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• Aβ42-hIAPP co-oligomers show 2.3–3.5 times higher toxicity than AβO. • Increased apoptosis in glutamatergic neurons exposed to Aβ42-hIAPP. • Aβ42-hIAPP co-oligomers induce more severe AD pathology than AβO. • Novel insights into AD pathogenesis, implicating hIAPP in AD pathology. • Potential for constructing animal models to study Alzheimer's disease. The Aβ hypothesis has long been central to Alzheimer's disease (AD) theory, with a recent surge in attention following drug approvals targeting Aβ plaque clearance. Aβ42 oligomers (AβO) are key neurotoxins. While β-amyloid (Aβ) buildup is a hallmark of AD, postmortem brain analyses have unveiled human islet amyloid polypeptide (hIAPP) deposition in AD patients, suggesting a potential role in Alzheimer's pathology. This study investigates the neurotoxic effects of co-aggregates of Aβ42 and hIAPP, specifically focusing on their impact on cell survival, apoptosis, and AD-like pathology. We analyzed and compared the impact of AβO and Aβ42-hIAPP on cell survival in SH-SY5Y cells, apoptosis and inducing AD-like pathology in glutamatergic neurons. Aβ42-hIAPP co-oligomers exhibited significantly greater toxicity, causing 2.3–3.5 times higher cell death compared to AβO alone. Furthermore, apoptosis rates were significantly exacerbated in glutamatergic neurons when exposed to Aβ42-hIAPP co-oligomers. The study also revealed that Aβ42-hIAPP co-oligomers induced typical AD-like pathology in glutamatergic neurons, including the presence of Aβ deposits (detected by 6E10 and 4G8 immunofluorescence) and alterations in tau protein (changes in total tau HT7, phosphorylated tau AT8, AT180). Notably, Aβ42-hIAPP co-oligomers induced a more severe AD pathology compared to AβO alone. These findings provide compelling evidence for the heightened toxicity of Aβ42-hIAPP co-oligomers on neurons and their role in exacerbating AD pathology. The study contributes novel insights into the pathogenesis of Alzheimer's disease, highlighting the potential involvement of hIAPP in AD pathology. Together, these findings offer novel insights into AD pathogenesis and routes for constructing animal models. [ABSTRACT FROM AUTHOR]

A lack of in vitro models that robustly represent neurodegeneration has resulted in a translational gap between in vitro and in vivo results. This has limited the development of novel therapeutics. There has been substantial progress in the development of neural organoids, neurospheroids, and scaffold-based models that aim to recapitulate neurodegenerative disease. However, many of these models are limited by impractical designs and low levels of validation. Novel 3D models of neurodegeneration must be validated across multiple areas of neurodegenerative pathology (protein aggregation, oxidative stress, metabolic dysfunction, synaptic pruning, and increased immune activation) and results should be compared to in vivo patient data. Novel 3D models, if characterised and validated in line with recommendations, could be implemented in many areas across drug discovery and development, from early target identification to toxicology screens. A lack of in vitro models that robustly represent the complex cellular pathologies underlying neurodegeneration has resulted in a translational gap between in vitro and in vivo results, creating a bottleneck in the development of new therapeutics. In the past decade, new and complex 3D models of the brain have been published at an exponential rate. However, many novel 3D models of neurodegeneration overlook the validation and throughput requirements for implementation in drug discovery. This therefore represents a knowledge gap that could hinder the translation of these models to drug discovery efforts. We review the recent progress in the development of 3D models of neurodegeneration, examining model design benefits and validation techniques, and discuss opportunities and standards for 3D models of neurodegeneration to be implemented in drug discovery and development. [ABSTRACT FROM AUTHOR]

Membrane remodelling is essential for the trafficking of macromolecules throughout the cell, a process that regulates various aspects of cellular health and pathology. Recent studies implicate the role of biomolecular condensates in regulating multiple steps of the membrane trafficking pathway including but not limited to the organization of the trafficking machinery, dynamic remodeling of membranes, spatial and functional regulation, and response to cellular signals. The implicated proteins contain key structural elements, most notably prion-like domains within intrinsically disordered regions that are necessary for biomolecular condensate formation at fusion sites in processes like endocytic assembly, autophagy, organelle biosynthesis and synaptic vesicle fusion. Experimental and theoretical advances in the field continue to demonstrate that protein condensates can perform mechanical work, the implications of which can be extrapolated to diverse areas of membrane biology. [ABSTRACT FROM AUTHOR]

Biodegradable poly(lactic- co -glycolic acid)(PLGA) nanoparticles have been used extensively in delivering drugs to target tissues due to their excellent biocompatibility. Evidence suggests that PLGA-conjugated drugs/agents can attenuate pathology in cellular/animal models of Alzheimer's disease (AD), which is initiated by increased level/aggregation of amyloid β (Aβ) peptide generated from amyloid precursor protein (APP). The beneficial effects were attributed to conjugated-drugs rather than to PLGA nanoparticles. Interestingly, we recently reported that PLGA without any drug/agent (native PLGA) can suppress Aβ aggregation/toxicity. However, very little is known about the internalization, subcellular localization or effects of PLGA in neurons. In this study, using primary mouse cortical neurons, we first showed that native PLGA is internalized by an energy-mediated clathrin-dependent/-independent pathway and is localized in endosomal-lysosomal-autophagic vesicles. By attenuating internalization, PLGA can protect neurons against Aβ-mediated toxicity. Additionally, PLGA treatment altered expression profiles of certain AD-associated genes and decreased the levels of APP, its cleaved products α-/β-CTFs and Aβ peptides in mouse as well as iPSC-derived neurons from control and AD patients. Collectively, these results suggest that native PLGA not only protects neurons against Aβ-induced toxicity but also influences the expression of AD-related genes/proteins – highlighting PLGA's implication in normal and AD-related pathology. • Native PLGA nanoparticles are endocytosed via clathrin-dependent/-independent pathway. • PLGA treatment can protect primary neurons by attenuating Aβ internalization. • Expression of multiple AD-associated genes/proteins is altered by PLGA treatment. • These results reveal native PLGA's unique ability to regulate AD-related pathology. [ABSTRACT FROM AUTHOR]

Frontotemporal dementia (FTD) is a primary cause of dementia encompassing a broad range of clinical phenotypes and cellular pathologies. Genetic discoveries in FTD have largely been driven by linkage studies in well-documented extended families, explaining most of the patients with a known pathogenic mutation. In the context of complex diseases, it is hypothesized that mutations with reduced penetrance or a combination of low-effect size variants with environmental factors drive disease. Furthermore, these genes are likely to be part of the interaction networks of known FTD genes, contributing to converging cellular processes. In this review, we examine gene discovery approaches in FTD and introduce network biology concepts as tools to assist gene identification studies in genetically complex disease. Most genetic findings in frontotemporal dementia (FTD) result from family-based linkage studies, while the discovery and replication rate of cohort-based gene identification studies are relatively low. Protein products of genes causing the same or related diseases are organized in modules, with more frequent interactions with each other than expected by random chance and contribute to converging cellular pathways. Several algorithms have been developed to identify disease modules to prioritize genetic findings in the context of complex diseases. In this review we discuss classical gene identification strategies and introduce network biology concepts through protein interaction networks as tools to assist gene identification studies in frontotemporal dementia. [ABSTRACT FROM AUTHOR]

• Brain ischemia in amyloid-β 25–35 injected rat increases basal forebrain microgliosis. • Increased striatal microglia inflammation in transgenic rat with ischemic stroke. • Memory dysfunction in both co-morbid stroke and Alzheimer's disease rats. • Antioxidant CAT-SKL decreased memory deficit and basal forebrain microgliosis. Ischemic stroke often co-occurs with Alzheimer's disease (AD) leading to a worsened clinical outcome. Neuroinflammation is a critical process implicated in AD and ischemic pathology, associated with cognitive decline. We sought to investigate the combined effects of ischemic stroke induced by endothelin-1 injection in two AD rat models, using motor function, memory and microglial inflammation in the basal forebrain and striatum as readouts. In addition, we sought to determine the effectiveness of the antioxidant biologic CAT-SKL in one of the models. The early AD model employed the bilateral intracerebroventricular injections of the toxic β-amyloid peptide Aβ 25–35 , the prodromal AD model used the transgenic Fischer 344 rat overexpressing a pathological mutant human amyloid precursor protein. Motor function was assessed using a cylinder, modified sticky tape and beam-walk tasks; learning and memory were tested in the Morris water maze. Microglial activation was examined using immunohistochemistry. Aβ 25–35 toxicity and stroke combination greatly increased microglial inflammation in the basal forebrain. Prodromal AD-pathology coupled with ischemia in the transgenic rat resulted in a greater microgliosis in the striatum. Combined transgenic rats showed balance alterations, comorbid Aβ 25–35 rats showed a transient sensorimotor deficit, and both demonstrated spatial reference memory deficit. CAT-SKL treatment ameliorated memory impairment and basal forebrain microgliosis in Aβ 25–35 rats with stroke. Our results suggest that neuroinflammation could be one of the early processes underlying the interaction of AD with stroke and contributing to the cognitive impairment, and that therapies such as antioxidant CAT-SKL could be a potential therapeutic strategy. [ABSTRACT FROM AUTHOR]

Protein S -acylation is a prevalent post-translational protein lipidation that is dynamically regulated by 'writer' protein S -acyltransferases and 'eraser' acylprotein thioesterases. The protein S -acyltransferases comprise 23 aspartate–histidine–histidine–cysteine (DHHC)–containing proteins, which transfer fatty acid acyl groups from acyl-coenzyme A onto protein substrates. DHHC proteins are increasingly recognized as critical regulators of S -acylation–mediated cellular processes and pathology. As our understanding of the importance and breadth of DHHC-mediated biology and pathology expands, so too does the need for chemical inhibitors of this class of proteins. In this review, we discuss the challenges and progress in DHHC inhibitor development, focusing on 2-bromopalmitate, the most commonly used inhibitor in the field, and N -cyanomethyl- N -myracrylamide, a new broad-spectrum DHHC inhibitor. We believe that current and ongoing advances in structure elucidation, mechanistic interrogation, and novel inhibitor design around DHHC proteins will spark innovative strategies to modulate these critical proteins in living systems. [ABSTRACT FROM AUTHOR]

The 2013 SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) Statement provides evidence-based recommendations for the minimum content to be included in a clinical trial protocol. Assessment of biospecimens is often required for trial eligibility or as part of an outcome evaluation, and precision molecular approaches are increasingly used in trial design. However, cellular and molecular pathology practices within trials have not been codified or formalised. We developed international consensus reporting guidelines for cellular and molecular pathology content in clinical trial protocols (the SPIRIT-Path extension) using an international Delphi process, which assesses candidate items generated from a previous systematic review, followed by an expert consensus meeting. 74 individuals from five continents responded, including clinicians, statisticians, laboratory scientists, patient advocates, funders, industry representatives, journal editors, and regulators. The SPIRIT-Path guidelines recommend 14 additional items (seven extensions to the SPIRIT checklist and seven elaborations) that should be addressed in trial protocols containing pathology content, alongside the SPIRIT 2013 Statement items. SPIRIT-Path recommends that protocols should document the individuals, processes, and standards for all cellular and molecular pathology components of the trial, including all stages of the specimen pathway and any digital pathology methods, with specific consideration of the value of trial data and biological tissues for additional translational studies. [ABSTRACT FROM AUTHOR]

• Paf1, but not Cdc73, Ctr9 and Leo1 components of Paf1C, undergoes ubiquitylation and 26S proteasomal degradation. • Not4 regulates the Paf1's abundance/stability. • The Rtf1 component of Paf1C undergoes ubiquitylation, but is not targeted for the 26S proteasomal degradation. Paf1 (P olymerase- a ssociated f actor 1) complex (Paf1C) is evolutionarily conserved from yeast to humans, and facilitates transcription elongation as well as co-transcriptional histone covalent modifications and mRNA 3′-end processing. Thus, Paf1C is a key player in regulation of eukaryotic gene expression. Paf1C consists of Paf1, Cdc73, Ctr9, Leo1 and Rtf1 in both yeast and humans, but it has an additional component, Ski8, in humans. The abundances of these components regulate the assembly of Paf1C and/or its functions, thus implying the mechanisms involved in regulating the abundances of the Paf1C components in altered gene expression and hence cellular pathologies. Towards finding the mechanisms associated with the abundances of the Paf1C components, we analyzed here whether the Paf1C components are regulated via targeted ubiquitylation and 26S proteasomal degradation. We find that the Paf1C components except Paf1 do not undergo the 26S proteasomal degradation in both yeast and humans. Paf1 is found to be regulated by the ubiquitin–proteasome system (UPS) in yeast and humans. Alteration of such regulation changes Paf1's abundance, leading to aberrant gene expression. Intriguingly, while the Rtf1 component of Paf1C does not undergo the 26S proteasomal degradation, it is found to be ubiquitylated, suggesting that Rtf1 ubiquitylation could be engaged in Paf1C assembly and/or functions. Collectively, our results reveal distinct UPS regulation of the Paf1C components, Paf1 and Rtf1, in a proteolysis-dependent and -independent manners, respectively, with functional implications. [ABSTRACT FROM AUTHOR]

[Display omitted] The stimulator of interferon genes (STING) is a crucial signaling hub in the immune system's antiviral and antimicrobial defense by detecting exogenous and endogenous DNA. The multifaceted functions of STING have been uncovered gradually during past decades, including homeostasis maintenance and overfull immunity or inflammation induction. However, the subcellular regulation of STING and mitochondria is poorly understood. The main functions of STING are outlined in this review. Moreover, we discuss how mitochondria and STING interact through multiple mechanisms, including the release of mitochondrial DNA (mtDNA), modulation of mitochondria-associated membrane (MAM) and mitochondrial dynamics, alterations in mitochondrial metabolism, regulation of reactive oxygen species (ROS) production, and mitochondria-related cell death. Finally, we discuss how STING is crucial to disease development, providing a novel perspective on its role in cellular physiology and pathology. [ABSTRACT FROM AUTHOR]

Nuclear segmentation in cervical cell images is a crucial technique for automatic cytopathology diagnosis. Experimental evaluation of nuclear segmentation methods with datasets is helpful in promoting the advancement of nuclear segmentation techniques. However, public datasets are not enough for a reasonable and comprehensive evaluation because of insufficient quantity, single data source, and low segmentation difficulty. Therefore, we provide the largest dataset for cervical nuclear segmentation (CNSeg). It contains 124,000 annotated nuclei collected from 1,530 patients under different conditions. The image styles in this dataset cover most practical application scenarios, including microbial infection, cytopathic heterogeneity, overlapping nuclei, etc. To evaluate the performance of segmentation methods from different aspects, we divided the CNSeg dataset into three subsets, namely the patch segmentation dataset (PatchSeg) with nuclei images collected under complex conditions, the cluster segmentation dataset (ClusterSeg) with cluster nuclei, and the domain segmentation dataset (DomainSeg) with data from different domains. Furthermore, we propose a post-processing method that processes overlapping nuclei single ones. Experiments show that our dataset can comprehensively evaluate cervical nuclear segmentation methods from different aspects. We provide guidelines for other researchers to use the dataset. https://github.com/jingzhaohlj/AL-Net • We public a new image dataset of cervical Nuclei. The dataset contains 124,353 annotated nuclei collected from 1,530 patients. • We released an open-source project and provide baseline validation of typical segmentation methods. • We evaluate instance segmentation models and classic segmentation models and conduct extensive comparative experiments on CNSeg datasets. [ABSTRACT FROM AUTHOR]

Tauopathies are neurodegenerative diseases characterized by abnormal conformational changes in tau protein. Early hyperphosphorylation-induced conformational changes are considered a hallmark of tauopathy, but real-time tracking methods are lacking. Here, we present two novel fluorescence resonance energy transfer (FRET)-based tau biosensors that detect such changes with high spatiotemporal resolution at the single-cell level. The TAUCON biosensor measures instantaneous conformational changes in hyperphosphorylated tau within 20 min, while the TAUCOM biosensor detects changes in the paper-clip structure of microtubule-associated tau. Our biosensors provide faster and more precise detection than conventional methods and can serve as valuable tools for investigating the initial causes, mechanisms, progression, and treatment of tauopathies. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is an important but short-lived signaling molecule that is released from living cells. Real-time monitoring of NO release is useful for understanding normal cellular physiology and pathology. Herein, a convenient and efficient NO sensor was developed using multiwalled carbon nanotubes (MWCNTs)-7,7,8,8-tetracyanoquinodimethan (TCNQ)-polylysine (PLL) modified screen-printed electrode (SPE). The construction of the sensor (MWCNTs/TCNQ/PLL/SPE) was based on the synergic effect of the good conductivity of TCNQ and the high surface area of MWCNTs. The introduction of the cell-adhesive molecule PLL significantly enhanced the cytocompatibility, resulting in excellent cell attachment and growth. The resulting MWCNTs/TCNQ/PLL/SPE was successfully used for the real-time detection of NO released from living human umbilical vein endothelial cells (HUVECs) cultured on it. The MWCNTs/TCNQ/PLL/SPE was further used to detect NO release from oxidative-injured HUVECs with and without resveratrol to also preliminarily assess the effect of resveratrol against oxidative damage. The sensor developed in this study showed good performance for the real-time detection of NO released by HUVECs under different conditions and has potential applications in the diagnosis of biological processes and the screening of drug treatment effects. [Display omitted] • MWCNTs-TCNQ-PLL was developed as a novel electrochemical sensing platform. • Sensor for real-time detection of NO released from living cells was proposed. • The effect of resveratrol on oxidative injured HUVECs was evaluated by the sensor. [ABSTRACT FROM AUTHOR]

Protein misfolding is prominent in early cellular pathology of Alzheimer's disease (AD), implicating pathophysiological significance of endoplasmic reticulum stress/unfolded protein response (ER stress/UPR) and highlighting it as a target for drug development. Experimental data from animal AD models and observations on human specimens are, however, inconsistent. ER stress and associated UPR are readily observed in in vitro AD cellular models and in some AD model animals. In the human brain, components and markers of ER stress as well as UPR transducers are observed at Braak stages III-VI associated with severe neuropathology and neuronal death. The picture, however, is further complicated by the brain region- and cell type-specificity of the AD-related pathology. Terms 'disturbed' or 'non-canonical' ER stress/UPR were used to describe the discrepancies between experimental data and the classic ER stress/UPR cascade. Here we discuss possible 'disturbing' or 'interfering' factors which may modify ER stress/UPR in the early AD pathogenesis. We focus on the dysregulation of the ER Ca2+ homeostasis, store-operated Ca2+ entry, and the interaction between the ER and mitochondria. We suggest that a detailed study of the CNS cell type-specific alterations of Ca2+ homeostasis in early AD may deepen our understanding of AD-related dysproteostasis. • ER stress/UPR is a reaction of cell to stress which results in either cell survival or death. • ER stress/UPR is implicated in AD pathogenesis and represents a target for therapy. • Human data do not support canonical ER stress/UPR during preclinical and prodromal AD. • Calcium and ER-mitochondria interaction alterations may interfere with ER stress/UPR in AD. [ABSTRACT FROM AUTHOR]

[Display omitted] • Proposes a standardized Raman measurement and data processing procedure. • Raman spectra analysis of different gastric pathologies at the tissue and cellular levels in situ. • Elucidated underlying mechanisms of EGC through dynamic changes in biomolecular components in the Correa's cascade. • Multivariate machine learning methods were used to construct diagnostic models. • Raman spectroscopy can be used as a powerful tool for detecting EGC while elucidating biomolecular dynamics in tumorigenesis. Despite universal endoscopic screening, early detection of gastric cancer is challenging, led researchers to seek for a novel approach in detecting. Raman spectroscopy measurements as a fingerprint of biochemical structure, enable accurate prediction of gastric lesions non-destructively. This study aimed to evaluate the diagnostic power of Raman spectroscopy in early gastric cancer (EGC), and reveal dynamic biomolecular changes in vitro from normal to EGC. To clarify the biochemical alterations in Correa's cascade, Raman spectra of human normal gastric mucosa, intestinal metaplasia, dysplasia, and adenocarcinoma were compared at tissue and cellular levels based on a self-developed data processing program. For effectively identify EGC, Raman spectroscopy was used combined with multiple machine learning methods, including partial least-squares discriminant analysis (PLS-DA), support vector machine (SVM), and convolutional neural network (CNN) with leave-one-out (LOO) cross validation. A total of 450 Raman spectra were investigated in this study. The upregulation of ν sym (O-P-O) backbone (p < 0.001) was identified as a favorable factor for the diagnosis of EGC, the area under the ROC curve (AUC) was up to 0.918. In addition, higher levels of lactic acid (p < 0.001), lipids (p < 0.001), phenylalanine (p = 0.002), and carotenoids (p < 0.001) were detected in EGC. Multivariate machine learning methods for diagnosis of EGC based on Raman spectroscopy, the sensitivity, specificity, accuracy, and AUC were 91.0%, 100%, 94.8%, and 95.8% for SVM, and 84.8%, 92.0%, 88.8%, and 95.5% for CNN, respectively. Raman spectroscopy can be used as a powerful tool for detecting EGC while elucidating biomolecular dynamics in tumorigenesis. (Chictr.org.cn, ChiCTR2200060720.) [ABSTRACT FROM AUTHOR]

The detection and segmentation of individual cells or nuclei is often involved in image analysis across a variety of biology and biomedical applications as an indispensable prerequisite. However, the ubiquitous presence of crowd clusters with morphological variations often hinders successful instance segmentation. In this paper, nuclei cluster focused annotation strategies and frameworks are proposed to overcome this challenging practical problem. Specifically, we design a nucleus segmentation framework, namely ClusterSeg, to tackle nuclei clusters, which consists of a convolutional-transformer hybrid encoder and a 2.5-path decoder for precise predictions of nuclei instance mask, contours, and clustered-edges. Additionally, an annotation-efficient clustered-edge pointed strategy pinpoints the salient and error-prone boundaries, where a partially-supervised PS-ClusterSeg is presented using ClusterSeg as the segmentation backbone. The framework is evaluated with four privately curated image sets and two public sets with characteristic severely clustered nuclei across a variety range of image modalities, e.g., microscope, cytopathology, and histopathology images. The proposed ClusterSeg and PS-ClusterSeg are modality-independent and generalizable, and superior to current state-of-the-art approaches in multiple metrics empirically. Our collected data, the elaborate annotations to both public and private set, as well the source code, are released publicly at https://github.com/lu-yizhou/ClusterSeg. • A convolution and transformer hybrid framework for cluster-aware nuclei segmentation. • A partially supervised framework for cluster-focused partial annotation and training. • Pixel-wise annotation on our clinical collection of microscope and pathology image. [ABSTRACT FROM AUTHOR]

Ageing is a complex process that is associated with changes in the composition and functions of gut microbiota. Reduction of gut commensals is the hallmarks of ageing, which favours the expansion of pathogens even in healthy centenarians. Interestingly, gut Enterobacteriaceae have been found to be increased with age and also consistently observed in the patients with metabolic diseases. Thus, they are associated with all-cause mortality, regardless of genetic origin, lifestyle, and fatality rate. Moreover, Enterobacteriaceae are also implicated in accelerating the ageing process through telomere attrition, cellular senescence, inflammasome activation and impairing the functions of mitochondria. However, acceleration of ageing is likely to be determined by intrinsic interactions between Enterobacteriaceae and other associated gut bacteria. Several studies suggested that Enterobacteriaceae possess genes for the synthesis of uraemic toxins. In addition to intestine, Enterobacteriaceae and their toxic metabolites have also been found in other organs, such as adipose tissue and liver and that are implicated in multiorgan dysfunction and age-related diseases. Therefore, targeting Enterobacteriaceae is a nuance approach for reducing inflammaging and enhancing the longevity of older people. This review is intended to highlight the current knowledge of Enterobacteriaceae-mediated acceleration of ageing process. • Reduction of resident gut microbiota is one of the hallmarks of ageing. • Gut Enterobacteriaceae is increased with age regardless of genetic origin, lifestyle. • Enterobacteriaceae harbour uraemic toxins encoding enzymes. • Enterobacteriaceae accelerate the ageing by disturbing several cellular pathways • Gut Enterobacteriaceae can be targeted to control ageing and ageing-related diseases [ABSTRACT FROM AUTHOR]

Astrocytes contribute to the complex cellular pathology of Alzheimer's disease (AD). Neurons and astrocytes function in close collaboration through neurotransmitter recycling, collectively known as the glutamate/GABA-glutamine cycle, which is essential to sustain neurotransmission. Neurotransmitter recycling is intimately linked to astrocyte energy metabolism. In the course of AD, astrocytes undergo extensive metabolic remodeling, which may profoundly affect the glutamate/GABA-glutamine cycle. The consequences of altered astrocyte function and metabolism in relation to neurotransmitter recycling are yet to be comprehended. Metabolic alterations of astrocytes in AD deprive neurons of metabolic support, thereby contributing to synaptic dysfunction and neurodegeneration. In addition, several astrocyte-specific components of the glutamate/GABA-glutamine cycle, including glutamine synthesis and synaptic neurotransmitter uptake, are perturbed in AD. Integration of the complex astrocyte biology within the context of AD is essential for understanding the fundamental mechanisms of the disease, while restoring astrocyte metabolism may serve as an approach to arrest or even revert clinical progression of AD. [Display omitted] • Astrocyte energy metabolism is impaired in Alzheimer's disease (AD). • Homeostasis of glutamine, glutamate and GABA relies on astrocyte metabolic function. • Malfunctional neurotransmitter recycling in AD impairs synaptic transmission. • In AD, neurons receive insufficient metabolic support from astrocytes. • Targeting astrocyte metabolism may restore neurotransmitter homeostasis in AD. [ABSTRACT FROM AUTHOR]

Cervical cytopathology image refocusing is important for addressing the problem of defocus blur in whole slide images. However, most of current deblurring methods are developed for global motion blur instead of local defocus blur and need a lot of supervised re-training for unseen domains. In this paper, we propose a refocusing method for cervical cytopathology images via multi-scale attention features and domain normalization. Our method consists of a domain normalization net (DNN) and a refocusing net (RFN). In DNN, we adopt registration-free cycle scheme for normalizing the unseen unsupervised domains into the seen supervised domain and introduce gray mask loss and hue-encoding mask loss to ensure the consistency of cell structure and basic hue. In RFN, combining the locality and sparseness characteristics of defocus blur, we design a multi-scale refocusing network to enhance the reconstruction of cell nucleus and cytoplasm, and introduce defocus intensity estimation mask to strengthen the reconstruction of local blur. We integrate hybrid learning strategy on the supervised and unsupervised domains to make RFN achieving well refocusing on the unsupervised domain. We build a cervical cytopathology image refocusing dataset and conduct extensive experiments to demonstrate the superiority of our method compared with current deblurring state-of-the-art models. Furthermore, we prove that the refocused images help improve the performance of subsequent high-level analysis tasks. We release the refocusing dataset and source codes to promote the development of this field. [Display omitted] • We propose a new refocusing method for cervical cytopathology images. • We design a multi-scale refocusing network to enhance the reconstruction of blurry cells. • We introduce defocus intensity estimation mask to strengthen the reconstruction of local blur. • We build a cytopathology image refocusing dataset and demonstrate the superiority of our method. • We prove that the refocused images help improve the performance of high-level analysis tasks. [ABSTRACT FROM AUTHOR]

Nitric oxide (NO) is a critical transcellular messenger involved in numerous cellular physiology and pathology. Although many electrochemical sensing platforms have been developed for the real-time detection of cellular NO, the dynamic recording of NO release from mechanical deformed cells remains a great challenge. In this communication, we developed a stretchable and transparent NO sensor by spin-coating of silver nanowires (AgNWs) and carbon nanotubes (CNTs) on flexible polydimethylsiloxane (PDMS) substrate. The formed sandwich structure endows the film with robust mechanical flexibility and desirable sensing performance. The developed CNTs/AgNWs/PDMS film exhibited satisfied detection ability toward NO with a wide linear range from 10 nM to 60.94 μM and the detection limit was 2.5 nM. The excellent biocompatibility and mechanical stability of the film provide a suitable environment for cell proliferation and adhesion, enabling the sensing interface to electrochemically detect trace amount of NO released from cells under both static and tensile states in real-time. This research opens a new way for the electrochemical sensing of chemical-signal molecules during mechanotransduction. Stretchable CNTs/AgNWs/PDMS film electrode was developed and used for the inducing and real-time recording transit NO secreted from cells during mechanotransduction. [Display omitted] • A stretchable and transparent CNTs/AgNWs/PDMS film was successfully developed. • The film exhibited high conductivity, excellent flexibility and biocompatibility. • The stretchable platform can integrate the mechanical stimulation with sensing signal molecule simultaneously. • The film electrode was applied for the real-time recording NO secreted from cells under both static and stretched states. [ABSTRACT FROM AUTHOR]

Deep learning algorithms and artificial intelligence (AI) are making great progress in their capacity to evaluate and interpret image data recent advancements in computer vision and machine learning. The first use of AI in a pathology lab was in cytopathology, when a computer-assisted Pap test screening was created. Initially designed to diagnose rather than screen, there was a lot of disagreement concerning their wide use to clinical specimens. However, whole-slide imaging of both gynaecological and non-gynaecological histopathology have been the subject of recent AI work. An overview of the literature on AI in cytopathology is provided in this brief review. To be more precise, it intends to emphasize the relevance of applications of AI algorithms to gynaecological and non-gynaecologic cytology. Between January 2000 and December 2021, a search on artificial intelligence in cytopathology was conducted in several well-known databases, including PubMed, Web of Science, Scopus, Embase, and Google Scholar. Only full-text papers that could be accessed online were evaluated. [ABSTRACT FROM AUTHOR]

In the late 19th century, pneumonia was one of the leading causes of death in Europe and the USA. Although at this time doctors knew about the infectious cause of pneumonia, they were not able to offer patients specific antimicrobial therapy. In the current paper, we translated into English for the first time and analyzed the almost forgotten medical report of a pneumonic patient written by the famous Russian writer and physician Anton Chekhov (1860–1904), which describes the classic stages of lobar pneumonia, now no longer observed in clinical practice due to antibacterial treatment. Despite the limited capabilities of lung disease diagnosis compared to the possibilities of modern medicine, physicians were able to diagnose lobar pneumonia using techniques of percussion and auscultation. Therapy in this case was limited to diet and symptomatic treatment and could only relieve some of the symptoms. This case history shows that in the early 1880s, in the one of the leading university clinics in Russia, despite the transition from humoral theory and ideas of natural philosophy to the concept of cellular pathology, there were still contradictory trends in the treatment of diseases. [ABSTRACT FROM AUTHOR]

The SARS-CoV-2 virus causes the coronavirus disease 19 emerged in 2020. The pandemic triggered a turmoil in public health and is having a tremendous social and economic impact around the globe. Upon entry into host cells, the SARS-CoV-2 virus hijacks cellular machineries to produce and maintain its own proteins, spreading the infection. Although the disease is known for prominent respiratory symptoms, accumulating evidence is also demonstrating the involvement of the central nervous system, with possible mid- and long-term neurological consequences. In this study, we conducted a detailed bioinformatic analysis of the SARS-CoV-2 proteome aggregation propensity by using several complementary computational tools. Our study identified 10 aggregation prone proteins in the reference SARS-CoV-2 strain: the non-structural proteins Nsp4, Nsp6 and Nsp7 as well as ORF3a, ORF6, ORF7a, ORF7b, ORF10, CovE and CovM. By searching for the available mutants of each protein, we have found that most proteins are conserved, while ORF3a and ORF7b are variable and characterized by the occurrence of a large number of mutants with increased aggregation propensity. The geographical distribution of the mutants revealed interesting differences in the localization of aggregation-prone mutants of each protein. Aggregation-prone mutants of ORF7b were found in 7 European countries, whereas those of ORF3a in only 2. Aggregation-prone sequences of ORF7b, but not of ORF3a, were identified in Australia, India, Nepal, China, and Thailand. Our results are important for future analysis of a possible correlation between higher transmissibility and infection, as well as the presence of neurological symptoms with aggregation propensity of SARS-CoV-2 proteins. • Viruses highjack the cells proteostasis network to replicate. • SARS-CoV-2 affects multiple organs and cell types. • 10 proteins in the reference SARS-CoV-2 strain were found to be aggregation prone. • ORF3a and 7b have a large number of mutants with increased aggregation propensity. • Our data highlights the importance of protein aggregation propensity in the SARS-CoV-2 biology. [ABSTRACT FROM AUTHOR]

Lipid oxidation products, like α , β -unsaturated aldehydes, can react with proteins and influence meat quality. Two such key end products are 4-hydroxy-2-nonenal (4-HNE) and 4-oxo-2-nonenal (4-ONE). These compounds are far more stable than the lipid hydroperoxides from which they form; so, they can diffuse from the site of generation and cause extensive cellular damage and oxidative pathology. Glycolytic enzymes involved in the reduction of metmyoglobin (e.g., lactate dehydrogenase) are highly reactive with 4-HNE, and subsequently become less functional. Other aldehydes, such as 4-ONE, are more reactive than 4-HNE with certain functional groups/moieties including mercapto groups and arginine residues of glycolytic enzymes. Yet, little research has considered the influence of 4-ONE on an in-vitro meat model system. Findings from this study establish that 4-ONE causes loss of lactate dehydrogenase activity compared to 4-HNE at similar effective concentrations. Myoglobin, when incubated with 4-ONE, exhibited a loss in its redox stability at pH 5.8. Both 4-HNE and 4-ONE were found to be potent covalent modifiers of myoglobin, disrupting functional and structural morphology of bovine heart mitochondria. This study reveals that 4-ONE is a novel and highly toxic chemical species, which causes damage to mitochondrial structure and impairment of myoglobin's redox stability. • Lipid peroxidation products react with the proteins that influence myoglobin stability. • 4-oxo-2-nonenal (4-ONE) cause oxidative cellular pathology in skeletal muscle. • 4-ONE reactivity caused loss of lactate dehydrogenase enzymatic activity. • When incubated with myoglobin, 4-ONE caused loss of redox stability of myoglobin. • 4-ONE is a novel but highly toxic specie causing damage of mitochondrial structure and functions. [ABSTRACT FROM AUTHOR]