounds with increasing intensity (i.e. appear to be looming towards the listener) are processed with increased attentional and physiological resources compared to receding sounds. However, the neurophysiological mechanism responsible for such cognitive amplification remains elusive. Here, we show that the large differences seen between cortical responses to looming and receding sounds are in fact almost entirely explained away by nonlinear encoding at the level of the auditory periphery. We collected EEG mismatch negativity (MMN) data in response to deviant stimuli with both dynamic (looming and receding) and constant level (flat) differences to the standard in the same participants. We then combined a computational model of the auditory periphery with generative EEG methods (temporal response functions, TRFs) to model the single-participant MMN responses to flat deviants, and used them to predict the effect of the same mechanism on looming and receding stimuli. The flat model explained a remarkable 45% variance of the looming response, and 33% of the receding response. This provide striking evidence that MMN responses to looming and receding sounds result from the same cortical mechanism that generate MMN to constant-level deviants: all such differences are the sole consequence of their particular physical morphology getting amplified and integrated by peripheral auditory mechanisms. Thus, not all effects seen cortically proceed from top-down modulations by high-level decision variables, but can rather be performed early and efficiently by feed-forward peripheral mechanisms that evolved precisely to sparing subsequent networks with the necessity to implement such mechanisms.
Engagement for Alcohol Escalates in the 5-Choice Serial Reaction Time Task After Intermittent Access
Authors: Starski Phillip , Siegle Addyson , Hopf Frederic
Published: December 2023

Uncontrollable binge drinking is becoming an increasingly prevalent issue in our society. This is a factor that plays a role in the development of alcohol use disorder (AUD). AUD impacts 15 million Americans annually, with approximately 88,000 dying from alcohol related deaths. There are several aspects of AUD that encourage a strong dependence on alcohol. Impulsivity, motivation, and attention are the primary behavioral facets we contribute to AUD. Many past studies have used the 5-Choice Serial Reaction Time Task (5-Choice) to analyze these types of behaviors using sugar as the reward. We have recently published a study where alcohol was used as a reward in the 5-Choice. 48 mice were trained to respond for alcohol in the 5-Choice, and the analyses for these animals were originally categorized by their alcohol preference and consumption. Upon looking at the data, we became more interested in a new way to classify these mice into groups. High engaged (HE) and low engaged (LE) mice were classified based on their number of correct responses in the last five late-stage sessions. During early-stage training, mice began to separate themselves into two groups based on their interaction with the task. The high-engaged (HE) mice were much more engaged with the task by having a high number of trials and correct responses, as well as a much lower percentage of omissions. The low engaged (LE) mice were not as engaged, this was apparent because of their lower number of trials and correct responses. They also had a much higher percentage of omissions in comparison to HE mice. LE mice presented no significant changes in late-stage training, while HE mice began responding and engaging more. These mice went through a period of intermittent access (IA), where they were allowed to drink alcohol in their cage for 3 weeks. After intermittent access, LE mice increased their responding which suggests an increase in motivation for alcohol as a reward. Engagement analysis presents two clearly different groups, one being motivated to work for alcohol and the other not wanting to work for this reward. These two distinct phenotypes in the 5-Choice could be used to model alcohol motivated behavior, which could help us further understand AUD.
Tradeoff Between Speed and Robustness in Primordium Initiation Mediated by Auxin-CUC1 Interaction
Authors: Kong Shuyao , Zhu Mingyuan , Pan David , Lane Brendan , Smith Richard S. , Roeder Adrienne H. K.
Published: December 2023

Robustness is the reproducible development of a phenotype despite stochastic noise. It often involves tradeoffs with other performance metrics, but the mechanisms underlying such tradeoffs were largely unknown. AnArabidopsisflower robustly develops four sepals from four precisely positioned auxin maxima. Thedevelopment related myb-like 1(drmy1)mutant generates noise in auxin signaling that disrupts robustness in sepal initiation. Here, we found that increased expression ofCUP-SHAPED COTYLEDON1(CUC1), a boundary specification transcription factor, indrmy1underlies this loss of robustness. CUC1 surrounds and amplifies stochastic auxin noise indrmy1to form variably positioned auxin maxima and sepal primordia. RemovingCUC1fromdrmy1provides time for noisy auxin signaling to resolve into four precisely positioned auxin maxima, restoring robust sepal initiation. However, removing CUC1 decreases auxin maxima intensity and slows down sepal initiation. Thus, CUC1 increases morphogenesis speed but impairs robustness against auxin noise. Further, using a computational model, we found that the observed phenotype can be explained by the effect of CUC1 in repolarizing PIN FORMED1 (PIN1), a polar auxin transporter. Lastly, our model predicts that reducing global growth rate improves developmental robustness, which we validated experimentally. Thus, our study illustrates a tradeoff between speed and robustness during development.
Protected areas enhance avian food webs
Authors: Thompson Lucie , Galiana Núria , Wells Konstans , Lurgi Miguel
Published: December 2023

Restoring and conserving habitat and the species they shelter has become a primary focus to mitigate the current extinction crisis. Setting aside land designated as protected areas (PAs) is an efficient way of achieving these aims. This strategy has been proven to enhance different aspects of species richness and abundance across ecosystems1–4. However, to truly understand the effects of global environmental change on biodiversity, and the efficiency of our mitigation measures, we must account for one of its fundamental dimensions: species interactions. Here we show that PAs enhance avian food webs across Europe by protecting key network and species traits. Using 376,556 observational records of 509 bird species from citizen science databases distributed across 45 networks of PAs, we found beneficial effects of protection on 10 out of 13 food web properties on an average of 25.9% of sites. PAs enhance food webs by harbouring large top predators, in turn increasing the length of biomass flow paths from basal to top species. Furthermore, we link these beneficial effects to environmental drivers and PA designations. PA benefits were augmented by specific protection goals such as European Directives for conservation. This study provides evidence for the effectiveness of PAs as a strategy to preserve fundamental aspects of biodiversity beyond species richness. We anticipate our study to be a starting point for the development of comprehensive frameworks to assess the critical role of PAs in safeguarding biodiversity worldwide. Improving the mapping of species occurrences and ecological interactions across the globe will is fundamental to develop optimal strategies for establishing networks of PAs aimed at protecting all aspects of ecosystem diversity.
Lens Placode Modulates Extracellular Matrix Formation During Early Eye Development
Authors: De Magalhães Cecília G. , Cvekl Ales , Jaeger Ruy G. , Yan C. Y. Irene
Published: December 2023

The role extracellular matrix (ECM) in multiple events of morphogenesis has been well described, little is known about its specific role in early eye development. One of the first morphogenic events in lens development is placodal thickening, which converts the presumptive lens ectoderm from cuboidal to pseudostratified epithelium. This process occurs in the anterior pre-placodal ectoderm when the optic vesicle approaches the cephalic ectoderm. Since cells and ECM have a dynamic relationship of interdependence and modulation, we hypothesized that the ECM evolves with cell shape changes during lens placode formation. This study investigates changes in optic ECM including both protein distribution deposition, extracellular gelatinase activity and gene expression patterns during early optic development using chicken and mouse models. In particular, the expression ofTimp2, a metalloprotease inhibitor, corresponds with a decrease in gelatinase activity within the optic ECM. Furthermore, we demonstrate that optic ECM remodeling depends on BMP signaling in the placode. Together, our findings suggest that the lens placode plays an active role in remodeling the optic ECM during early eye development.
Diploid genome assembly of the Malbec grapevine cultivar enables haplotype-aware analysis of transcriptomic differences underlying clonal phenotypic variation
Authors: Calderón Luciano , Carbonell-Bejerano Pablo , Muñoz Claudio , Bree Laura , Sola Cristobal , Bergamin Daniel , Tulle Walter , Gomez-Talquenca Sebastian , Lanz Christa , Royo Carolina , Ibáñez Javier , Martinez-Zapater José Miguel , Weigel Detlef , Lijavetzky Diego
Published: December 2023

Grapevine cultivars (Vitis viniferaL. ssp.vinifera) must be clonally propagated because of their highly heterozygous genomes. Malbec, a France-originated cultivar appreciated for the production of high-quality wines, is the offspring of cultivars Prunelard and Magdeleine Noire des Charentes. Here, we have built a diploid genome assembly of Malbec, after trio binning of PacBio long reads into the two haploid complements inherited from either parent. After haplotype-aware deduplication and corrections, complete assemblies for the two haplophases were obtained with very low haplotype switch-error rate (<0.025). The haplophases alignment identified >25% of polymorphic regions. Gene annotation including RNA-seq transcriptome assembly andab initioprediction evidence resulted in similar gene model numbers for both haplophases. The annotated diploid assembly was exploited in the transcriptomic comparison of four clonal accessions of Malbec that exhibited variation in berry composition traits. Analysis of the ripening pericarp transcriptome using either haplophases as reference yielded similar results, although some differences were observed. Particularly, among the differentially expressed genes in the Magdeleine-inherited haplotype, we observed an over-representation of hypothetically hemizygous genes. The higher berry anthocyanin content of clonal accession 595 was associated with increased abscisic acid responses, leading to overexpression of secondary metabolism genes and deregulation of genes associated to abiotic stress response. Overall, the results highlight the importance of producing diploid assemblies to fully represent the genomic diversity of highly heterozygous woody crop cultivars and to unveil the molecular bases of clonal phenotypic variation.
The ALS-associated TDP-43M337Vmutation dysregulates microglia-derived extracellular microRNAs in a sex-specific manner
Authors: Christoforidou Eleni , Moody Libby , Joilin Greig , Simoes Fabio A. , Gordon David , Talbot Kevin , Hafezparast Majid
Published: December 2023

Evidence suggests the presence of microglial activation and microRNA (miRNA) dysregulation in amyotrophic lateral sclerosis (ALS), the most common form of adult motor neuron disease. However, few studies have investigated whether the miRNA dysregulation may originate from microglia. Furthermore, TDP-43, involved in miRNA biogenesis, aggregates in tissues of ∼98% of ALS cases. Thus, this study aimed to determine whether expression of the ALS-linked TDP-43M337Vmutation in a transgenic mouse model dysregulates microglia-derived miRNAs. RNA sequencing identified several dysregulated miRNAs released by transgenic microglia, and a differential miRNA release by lipopolysaccharide-stimulated microglia, which was more pronounced in cells from female mice. We validated the downregulation of two candidate miRNAs, miR-16-5p and miR-99a-5p by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR), and identified their predicted targets, which include primarily genes involved in neuronal development and function. These results suggest that altered TDP-43 function leads to changes in the miRNA population released by microglia in a sex dependent manner, which may in turn influence disease progression in ALS. This has important implications for the role of neuroinflammation in ALS pathology and could provide potential therapeutic targets.
Testing SIPA1L2 as a modifier of CMT1A using mouse models
Authors: Murray George C. , Hines Timothy J. , Tadenev Abigail L.D. , Xu Isaac , Züchner Stephan , Burgess Robert W.
Published: December 2023

Charcot-Marie-Tooth 1A is a demyelinating peripheral neuropathy caused by the duplication of peripheral myelin protein 22 (PMP22), which produces muscle weakness and loss of sensation in the hands and feet. A recent case-only genome wide association study by the Inherited Neuropathy Consortium identified a strong association between variants in signal induced proliferation associated 1 like 2 (SIPA1L2) and strength of foot dorsiflexion. To validateSIPA1L2as a candidate modifier, and to assess its potential as a therapeutic target, we engineered mice with a deletion inSIPA1L2and crossed them to the C3-PMP22 mouse model of CMT1A. We performed neuromuscular phenotyping and identified an interaction betweenSipa1l2deletion and muscular endurance decrements assayed by wire-hang duration in C3-PMP22 mice, as well as several interactions in femoral nerve axon morphometrics such as myelin thickness. Gene expression changes suggested an involvement ofSipa1l2in cholesterol biosynthesis, which was also implicated in C3-PMP22 mice. Though several interactions betweenSipa1l2deletion and CMT1A-associated phenotypes were identified, validating a genetic interaction, the overall effect on neuropathy was small.
Genomic and epigenomic analysis of plasma cell-free DNA identifies stemness features associated with worse survival inAR-altered lethal prostate cancer
Authors: Chauhan Pradeep S. , Alahi Irfan , Sinha Savar , Shiang Alexander L. , Mueller Ryan , Webster Jace , Dang Ha X. , Saha Debanjan , Greiner Lilli , Yang Breanna , Ni Gabris , Ledet Elisa M. , Babbra Ramandeep K. , Feng Wenjia , Harris Peter K. , Qaium Faridi , Jaeger Ellen B. , Miller Patrick J. , Caputo Sydney A. , Sartor Oliver , Pachynski Russell K. , Maher Christopher A. , Chaudhuri Aadel A.
Published: December 2023

Metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor (AR)-targeted agents is often lethal. Unfortunately, biomarkers for this deadly disease remain under investigation, and underpinning mechanisms are ill-understood. Here, we applied deep sequencing to ∼100 mCRPC patients prior to the initiation of first-line AR-targeted therapy, which detectedAR/enhancer alterations in over a third of patients, which correlated with lethality. To delve into the mechanism underlying why these patients with cell-freeAR/enhancer alterations developed more lethal prostate cancer, we next performed genome-wide cell-free DNA epigenomics. Strikingly, we found that binding sites for transcription factors associated with developmental stemness were nucleosomally more accessible. These results were corroborated using cell-free DNA methylation data, as well as tumor RNA sequencing from a held-out cohort of mCRPC patients. Thus, we validated the importance ofAR/enhancer alterations as a prognostic biomarker in lethal mCRPC, and showed that the underlying mechanism for lethality involves reprogramming developmental states toward increased stemness.
Gut microbial changes associated with obesity in youth with type 1 diabetes
Authors: Ismail Heba M , Perera Dimuthu , Mandal Rabindra , DiMeglio Linda A , Evans-Molina Carmella , Hannon Tamara , Petrosino Joseph , Javornick CreGreen Sarah , Schmidt Nathan W
Published: December 2023

Obesity is increasingly prevalent in type 1 diabetes (T1D) and is associated with management problems and higher risk for diabetes complications. Gut microbiome changes have been described separately in each of T1D and obesity, however, it is unknown to what extent gut microbiome changes are seen when obesity and T1D concomitantly occur. Objective: To describe the gut microbiome and microbial metabolite changes associated with obesity in T1D. We hypothesized significant gut microbial and metabolite differences between T1D youth who are lean (BMI: 5-<85%) vs. those with obesity (BMI: ≥95%). Methods: We analyzed stool samples for gut microbial (using metagenomic shotgun sequencing) and short-chain fatty acid (SCFA) metabolite differences in lean (n=27) and obese (n=21) T1D youth. The mean±SD age was 15.3±2.2yrs, A1c 7.8±1.3%, diabetes duration 5.1±4.4yrs, 42.0% females, and 94.0% were White. Linear discriminant analysis (LDA) effect size (LEfSe) was used to identify taxa that best discriminated between the BMI groups. Results: Bacterial community composition showed differences in species type (β-diversity) by BMI group (p=0.013). At the genus level, there was a higher ratio ofPrevotellatoBacteroidesin the obese group (p=0.0058). LEfSe analysis showed a differential distribution of significantly abundant taxa in either the lean or obese groups, including increased relative abundance ofPrevotella copri, among other taxa in the obese group. Functional profiling showed that pathways associated with decreased insulin sensitivity were upregulated in the obese group. Stool SCFAs (acetate, propionate and butyrate) were higher in the obese compared to the lean group (p<0.05 for all). Conclusions: Our findings identify gut microbiome, microbial metabolite and functional pathways differences associated with obesity in T1D. These findings could be helpful in identifying gut microbiome targeted therapies to manage obesity in T1D.