bluuebunny/crossref_metadata_2025_split huggingface dataset:
Meiotic recombination dynamics in plants with repeat-based holocentromeres shed light on the primary drivers of crossover patterning
Authors: Castellani Marco , Zhang Meng , Thangavel Gokilavani , Mata Sucre Yennifer , Lux Thomas , Campoy José A. , Marek Magdalena , Huettel Bruno , Sun Hequan , Mayer Klaus F. X. , Schneeberger Korbinian , Marques André 
Published: April 2023

AbstractCentromeres strongly affect (epi)genomic architecture and meiotic recombination dynamics influencing the overall distribution and frequency of crossovers. Here, we studied how recombination is regulated and distributed in the holocentric plantRhynchospora breviuscula, a species lacking localised centromeres. Combining immunocytochemistry, chromatin analysis and high-throughput single-pollen sequencing, we discovered that crossover frequency is higher at ends related to centred chromosomal regions. Contrasting the diffused distribution of (epi)genetic features and hundreds of repeat-based centromeric units. Remarkably, we found that crossovers were abolished at core centromeric units but not at their vicinity indicating the absence of a centromere effect across repeat-based holocentromeres. We further show that telomere-led pairing and synapsis of homologous chromosomes appear to be the primary force determining the observed U-shaped recombination landscape. While centromere and (epi)genetic properties only affect crossover positioning locally. Our results suggest that the conserved U-shaped crossover distribution of eukaryotes is independent of chromosome compartmentalisation and centromere organisation.
Basolateral amygdala oscillations enable fear learning in a biophysical model
Authors: Cattani Anna , Arnold Don B , McCarthy Michelle , Kopell Nancy 
Published: April 2023

AbstractThe basolateral amygdala (BLA) is a key site where fear learning takes place through synaptic plasticity. Rodent research shows prominent low theta (∼3-6 Hz), high theta (∼6-12 Hz), and gamma (>30 Hz) rhythms in the BLA local field potential recordings. However, it is not understood what role these rhythms play in supporting the plasticity. Here, we create a biophysically detailed model of the BLA circuit to show that several classes of interneurons (PV, SOM, and VIP) in the BLA can be critically involved in producing the rhythms; these rhythms promote the formation of a dedicated fear circuit shaped through spike-timing-dependent plasticity. Each class of interneurons is necessary for the plasticity. We find that the low theta rhythm is a biomarker of successful fear conditioning. The model makes use of interneurons commonly found in the cortex and, hence, may apply to a wide variety of associative learning situations.SignificanceOur paper accounts for the experimental evidence showing that amygdalar rhythms exist, suggests network origins for these rhythms, and points to their central role in the mechanisms of plasticity involved in associative learning. It is one of the few papers to address high-order cognition with biophysically detailed models, which are sometimes thought to be too detailed to be adequately constrained. Our paper provides a template for how to use information about brain rhythms to constrain biophysical models. It shows in detail, for the first time, how multiple interneurons help to provide time scales necessary for some kinds of spike-timing-dependent plasticity (STDP). It spells out the conditions under which such interactions between interneurons are needed for STDP and why. Finally, our work helps to provide a framework by which some of the discrepancies in the fear learning literature might be reevaluated. In particular, we discuss issues about Hebbian plasticity in fear learning; we show in the context of our model how neuromodulation might resolve some of those issues. The model addresses issues more general than that of fear learning since it is based on interactions of interneurons that are prominent in the cortex, as well as the amygdala.
Data-based large-scale models provide a window into the organization of cortical computations
Authors: Chen Guozhang , Scherr Franz , Maass Wolfgang 
Published: April 2023

AbstractThe neocortex of the brain is one of the most powerful computing devices that exists, but it remains largely open how its computations are organized. Since the neocortex is a 2D tapestry consisting of repeating stereotypical local cortical microcircuits, a key step for solving this problem is to understand how cortical microcircuits compute. We know by now a lot about their connectivity structure and their neuron types, but we are lacking tools for elucidating causal relations between this structure and their computational function. We present a new tool for elucidating this relation: We train large-scale models of cortical microcircuits, which integrate most current knowledge about their structure, for carrying out similar computational tasks as in the brain. We show that the trained model achieves a similar computational performance as the brain, and that it reproduces experimentally found traits of cortical computation and coding that do not appear in neural network models from AI. Furthermore, we reverse-engineer how computations are organized in the model, thereby producing specific hypotheses that can be tested in experimental neuroscience. Altogether we show that cortical microcircuits provide a distinct new neural network paradigm that is of particular interest for neuromorphic engineering because it computes with highly energy-efficient sparse activity.TeaserReverse engineering of cortical computations
Brucellatargets host USP8 through the effector protein TcpB to facilitate infection of macrophages
Authors: Radhakrishnan Girish , Joshi Kiranmai , Mujumdar Varad 
Published: April 2023

AbstractBrucellaspecies are Gram-negative intracellular bacterial pathogens that cause the worldwide zoonotic disease brucellosis.Brucellacan infect many mammals, including humans and domestic and wild animals.Brucellamanipulates various host cellular processes to invade and multiply in professional and non-professional phagocytic cells. However, the host targets and their modulation byBrucellato facilitate the infection process remain obscure. Here, we report that the host Ubiquitin Specific Protease, USP8 negatively regulates the invasion ofBrucellainto macrophages through the plasma membrane receptor, CXCR4.Brucellasuppressed the expression of USP8 at its early stage of infection in the infected macrophages. Subsequent studies revealed that theBrucellaeffector protein, TIR-domain containing protein fromBrucella, TcpB plays a significant role in downregulating the expression of USP8 by targeting the CREB pathway. Treatment of mice with USP8 inhibitor resulted in enhanced survival ofB. melitensis,whereas mice treated with CXCR4 or 14-3-3 antagonist showed a diminished bacterial load. Our experimental data demonstrate a novel role of USP8 in the host defence against microbial intrusion and microbial subversion of host defences.
Cerebellar state estimation enables resilient coupling across behavioural domains
Authors: Palacios Ensor Rafael , Chadderton Paul , Friston Karl , Houghton Conor 
Published: April 2023

AbstractCerebellar computations are necessary for fine behavioural control and are thought to rely on internal probabilistic models performing state estimation. We propose that the cerebellum infers how states contextualise (i.e., interact with) each other, and coordinates extra-cerebellar neuronal dynamics underpinning a range of behaviours. To support this claim, we describe a cerebellar model for state estimation that includes states interactions, and link the underlying inference with the neuronal architecture and dynamics observed empirically. This is formalised using the free energy principle, which provides a dual perspective on a system in terms of both the dynamics of its physical – in this case neuronal – states, and the inference process they entail. As a proof of principle, we simulate cerebellar-dependent synchronisation of whisking and respiration, which are known to be tightly coupled in rodents. In summary, we suggest that cerebellar-dependent contextualisation of behaviour can explain its ubiquitous involvement in most aspects of behaviour.
Sensorimotor Confidence for Tracking Eye Movements
Authors: Goettker Alexander , Locke Shannon M. , Gegenfurtner Karl R. , Mamassian Pascal 
Published: April 2023

AbstractFor successful interactions with the world, we often have to evaluate our own performance. Such metacognitive evaluations have been studied with perceptual decisions, but much less with respect to the evaluation of our own actions. While eye movements are one of the most frequent actions we perform, we are typically unaware of them. Here, we investigated if there is any evidence for metacognitive sensitivity for the accuracy of eye movements. Participants tracked a dot cloud as it followed an unpredictable sinusoidal trajectory for six seconds, and then reported if they thought their performance was better or worse than their average tracking performance. Our results show above chance identification of better tracking behavior across all trials and also for repeated attempts of the same target trajectories. While the sensitivity in discriminating performance between better and worse trials was stable across sessions, for their judgements participants relied more on performance in the final seconds of each trial. This behavior matched previous reports when judging the quality of hand movements, although overall metacognitive sensitivity for eye movements was significantly lower. Together, these results provide an additional piece of evidence for sensorimotor confidence, and open interesting questions about why it differs across actions and how it could be related to other instances of confidence.Statement of RelevanceIn everyday life, it is often critical to be able to evaluate the quality of our own cognitive decisions and actions. However, one of our most frequent actions often does not even reach our awareness: eye movements. We investigated whether observers were able to successfully judge the accuracy of their eye movements when tracking a cloud of dots that followed an unpredictable trajectory. We found that observers were able to distinguish good from bad trials, although sensitivity was lower compared to equivalent previous reports when judging the quality of hand movements. These results add an item to the growing list of our metacognitive abilities, but critically for eye movements that we are typically unaware of. They lead to important novel questions about why metacognitive abilities differ across decisions or different types of actions, and what the potential components of metacognitive abilities might be.
Fluctuation dominated ligand binding in molten globule protein
Authors: Moulick Abhik Ghosh , Chakrabarti J. 
Published: April 2023

AbstractA molten globule (MG) state is an intermediate state of protein observed during the unfolding of the native structure. In MG states, milk proteinα-Lactalbumin (aLA) binds to oleic acid (OLA). This MG-aLA-OLA complex, popularly known as XAM-LET performs cytotoxic activities against cancer cell lines. However, the microscopic understanding of ligand recognition ability in MG state of protein is not yet explored. Motivated by this, we explore binding of bovine aLA with OLA (BAMLET) using all atom molecular dynamics(MD) simulations. We find the binding mode between MG-aLA and OLA using the conformational thermodynamics method. We also estimate the binding free energy using the umbrella sampling (US) method for both MG state and neutral state. We find that the binding free energy obtained from US is comparable with earlier experimental results. We characterize the dihedral fluctuations as the ligand is liberated from the active site of the protein using steered molecular dynamics. The long-live fluctuations occur near the ligand binding site, which eventually transfers towards Ca2+binding site as the ligand is taken away from the protein.TOC Graphic
Removal of a genomic duplication by double-nicking CRISPR restores synaptic transmission and behavior in the MyosinVA mutant mouse Flailer
Authors: Bustos Fernando J , Pandian Swarna , Haensgen Henny , Zhao Jian-Ping , Strouf Haley , Heidenreich Matthias , Swiech Lukasz , Deverman Benjamin , Gradinaru Viviana , Zhang Feng , Constantine-Paton Martha 
Published: April 2023

AbstractCopy number variations, and particularly duplications of genomic regions, have been strongly associated with various neurodegenerative conditions including autism spectrum disorder (ASD). These genetic variations have been found to have a significant impact on brain development and function, which can lead to the emergence of neurological and behavioral symptoms. Developing strategies to target these genomic duplications has been challenging, as the presence of endogenous copies of the duplicate genes often complicates the editing strategies. Using the ASD and anxiety mouse model Flailer, that contains a duplication working as a dominant negative for MyoVa, we demonstrate the use of DN-CRISPRs to remove a 700bp genomic duplicationin vitroandin vivo. Importantly, DN-CRISPRs have not been used to remove more gene regions <100bp successfully and with high efficiency. We found that editing theflailergene in primary cortical neurons reverts synaptic transport and transmission defects. Moreover, long-term depression (LTD), disrupted in Flailer animals, is recovered after gene edition. Delivery of DN-CRISPRsin vivoshows that local delivery to the ventral hippocampus can rescues some of the mutant behaviors, while intracerebroventricular delivery, completely recovers Flailer animal phenotype associated to anxiety and ASD. Our results demonstrate the potential of DN-CRISPR to efficiently (>60% editingin vivo) removelarge genomic duplications, working as a new gene therapy approach for treating neurodegenerative diseases.
Post-translational modification of SPATULA by SECRET AGENT and SPINDLY promotes organ symmetry transition at the gynoecium apex
Authors: Jiang Yuxiang , Curran-French Seamus , Koh Samuel W.H. , Jamil Iqra , Argirò Luca , Lopez Sergio , Martins Carlo , Saalbach Gerhard , Moubayidin Laila 
Published: April 2023

ABSTRACTThe establishment of organ symmetry during multicellular development is a fundamental process shared by most living organisms. Here, we investigated how twoO-glycosyltransferases ofArabidopsis thaliana, SPINDLY (SPY) and SECRET AGENT (SEC) synergistically promote a rare bilateral-to-radial symmetry transition during patterning of the plant reproductive organ, the gynoecium. SPY and SEC modify N-terminal residues of the bHLH transcription factor SPATULA (SPT)in vivoandin vitroby attachingO-fucose andO-linked-β-N-Acetylglucosamine (O-GlcNAc), to promote style development. This post-translational regulation does not impact SPT homo- and hetero-dimerisation events with INDEHISCENT (IND) and HECATE 1 (HEC1), although it enhances the affinity of SPT for the kinasePINOID(PID) gene locus to promote transcriptional repression. Our findings reveal a previously unrecognized mechanism forO-GlcNAc andO-fucose post-translational decorations in controlling style development and offer the first molecular example of a synergistic role for SEC and SPY in plant post-embryonic organ patterning.
Base editing strategies to convert CAG to CAA diminish the disease-causing mutation in Huntington's disease
Authors: Choi Doo Eun , Shin Jun Wan , Zeng Sophia , Hong Eun Pyo , Jang Jae-Hyun , Loupe Jacob M. , Wheeler Vanessa C. , Stutzman Hannah E. , Kleinstiver Benjamin P. , Lee Jong-Min 
Published: April 2023

AbstractAn expanded CAG repeat in the huntingtin gene (HTT) causes Huntington’s disease (HD). Since the length of uninterrupted CAG repeat, not polyglutamine, determines the age-at-onset in HD, base editing strategies to convert CAG to CAA are anticipated to delay onset by shortening the uninterrupted CAG repeat. Here, we developed base editing strategies to convert CAG in the repeat to CAA and determined their molecular outcomes and effects on relevant disease phenotypes. Base editing strategies employing combinations of cytosine base editors and gRNAs efficiently converted CAG to CAA at various sites in the CAG repeat without generating significant indels, off-target edits, or transcriptome alterations, demonstrating their feasibility and specificity. Candidate BE strategies converted CAG to CAA on both expanded and non-expanded CAG repeats without alteringHTTmRNA and protein levels. In addition, somatic CAG repeat expansion, which is the major disease driver in HD, was significantly decreased by a candidate BE strategy treatment in HD knock-in mice carrying canonical CAG repeats. Notably, CAG repeat expansion was abolished entirely in HD knock-in mice carrying CAA-interrupted repeats, supporting the therapeutic potential of CAG-to-CAA conversion base editing strategies in HD and potentially other repeat expansion disorders.
Tasting to preserve: An educational activity to promote children’s positive attitudes towards intraspecific diversity conservation
Authors: Pessoa Patrícia , Aboim Sara , Afonso Lisa , Lopes J. Bernardino , Sá-Pinto Xana 
Published: April 2023

AbstractOn the edge of causing the sixth big mass extinction event, the development of positive attitudes towards the conservation of intraspecific diversity from early ages is essential to overcome the biodiversity crisis we currently face. However, there is no information available on elementary school students’ attitudes toward intraspecific diversity conservation nor is there a framework available to perform such analysis. For this study we designed, implemented, and evaluated an educational activity planned for third graders (8 to 13 years old) to explore the intraspecific diversity of vegetables and to promote healthy eating habits. Additionally, a framework was developed to evaluate students’ attitudes towards intraspecific diversity conservation and applied to semi-structured interviews conducted with students before and after engaging in the educational activity. In this paper we present a reliable framework, developed aligned with the ABC model of attitudes, based on literature, and adapted to elementary school students’ responses, to evaluate students’ attitudes toward intraspecific diversity. Our results show that, before the educational activity, most students choose a non-biodiverse option, justifying this choice with the affective component of attitudes: mostly emotional factors but also aesthetic and social/cultural factors. After the educational activity, we observed a significant increase in the frequency of students that choose the biodiverse option and that justified it with the cognitive component of attitudes: mainly with biology and health knowledge factors, but also with economic and ethical knowledge factors. Our findings support the positive impact of educational activities that explore vegetable varieties on students’ attitudes toward intraspecific diversity conservation.
Tryptophan-based motifs in the LLP3 Region of the HIV-1 envelope glycoprotein cytoplasmic tail direct trafficking to the endosomal recycling compartment and mediate particle incorporation
Authors: Lerner Grigoriy , Ding Lingmei , Spearman Paul 
Published: April 2023

ABSTRACTThe HIV-1 envelope glycoprotein complex (Env) is incorporated into developing particles at the plasma membrane (PM). The cytoplasmic tail (CT) of Env is known to play an essential role in particle incorporation, while the exact mechanisms underlying this function of the CT remain uncertain. Upon reaching the PM, trafficking signals in the CT interact with host cell endocytic machinery, directing Env into endosomal compartments within the cell. Prior studies have suggested that Env must traffic through the endosomal recycling compartment (ERC) in order for Env to return to the plasma membrane (PM) site of particle assembly. Expression of a truncated form of the ERC-resident trafficking adaptor Rab11-Family Interacting Proteins C (FIP1C) resulted in CT-dependent sequestration of Env in the condensed ERC, preventing recycling of Env to the PM. In this work, the motifs within the CT responsible for ERC localization of Env were systematically mapped. A small deletion encompassing the N-terminal portion of LLP3 eliminated ERC localization. Site-directed mutagenesis identified two tryptophan-based motifs (WE790-791and WW796-797) within the N-terminus of LLP3 that were essential for ERC localization of Env. Mutant viruses bearing substitutions in these motifs were deficient in Env incorporation, with a corresponding loss of particle infectivity and a significant defect in replication in a spreading infection assay. These results identify two tryptophan-based motifs at the N-terminal portion of LLP3 that mediate ERC localization and Env incorporation, providing additional supporting evidence for the importance of cellular recycling pathways in HIV-1 particle assembly.IMPORTANCEThe HIV-1 envelope glycoprotein (Env) is an essential component of the virus, and has an exceedingly long cytoplasmic tail (CT). Previous studies have suggested that trafficking signals in the CT interact with host factors to regulate the incorporation of Env into particles. One particular area of interest is termed lentiviral lytic peptide 3 (LLP3), as small deletions in this region have been shown to disrupt Env incorporation. In this study, we identify a small region within LLP3 that regulates how Env associates with cellular recycling compartments. Mutants that reduced or eliminated Env from the recycling compartment also reduced Env incorporation into particles. These findings emphasize the importance of two tryptophan motifs in LLP3 to the incorporation of Env into particles, and provide additional support for the idea that the CT interacts with host recycling pathways to determine particle incorporation.