bluuebunny/crossref_metadata_2025_split huggingface dataset:
Brief and diverse excitotoxic insults cause an increase in neuronal nuclear membrane permeability in the neonatal brain
Authors: Suryavanshi P. , Langton R. , Fairhead K. , Glykys J. 
Published: August 2023

AbstractNeuronal swelling after excitotoxic insults is implicated in neuronal injury and death in the developing brain, yet mitigating brain edema with osmotic and surgical interventions yields poor clinical outcomes. Importantly, neuronal swelling and its downstream consequences during early brain development remain poorly investigated. Using multiphoton Ca2+imagingin vivo(P12-17) and in acute brain slices (P8-12), we explored Ca2+-dependent downstream effects after neuronal cytotoxic edema. We observed the translocation of cytosolic GCaMP6s into the nucleus of a subpopulation of neurons minutes after various excitotoxic insults. We used automated morphology-detection algorithms for neuronal segmentation and quantified the nuclear translocation of GCaMP6s as the ratio of nuclear and cytosolic intensity (N/C ratio). Elevated neuronal N/C ratios were correlated to higher Ca2+loads and could occur independently of neuronal swelling. Electron microscopy revealed that the nuclear translocation was associated with increased nuclear pore size. Inhibiting calpains prevented elevated N/C ratios and neuronal swelling. Thus, our results indicate altered nuclear transport in a subpopulation of neurons shortly after injury in the developing brain, which can be used as an early biomarker of acute neuronal injury.
The ventral tegmental area dopamine to lateral amygdala projection supports cocaine cue associative learning
Authors: Smith Dana M. , Torregrossa Mary M. 
Published: August 2023

AbstractLearning and memory mechanisms are critically involved in drug craving and relapse. Environmental cues paired with repeated drug use acquire incentive value such that exposure to the cues alone can trigger craving and relapse. The amygdala, particularly the lateral amygdala (LA), underlies cue-related learning processes that assign valence to environmental stimuli including drug-paired cues. Evidence suggests that the ventral tegmental area (VTA) dopamine (DA) projection to the LA participates in encoding reinforcing effects that act as a US in conditioned cue reward-seeking as DA released in the amygdala is important for emotional and behavioral functions. Here we used chemogenetics to manipulate these VTA DA inputs to the LA to determine the role of this projection for acquisition of drug-cue associations and reinstatement of drug-seeking. We found inhibiting DA input to the LA during cocaine self-administration slowed acquisition and weakened the ability of the previously cocaine-paired cue to elicit cocaine-seeking. Conversely, exciting the projection during self-administration boosted the salience of the cocaine-paired cue as indicated by enhanced responding during cue-induced reinstatement. Importantly, interfering with DA input to the LA had no impact on the ability of cocaine to elicit a place preference or induce reinstatement in response to a priming cocaine injection. Overall, we show that manipulation of projections underlying DA signaling in the LA may be useful for developing therapeutic interventions for substance use disorders.
Extreme high-elevation mammal surveys reveal unexpectedly high upper range limits of Andean mice
Authors: Storz Jay F. , Quiroga-Carmona Marcial , Liphardt Schuyler , Bautista Naim M. , Opazo Juan C. , Rico Cernohorska Adriana , Salazar-Bravo Jorge , Good Jeffrey M. , D’Elía Guillermo 
Published: August 2023

ABSTRACTIn the world’s highest mountain ranges, uncertainty about the upper elevational range limits of alpine animals represents a critical knowledge gap regarding the environmental limits of life and presents a problem for detecting range shifts in response to climate change. Here we report results of mountaineering mammal surveys in the Central Andes, which led to the discovery of multiple species of mice living at extreme elevations that far surpass previously assumed range limits for mammals. We live-trapped small mammals from ecologically diverse sites spanning >6700 m of vertical relief, from the desert coast of northern Chile to the summits of the highest volcanoes in the Andes. We used molecular sequence data and whole-genome sequence data to confirm the identities of species that represent new elevational records and to test hypotheses regarding species limits. These discoveries contribute to a new appreciation of the environmental limits of vertebrate life.
Preclinical evaluation of the efficacy and safety of AAV1-hOTOF in mice and non-human primates
Authors: Zhang Longlong , Wang Hui , Xun Mengzhao , Tang Honghai , Wang Jinghan , Lv Jun , Zhu Biyun , Chen Yuxin , Wang Daqi , Hu Shaowei , Gao Ziwen , Liu Jianping , Chen Zheng-Yi , Chen Bing , Li Huawei , Shu Yilai 
Published: August 2023

AbstractPathogenic mutations in theOTOFgene cause autosomal recessive hearing loss 9 (DFNB9), one of the most common forms of auditory neuropathy. There is no biological treatment for DFNB9. Here, we designed anOTOFgene therapy agent by dual AAV1 carrying humanOTOFcoding sequences with the expression driven by the hair cell-specific promoterMyo15, AAV1-hOTOF. To develop a clinical application of AAV1-hOTOF gene therapy, we evaluated its efficacy and safety in animal models by pharmacodynamics, behavior, and histopathology. AAV1-hOTOF inner ear delivery significantly improved hearing inOtof−/−mice without affecting normal hearing in wild-type mice. AAV1 was predominately distributed to the cochlea although it was detected in other organs such as the central nervous system and the liver, and no obvious toxic effects of AAV1-hOTOF were observed in mice. To further evaluate the safety ofMyo15promoter-driven AAV1-transgene, AAV1-GFP was delivered into the inner ear ofMacaca fascicularisvia the round window membrane. AAV1-GFP transduced 60-94% of the inner hair cells along the cochlear turns. AAV1-GFP was detected in isolated organs and no significant adverse effects were detected. These results suggest that AAV1-hOTOF is well tolerated and effective in animals, providing critical support for its clinical translation.
Overestimation in time reproduction: Influences of accuracy feedback and attentional sharing
Authors: Chen Lingyue , Shi Zhuanghua 
Published: August 2023

AbstractDuration reproduction is often subjective to biases, with a general tendency to overestimate durations, which has been observed in many studies. Yet, this overestimation is frequently dismissed as a nuisance error, and its underlying mechanisms remain elusive. Here, we conducted two experiments to investigate this general overestimation in duration reproduction. To pin down the origin of the error, we manipulated the reproduction output through shortened visual feedback in Experiment 1, while varying the presence of accuracy feedback in Experiment 2. Across both experiments, we observed a consistent overestimation in reproduction when accuracy feedback was absent. This overestimation, amounting to approximately 13.5% on a ratio basis across different durations and sessions, was unaffected by shortened visual feedback. We propose that this consistent overestimation is likely due to the attentional sharing between the action execution and the monitoring of the passage of time during the reproduction process.
Apoptosis-mediated ADAM10 activation removes a mucin barrier promoting T cell efferocytosis
Authors: Drexhage Linnea Z. , Zhang Shengpan , DuPont Maeva , Ragaller Franziska , Sjule Ellen , Caballero Jose Cabezas , Deimel Lachlan , Robertson Helen , Russell Rebecca A , Dushek Omer , Sezgin Erdinc , Karaji Niloofar , Sattentau Quentin J 
Published: August 2023

AbstractEfferocytic clearance of apoptotic cells in general, and T cells in particular, is required for tissue and immune homeostasis. Transmembrane mucins are extended glycoproteins highly expressed in the cell glycocalyx that act as a barrier to phagocytosis. Whether and how mucins may be regulated during cell death to facilitate efferocytic corpse clearance is not understood. Here we show that normal and transformed human T cells express a subset of mucins which are rapidly and selectively removed from the cell surface during apoptosis. This process is mediated by the ADAM10 sheddase, the activity of which is associated with XKR8-catalyzed flipping of phosphatidylserine to the outer leaflet of the plasma membrane. Mucin clearance enhances uptake of apoptotic T cells by macrophages, confirming mucins as an enzymatically-modulatable barrier to efferocytosis. Together these findings reveal a novel glycocalyx regulatory pathway with implications for therapeutic intervention in the clearance of normal and transformed apoptotic T cells.
Loss-of-function cancer-associated mutations in the EIF4G2 non-canonical translation initiation factor
Authors: Meril Sara , Bahlsen Marcela , Eisenstein Miriam , Savidor Alon , Levin Yishai , Bialik Shani , Pietrokovski Shmuel , Kimchi Adi 
Published: August 2023

AbstractTumor cells often exploit the protein translation machinery, resulting in enhanced protein expression essential for tumor growth. Since canonical translation initiation is often suppressed due to cell stress in the tumor microenvironment, non-canonical translation initiation mechanisms become particularly important for shaping the tumor proteome. EIF4G2 is a non-canonical translation initiation factor that mediates internal ribosome entry site [IRES] and upstream open reading frame [uORF] dependent initiation mechanisms, which can be used to modulate protein expression in cancer. Here we explored the contribution of EIF4G2 to cancer by screening the COSMIC database for EIF4G2 somatic mutations in cancer patients. Functional examination of missense mutations revealed deleterious effects on EIF4G2 protein-protein interactions, and importantly, on its ability to mediate non-canonical translation initiation. Specifically, one mutation, R178Q, led to reductions in protein expression and near complete loss-of-function. Two other mutations within the MIF4G domain specifically affected EIF4G2’s ability to mediate IRES-dependent translation initiation but not that of target mRNAs with uORFs. These results shed light on both the structure-function of EIF4G2 and its potential tumor suppressor effects.
Fatty acid desaturation and lipoxygenase pathways support trained immunity
Authors: Ferreira Anaísa V. , Alarcon-Barrera Juan Carlos , Domínguez-Andrés Jorge , Bulut Ozlem , Kilic Gizem , Debisarun Priya A. , Röring Rutger J. , Özhan Hatice N. , Terschlüsen Eva , Ziogas Athanasios , Kostidis Sarantos , Mohammed Yassene , Matzaraki Vasiliki , Renieris George , Giamarellos-Bourboulis Evangelos J , Netea Mihai G. , Giera Martin 
Published: August 2023

AbstractInfections and vaccinations can induce long-term enhanced responses of innate immune cells to heterologous stimuli, establishing ade factoinnate immunological memory termedtrained immunity. Monocytes exposed to the Bacillus Calmette-Guérin (BCG) vaccine, have a trained immunity phenotype, characterized by an increased biosynthesis of different lipid mediators (LMs) derived from long-chain polyunsaturated fatty acids (PUFAs). Pharmacological and genetic approaches showed that long-chain PUFA synthesis and lipoxygenase (LOX)-derived LMs are crucial for the BCG trained immunity responses of human monocytes. Furthermore, monocytes of healthy individuals vaccinated with BCG are enriched in 12-LOX products. The elucidation of the lipid metabolic pathways that promote innate immune memory contributes to our understanding of trained immunity and may help identify therapeutic tools and targets for the modulation of innate immune responses.
Critical importance of DNA binding for CSL protein functions in fission yeast
Authors: Marešová Anna , Oravcová Martina , Hradilová Miluše , Zemlianski Viacheslav , Häsler Robert , Převorovský Martin 
Published: August 2023

ABSTRACTCSL (CBF1/RBP-Jκ/Suppressor of Hairless/LAG-1) proteins are conserved transcription factors found in animals and fungi. In fission yeast, they regulate various cellular processes, including cell cycle progression, lipid metabolism, and cell adhesion. CSL proteins bind to DNA through their N-terminal Rel-like domain and central beta-trefoil domain. Here, we investigated the importance of DNA binding for CSL functions in the fission yeastSchizosaccharomyces pombe. We created CSL mutants with disrupted DNA binding and found that the vast majority of CSL functions depend on intact DNA binding. Specifically, DNA binding is crucial for the regulation of cell adhesion, lipid metabolism, cell cycle progression, long non-coding RNA expression, and genome integrity maintenance. Interestingly, perturbed lipid metabolism leads to chromatin structure changes, potentially linking lipid metabolism to the diverse CSL-associated phenotypes. Our study highlights the critical role of DNA binding for CSL protein functions in fission yeast.SUMMARY STATEMENTCSL transcription factors regulate a diverse set of processes, but the mechanisms are not always clear. We show thatS. pombeCSL proteins need the ability to bind DNA for most of their roles.
Integrating habitat suitability modeling with gene flow improves delineation of landscape connections among African savanna elephants
Authors: de Flamingh Alida , Alexander Nathan , Perrin-Stowe Tolulope I.N. , Donnelly Cassidy , Guldemondt Robert A.R. , Schooley Robert L. , van Aarde Rudi J. , Roca Alfred L. 
Published: August 2023

ABSTRACTAcross Africa, space for conservation is sometimes limited to formally protected areas that have become progressively more isolated. There is a need for targeted conservation initiatives such as the demarcation of landscape connections, defined as areas that encompass environmental variables that promote the natural movement of individuals between populations, which can facilitate gene flow. Landscape connections can mitigate genetic isolation, genetic drift, and inbreeding, which can occur in isolated populations in protected areas. Promoting gene flow can reduce the risk of extirpation often associated with isolated populations. Here we develop and test models for identifying landscape connections among African savannah elephant (Loxodonta africana) populations by combining habitat suitability modeling with gene flow estimates across a large region including seven countries. We find a pronounced non-linear response to unsuitable habitat, consistent with previous studies showing that non-transformed habitat models are poor predictors of gene flow. We generated a landscape connections map that considers both suitable habitats based on telemetry occurrence data and gene flow estimated as the inverse of individual genetic distance, delineating areas that are important for maintaining elephant population connectivity. Our approach represents a novel framework for developing spatially and genetically informed conservation strategies for elephants and many other taxa distributed across heterogeneous and fragmented landscapes.GRAPHICAL ABSTRACT
Turnover of retroelements and satellite DNA drives centromere reorganization over short evolutionary timescales in Drosophila
Authors: Courret Cécile , Hemmer Lucas W. , Wei Xiaolu , Patel Prachi D. , Chabot Bryce J. , Fuda Nicholas J. , Geng Xuewen , Chang Ching-Ho , Mellone Barbara , Larracuente Amanda M. 
Published: August 2023

ABSTRACTCentromeres reside in rapidly evolving, repeat-rich genomic regions, despite their essential function in chromosome segregation. Across organisms, centromeres are rich in selfish genetic elements such as transposable elements and satellite DNAs that can bias their transmission through meiosis. However, these elements still need to cooperate at some level and contribute to, or avoid interfering with, centromere function. To gain insight into the balance between conflict and cooperation at centromeric DNA, we take advantage of the close evolutionary relationships within theDrosophila simulansclade –D. simulans, D. sechellia,andD. mauritiana –and their relative,D. melanogaster. Using chromatin profiling combined with high resolution fluorescence in situ hybridization on stretched DNA, we characterize all centromeres across these species. We discovered dramatic centromere reorganization involving recurrent shifts between retroelements and satellite DNAs over short evolutionary timescales. We also reveal the recent origin (<240 Kya) of telocentric chromosomes inD. sechellia,where the X and 4thcentromeres now sit on telomere-specific retroelements. Finally, the Y chromosome centromeres, which are the only chromosomes that do not experience female meiosis, do not show dynamic cycling between satDNA and TEs. The patterns of rapid centromere turnover in these species are consistent with genetic conflicts in the female germline and have implications for centromeric DNA function and karyotype evolution. Regardless of the evolutionary forces driving this turnover, the rapid reorganization of centromeric sequences over short evolutionary timescales highlights their potential as hotspots for evolutionary innovation.
Cucurbit[7]uril Enhances Distance Measurements of Spin-Labeled Proteins
Authors: Yang Zhimin , Stein Richard A. , Pink Maren , Madzelan Peter , Ngendahimana Thacien , Rajca Suchada , Wilson Mark A. , Eaton Sandra S. , Eaton Gareth R. , Mchaourab Hassane S. , Rajca Andrzej 
Published: August 2023

ABSTRACTWe report complex formation between the chloroacetamide 2,6-diazaadamantane nitroxide radical (ClA-DZD) and cucurbit[7]uril (CB-7), for which the association constant in water,Ka= 1.9 × 106M-1, is at least one order of magnitude higher than the previously studied organic radicals. The radical is highly immobilized by CB-7, as indicated by the increase of the rotational correlation time,τrot, by a factor of 36, relative to that in the buffer solution. The X-ray structure of ClA-DZD@CB-7 shows the encapsulated DZD guest inside the undistorted CB-7 host, with the pendant group protruding outside. Upon addition of CB-7 to T4 Lysozyme (T4L) doubly spin-labeled with the iodoacetamide derivative of DZD, we observe the increase inτrotand electron spin coherence time,Tm, along with the narrowing of inter-spin distance distributions. Sensitivity of the DEER measurements at 83 K increases by a factor 4 – 9, compared to the common spin label such as MTSL, which is not affected by CB-7. Inter-spin distances of 3-nm could be reliably measured in water/glycerol up to temperatures near the glass transition/melting temperature of the matrix at 200 K, thus bringing us closer to the goal of supramolecular recognition-enabled long-distance DEER measurements at near physiological temperatures. The X-ray structure of DZD-T4L 65 at 1.12 Å resolution allows for unambiguous modeling of the DZD label (0.88 occupancy), indicating undisturbed structure and conformation of the protein.Abstract Figure
Morphological hallmarks of dopaminergic neurodegeneration are associated with altered neuron function inCaenorhabditis elegans
Authors: Clark Andrew S. , Huayta Javier , Morton Katherine S. , Meyer Joel N. , San-Miguel Adriana 
Published: August 2023

AbstractCaenorhabditis elegans(C. elegans) is an excellent model system to study neurodegenerative diseases, such as Parkinson’s disease, as it enables analysis of both neuron morphology and function in live animals. Multiple structural changes in neurons, such as cephalic dendrite morphological abnormalities, have been considered hallmarks of neurodegeneration in this model, but their relevance to changes in neuron function are not entirely clear. We sought to test whether hallmark morphological changes associated with chemically induced dopaminergic neuron degeneration, such as dendrite blebbing, breakage, and loss, are indicative of neuronal malfunction and result in changes in behavior. We adapted an established dopaminergic neuronal function assay by measuring paralysis in the presence of exogenous dopamine, which revealed clear differences betweencat-2dopamine deficient mutants, wildtype worms, anddat-1dopamine abundant mutants. Next, we integrated an automated image processing algorithm and a microfluidic device to segregate worm populations by their cephalic dendrite morphologies. We show that nematodes with dopaminergic dendrite degeneration markers, such as blebbing or breakage, paralyze at higher rates in a dopamine solution, providing evidence that dopaminergic neurodegeneration morphologies are correlated with functional neuronal outputs.
REVEALS: An Open Source Multi Camera GUI For Rodent Behavior Acquisition
Authors: Phadke Rhushikesh A. , Wetzel Austin M. , Fournier Luke A. , Sha Mingqi , Padró-Luna Nicole M. , Cruz-Martín Alberto 
Published: August 2023

ABSTRACTUnderstanding the rich behavioral data generated by mice is essential for deciphering the function of the healthy and diseased brain. However, the current landscape lacks effective, affordable, and accessible methods for acquiring such data, especially when employing multiple cameras simultaneously. We have developed REVEALS (Rodent BEhaVior Multi-camErA Laboratory AcquiSition), a graphical user interface (GUI) written in python for acquiring rodent behavioral data via commonly used USB3 cameras. REVEALS allows for user-friendly control of recording from one or multiple cameras simultaneously while streamlining the data acquisition process, enabling researchers to collect and analyze large datasets efficiently. We release this software package as a stand-alone, open-source framework for researchers to use and modify according to their needs. We describe the details of the GUI implementation, including the camera control software and the video recording functionality. We validate results demonstrating the GUI’s stability, reliability, and accuracy for capturing and analyzing rodent behavior using DeepLabCut pose estimation in both an object and social interaction assay. REVEALS can also be incorporated into other custom pipelines to analyze complex behavior, such as MoSeq. In summary, REVEALS provides an interface for collecting behavioral data from one or multiple perspectives that, combined with deep learning algorithms, will allow the scientific community to discover and characterize complex behavioral phenotypes to understand brain function better.