Biology subjects

Cai, C.

Publications and source records attributed to Cai, C..

At least 55 records · Page 3Linked to original sources

bioRxiv2024

Suppression of T cell function by phosphoethanolamine, a metabolite enriched in tumor interstitial fluid

Nutrient stress represents a significant barrier for antitumor immunity, and tumor interstitial fluid (TIF) often contains metabolites that hinder immune function. However, it is difficult to isolate the effects of tumor nutrient stress from other suppressive factors. Thus, we employed a chemically-defined cell culture medium based on the metabolomic profile of TIF: Tumor Interstitial Fluid Medium (TIFM). Culture of CD8+ T cells in TIFM limited cell expansion and impaired CD8+ T cell effector functions upon restimulation, suggesting tumor nutrient stress alone is sufficient to drive T cell dysfunction. We identified phosphoethanolamine (pEtn), a phospholipid intermediate, as a driver of T cell dysfunction. pEtn dampened TCR signaling by depleting T cells of diacylglycerol required for TCR signal transduction. Reduction of pEtn accumulation in tumors improved intratumoral T cell function and tumor control, suggesting pEtn accumulation plays a dominant role in TME immunosuppression.

immunology↗

bioRxiv2024

Spatial Single-cell Analysis Decodes Cortical Layer and Area Specification

The human cerebral cortex, pivotal for advanced cognitive functions, is composed of six distinct layers and dozens of functionally specialized areas1,2. The layers and areas are distinguished both molecularly, by diverse neuronal and glial cell subtypes, and structurally, through intricate spatial organization3,4. While single-cell transcriptomics studies have advanced molecular characterization of human cortical development, a critical gap exists due to the loss of spatial context during cell dissociation5,6,7,8. Here, we utilized multiplexed error-robust fluorescence in situ hybridization (MERFISH)9, augmented with deep-learning-based cell segmentation, to examine the molecular, cellular, and cytoarchitectural development of human fetal cortex with spatially resolved single-cell resolution. Our extensive spatial atlas, encompassing 16 million single cells, spans eight cortical areas across four time points in the second and third trimesters. We uncovered an early establishment of the six-layer structure, identifiable in the laminar distribution of excitatory neuronal subtypes by mid-gestation, long before the emergence of cytoarchitectural layers. Notably, while anterior-posterior gradients of neuronal subtypes were generally observed in most cortical areas, a striking exception was the sharp molecular border between primary (V1) and secondary visual cortices (V2) at gestational week 20. Here we discovered an abrupt binary shift in neuronal subtype specification at the earliest stages, challenging the notion that continuous morphogen gradients dictate mid-gestation cortical arealization6,10. Moreover, integrating single-nuclei RNA-sequencing and in situ whole transcriptomics revealed an early upregulation of synaptogenesis in V1-specific Layer 4 neurons, suggesting a role of synaptogenesis in this discrete border formation. Collectively, our findings underscore the crucial role of spatial relationships in determining the molecular specification of cortical layers and areas. This work not only provides a valuable resource for the field, but also establishes a spatially resolved single-cell analysis paradigm that paves the way for a comprehensive developmental atlas of the human brain.

neuroscience↗

bioRxiv2024

Cell-type-specific effects of autism-associated chromosome 15q11.2-13.1 duplications in human brain

Recurrent copy number variation represents one of the most well-established genetic drivers in neurodevelopmental disorders, including autism spectrum disorder (ASD). Duplication of 15q11.2-13.1 (dup15q) is a well-described neurodevelopmental syndrome that increases the risk of ASD by over 40-fold. However, the effects of this duplication on gene expression and chromatin accessibility in specific cell types in the human brain remain unknown. To identify the cell-type-specific transcriptional and epigenetic effects of dup15q in the human frontal cortex we conducted single-nucleus RNA-sequencing and multi-omic sequencing on dup15q cases (n=6) as well as non-dup15q ASD (n=7) and neurotypical controls (n=7). Cell-type-specific differential expression analysis identified significantly regulated genes, critical biological pathways, and differentially accessible genomic regions. Although there was overall increased gene expression across the duplicated genomic region, cellular identity represented an important factor mediating gene expression changes. Neuronal subtypes, showed greater upregulation of gene expression across a critical region within the duplication as compared to other cell types. Genes within the duplicated region that had high baseline expression in control individuals showed only modest changes in dup15q, regardless of cell type. Of note, dup15q and ASD had largely distinct signatures of chromatin accessibility, but shared the majority of transcriptional regulatory motifs, suggesting convergent biological pathways. However, the transcriptional binding factor motifs implicated in each condition implicated distinct biological mechanisms; neuronal JUN/FOS networks in ASD vs. an inflammatory transcriptional network in dup15q microglia. This work provides a cell-type-specific analysis of how dup15q changes gene expression and chromatin accessibility in the human brain and finds evidence of marked cell-type-specific effects of this genetic driver. These findings have implications for guiding therapeutic development in dup15q syndrome, as well as understanding the functional effects CNVs more broadly in neurodevelopmental disorders.

genetics↗

bioRxiv2024

Non-physiologic interaction of MG53 with insulin receptor and lack of evidence for MG53's role in controlling insulin-stimulated Akt phosphorylation in muscle, heart and liver tissues.

RationaleMG53s known function in facilitating tissue repair and anti-inflammation has broad applications to regenerative medicine. There is controversy regarding MG53s role in the development of type 2 diabetes mellitus (T2DM). ObjectiveThis study aims to address this controversy - whether MG53s myokine function contributes to inhibition of insulin signaling in muscle, heart, and liver tissues. Study DesignWe determined the binding affinity of the recombinant human MG53 (rhMG53) to the insulin receptor extracellular domain (IR-ECD) and found low affinity of interaction with Kd (>480 nM). Using cultured C2C12 myotubes and HepG2 cells, we found no effect of rhMG53 on insulin-stimulated Akt phosphorylation (p-Akt). We performed in vivo assay with C57BL/6J mice subjected to insulin stimulation (1 U/kg, intraperitoneal injection) and observed no effect of rhMG53 on insulin-stimulated p-Akt in muscle, heart and liver tissues. ConclusionOverall, our data suggest that rhMG53 can bind to the IR-ECD, however has a low likelihood of a physiologic role, as the Kd for binding is [~]10,000 higher than the physiologic level of MG53 present in the serum of rodents and humans ([~]10 pM). Our findings question the notion proposed by Xiao and colleagues - whether targeting circulating MG53 opens a new therapeutic avenue for T2DM and its complications.

physiology↗

bioRxiv2024

A new story of four Hexapoda classes: Protura as the sister to all other hexapods

Insects represent the most diverse animal group, yet previous phylogenetic analyses based on the morphological and molecular data have failed to agree on the evolutionary relationships of early insects and their six-legged relatives (together constituting the clade Hexapoda). In particular, the phylogenetic positions of the three early-diverging hexapod groups, the coneheads (Protura), springtails (Collembola), and two-pronged bristletails (Diplura), have been debated for over a century, with alternative topologies implying drastically different scenarios of the evolution of the insect body plan and hexapod terrestrialisation. We addressed this issue by sampling of all hexapod orders, and experimented with a broad range of across-site compositional heterogeneous models designed to tackle ancient divergences. Our analyses support Protura as the earliest-diverging hexapod lineage (Protura-sister) and Collembola as a sister group to the Diplura, a clade we refer to as Antennomusculata characterised by the shared possession of internal muscles in the antennal flagellum. The universally recognized Ellipura hypothesis is recovered under the site-homogenous LG model. Our cross-validation analysis shows that the CAT-GTR model that recovers Protura-sister fits significantly better than homogenous model. Furthermore, as a very unusual group, Protura as the first diverging lineage of hexapods is also supported by other lines of evidence, such as mitogenomics, comparative embryology, and sperm morphology. The backbone phylogeny of hexapods recovered in this study will facilitate the exploration of the underpinnings of hexapod terrestrialisation and mega-diversity.

evolutionary biology↗

bioRxiv2023

Synthetic Lethality Screening with Recursive Feature Machines

Synthetic lethality refers to a genetic interaction where the simultaneous perturbation of gene pairs leads to cell death. Synthetically lethal gene pairs (SL pairs) provide a potential avenue for selectively targeting cancer cells based on genetic vulnerabilities. The rise of large-scale gene perturbation screens such as the Cancer Dependency Map (DepMap) offers the opportunity to identify SL pairs automatically using machine learning. We build on a recently developed class of feature learning kernel machines known as Recursive Feature Machines (RFMs) to develop a pipeline for identifying SL pairs based on CRISPR viability data from DepMap. In particular, we first train RFMs to predict viability scores for a given CRISPR gene knockout from cell line embeddings consisting of gene expression and mutation features. After training, RFMs use a statistical operator known as average gradient outer product to provide weights for each feature indicating the importance of each feature in predicting cellular viability. We subsequently apply correlation-based filters to re-weight RFM feature importances and identify those features that are most indicative of low cellular viability. Our resulting pipeline is computationally efficient, taking under 3 minutes for analyzing all 17, 453 knockouts from DepMap for candidate SL pairs. We show that our pipeline more accurately recovers experimentally verified SL pairs than prior approaches. Moreover, our pipeline finds new candidate SL pairs, thereby opening novel avenues for identifying genetic vulnerabilities in cancer.

bioinformatics↗

bioRxiv2023

Investigation of contributions from cortical and subcortical brain structures for speech decoding

Language impairments often arise from severe neurological disorders, prompting the development of neural prosthetics based on electrophysiological signals for the restoration of comprehensible language information. Previous decoding efforts have focused mainly on signals from the cerebral cortex, neglecting the potential contributions of subcortical brain structures to speech decoding in brain-computer interfaces (BCIs). This study aims to explore the role of subcortical structures for speech decoding by utilizing stereotactic electroencephalography (sEEG). Two native Mandarin Chinese speakers, who underwent sEEG implantation for pharmaco-resistant epilepsy, participated in this study. sEEG contacts were primarily located in the superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus, thalamus, hippocampus, insular gyrus, amygdala, and parahippocampal gyrus. The participants were asked to read Chinese text, which included 407 Chinese characters (covering all Chinese syllables), displayed on a screen after receiving prompts. 1-30, 30-70 and 70-150 Hz frequency band powers of sEEG signals were used as key features. A deep learning model based on long short-term memory (LSTM) was developed to evaluate the contribution of different brain structures during encoding of speech. Prediction of speech characteristics of consonants (articulatory place and manner) and tone within single words based on the selected features and electrode contact locations was made. Cortical signals were generally better at articulatory place prediction (86.5% accuracy, chance level = 12.5%), while cortical and subcortical signals predicted articulatory manner at similar level (51.5% vs 51.7% accuracy, respectively, chance level = 14.3%). Subcortical signals generated better prediction for tone (around 58.3% accuracy, chance level = 25%). Superior temporal gyrus remains highly relevant during speech decoding for both consonants and tone. Prediction reached the highest level when cortical and subcortical inputs were combined, especially for tone prediction. Our findings indicate that both cortical and subcortical structures can play crucial roles for speech decoding, each contributing to different aspects of speech.

neuroscience↗

bioRxiv2023

Asymmetric distribution of color-opponent response types across mouse visual cortex supports superior color vision in the sky

Color is an important visual feature that informs behavior, and the retinal basis for color vision has been studied across various vertebrate species. While many studies have investigated how color information is processed in visual brain areas of primate species, we have limited understanding of how it is organized beyond the retina in other species, including most dichromatic mammals. In this study, we systematically characterized how color is represented in the primary visual cortex (V1) of mice. Using large-scale neuronal recordings and a luminance and color noise stimulus, we found that more than a third of neurons in mouse V1 are color-opponent in their receptive field center, while the receptive field surround predominantly captures luminance contrast. Furthermore, we found that color-opponency is especially pronounced in posterior V1 that encodes the sky, matching the statistics of natural scenes experienced by mice. Using unsupervised clustering, we demonstrate that the asymmetry in color representations across cortex can be explained by an uneven distribution of green-On/UV-Off color-opponent response types that are represented in the upper visual field. Finally, a simple model with natural scene-inspired parametric stimuli shows that green-On/UV-Off color-opponent response types may enhance the detection of "predatory"-like dark UV-objects in noisy daylight scenes. The results from this study highlight the relevance of color processing in the mouse visual system and contribute to our understanding of how color information is organized in the visual hierarchy across species.

neuroscience↗

bioRxiv2023

Novel psilocin prodrugs with altered pharmacological properties as candidate therapies for treatment-resistant anxiety disorders

The psychedelic compound psilocybin has shown therapeutic benefit in the treatment of numerous psychiatric diseases. A recent randomized clinical trial conducted at Johns Hopkins Bayview Medical Center demonstrated the efficacy of psilocybin-assisted therapy in the treatment of Major Depressive Disorder (MDD). Similarly, a phase IIb study evaluating psilocybin-assisted therapy for treatment-resistant depression (TRD) presented statistically meaningful and long-term reduction in depressive symptoms. Also, many studies have reported the successful treatment of severe anxiety after a single oral dose of psilocybin, especially in patients struggling with cancer-related distress (CRD). Despite these compelling clinical results, concerns regarding the duration of the psychedelic experience produced by psilocybin pose a significant barrier to its widespread therapeutic application. Psilocybin, derived from magic mushrooms is the naturally occurring prodrug of the neuroactive compound psilocin. When orally administered, exposure to the acidic gastrointestinal (GI) environment together with enzymatic processing by intestinal and hepatic alkaline phosphatase lead to the dephosphorylation of psilocybin producing elevated levels of systemic psilocin. These plasma levels are detectable up to 24 h and produce a psychoactive episode lasting as long as 6 h post-ingestion. In order to positively modify the kinetics of the acute psychedelic response, we have engineered a library of novel prodrug derivatives (NPDs) of psilocin, introducing a diversity of alternative metabolically cleavable moieties modified at the 4-carbon position of the core indole ring. This library consists of twenty-eight unique compounds represented by nine distinct prodrug classes. Each molecule was screened in vitro for metabolic stability using isolated human serum, and human cellular fractions derived from liver and intestinal tissues. This screen revealed fifteen prodrugs that produced measurable levels of psilocin in vitro, with ester and thiocarbonate-based prodrug derivatives significantly represented. These fifteen NPDs were further evaluated for pharmacokinetic (PK) profiles in mice, assessing plasma levels of both residual prodrug and resultant psilocin. PK results confirmed the efficiency of ester and thiocarbonate-based prodrug metabolism upon oral and intravenous administration, achieving levels reduced, albeit comparable to levels of psilocybin-derived psilocin. Of note, almost all NPDs tested maintained reduced overall exposure of psilocin relative to psilocybin, with no measurable levels detected at 24 h post-dose. Finally, all NPDs were screened for CNS bioavailability in healthy mice using the Head Twitch Response (HTR), a behavioural biomarker of 5-HT2A receptor stimulation and an established proxy for psychoactive potential. Interestingly, five NPDs produced peak HTR that approached or exceeded levels induced by an equivalent dose of psilocybin. Among these bioactive prodrugs, an ester-based and thiocarbonate-based molecule produced long-term anxiolytic benefit in chronically stressed mice evaluated in the marble burying psychiatric model. Overall, this screening campaign identified novel candidate prodrugs of psilocin with altered metabolic profiles and reduced pharmacological exposure, potentially attenuating the duration of the psychedelic response. These molecules still maintained the long-term psychiatric and physiological benefits characteristic of psilocybin therapy. Additionally, these modified parameters also offer the opportunity for altered routes of administration bypassing conventional oral dosing.

pharmacology and toxicology↗

bioRxiv2023

Consolidated Bioprocessing of Lignocellulosic Biomass Poplar to Produce Short-Chain Esters by Clostridium thermocellum

Consolidated bioprocessing (CBP) of lignocellulosic biomass using cellulolytic microorganisms presents a promising sustainable and economical biomanufacturing platform where enzyme production, biomass hydrolysis, and fermentation to produce biofuels, biochemicals, and biomaterials occur in a single step. However, understanding and redirecting metabolism of microorganisms to be compatible with CBP to produce non-native metabolites are limited. In this study, we metabolically engineered a cellulolytic thermophile Clostridium thermocellum and demonstrated its compatibility with CBP integrated with a mild Co-solvent Enhanced Lignocellulosic Fractionation (CELF) pretreatment for conversion of hardwood poplar into short-chain esters (i.e., ethyl acetate, ethyl isobutyrate, isobutyl acetate, isobutyl isobutyrate) with broad use as solvents, flavors, fragrances, and biofuels. A recombinant C. thermocellum engineered with deletion of carbohydrate esterases and stable overexpression of a thermostable alcohol acetyltransferase improved the target esters production without compromised deacetylation activities. We discovered these esterases exhibited promiscuous thioesterase activities and their deletion improved ester production by increasing isobutanol flux and rerouting the native electron and carbon fermentative metabolism besides their known major function of ester degradation. The total ester production could be further enhanced up to 80-fold and the composition of short-chain esters could be modified by deleting lactate biosynthesis and/or CELF-pretreated poplar under different pretreatment conditions.

bioengineering↗

bioRxiv2023

Bayesian Inference for Brain Source Imaging with Joint Estimation of Structured Low-rank Noise

The inverse problem in brain source imaging is the reconstruction of brain activity from non-invasive recordings of electroencephalography (EEG) and magnetoencephalography (MEG). One key challenge is the efficient recovery of sparse brain activity when the data is corrupted by structured noise that is low-rank noise. This is often the case when there are a few active sources of environmental noise and the MEG/EEG sensor noise is highly correlated. In this paper, we propose a novel robust empirical Bayesian framework which provides us a tractable algorithm for jointly estimating a low-rank noise covariance and brain source activity. Specifically, we use a factor analysis model for the structured noise, and infer a sparse set of variance parameters for source activity, while performing Variational Bayesian inference for the noise. One key aspect of this algorithm is that it does not require any additional baseline measurements to estimate the noise covariance from the sensor data. We perform exhaustive experiments on both simulated and real datasets. Our algorithm achieves superior performance as compared to several existing benchmark algorithms.

bioengineering↗

bioRxiv2023

Loss of Gasdermin D is protective against influenza virus-induced inflammation and mortality

Influenza virus activates cellular inflammasome pathways, which can be either beneficial or detrimental to infection outcomes. Here, we investigated the role of the inflammasome-activated pore-forming protein gasdermin D (GSDMD) during infection. Ablation of GSDMD in knockout (KO) mice significantly attenuated virus-induced weight loss, lung dysfunction, lung histopathology, and mortality compared with wild type (WT) mice, despite similar viral loads. Infected GSDMD KO mice exhibited decreased inflammatory gene signatures revealed by lung transcriptomics, which also implicated a diminished neutrophil response. Importantly, neutrophil depletion in infected WT mice recapitulated the reduced mortality and lung inflammation observed in GSDMD KO animals, while having no additional protective effects in GSDMD KOs. These findings reveal a new function for GSDMD in promoting lung neutrophil responses that amplify influenza virus-induced inflammation and pathogenesis. Targeting the GSDMD/neutrophil axis may provide a new therapeutic avenue for treating severe influenza.

immunology↗

bioRxiv2023

A cleaved METTL3 potentiates the METTL3-WTAP interaction and breast cancer progression

N6-methyladenosine (m6A) methylation of RNA by the methyltransferase complex (MTC), with core components including METTL3-METTL14 heterodimers and Wilms tumor 1-associated protein (WTAP), contributes to breast tumorigenesis, but the underlying regulatory mechanisms remain elusive. Here, we identify a novel cleaved form METTL3a (residues 239-580 of METTL3). We find that METTL3a is required for the METTL3-WTAP interaction, RNA m6A deposition, as well as cancer cell proliferation. Mechanistically, we find that METTL3a is essential for the METTL3-METTL3 interaction, which is a prerequisite step for recruitment of WTAP in MTC. Analysis of m6A sequencing data shows that depletion of METTL3a globally disrupts m6A deposition, and METTL3a mediates mTOR activation via m6A-mediated suppression of TMEM127 expression. Moreover, we find that METTL3 cleavage is mediated by proteasome in an mTOR-dependent manner, revealing positive regulatory feedback between METTL3a and mTOR signaling. Our findings reveal METTL3a as an important component of MTC, and suggest the METTL3a-mTOR axis as a potential therapeutic target for breast cancer.

cell biology↗

bioRxiv2022

Chromosome-scale genome assemblies of five different Brassica oleracea morphotypes provide insights in intraspecific diversification

Brassica oleracea is an economically important vegetable and fodder crop species that includes many morphotypes exhibiting enormous phenotypic variations. Previously, a pan-genome study based on short reads mapping approach has shown extensive structural variations between B. oleracea morphotypes. Here, to capture more complete genome sequences of B. oleracea, we report new chromosome-scale genome assemblies for five different morphotypes, namely broccoli, cauliflower, kale, kohlrabi and white cabbage, which were created by combining long-read sequencing data and Bionano DLS optical maps. The five assemblies are the most continuous and complete B. oleracea genomes to date (contig N50 > 10 Mb). Comparative analysis revealed both highly syntenic relationships and extensive structural variants among the five genomes. Dispensable and specific gene clusters accounted for ~38.19% of total gene clusters based on a pan-genome analysis including our five newly assembled genomes and four previously reported genomes. Using the pan-genome of B. oleracea and B. rapa, we revealed their different evolutionary dynamics of LTR-RTs. Furthermore, we inferred the ancestral genome of B. oleracea and the common ancestral genome of B. oleracea and B. rapa via a pan-genome approach. We observed faster WGT-derived gene loss in B. rapa than in B. oleracea before intraspecific diversification. We also revealed continuing gene loss bias during intraspecific diversification of the two species and a strong bias towards losing only one copy among the three paralogous genes. This study provides valuable genomic resources for B. oleracea improvement and insights towards understanding genome evolution during the intraspecific diversification of B. oleracea and B. rapa.

genomics↗

bioRxiv2022

CXCL12 in late-stage osteoblasts and osteocytes is required for load induced bone formation in mice

Increased physical loading of the skeleton activates new bone formation ensuring its ability to meet mechanical demands over time; however, the capacity of bone to respond to mechanical stimulation diminishes with age. Osteocytes, the cells embedded and dispersed throughout mineralized bone matrix, are master regulators of mechanoadaptation through recruitment of new bone-forming cells, the osteoblasts, via signaling to osteoprogenitors located on bone surfaces. We previously demonstrated that in vivo and in vitro mechanical stimulation significantly upregulated the chemokine C-X-C Motif Chemokine Ligand 12 (CXCL12) and its receptor, CXCR4, in osteocytes and bone lining cells, and that CXCR4 antagonism with AMD3100 attenuated in vivo load-induced bone formation. Here, we extended this work by showing that ablation of CXCL12+ cells and deletion of cxcl12 in late-stage osteoblasts and osteocytes significantly attenuated in vivo load-induced bone formation in the mouse tibia. This bone loading phenotype was rescued by treatment with recombinant CXCL12. To address mechanism, we showed that in vitro deletion of cxcl12 and cxcr4, separately, in bone marrow stromal cells resulted in significantly reduced osteogenic differentiation. Furthermore, CXCL12 treatment enhanced GSK-3b phosphorylation and {beta}-catenin translocation to the nucleus, the former of which was partially blocked by AMD3100. Finally, CXCL12 synergized Wnt signaling leading to significantly increased total {beta}-catenin protein and Axin2 expression, a Wnt signaling target gene. These findings together demonstrate that CXCL12 expression in late-stage osteoblasts and osteocytes is essential for load-induced bone formation, in part, by regulating osteogenic differentiation through activation of the Wnt signaling pathway. SignificanceSkeletal adaptation to mechanical loading is contingent on the recruitment of new osteoblasts to bone surfaces. CXCL12, a chemokine expressed by osteolineage cells, targets effector cells expressing its receptor CXCR4, including osteoprogenitors. Exogenous mechanical loading of mouse hind limbs upregulates CXCL12 in osteocytes, bone lining cells and marrow cells, while antagonizing CXCR4 led to significantly attenuated load-induced bone formation. Here, we show that CXCL12 expression in late-stage osteoblasts and osteocytes is required for load-induced bone formation. Treatment with recombinant CXCL12 rescued the bone loading phenotype suggesting that the CXCL12/CXCR4 signaling pathway may be a feasible drug target for promoting load-induced bone formation when exercise alone is insufficient to counteract low bone mass and osteoporosis.

cell biology↗

bioRxiv2022

Subcellular Redox Responses Reveal Different Cu-dependent Antioxidant Defenses between Mitochondria and Cytosol

Excess intracellular Cu perturbs cellular redox balance and thus causes diseases. However, the relationship between cellular redox status and Cu homeostasis and how such an interplay is coordinated within cellular compartments has not yet been well established. Using combined approaches of organelle-specific redox sensor Grx1-roGFP2 and non-targeted proteomics, we investigate the real-time Cu-dependent antioxidant defenses of mitochondria and cytosol in live HEK293 cells. The Cu-dependent real-time imaging experiments show that CuCl2 treatment results in increased oxidative stress in both cytosol and mitochondria. In contrast, subsequent Cu depletion by BCS, a Cu chelating reagent, lowers oxidative stress in mitochondria but causes even higher oxidative stress in the cytosol. The proteomic data reveal that several mitochondrial proteins, but not cytosolic ones, undergo significant abundance change under Cu treatments. The proteomic analysis also shows that proteins with significant changes are related to mitochondrial oxidative phosphorylation and glutathione synthesis. The differences in redox behaviors and protein profiles in different cellular compartments reveal distinct mitochondrial and cytosolic response mechanisms upon Cu-induced oxidative stress. These findings provide insights into how redox and Cu homeostasis interplay by modulating specific protein expressions at the subcellular levels, shedding light on understanding the effects of Cu-induced redox misregulation on the diseases. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=194 SRC="FIGDIR/small/500983v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@849766org.highwire.dtl.DTLVardef@efb723org.highwire.dtl.DTLVardef@1e097d5org.highwire.dtl.DTLVardef@105c62_HPS_FORMAT_FIGEXP M_FIG C_FIG

biophysics↗

bioRxiv2022

Longitudinal white matter alterations in SIVmac239 infected rhesus monkeys with and without regular cART treatment

ObjectiveWe use the SIV-mac239 infected Chinese rhesus monkeys to longitudinally investigate white matters alterations with and without regular combined antiretroviral therapy (cART) treatment, and its relationship with clinical tests. Material and methodsDiffusion tensor imaging (DTI), CD4 T cell counts, and CD4/CD8 were obtained at baseline, 10 days, 4th week,12th week, 24th week, and 36th week post virus inoculation. postinfection (wpi). Microstructural properties were examined within 76 white matter defined by DTI-WM atlas for rhesus macaques. Corrections for multiple comparisons were performed using a false discovery rate (p < 0.05, FDR). Correlation analyses between imaging markers and clinical measures (CD4 T-cell counts, CD4/CD8 ratio) were determined using Pearsons correlations. ResultsIn our model, White matter alterations in SIV-infected macaques can be detected as soon as 4 weeks post inoculation in several brain regions. And with time proceeding, the cART can reverse, relieve, or even progressive effects. CD4 T-cell count is mainly associated with DTI metrics before the cART, whereas CD4/CD8 ratio was associated with white matter alteration with and without cART. ConclusionSIV-mac239 infection can be an idol modal to explore HIV induced HIV associated brain alterations, and the first group of white matter alterations was as soon as 4 weeks post inoculation in structure next to the periventricular area. As the time progressed, cART can bring different effect to each region, including reversed, relieved, and even progressive effects. In addition, these changes are closely linked to CD4/CD8 ratio even after cART. Importance

animal behavior and cognition↗

bioRxiv2022

Altered excitatory and inhibitory neuronal subpopulation parameters are distinctly associated with tau and amyloid in Alzheimer's disease

BackgroundNeuronal and circuit level abnormalities of excitation and inhibition are shown to be associated with tau and amyloid-beta (A{beta}) in preclinical models of Alzheimers disease (AD). These relationships remain poorly understood in patients with AD. MethodsUsing empirical spectra from magnetoencephalography (MEG) and computational modeling (neural mass model; NMM) we examined excitatory and inhibitory parameters of neuronal subpopulations and investigated their specific associations to regional tau and A{beta}, measured by positron emission tomography (PET), in patients with AD. ResultsPatients with AD showed abnormal excitatory and inhibitory time-constants and neural gains compared to age-matched controls. Increased excitatory time-constants distinctly correlated with higher tau depositions while increased inhibitory time-constants distinctly correlated with higher A{beta} depositions. ConclusionsOur results provide critical insights about potential mechanistic links between abnormal neural oscillations and cellular correlates of impaired excitatory and inhibitory synaptic functions associated with tau and A{beta} in patients with AD. FundingThis study was supported by the National Institutes of Health grants: K08AG058749 (KGR), F32AG050434-01A1 (KGR), K23 AG038357 (KAV), P50 AG023501, P01 AG19724 (BLM), P50-AG023501 (BLM & GDR), R01 AG045611 (GDR); AG034570, AG062542 (WJ); NS100440 (SSN), DC176960 (SSN), DC017091 (SSN), AG062196 (SSN); a grant from John Douglas French Alzheimers Foundation (KAV); grants from Larry L. Hillblom Foundation: 2015-A-034-FEL and (KGR); 2019-A-013-SUP (KGR); a grant from the Alzheimers Association: (PCTRB-13-288476) (KAV), and made possible by Part the CloudTM, (ETAC-09-133596); a grant from Tau Consortium (GDR & WJJ), and a gift from the S. D. Bechtel Jr. Foundation.

neuroscience↗