bluuebunny/crossref_metadata_2025_split huggingface dataset:
Compositional restrictions in the flanking regions give potential specificity and strength boost to binding in short linear motifs
Authors: Acs Veronika , Hatos Andras , Tantos Agnes , Kalmar Lajos 
Published: May 2024

AbstractShort linear motif (SLiM)-mediated protein–protein interactions play important roles in several biological processes where transient binding is needed. They usually reside in intrinsically disordered regions (IDRs), which makes them accessible for interaction. Although information about the possible necessity of the flanking regions surrounding the motifs is increasingly available, it is still unclear if there are any generic amino acid attributes that need to be functionally preserved in these segments. Here, we describe the currently known ligand-binding SLiMs and their flanking regions with biologically relevant residue features and analyse them based on their simplified characteristics. Our bioinformatics analysis reveals several important properties in the widely diverse motif environment that presumably need to be preserved for proper motif function, but remained hidden so far. Our results will facilitate the understanding of the evolution of SLiMs, while also hold potential for expanding and increasing the precision of current motif prediction methods.Author summaryProtein–protein interactions between short linear motifs and their binding domains play key roles in several molecular processes. Mutations in these binding sites have been linked to severe diseases, therefore, the interest in the motif research field has been dramatically increasing. Based on the accumulated knowledge, it became evident that not only the short motif sequences themselves, but their surrounding flanking regions also play crucial roles in motif structure and function. Since most of the motifs tend to be located within highly variable disordered protein regions, searching for functionally important physico-chemical properties in their proximity could facilitate novel discoveries in this field. Here we show that the investigation of the motif flanking regions based on different amino acid attributes can provide further information on motif function. Based on our bioinformatics approach we have found so far hidden features that are generally present within certain motif categories, thus could be used as additional information in motif searching methods as well.
Impact of U2-type introns on splice site prediction inArabidopsis thalianausing deep learning
Authors: Kabanga Espoir , Yun Soeun , Van Messem Arnout , De Neve Wesley 
Published: May 2024

AbstractIn this study, we investigate the impact of introns on the effectiveness of splice site prediction using deep learning models, focusing onArabidopsis thaliana. We specifically utilize U2-type introns due to their ubiquity in plant genomes and the rich datasets available. We formulate two hypotheses: first, that short introns would lead to a higher effectiveness of splice site prediction than long introns due to reduced spatial complexity; and second, that sequences containing multiple introns would improve prediction effectiveness by providing a richer context for splicing events. Our findings indicate that (1) models trained on datasets with shorter introns consistently outperform those trained on datasets with longer introns, highlighting the importance of intron length in splice site prediction, and (2) models trained with datasets containing multiple introns per sequence demonstrate superior effectiveness over those trained with datasets containing a single intron per sequence. Furthermore, our findings not only align with the two hypotheses we put forward but also confirm existing observations from wet lab experiments regarding the impact of length of an intron and the number of introns present in a sequence on splice site prediction effectiveness, suggesting that our computational insights come with biological relevance.Author summaryIn this study, we explore how intron characteristics affect the effectiveness of splice site predictions inArabidopsis thalianausing deep learning. In particular, focusing on U2-type introns due to their prevalence in plant genomes and their relevance for large-scale data analysis, we demonstrate that both the length of these introns and the number of introns present in a sequence substantially influence prediction outcomes. Our findings highlight that deep learning models trained on data with shorter introns or multiple introns per sequence produce better predictions, aligning with observations from wet lab experiments regarding the impact of intron length and the number of introns per sequences on splice site prediction effectiveness.
The histone variant H2A.Z is required for efficient transcription-coupled NER and to maintain genome integrity in UV challenged yeast cells
Authors: Gaillard Hélène , Ciudad Toni , Aguilera A. , Wellinger Ralf E. 
Published: May 2024

AbstractThe genome of living cells is constantly challenged by DNA lesions that interfere with cellular processes such as transcription and replication. A manifold of mechanisms act in concert to ensure adequate DNA repair, gene expression, and genome stability. Bulky DNA lesions, such as those induced by UV light or the DNA-damaging agent 4-nitroquinoline oxide, act as transcriptional and replicational roadblock and thus represent a major threat to cell metabolism. When located on the transcribed strand of active genes, these lesions are handled by transcription-coupled nucleotide excision repair (TC-NER), a yet incompletely understood NER sub-pathway. Here, using a genetic screen in the yeastSaccharomyces cerevisiae, we identified histone variant H2A.Z as an important component to safeguard transcription and DNA integrity following UV irradiation. In the absence of H2A.Z, repair by TC-NER is severely impaired and RNA polymerase II clearance reduced, leading to an increase in double-strand breaks. Thus, H2A.Z enables proficient TC-NER and plays a major role in the maintenance of genome stability upon UV irradiation.Author summaryThe genome of living organisms is constantly challenged by intrinsic and extrinsic DNA damaging agents. The resulting DNA lesions must be readily repaired to maintain genome integrity. This is particularly important for bulky DNA lesions, such as those produced by UV light, as they will block the progress of elongating RNA polymerases on transcribed genes. These DNA lesions are repaired by a specific pathway called transcription-coupled nucleotide excision repair (TC-NER), the dysfunction of which is associated with severe human diseases. In this work, we used budding yeast as a eukaryotic model organism to perform a genetic screen for new TC-NER factors. We discovered that theHTZ1gene, encoding the histone variant H2A.Z, is required for efficient DNA repair by TC-NER. Our molecular and genetic analyses showed that in the absence of H2A.Z, RNA polymerases persist on damaged DNA, causing interference with DNA replication and genome instability. Our findings further highlight the importance of chromatin plasticity for the maintenance of genome integrity.
Hijacking a dedicated entorhinal-hippocampal extinction circuit to remove traumatic memory
Authors: Lin Ze-Jie , Gu Xue , Gong Wan-Kun , Wang Mo , Wu Yan-Jiao , Wang Qi , Wu Xin-Rong , Zhao Xin-Yu , Zhu Michael X. , Wang Lu-Yang , Liu Quanying , Yuan Ti-Fei , Li Wei-Guang , Xu Tian-Le 
Published: May 2024

AbstractEffective psychotherapy of post-traumatic stress disorder (PTSD) remains challenging due to the fragile nature of fear extinction, for which ventral hippocampal CA1 (vCA1) region is considered as a central hub. However, neither the core pathway nor the cellular mechanisms involved in implementing extinction are known. Here, we unveil a direct pathway, where layer 2a fan cells in the lateral entorhinal cortex (LEC) target parvalbumin-expressing interneurons (PV-INs) in the vCA1 region to propel low gamma-band synchronization of the LEC-vCA1 activity during extinction learning. Bidirectional manipulations of either hippocampal PV-INs or LEC fan cells suffice fear extinction. Gamma entrainment of vCA1 by deep brain stimulation (DBS) or noninvasive transcranial alternating current stimulation (tACS) of LEC persistently enhances the PV-IN activity in vCA1, thereby promoting fear extinction. These results demonstrate that the LEC-vCA1 pathway forms a top-down motif to empower low gamma-band oscillations that facilitate fear extinction. Finally, application of low gamma DBS and tACS to a mouse model with persistent PTSD shows potent efficacy, suggesting that the dedicated LEC-vCA1 pathway can be hijacked for therapy to remove traumatic memory trace.Graphical Abstract
Investigating the impact of X-rays on decay: X-ray computed tomography as a non-invasive visualisation technique for sediment-based decay experiments
Authors: Cavicchini Iacopo , Wilson Paul F. , Giles Sam , Atterby Jake , Jones Andy S. , Williams Mark A. , Clements Thomas 
Published: May 2024

AbstractDecay experiments are ever increasing in complexity to better understand taphonomic processes. However, adding new variables, such as sediment, can create methodological biases, such as artificial anatomical character loss during exhumation. Non-invasive in situ imaging techniques such as X-ray computed tomography (XCT scanning) could mitigate this, but the consequences of exposing carcasses to X-rays are not fully understood, and evidence regarding the impact of X-rays on internal microbial faunas that drive decay is conflicting. Here, we test whether XCT scanning impacts the decay ofDanio reriocarcasses within a substrate. Our control experiments show that quartz sand sediment physically stabilises the carcass throughout decay and the sequence of anatomical character loss remains constant, however, both the onset and rate of decay of soft tissues are initially accelerated. Our XCT data show that exposure to X-rays does not cause a deviation from the normal sequence of decay, validating XCT as a non-destructive visualisation method for decay experiments. Furthermore, when accompanied with traditional exhumation and dissection, XCT provides decay data with higher accuracy of character analysis than traditional methods, and allows novel quantitative techniques to monitor physical changes in the decaying carcass (e.g., total volume, build-up of gases, collapse of the body cavity etc.). We also underline limitations with the technique, but our experiment acts as an important ‘stepping stone’ for progression toward non-invasive designs of decay experiments.
Drosophilamales require the longitudinal stretch receptors to tremulate their abdomen and produce substrate-borne signals during courtship
Authors: Lee Jonathan K. M. , Yen Eugenie C. , Fabre Caroline C. G. 
Published: May 2024

AbstractSubstrate-borne cues are important species-specific signals that are widely used during courtship of many animals, from arthropods to vertebrates. They allow mating partners to communicate with, recognise and choose one another. Animals often produce substrate-borne signals by vibrating a body part, such as the abdomen. DuringDrosophilacourtship, species-specific substrate-borne vibrations are generated by the male’s regular up-and-down abdominal tremulations and these must be precisely controlled to produce an effective and specific signal. The vibrations immobilise the female, therefore facilitating copulation. It is not known how the male’s nervous system regulates this abdominal tremulation. Here, we demonstrate a role for the dorsal abdominal longitudinal stretch receptors (LSR), which include the dorsal bipolar dendritic (dbd) neurons. These neurons are a set of conserved proprioceptors found throughout Insecta. We show that impairing the function of dbd neurons through general inhibition results in males exhibiting high level of arhythmic abdominal movements (referred to as bobbing) and decreased level of tremulation. Strikingly, this causes a failure in the females’ response during courtship. We show that depleting the mechanosensitive ion channel TRPA1 (but not Piezo) in the dbd neurons leads to a similar increase in bobbing movements. Thus, we identify neurons and a key molecular player necessary for males to perform this important mode of communication.
The nucleating agent crystallophore induces instant protein crystallization
Authors: Sauter Claude , Housset Dominique , Orlans Julien , de Wijn Raphaël , Rollet Kévin , Rose Samuel , Basu Shibom , Bénas Philippe , Perez Javier , de Sanctis Daniele , Maury Olivier , Girard Eric 
Published: May 2024

ABSTRACTThe rapid preparation of homogeneous suspensions of micro- or nano-crystals is a crucial step in serial crystallography. We show how additives, such as the crystallophore (TbXo4) that acts as a molecular glue by promoting protein-protein interactions, can facilitate sample preparation for both serial synchrotron crystallography (SSX) and micro electron diffraction (3D ED). This lanthanide complex was used here for its nucleating properties to crystallize hen egg white lysozyme. SAXS monitoring indicates that crystals formed in a few minutes in low salt conditions that would not lead to spontaneous nucleation. Resulting micro- and nano-crystals were successfully used to determine the structure of the lysozyme-TbXo4 complex by SSX and 3D ED, illustrating the diffraction quality of the produced crystals and the usefulness of such compounds in the sample preparation pipeline for serial crystallography.
The interplay of spontaneous pupil-size fluctuations and EEG power in near-threshold detection
Authors: Ruuskanen Veera , Boehler C. Nico , Mathôt Sebastiaan 
Published: May 2024

AbstractDetection of near-threshold stimuli depends on the properties of the stimulus and the state of the observer. In visual detection tasks, improved sensitivity is associated with larger pre-stimulus pupil size. However, it is still unclear whether this association is due to optical effects (more light entering the eye), correlations with arousal, correlations with cortical excitability (as reflected in alpha power), or a mix of these. To better understand this, we investigated the relative contributions of pupil size and power in the alpha, beta, and theta frequency bands on near-threshold detection. We found that larger pre-stimulus pupil size is associated with improved sensitivity and a more liberal criterion (the likelihood of reporting that a stimulus was detected). Importantly, the relationship between pupil size and sensitivity was not mediated by any of the measured neural variables; the relationship with criterion however was mediated by power in the beta band (12-30 Hz). Pupil size was positively correlated with power in the alpha and beta bands. Additionally, we show that pre-stimulus theta suppression (4 - 8 Hz) is associated with improved sensitivity and a more liberal criterion. Taken together, our results show an independent effect of pupil size on detection sensitivity that is not driven by cortical excitability, but may be driven by optical effects, arousal, or a mix of both.
An algorithm for identifying task-specific brain subnetworks using the visuomotor system as an example
Authors: Ellison Ryan , Matar Mona , Gokoglu Suleyman A. , Prabhu Raj K. , Hooper Scott L. 
Published: May 2024

AbstractWe describe an algorithm that identifies a subnetwork of brain regions involved in producing a task-specific behavior, here visuomotor behavior, from an anatomically defined primate brain connectome. The algorithm first finds the brain regions connected to an output region (here, primary motor cortex, M1) by one connection. It then identifies all regions, termed “layer 2” regions, connected to these “layer 1” regions by one connection. This process continues until the layer containing the input region (here, primary visual cortex, V1) is reached. The algorithm then finds, subject to a user-set maximum step number, all paths linking the input and output regions. The brain regions in these paths constitute the initial subnetwork identification that performs the task. Regions known not to be task-involved (for example, regions in the ventral stream of visual information vs. the dorsal stream, which helps generate visuomotor behavior) are then removed. Structural subnetwork analysis showed that the intraparietal sulcus of the parietal cortex (PCIP) was most, and the secondary visual (V2) and superior parietal (PCS) cortices second-most, central to local network activity. Changing PCIP, V2 and PCS activity was thus most likely to alter activity of the entire subnetwork. Model sufficiency was tested by instantiating each brain region’s inherent activity with multiple versions of a simple two-dimensional (2D) model that can produce oscillatory activity and synaptically interconnecting the regions to produce a macroscopic visuomotor model. The model reproduced the experimental local field potential (LFP) activity of the brain regions identified as part of the visuomotor subnetwork.
Mitochondrial dysfunction heightens the integrated stress response to drive ALS pathogenesis
Authors: Landry Curran , Costanzo James , Mitne-Neto Miguel , Zatz Mayana , Schaffer Ashleigh , Hatzoglou Maria , Muotri Alysson , Miranda Helen Cristina 
Published: May 2024

ABSTRACTVesicle-associated membrane protein-associated protein-B (VAPB) is an ER membrane bound protein. VAPB P56S causes a dominant, familial form of amyotrophic lateral sclerosis (ALS), however, the mechanism through which this mutation causes motor neuron (MN) disease remains unknown. Using inducible wild type (WT) and VAPB P56S expressing iPSC-derived MNs we show that VAPB P56S, but not WT, protein decreased neuronal firing and mitochondrial-ER contact (MERC) with an associated age-dependent decrease in mitochondrial membrane potential (MMP); all typical characteristics of MN-disease. We further show that VAPB P56S expressing iPSC-derived MNs have enhanced age-dependent sensitivity to ER stress. We identified elevated expression of the master regulator of the Integrated Stress Response (ISR) marker ATF4 and decreased protein synthesis in the VAPB P56S iPSC-derived MNs. Chemical inhibition of ISR with the compound, ISRIB, rescued all MN disease phenotype in VAPB P56S MNs. Thus, our results not only support ISR inhibition as a potential therapeutic target for ALS patients, but also provides evidence to pathogenesis.
Oxidized low-density lipoprotein potentiates angiotensin II-induced Gq activation through the AT1-LOX1 receptor complex: Implications for renal dysfunction
Authors: Ihara Jittoku , Huang Yibin , Takami Yoichi , Nozato Yoichi , Takahashi Toshimasa , Kakino Akemi , Wang Cheng , Wang Ziwei , Guo Yu , Liu Weidong , Yin Nanxiang , Ohara Ryoichi , Fujimoto Taku , Yoshida Shino , Hongyo Kazuhiro , Koriyama Hiroshi , Akasaka Hiroshi , Takeshita Hikari , Sakai Shinsuke , Inoue Kazunori , Isaka Yoshitaka , Rakugi Hiromi , Sawamura Tatsuya , Yamamoto Koichi 
Published: May 2024

AbstractChronic kidney disease (CKD) and atherosclerotic heart disease, frequently associated with dyslipidemia and hypertension, represent significant health concerns. We investigated the interplay among these conditions, focusing on the role of oxidized low-density lipoprotein (oxLDL) and angiotensin II (Ang II) in renal injury via G protein αq subunit (Gq) signaling. We hypothesized that oxLDL enhances Ang II-induced Gq signaling via the AT1 (Ang II type 1 receptor)-LOX1 (lectin-like oxLDL receptor) complex. Based on CHO and renal cell model experiments, oxLDL alone did not activate Gq signaling. However, when combined with Ang II, it significantly potentiated Gq-mediated inositol phosphate 1 production and calcium influx in cells expressing both LOX-1 and AT1 but not in AT1-expressing cells. This suggests a critical synergistic interaction between oxLDL and Ang II in the AT1-LOX1 complex. Conformational studies using AT1 biosensors have indicated a unique receptor conformational change due to the oxLDL-Ang II combination. In vivo, wild-type mice fed a high-fat diet with Ang II infusion presented exacerbated renal dysfunction, whereas LOX-1 knockout mice did not, underscoring the pathophysiological relevance of the AT1-LOX1 interaction in renal damage. These findings highlight a novel mechanism of renal dysfunction in CKD driven by dyslipidemia and hypertension and suggest the therapeutic potential of AT1-LOX1 receptor complex in patients with these comorbidities.
SAUSI: an integrative assay for measuring social aversion and motivation
Authors: Grammer Jordan , Valles Rene , Bowles Alexis , Zelikowsky Moriel 
Published: May 2024

ABSTRACTSocial aversion is a key feature of numerous mental health disorders such as Social Anxiety and Autism Spectrum Disorders. Nevertheless, the biobehavioral mechanisms underlying social aversion remain poorly understood. Progress in understanding the etiology of social aversion has been hindered by the lack of comprehensive tools to assess social aversion in model systems. Here, we created a new behavioral task – Selective Access to Unrestricted Social Interaction (SAUSI), which integrates elements of social motivation, hesitancy, decision-making, and free interaction to enable the wholistic assessment of social aversion in mice. Using this novel assay, we found that social isolation-induced social aversion in mice is largely driven by increases in social fear and social motivation. Deep learning analyses revealed a unique behavioral footprint underlying the socially aversive state produced by isolation, demonstrating the compatibility of modern computational approaches with SAUSI. Social aversion was further assessed using traditional assays – including the 3-chamber sociability assay and the resident intruder assay – which were sufficient to reveal fragments of a social aversion phenotype, including changes to either social motivation or social interaction, but which failed to provide a wholistic assessment of social aversion. Critically, these assays were not sufficient to reveal key components of social aversion, including social freezing and social hesitancy behaviors. Lastly, we demonstrated that SAUSI is generalizable, as it can be used to assess social aversion induced by non-social stressors, such as foot shock. Our findings debut a novel task for the behavioral toolbox – one which overcomes limitations of previous assays, allowing for both social choice as well as free interaction, and offers a new approach for assessing social aversion in rodents.