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Results for “Pathology”

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bioRxiv2022

Vascular ultrasound for in vivo assessment of arterial pathologies in a murine model of atherosclerosis and aortic aneurysm

BackgroundVascular diseases like atherosclerosis or aortic aneurysms are common pathologies in the western world, promoting various, potentially fatal conditions. Hence, a plethora of animal models have been developed to investigate underlying mechanisms and potential therapeutics. Here we evaluate high resolution (HR) ultrasound in mouse models of atherosclerosis and abdominal aortic aneurysm (AAA) for noninvasive monitoring of morphological and functional vascular changes in vivo. MethodsEight-week-old ApoE-/- mice were used for disease models. For induction of atherosclerosis, mice were fed a western diet over 12 weeks. To trigger AAA development, osmotic minipumps were implanted, permanently releasing Angiotensin II continuously for 28 days. All animals were on C57Bl6/J background. HR vascular ultrasound of the carotid artery or the abdominal aorta was performed, respectively. Images obtained were analyzed by a speckle tracking algorithm (VevoVasc software) and were correlated with histological analyses by Picro Sirius Red staining and automated collagen quantification. ResultsArterial wall distensibility and global radial strain (GRS) as measures of arterial wall elasticity were reduced in the carotids of atherosclerotic mice as well as in the aortas of AAA mice. Pulse wave velocity (PWV) was elevated in both disease models. Intima-media thickness (IMT) was significantly increased in the atherosclerosis model. Matching those findings, area of the tunica media was enlarged in ApoE-/- mice fed a western diet, and in Angiotensin II treated mice as measured by automated image analysis, depicting higher collagen depositions in diseased arteries. Simple regression analysis revealed a strong correlation of media collagen content and area in AAA with IMT and GRS, respectively. In atherosclerosis, media collagen content significantly correlated with PWV and GRS, whereas wall distensibility was associated with the size of media area. ConclusionVascular imaging using latest generation HR ultrasound devices is suitable to trace changes of arterial wall properties in murine models of atherosclerosis and AAA. Obtained results not only correlate with histological findings but deliver information on functional parameters which may be used as early disease and risk markers in a longitudinal experimental approach.

physiology↗

bioRxiv2022

Linking acetylated alpha-Tubulin redistribution to alpha-Synuclein pathology in brain of Parkinson's disease patients

Highly specialized microtubules in neurons are crucial to the health and disease of the nervous system, and their properties are strictly regulated by different post-translational modifications, including -Tubulin acetylation. An imbalance in the levels of acetylated -Tubulin has been reported in experimental models of Parkinsons disease (PD) whereas pharmacological or genetic modulation that leads to increased acetylated -Tubulin successfully rescues axonal transport defects and inhibits -Synuclein aggregation. However, the role of acetylation of -Tubulin in the human nervous system is largely unknown as most studies are based on in vitro evidence. To capture the complexity of the pathological processes in vivo, we analysed post-mortem human brain of PD patients and control subjects. In the brain of PD patients at Braak stage 6, we found a redistribution of acetylated -Tubulin, which accumulates in the neuronal cell bodies in subcortical structures but not in the cerebral cortex, and decreases in the axonal compartment, both in the central and peripheral nervous system. High-resolution and 3D reconstruction analysis linked acetylated -Tubulin redistribution to -Synuclein oligomerization, leading us to propose a model for Lewy body (LB) morphogenesis. Finally, for the first time in post-mortem human brain, we observed threadlike structures, resembling tunnelling nanotubes that contain -Synuclein oligomers and are associated with acetylated -Tubulin enriched neurons. In conclusion, we disclose a novel aspect of LB morphogenesis, indicating the role of acetylated -Tubulin in PD, that may provide clues to design novel therapeutic interventions.

neuroscience↗

bioRxiv2023

Adult stem cell characterization from the Medial Gastrocnemius and Semitendinosus muscles in early development of cerebral palsy pathology

Cerebral palsy (CP) is one of the most common lifelong conditions leading to childhood physical disability. Literature reported previously altered muscle properties such as lower number of satellite cells (SCs), with altered fusion capacity. However, these observations highly vary among studies, possibly due to heterogeneity in patient population, lack of appropriate control data, methodology and different assessed muscle. In this study we aimed to strengthen previous observations and to understand the heterogeneity of CP muscle pathology. Myogenic differentiation of SCs from the Medial Gastrocnemius (MG) muscle of patients with CP (n=16, 3-9 years old) showed higher fusion capacity compared to age-matched typically developing children (TD, n=13). Furthermore, we uniquely assessed cells of two different lower limb muscles and showed a decreased myogenic potency in cells from the Semitendinosus (ST) compared to the MG. Longitudinal assessments, one year after the first botulinum toxin treatment, showed slightly reduced SC representations and lower fusion capacity. Finally, we proved the robustness of our data, by assessing in parallel the myogenic capacity of two samples from the same TD muscle. In conclusion, these data confirmed previous findings of increased SC fusion capacity from MG muscle of young patients with CP compared to age-matched TD. Further elaboration is reported on potential factors contributing to heterogeneity, such as assessed muscle, CP progression and reliability of primary outcome parameters.

developmental biology↗

bioRxiv2023

Region-specific homeostatic identity of astrocytes is essential for defining their reactive phenotypes following pathological insults

The transformation of astrocytes into reactive states constitutes a biological response of the central nervous system under a variety of pathological insults. Astrocytes display diverse homeostatic identities, which are developmentally predetermined and regionally specified. Upon transformation into reactive states associated with neurodegenerative diseases and other neurological disorders, astrocytes acquire diverse reactive phenotypes. However, it is not clear whether their reactive phenotypes are dictated by regionspecific homeostatic identity or, alternatively, by the nature of an insult. To address this question, regionspecific gene expression profiling was performed for four brain regions (cortex, hippocampus, thalamus and hypothalamus) in mice using a custom Nanostring panel consisting of selected sets of genes that report on astrocyte functions and their reactivity for five conditions: prion disease, traumatic brain injury, brain ischemia, 5XFAD Alzheimers disease model and normal aging. Upon transformation into reactive states, genes that are associated predominantly with astrocytes were found to preserve region-specific signatures suggesting that they respond to insults in a region-specific manner. A common gene set was found to be involved in astrocyte remodeling across insults and normal aging. Regardless of the nature of an insult or insult-specificity of astrocyte response, strong correlations between the degree of astrocyte reactivity and perturbations in their homeostasis-associated genes were observed within each individual brain region. The insult-specific populations did not separate well from each other and instead partially overlapped, forming continuums of phenotypes. The current study demonstrates that astrocytes acquire their reactive phenotypes according to their region-specific homeostatic identities. Within these region-specified identities, reactive phenotypes show continuums of states, partially overlapping between individual insults.

neuroscience↗

bioRxiv2023

5-HT4 receptor agonists treatment reduces tau pathology and behavioral deficit in the PS19 mouse model of tauopathy

Accumulation of tau in synapses in Alzheimers disease (AD) has been shown to cause synaptic damage, synaptic loss, and the spread of pathology through synaptically connected neurons. Synaptic loss correlates with a decline in cognition, providing an opportunity to investigate strategies to target synaptic tau to rescue or prevent cognitive decline. One of the promising synaptic targets is the 5-HT4 receptor present post-synaptically in the brain areas involved in the memory processes. 5-HT4R activation exerts synaptogenic and pro-cognitive effects involving synapse-to-nucleus signaling essential for synaptic plasticity. However, it is not known whether 5-HT4R activation has a therapeutic effect on tauopathy. The goal of this study was to investigate the impact of stimulation of 5-HT4R in tauopathy mice. Our results show that 5-HT4R agonism led to reduced tauopathy and synaptic tau and correlated with increased proteasome activity and improved cognitive functioning in PS19 mice. Thus, stimulation of 5-HT4R offers a promising therapy to rescue synapses from toxic synaptic tau.

neuroscience↗

bioRxiv2023

A subset of CD4+ effector memory T cells limit immunity to pulmonary viral infection and prevent tissue pathology via activation of latent TGFβ

A rapid immune response to pathogen re-exposure underpins immunological memory, with protection against divergent pathogens such as heterologous or novel viral strains requiring cross-reactive memory T cells. Understanding the pathways that control memory T cell function is therefore important for the rational design of viral vaccines and will aid the discovery of therapies to boost anti-viral immunity. Here, we identify a sub-population of memory T cells that limit secondary immune responses to viral re-infection, which is crucial in preventing host tissue damage. We show that a population of CD4+ effector memory T (TEM) cells activate the important immunoregulatory cytokine TGF{beta}, via expression of an integrin, v{beta}8. Integrin v{beta}8 expression marks a transcriptionally distinct sub-population of CD4+ TEM, enriched for anti-inflammatory pathways. Loss of integrin v{beta}8 on murine CD4+ TEM, but not Foxp3+ regulatory T cells (TREG), led to exacerbated virus-specific CD8+ T cell responses following secondary influenza A virus (IAV) infection, which was associated with enhanced viral clearance. However, although accelerating clearance, loss of integrin v{beta}8 expression on CD4+ TEM resulted in enhanced lung pathology following secondary IAV infection, which was completely reversed by adoptive transfer of v{beta}8+ CD4+ TEM cells. These data highlight a new pathway by which a distinct CD4+ memory T cell subset restrains anti-viral immunity to prevent host tissue damage during secondary viral infection. Such pathways could be targeted therapeutically to either boost memory T-cell-mediated immunity or restrain host tissue damage during viral infection.

immunology↗

bioRxiv2023

O-GlcNAc modification forces the formation of an α-Synuclein amyloid-strain with notably diminished seeding activity and pathology

The process of amyloid fibril formation remains one of the primary targets for developing diagnostics and treatments for several neurodegenerative diseases (NDDs). Amyloid-forming proteins such -Synuclein and Tau, which are implicated in the pathogenesis of Alzheimers and Parkinsons disease, can form different types of fibril structure, or strains, that exhibit distinct structures, toxic properties, seeding activities, and pathology spreading patterns in the brain. Therefore, understanding the molecular and structural determinants contributing to the formation of different amyloid strains or their distinct features could open new avenues for developing disease-specific diagnostics and therapies. In this work, we report that O-GlcNAc modification of -Synuclein monomers results in the formation of amyloid fibril with distinct core structure, as revealed by Cryo-EM, and diminished seeding activity in seeding-based neuronal and rodent models of Parkinsons disease. Although the mechanisms underpinning the seeding neutralization activity of the O-GlcNAc modified fibrils remain unclear, our in vitro mechanistic studies indicate that heat shock proteins interactions with O-GlcNAc fibril inhibit their seeding activity, suggesting that the O-GlcNAc modification may alter the interactome of the -Synuclein fibrils in ways that lead to reduce seeding activity in vivo. Our results show that post-translational modifications, such as O-GlcNAc modification, of -Synuclein are key determinants of -Synuclein amyloid strains and pathogenicity. These findings have significant implications for how we investigate and target amyloids in the brain and could possibly explain the lack of correlation between amyloid burden and neurodegeneration or cognitive decline in some subtypes of NDDs.

biochemistry↗

bioRxiv2023

Pathologic polyglutamine aggregation begins with a self-poisoning polymer crystal

A long-standing goal of amyloid research has been to characterize the structural basis of the rate-determining nucleating event. However, the ephemeral nature of nucleation has made this goal unachievable with existing biochemistry, structural biology, and computational approaches. Here, we addressed that limitation for polyglutamine (polyQ), a polypeptide sequence that causes Huntingtons and other amyloid-associated neurodegenerative diseases when its length exceeds a characteristic threshold. To identify essential features of the polyQ amyloid nucleus, we used a direct intracellular reporter of self-association to quantify frequencies of amyloid appearance as a function of concentration, conformational templates, and rational polyQ sequence permutations. We found that nucleation of pathologically expanded polyQ involves segments of three glutamine (Q) residues at every other position. We demonstrate using molecular simulations that this pattern encodes a four-stranded steric zipper with interdigitated Q side chains. Once formed, the zipper poisoned its own growth by engaging naive polypeptides on orthogonal faces, in a fashion characteristic of polymer crystals with intramolecular nuclei. We further show that self-poisoning can be exploited to block amyloid formation, by genetically oligomerizing polyQ prior to nucleation. By uncovering the physical nature of the rate-limiting event for polyQ aggregation in cells, our findings elucidate the molecular etiology of polyQ diseases.

biophysics↗

bioRxiv2023

Motor-targeted spinal stimulation promotes concurrent rebalancing of pathologic nociceptive transmission in chronic spinal cord injury

Electrical stimulation of spinal networks below a spinal cord injury (SCI) is a promising approach to restore functions compromised by inadequate excitatory neural drive. The most translationally successful examples are paradigms intended to increase neural transmission in weakened yet spared motor pathways and spinal motor networks rendered dormant after being severed from their inputs by lesion. Less well understood is whether spinal stimulation is also capable of reducing neural transmission in pathways made pathologically overactive by SCI. Debilitating spasms, spasticity, and neuropathic pain are all common manifestations of hyperexcitable spinal responses to sensory feedback. But whereas spasms and spasticity can often be managed pharmacologically, SCI-related neuropathic pain is notoriously medically refractory. Interestingly, however, spinal stimulation is a clinically available option for ameliorating neuropathic pain arising from etiologies other than SCI, and it has traditionally been assumed to modulate sensorimotor networks overlapping with those engaged by spinal stimulation for motor rehabilitation. Thus, we reasoned that spinal stimulation intended to increase transmission in motor pathways may simultaneously reduce transmission in spinal pain pathways. Using a well-validated pre-clinical model of SCI that results in severe bilateral motor impairments and SCI-related neuropathic pain, we show that the responsiveness of neurons integral to the development and persistence of the neuropathic pain state can be enduringly reduced by motor-targeted spinal stimulation while preserving spinal responses to non-pain-related sensory feedback. These results suggest that spinal stimulation paradigms could be intentionally designed to afford multi-modal therapeutic benefits, directly addressing the diverse, intersectional rehabilitation goals of people living with SCI.

neuroscience↗

bioRxiv2023

Computational pathology infer clinically relevant protein levels and drug efficacy in breast cancer by weakly supervised contrastive learning

Visual inspection of histopathology slides via optical microscope is the routine medical examination for clinical diagnosis of tumors. Recent studies have demonstrated that computational pathology not only automate the tumor diagnosis, but also showed great potential to uncover tumor-related genetic alterations and transcriptomic patterns. In this paper, we propose wsi2rppa, a weakly supervised contrastive learning framework to infer the protein levels of tumor biomarkers from whole slide images (WSIs) in breast cancer. We firstly conducted contrastive learning-based pre-training on tessellated tiles to extract histopathological features, which are then aggregated by attention pooling and adapted to downstream tasks. Our extensive experiments showed that our method achieved state-of-the-art performance in tumor diagnostic task, and also performed well in predicting clinically relevant protein levels and drug response. To show the model interpretability, we spatially visualized the WSIs colored the tiles by their attention scores, and found that the regions with high scores were highly consistent with the tumor and necrotic regions annotated by a 10-year experienced pathologist. Moreover, spatial transcriptomic data further verified that the heatmap generated by attention scores agree greatly with the spatial expression landscape of two typical tumor biomarker genes. In particular, our method achieved 0.79 AUC value in predicting the response of breast cancer patients to the drug trastuzumab treatment. These findings showed the remarkable potential of deep learning-based morphological feature is very indicative of clinically relevant protein levels, drug response and clinical outcomes.

bioinformatics↗

bioRxiv2023

Amyloid pathology impairs homeostatic inhibitory synaptic plasticity

Alzheimers disease patients and mouse models exhibit aberrant neuronal activity and altered excitatory-to-inhibitory synaptic ratio. Using multicolor two-photon microscopy, we test how amyloid pathology alters the structural dynamics of excitatory and inhibitory synapses and their adaptation to altered visual experience in vivo in the visual cortex. We show that the baseline dynamics of mature excitatory synapses and their adaptation to visual deprivation are not altered in amyloidosis. Likewise, the baseline dynamics of inhibitory synapses are not affected. In contrast, visual deprivation fails to induce inhibitory synapse loss in amyloidosis, a phenomenon observed in nonpathological conditions. Intriguingly, inhibitory synapse loss associated with visual deprivation in nonpathological mice is accompanied by the broadening of spontaneous but not visually evoked calcium transients. However, such broadening does not manifest in the context of amyloidosis. We also show that excitatory and inhibitory synapse loss is locally clustered under the nonpathological state. In contrast, a fraction of synapse loss is not locally clustered in amyloidosis, indicating an impairment in inhibitory synapse adaptation to changes in excitatory synaptic activity.

neuroscience↗

bioRxiv2023

Isolated loss of the AUTS2 long isoform, brain-wide or targeted to Calbindin-lineage cells, generates a specific suite of brain, behavioral and molecular pathologies

Rearrangements within the AUTS2 region are associated with a rare syndromic disorder with intellectual disability, developmental delay and behavioral abnormalities as core features. In addition, smaller regional variants are linked to wide range of neuropsychiatric disorders, underscoring the genes essential role in brain development. Like many essential neurodevelopmental genes, AUTS2 is large and complex, generating distinct long (AUTS2-l) and short (AUTS2-s) protein isoforms from alternative promoters. Although evidence suggests unique isoform functions, the contributions of each isoform to specific AUTS2-linked phenotypes have not been clearly resolved. Furthermore, Auts2 is widely expressed across the developing brain, but cell populations most central to disease presentation have not been determined. In this study, we focused on the specific roles of AUTS2-l in brain development, behavior, and postnatal brain gene expression, showing that brain-wide AUTS2-l ablation leads to specific subsets of the recessive pathologies associated with C-terminal mutations that disrupt both isoforms. We identify downstream genes that could explain expressed phenotypes including hundreds of putative direct AUTS2- l target genes. Furthermore, in contrast to C-terminal Auts2 mutations which lead to dominant hypoactivity, AUTS2-l loss-of-function is associated with dominant hyperactivity, a phenotype exhibited by many human patients. Finally, we show that AUTS2-l ablation in Calbindin 1-expressing cell lineages is sufficient to yield learning/memory deficits and hyperactivity with abnormal dentate gyrus granule cell maturation, but not other phenotypic effects. These data provide new clues to in vivo AUTS2-l functions and novel information relevant to genotype-phenotype correlations in the human AUTS2 region.

genetics↗

bioRxiv2023

Antibodies Raised Against an Aβ Oligomer Mimic Recognize Pathological Features in Alzheimer's Disease and Associated Amyloid-Disease Brain Tissue

Antibodies that target the {beta}-amyloid peptide (A{beta}) and its associated assemblies are important tools in Alzheimers disease research and have emerged as promising Alzheimers disease therapies. This paper reports the creation and characterization of a triangular A{beta} trimer mimic composed of A{beta}l7-36 {beta}-hairpins, and the generation and study of polyclonal antibodies raised against the A{beta} trimer mimic. The A{beta} trimer mimic is covalently stabilized by three disulfide bonds at the corners of the triangular trimer to create a homogeneous oligomer. Structural, biophysical, and cell-based studies demonstrate that the A{beta} trimer mimic shares characteristics with oligomers of full-length A{beta}: X-ray crystallography elucidates the high-resolution structure of the trimer and reveals that four copies of the trimer assemble to form a dodecamer; SDS-PAGE, size exclusion chromatography, and dynamic light scattering reveal that the trimer also forms higher-order assemblies in solution; cell-based toxicity assays show that the trimer elicits LDH release, decreases ATP levels, and activates caspase-3/7 mediated apoptosis. Tmmunostaining studies on brain slices from people who lived with Alzheimers disease as well as people who lived with Down syndrome reveal that the polyclonal antibodies raised against the A{beta} trimer mimic recognize pathological features including different types of A{beta} plaques and cerebral amyloid angiopathy. These findings suggest that the triangular trimer structural motif is important in Alzheimers disease and may thus constitute a new structurally defined molecular target for diagnostic and therapy development. SYNOPSISA structurally defined A{beta} oligomer mimic is created and studied, and antibodies raised against the A{beta} oligomer mimic are used to investigate its relevance to Alzheimers disease.

neuroscience↗

bioRxiv2023

Marginated aberrant red blood cells induce pathologic vascular stress fluctuations in a computational model of hematologic disorders

Red blood cell (RBC) disorders affect billions worldwide. While alterations in the physical properties of aberrant RBCs and associated hemodynamic changes are readily observed, in conditions such as sickle cell disease and iron deficiency, RBC disorders can also be associated with vascular dysfunction. The mechanisms of vasculopathy in those diseases remain unclear and scant research has explored whether biophysical alterations of RBCs can directly affect vascular function. Here we hypothesize that the purely physical interactions between aberrant RBCs and endothelial cells, due to the margination of stiff aberrant RBCs, play a key role in this phenomenon for a range of disorders. This hypothesis is tested by direct simulations of a cellular scale computational model of blood flow in sickle cell disease, iron deficiency anemia, COVID-19, and spherocytosis. We characterize cell distributions for normal and aberrant RBC mixtures in straight and curved tubes, the latter to address issues of geometric complexity that arise in the microcirculation. In all cases aberrant RBCs strongly localize near the vessel walls (margination) due to contrasts in cell size, shape, and deformability from the normal cells. In the curved channel, the distribution of marginated cells is very heterogeneous, indicating a key role for vascular geometry. Finally, we characterize the shear stresses on the vessel walls; consistent with our hypothesis, the marginated aberrant cells generate large transient stress fluctuations due to the high velocity gradients induced by their near-wall motions. The anomalous stress fluctuations experienced by endothelial cells may be responsible for the observed vascular inflammation. Significance StatementA common and potentially life-threatening complication of blood cell disorders is inflammation and dysfunction of the vascular wall, for reasons that remain unclear. To address this issue, we explore a purely biophysical hypothesis involving red blood cells using detailed computational simulations. Our results show that red blood cells that are pathologically altered in cell shape, size, and stiffness, which occurs in various blood disorders, strongly marginate, residing primarily in the cell-free layer near blood vessel walls, generating large shear stress fluctuations at the vessel wall that may be responsible for endothelial damage and inflammation.

biophysics↗

bioRxiv2023

Chronic activation of the aryl hydrocarbon receptor in muscle exacerbates ischemic pathology in chronic kidney disease

Chronic kidney disease (CKD) accelerates the development of atherosclerosis, decreases muscle function, and increases the risk of amputation or death in patients with peripheral artery disease (PAD). However, the cellular and physiological mechanisms underlying this pathobiology are ill-defined. Recent work has indicated that tryptophan-derived uremic toxins, many of which are ligands for the aryl hydrocarbon receptor (AHR), are associated with adverse limb outcomes in PAD. We hypothesized that chronic AHR activation, driven by the accumulation of tryptophan-derived uremic metabolites, may mediate the myopathic condition in the presence of CKD and PAD. Both PAD patients with CKD and mice with CKD subjected to femoral artery ligation (FAL) displayed significantly higher mRNA expression of classical AHR-dependent genes (Cyp1a1, Cyp1b1, and Aldh3a1) when compared to either muscle from the PAD condition with normal renal function (P<0.05 for all three genes) or non-ischemic controls. Skeletal-muscle-specific AHR deletion in mice (AHRmKO) significantly improved limb muscle perfusion recovery and arteriogenesis, preserved vasculogenic paracrine signaling from myofibers, increased muscle mass and contractile function, as well as enhanced mitochondrial oxidative phosphorylation and respiratory capacity in an experimental model of PAD/CKD. Moreover, viral-mediated skeletal muscle-specific expression of a constitutively active AHR in mice with normal kidney function exacerbated the ischemic myopathy evidenced by smaller muscle masses, reduced contractile function, histopathology, altered vasculogenic signaling, and lower mitochondrial respiratory function. These findings establish chronic AHR activation in muscle as a pivotal regulator of the ischemic limb pathology in PAD. Further, the totality of the results provide support for testing of clinical interventions that diminish AHR signaling in these conditions.

physiology↗

bioRxiv2023

SARS-CoV-2 infection leads to Tau pathological signature in neurons

BackgroundThe coronavirus disease 19 (COVID-19) has represented an issue for global health since its outbreak in March 2020. It is now evident that the SARS-CoV-2 infection results in a wide range of long-term neurological symptoms and is worryingly associated with the aggravation of Alzheimers disease. Little is known about the molecular basis of these manifestations. MethodsSeveral SARS-CoV-2 strain variants were used to infect SH-SY5Y neuroblastoma cells and K18-hACE C57BL/6J mice. The Tau phosphorylation profile and aggregation propensity upon infection were investigated using immunoblot and immunofluorescence on cellular extracts, subcellular fractions, and brain tissue. The viral proteins Spike, Nucleocapsid, and Membrane were overexpressed in SH-SY5Y cells and the direct effect on Tau phosphorylation was checked using immunoblot experiments. ResultsUpon infection, Tau is phosphorylated at several pathological epitopes associated with Alzheimers disease and other tauopathies. Moreover, this event increases Taus propensity to form insoluble aggregates and alters its subcellular localization. ConclusionsOur data support the evidence that SARS-CoV-2 infection in the Central Nervous System triggers downstream effects altering Tau function, eventually leading to the impairment of neuronal function.

neuroscience↗

bioRxiv2023

Heterogeneous subpopulations of GABAAR-responding neurons coexist in physiological and pathological mature neuronal networks at increasing scales of complexity

GABA is the main inhibitory neurotransmitter in adults. Depolarizing/excitatory GABA responses have been well characterized at the level of neuronal-population average during typical neurodevelopment and partially in pathology. However, no investigation has specifically assessed whether a mosaicism of cells with either depolarizing/excitatory or hyperpolarizing/inhibitory GABAergic responses exists in adult animals in health/disease. Here, we showed that such mosaicism is present both in adult WT and Down syndrome (DS) mice, as assessed at increasing scales of neuronal-network complexity (cultures, brain- slices, behaving mice). Nevertheless, WT mice presented a lower percentage of cells with depolarizing GABA than DS mice. Restoring the mosaicism of hyperpolarizing and depolarizing GABA-responding neurons to WT levels rescued anxiety behaviour in DS mice. We also found heterogeneous GABAergic responses in mature control and trisomic human iPSC-derived neurons. Thus, a heterogeneous population of GABA-responding cells exists in physiological/pathological conditions in mature mouse and human neurons, possibly contributing to disease-associated behaviours.

neuroscience↗

bioRxiv2023

Deep-learning Based Pathological Assessment of Frozen Procurement Kidney Biopsies Predicts Graft Loss and Guides Organ Utilization: A Large-scale Retrospective Study

BackgroundLesion scores on procurement donor biopsies are commonly used to guide organ utilization. However, frozen sections present challenges for histological scoring, leading to inter- and intra-observer variability and inappropriate discard. MethodsWe constructed deep-learning based models to recognize kidney tissue compartments in H&E stained sections from procurement biopsies performed at 583 hospitals nationwide in year 2011-2020. The models were trained and tested respectively on 11473 and 3986 images sliced from 100 slides. We then extracted whole-slide abnormality features from 2431 kidneys, and correlated with pathologists scores and transplant outcomes. Finally, a Kidney Donor Quality Score (KDQS) incorporating digital features and the Kidney Donor Profile Index (KDPI) was derived and used in combination with recipient demographic and peri-transplant characteristics to predict graft loss or assist organ utilization. ResultsOur model accurately identified 96% and 91% of normal/sclerotic glomeruli respectively; 94% of arteries/arterial intimal fibrosis regions; 90% of tubules. Three whole-slide features (Sclerotic Glomeruli%, Arterial Intimal Fibrosis%, and Interstitial Fibrosis%) demonstrated strong correlations with corresponding pathologists scores (n=2431), but had superior associations with post-transplant eGFR (n=2033) and graft loss (n=1560). The combination of KDQS and other factors predicted 1- and 4-year graft loss (discovery: n=520, validation: n=1040). Finally, by matching 398 discarded kidneys due to "biopsy findings" to transplanted population, the matched transplants from discarded KDQS<4 group (110/398, 27.6%) showed similar graft survival rate to unmatched transplanted kidneys (2-, 5-year survival rate: 97%, 86%). KDQS [≥] 7 (37/398, 9.3%) and 1-year survival model score [≥] 0.55 were determined to identify possible discards (PPV=0.92). ConclusionThis deep-learning based approach provides automatic and reliable pathological assessment of procurement kidney biopsies, which could facilitate graft loss risk stratification and organ utilization. Translational StatementThis deep-learning based approach provides rapid but more objective, sensitive and reliable assessment of deceased-donor kidneys before transplantation, and improves the prognostic value of procurement biopsies, thus could potentially reduce inappropriate discard and stratify patients needing monitoring or preventative measures after transplantation. The pipeline can be integrated into various types of scanners and conveniently generates report after slide scanning. Such report can be used in conjunction with pathologists report or independently for centers lacking renal pathologists.

bioinformatics↗