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Cortico-amygdala synaptic structural abnormalities produced by templated aggregation of α-synuclein.BioRxiv : the Preprint Server For... May 2024Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal α-synuclein (α-syn) inclusions termed Lewy Pathology, which are abundant in...
Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal α-synuclein (α-syn) inclusions termed Lewy Pathology, which are abundant in the amygdala. The basolateral amygdala (BLA), in particular, receives projections from the thalamus and cortex. These projections play a role in cognition and emotional processing, behaviors which are impaired in α-synucleinopathies. To understand if and how pathologic α-syn impacts the BLA requires animal models of α-syn aggregation. Injection of α-synuclein pre-formed fibrils (PFFs) into the striatum induces robust α-synuclein aggregation in excitatory neurons in the BLA that corresponds with reduced contextual fear conditioning. At early time points after aggregate formation, cortico-amygdala excitatory transmission is abolished. The goal of this project was to determine if α-syn inclusions in the BLA induce synaptic degeneration and/or morphological changes. In this study, we used C57BL/6J mice injected bilaterally with PFFs in the dorsal striatum to induce α-syn aggregate formation in the BLA. A method was developed using immunofluorescence and three-dimensional reconstruction to analyze excitatory cortico-amygdala and thalamo-amygdala presynaptic terminals closely juxtaposed to postsynaptic densities. The abundance and morphology of synapses were analyzed at 6- or 12-weeks post-injection of PFFs. α-Syn aggregate formation in the BLA did not cause a significant loss of synapses, but cortico-amygdala and thalamo-amygdala presynaptic terminals and postsynaptic densities with aggregates of α-synuclein show increased volumes, similar to previous findings in human DLB cortex, and in non-human primate models of PD. Transmission electron microscopy showed that PFF-injected mice showed reduced intervesicular distances similar to a recent study showing phospho-serine-129 α-synuclein increases synaptic vesicle clustering. Thus, pathologic α-synuclein causes major alterations to synaptic architecture in the BLA, potentially contributing to behavioral impairment and amygdala dysfunction observed in synucleinopathies.
PubMed: 38798467
DOI: 10.1101/2024.05.15.594419 -
Microbiology Spectrum May 2024Sweet orange () is one of the most important fruit crops worldwide. Virus infections in this crop can interfere with cellular processes, causing dramatic economic...
Sweet orange () is one of the most important fruit crops worldwide. Virus infections in this crop can interfere with cellular processes, causing dramatic economic losses. By performing RT-qPCR analyses, we demonstrated that citrus psorosis virus (CPsV)-infected orange plants exhibited higher levels of unprocessed microRNA (miRNA) precursors than healthy plants. This result correlated with the reported reduction of mature miRNAs species. The protein 24K, the CPsV suppressor of RNA silencing (VSR), interacts with miRNA precursors . Thus, this protein becomes a candidate responsible for the increased accumulation of unprocessed miRNAs. We analyzed 24K RNA-binding and protein-protein interaction domains and described patterns of its subcellular localization. We also showed that 24K colocalizes within nuclear D-bodies with the miRNA biogenesis proteins DICER-LIKE 1 (DCL1), HYPONASTIC LEAVES 1 (HYL1), and SERRATE (SE). According to the results of bimolecular fluorescence complementation and co-immunoprecipitation assays, the 24K protein interacts with HYL1 and SE. Thus, 24K may inhibit miRNA processing in CPsV-infected citrus plants by direct interaction with the miRNA processing complex. This work contributes to the understanding of how a virus can alter the regulatory mechanisms of the host, particularly miRNA biogenesis and function.IMPORTANCESweet oranges can suffer from disease symptoms induced by virus infections, thus resulting in drastic economic losses. In sweet orange plants, CPsV alters the accumulation of some precursors from the regulatory molecules called miRNAs. This alteration leads to a decreased level of mature miRNA species. This misregulation may be due to a direct association of one of the viral proteins (24K) with miRNA precursors. On the other hand, 24K may act with components of the cell miRNA processing machinery through a series of predicted RNA-binding and protein-protein interaction domains.
PubMed: 38785434
DOI: 10.1128/spectrum.03513-23 -
BioRxiv : the Preprint Server For... May 2024Precision nuclear run-on (PRO) sequencing (PRO-seq) is a powerful technique for mapping polymerase active sites with nucleotide resolution and measuring newly...
Precision nuclear run-on (PRO) sequencing (PRO-seq) is a powerful technique for mapping polymerase active sites with nucleotide resolution and measuring newly synthesized transcripts at both promoters and enhancer elements. The current PRO-seq protocol is time-intensive, technically challenging, and requires a large amount of starting material. To overcome these limitations, we developed rapid PRO-seq (rPRO-seq) which utilizes pre-adenylated single-stranded DNAs (AppDNA), a dimer blocking oligonucleotide (DBO), on-bead 5' RNA end repair, and column-based purification. These modifications enabled efficient transcriptome mapping within a single day (∼12 hours) increasing ligation efficiency, abolished adapter dimers, and reduced sample loss and RNA degradation. We demonstrate the reproducibility of rPRO-seq in measuring polymerases at promoters, gene bodies, and enhancers as compared to original PRO-seq protocols. Additionally, rPRO-seq is scalable, allowing for transcriptome mapping with as little as 25,000 cells. We apply rPRO-seq to study the role of Integrator in mouse hematopoietic stem and progenitor cell (mHSPC) homeostasis, identifying as an essential component of transcriptional regulation and RNA processing in mHSPC homeostasis. Overall, rPRO-seq represents a significant advance in the field of nascent transcript analyses and will be a valuable tool for generating patient-specific genome-wide transcription profiles with minimal sample requirements.
PubMed: 38766081
DOI: 10.1101/2024.05.08.593182 -
International Journal of Health... May 2024In the near future, the incidence of mosquito-borne diseases may expand to new sites due to changes in temperature and rainfall patterns caused by climate change....
BACKGROUND
In the near future, the incidence of mosquito-borne diseases may expand to new sites due to changes in temperature and rainfall patterns caused by climate change. Therefore, there is a need to use recent technological advances to improve vector surveillance methodologies. Unoccupied Aerial Vehicles (UAVs), often called drones, have been used to collect high-resolution imagery to map detailed information on mosquito habitats and direct control measures to specific areas. Supervised classification approaches have been largely used to automatically detect vector habitats. However, manual data labelling for model training limits their use for rapid responses. Open-source foundation models such as the Meta AI Segment Anything Model (SAM) can facilitate the manual digitalization of high-resolution images. This pre-trained model can assist in extracting features of interest in a diverse range of images. Here, we evaluated the performance of SAM through the Samgeo package, a Python-based wrapper for geospatial data, as it has not been applied to analyse remote sensing images for epidemiological studies.
RESULTS
We tested the identification of two land cover classes of interest: water bodies and human settlements, using different UAV acquired imagery across five malaria-endemic areas in Africa, South America, and Southeast Asia. We employed manually placed point prompts and text prompts associated with specific classes of interest to guide the image segmentation and assessed the performance in the different geographic contexts. An average Dice coefficient value of 0.67 was obtained for buildings segmentation and 0.73 for water bodies using point prompts. Regarding the use of text prompts, the highest Dice coefficient value reached 0.72 for buildings and 0.70 for water bodies. Nevertheless, the performance was closely dependent on each object, landscape characteristics and selected words, resulting in varying performance.
CONCLUSIONS
Recent models such as SAM can potentially assist manual digitalization of imagery by vector control programs, quickly identifying key features when surveying an area of interest. However, accurate segmentation still requires user-provided manual prompts and corrections to obtain precise segmentation. Further evaluations are necessary, especially for applications in rural areas.
Topics: Humans; Animals; Climate Change; Malaria; Mosquito Vectors; Remote Sensing Technology; Geographic Information Systems; Image Processing, Computer-Assisted
PubMed: 38764024
DOI: 10.1186/s12942-024-00371-w -
European Journal of Pharmacology Jul 2024Parkinson's Disease (PD) is a progressive neurodegenerative disorder expected to increase by over 50% by 2030 due to increasing life expectancy. The disease's hallmarks... (Review)
Review
Parkinson's Disease (PD) is a progressive neurodegenerative disorder expected to increase by over 50% by 2030 due to increasing life expectancy. The disease's hallmarks include slow movement, tremors, and postural instability. Impaired protein processing is a major factor in the pathophysiology of PD, leading to the buildup of aberrant protein aggregates, particularly misfolded α-synuclein, also known as Lewy bodies. These Lewy bodies lead to inflammation and further death of dopaminergic neurons, leading to imbalances in excitatory and inhibitory neurotransmitters, causing excessive uncontrollable movements called dyskinesias. It was previously suggested that a complex interplay involving hereditary and environmental variables causes the specific death of neurons in PD; however, the exact mechanism of the association involving the two primary modifiers is yet unknown. An increasing amount of research points to the involvement of epigenetics in the onset and course of several neurological conditions, such as PD. DNA methylation, post-modifications of histones, and non-coding RNAs are the primary examples of epigenetic alterations, that is defined as alterations to the expression of genes and functioning without modifications in DNA sequence. Epigenetic modifications play a significant role in the development of PD, with genes such as Parkin, PTEN-induced kinase 1 (PINK1), DJ1, Leucine-Rich Repeat Kinase 2 (LRRK2), and alpha-synuclein associated with the disease. The aberrant epigenetic changes implicated in the pathophysiology of PD and their impact on the design of novel therapeutic approaches are the primary focus of this review.
Topics: Humans; Parkinson Disease; Epigenesis, Genetic; Animals; DNA Methylation; alpha-Synuclein
PubMed: 38754537
DOI: 10.1016/j.ejphar.2024.176641 -
Nanoscale May 2024With continuous advances in medical technology, non-invasive embolization has emerged as a minimally invasive treatment, offering new possibilities in cancer therapy....
With continuous advances in medical technology, non-invasive embolization has emerged as a minimally invasive treatment, offering new possibilities in cancer therapy. Fluorescent labeling can achieve visualization of therapeutic agents , providing technical support for precise treatment. This paper introduces a novel non-invasive embolization composite material, Au NPs@(PEG-PLGTs), created through the electrostatic combination of L-cysteine-modified gold nanoparticles (Au NPs) and methoxy polyethylene glycol amine-poly[(L-glutamic acid)-(L-tyrosine)] (PEG-PLGTs). Experiments were undertaken to confirm the biocompatibility, degradability, stability and performance of this tumor therapy. The research results demonstrated a reduction in tumor size as early as the fifth day after the initial injection, with a significant 90% shrinkage in tumor volume observed after a 20-day treatment cycle, successfully inhibiting tumor growth and exhibiting excellent anti-tumor effects. Utilizing near-infrared imaging, Au NPs@(PEG-PLGTs) displayed effective fluorescence tracking within the bodies of nude BALB-c mice. This study provides a novel direction for the further development and innovation of non-invasive embolization in the field, highlighting its potential for rapid, significant therapeutic effects with minimal invasiveness and enhanced safety.
Topics: Gold; Animals; Metal Nanoparticles; Mice; Mice, Nude; Mice, Inbred BALB C; Polyethylene Glycols; Cell Line, Tumor; Humans; Hydrogen-Ion Concentration; Embolization, Therapeutic; Polyglutamic Acid
PubMed: 38752569
DOI: 10.1039/d4nr00989d -
Biology Letters May 2024Neural circuits govern the interface between the external environment, internal cues and outwardly directed behaviours. To process multiple environmental stimuli and... (Review)
Review
Neural circuits govern the interface between the external environment, internal cues and outwardly directed behaviours. To process multiple environmental stimuli and integrate these with internal state requires considerable neural computation. Expansion in neural network size, most readily represented by whole brain size, has historically been linked to behavioural complexity, or the predominance of cognitive behaviours. Yet, it is largely unclear which aspects of circuit variation impact variation in performance. A key question in the field of evolutionary neurobiology is therefore how neural circuits evolve to allow improved behavioural performance or innovation. We discuss this question by first exploring how volumetric changes in brain areas reflect actual neural circuit change. We explore three major axes of neural circuit evolution-replication, restructuring and reconditioning of cells and circuits-and discuss how these could relate to broader phenotypes and behavioural variation. This discussion touches on the relevant uses and limitations of volumetrics, while advocating a more circuit-based view of cognition. We then use this framework to showcase an example from the insect brain, the multi-sensory integration and internal processing that is shared between the mushroom bodies and central complex. We end by identifying future trends in this research area, which promise to advance the field of evolutionary neurobiology.
Topics: Cognition; Animals; Biological Evolution; Brain; Nerve Net; Insecta; Mushroom Bodies
PubMed: 38747685
DOI: 10.1098/rsbl.2023.0576 -
Frontiers in Plant Science 2024Rice blast disease caused by has long been the main cause of rice ( L.) yield reduction worldwide. The quinone external inhibitor pyraclostrobin is widely used as a...
INTRODUCTION
Rice blast disease caused by has long been the main cause of rice ( L.) yield reduction worldwide. The quinone external inhibitor pyraclostrobin is widely used as a fungicide to effectively control the spread of pathogenic fungi, including . However, can develop resistance through multiple levels of mutation, such as target protein cytb mutation G143A/S, leading to a decrease in the effectiveness of the biocide after a period of application. Therefore, uncovering the possible mutational mechanisms from multiple perspectives will further provide feasible targets for drug development.
METHODS
In this work, we determined the gene expression changes in in response to pyraclostrobin stress and their relationship with DNA methylation by transcriptome and methylome.
RESULTS
The results showed that under pyraclostrobin treatment, endoplasmic reticulum (ER)-associated and ubiquitin-mediated proteolysis were enhanced, suggesting that more aberrant proteins may be generated that need to be cleared. DNA replication and repair processes were inhibited. Glutathione metabolism was enhanced, while lipid metabolism was impaired. The number of alternative splicing events increased. These changes may be related to the elevated methylation levels of cytosine and adenine in gene bodies. Both hypermethylation and hypomethylation of differentially methylated genes (DMGs) mainly occurred in exons and promoters. Some DMGs and differentially expressed genes (DEGs) were annotated to the same pathways by GO and KEGG, including protein processing in the ER, ubiquitin-mediated proteolysis, RNA transport and glutathione metabolism, suggesting that pyraclostrobin may affect gene expression by altering the methylation patterns of cytosine and adenine.
DISCUSSION
Our results revealed that 5mC and 6mA in the gene body are associated with gene expression and contribute to adversity adaptation in . This enriched the understanding for potential mechanism of quinone inhibitor resistance, which will facilitate the development of feasible strategies for maintaining the high efficacy of this kind of fungicide.
PubMed: 38745924
DOI: 10.3389/fpls.2024.1391900 -
PLoS Biology May 2024The processing of sensory information, even at early stages, is influenced by the internal state of the animal. Internal states, such as arousal, are often characterized...
The processing of sensory information, even at early stages, is influenced by the internal state of the animal. Internal states, such as arousal, are often characterized by relating neural activity to a single "level" of arousal, defined by a behavioral indicator such as pupil size. In this study, we expand the understanding of arousal-related modulations in sensory systems by uncovering multiple timescales of pupil dynamics and their relationship to neural activity. Specifically, we observed a robust coupling between spiking activity in the mouse dorsolateral geniculate nucleus (dLGN) of the thalamus and pupil dynamics across timescales spanning a few seconds to several minutes. Throughout all these timescales, 2 distinct spiking modes-individual tonic spikes and tightly clustered bursts of spikes-preferred opposite phases of pupil dynamics. This multi-scale coupling reveals modulations distinct from those captured by pupil size per se, locomotion, and eye movements. Furthermore, coupling persisted even during viewing of a naturalistic movie, where it contributed to differences in the encoding of visual information. We conclude that dLGN spiking activity is under the simultaneous influence of multiple arousal-related processes associated with pupil dynamics occurring over a broad range of timescales.
Topics: Animals; Pupil; Geniculate Bodies; Mice; Action Potentials; Arousal; Male; Mice, Inbred C57BL; Photic Stimulation; Neurons; Thalamus; Eye Movements; Time Factors; Visual Pathways
PubMed: 38743775
DOI: 10.1371/journal.pbio.3002614 -
Philosophical Transactions. Series A,... Jun 2024The Cassini mission provided evidence for a global subsurface ocean and ongoing hydrothermal activity on Enceladus, based on results from Cassini's mass spectrometers....
The Cassini mission provided evidence for a global subsurface ocean and ongoing hydrothermal activity on Enceladus, based on results from Cassini's mass spectrometers. Laboratory simulations of hydrothermal conditions on icy moons are needed to further constrain the composition of ejected ice grains containing hydrothermally altered organic material. Here, we present results from our newly established facility to simulate the processing of ocean material within the temperature range 80-150°C and the pressure range 80-130 bar, representing conditions suggested for the water-rock interface on Enceladus. With this new facility, we investigate the hydrothermal processing of triglycine (GGG) peptide and, for the first time, analyse the extracted samples using laser-induced liquid beam ion desorption (LILBID) mass spectrometry, a laboratory analogue for impact ionization mass spectrometry of ice grains in space. We outline an approach to elucidate hydrothermally processed GGG in ice grains ejected from icy moons based on characteristic differences between GGG anion and cation mass spectra. These differences are linked to hydrothermal processing and thus provide a fingerprint of hydrothermal activity on extraterrestrial bodies. These results will serve as important guidelines for biosignatures potentially obtained by a future Enceladus mission and the SUrface Dust Analyzer (SUDA) instrument onboard Europa Clipper. This article is part of the theme issue 'Dust in the Solar System and beyond'.
PubMed: 38736335
DOI: 10.1098/rsta.2023.0201