Features Of Disease Research Articles

A Novel Cyanine-Based Fluorescent Dye for Targeted Mitochondrial Imaging in Neurotoxic Conditions and In Vivo Brain Studies.

Mitochondrial dysfunction is a key feature of neurodegenerative diseases, often preceding symptoms and influencing disease progression. However, real-time in vivo imaging of mitochondria in the brain is limited by existing dyes like MitoTrackers, which struggle with poor tissue penetration, phototoxicity, and inability to cross the blood-brain barrier (BBB). This study introduces Cy5-PEG4, a novel mitochondrial-targeting dye that overcomes these limitations, enabling high-resolution, non-invasive imaging of mitochondrial dynamics. Cy5-PEG4 effectively labels mitochondria in primary neuronal cells exposed to the SARS-CoV-2 RNYIAQVD peptide, revealing dose-dependent alterations in mitochondrial function that may contribute to COVID-19-related neurodegeneration. Importantly, Cy5-PEG4 crosses the BBB without causing neuroinflammation or toxicity, making it a safe tool for in vivo brain imaging and detailed studies of mitochondrial responses. In 3D cultured cells, Cy5-PEG4 captures dynamic changes in mitochondrial distribution and morphology as cell structures mature, highlighting its potential in neurobiological research, diagnostics, and therapeutic development. These findings support Cy5-PEG4 as a powerful tool for studying disease progression, identifying early biomarkers, and evaluating therapeutic strategies in neurodegenerative disorders and COVID-19.

Adjustment Analysis of the Teaching Content of Parasitology Examination in Higher Vocational Colleges

At present, the infection rate of human parasitic diseases has changed greatly in our country, and foodborne parasitic diseases have become the mainstream of human parasitic diseases, among which the more frequent foodborne parasites are a liver fluke, taeniasis, cysticercus, trichinella, toxoplasma gondii and so on. The test methods for parasitic diseases are pathogenetic examination, immunological examination, molecular biological examination and combined diagnosis. Based on the current epidemic characteristics of human parasitic diseases in China and their examination and analysis, the teaching content of the course Parasitology Examination in higher vocational colleges is adjusted, and the main popular human parasitic diseases and their examination methods are listed as the teaching focus, and other parasitic diseases that have been eliminated or reached the control standard are transferred to the familiar or understood teaching content. To make the teaching of medical laboratory technology in higher vocational colleges closer to the needs of vocational posts and improve the adaptability of students to their posts.

Bone marrow transplantation increases sulfatase activity in somatic tissues in a multiple sulfatase deficiency mouse model

BackgroundMultiple Sulfatase Deficiency (MSD) is an ultra-rare autosomal recessive disorder characterized by deficient enzymatic activity of all known sulfatases. MSD patients frequently carry two loss of function mutations in the SUMF1 gene, encoding a formylglycine-generating enzyme (FGE) that activates 17 different sulfatases. MSD patients show common features of other lysosomal diseases like mucopolysaccharidosis and metachromatic leukodystrophy, including neurologic impairments, developmental delay, and visceromegaly. There are currently no approved therapies for MSD patients. Hematopoietic stem cell transplant (HSCT) has been applied with success in the treatment of certain lysosomal diseases. In HSCT, donor-derived myeloid cells are a continuous source of active sulfatase enzymes that can be taken up by sulfatase-deficient host cells. Thus, HSCT could be a potential approach for the treatment of MSD.MethodsTo test this hypothesis, we used a clinically relevant mouse model for MSD, B6-Sumf1(S153P/S153P) mice, engrafted with bone marrow cells, Sumf1+/+, from B6-PtprcK302E mice (CD45.1 immunoreactive).ResultsAfter 10 months post-transplant, flow cytometric analysis shows an average of 90% of circulating leukocytes of donor origin (Sumf1(+/+)). Enzymatic activity for ARSA, ARSB, and SGSH is significantly increased in spleen of B6-Sumf1(S153P/S153P) recipient mice. In non-lymphoid organs, only liver and heart show a significant correction of sulfatase activity and GAG accumulation. Frequency of inflammatory cells and lysosomal pathology is significantly reduced in liver and heart, while no significant improvement is detected in brain.ConclusionsOur results indicate that HSCT could be a suitable approach to treat MSD-pathology affecting peripheral organs, however that benefit to CNS pathology might be limited.

Cerebral hyperactivation across the Alzheimer's disease pathological cascade.

Neuronal dysfunction in specific brain regions or across distributed brain networks is a known feature of Alzheimer's disease. An often reported finding in the early stage of the disease is the presence of increased functional MRI (fMRI) blood oxygenation level-dependent signal under task conditions relative to cognitively normal controls, a phenomenon known as 'hyperactivation'. However, research in the past decades yielded complex, sometimes conflicting results. The magnitude and topology of fMRI hyperactivation patterns have been found to vary across the preclinical and clinical spectrum of Alzheimer's disease, including concomitant 'hypoactivation' in some cases. These incongruences are likely due to a range of factors, including the disease stage at which the cohort is examined, the brain areas or networks studied and the fMRI paradigm utilized to evoke these functional abnormalities. Additionally, a perennial question pertains to the nature of hyperactivation in the context of Alzheimer's disease. Some propose it reflects compensatory mechanisms to sustain cognitive performance, while others suggest it is linked to the pathological disruption of a highly regulated homeostatic cycle that contributes to, or even drives, disease progression. Providing a coherent narrative for these empirical and conceptual discrepancies is paramount to develop disease models, understand the synergy between hyperactivation and the Alzheimer's disease pathological cascade and tailor effective interventions. We first provide a comprehensive overview of functional brain changes spanning the course from normal ageing to the clinical spectrum of Alzheimer's disease. We then highlight evidence supporting a close relationship between fMRI hyperactivation and in vivo markers of Alzheimer's pathology. We primarily focus on task-based fMRI studies in humans, but also consider studies using different functional imaging techniques and animal models. We then discuss the potential mechanisms underlying hyperactivation in the context of Alzheimer's disease and provide a testable framework bridging hyperactivation, ageing, cognition and the Alzheimer's disease pathological cascade. We conclude with a discussion of future challenges and opportunities to advance our understanding of the fundamental disease mechanisms of Alzheimer's disease, and the promising development of therapeutic interventions incorporating or aimed at hyperactivation and large-scale functional systems.

Molecular mechanisms underlying amyloid beta peptide mediated upregulation of vascular cell adhesion molecule-1 in Alzheimer's disease.

Amyloid beta (Aβ) deposition and neurofibrillary tangles are widely considered as the primary pathological hallmarks of familial and sporadic forms of Alzheimer's disease (AD). However, cerebrovascular inflammation, which is prevalent in 70% of AD patients is emerging as another core feature of AD pathology. In addition, activation of inflammatory signaling pathways have been observed in AD patients; specifically, cerebrovascular inflammation was found to be augmented in Alzheimer's patients. Our studies have demonstrated that the inflammation signaling pathway is upregulated in AD patient brains. Moreover, vascular cell adhesion molecule-1 (VCAM-1), a cerebrovascular inflammatory marker expressed on the blood-brain barrier (BBB) endothelium, was observed to be upregulated in APP,PS1 mice (a mouse model that overexpresses Ab42), as detected by dynamic SPEC/CT imaging. While there is a strong association between Aβ42 exposure and an increase in VCAM-1 expression, the mechanisms underlying the influence of Aβ42 on VCAM-1 expression remain understudied. Therefore, we investigated the hypothesis that Ab42 exposure increases VCAM-1 expression in human cerebral microvascular endothelial cell (hCMEC/D3) monolayers. In addition, reverse phase protein array assays (RPPA) and immunocytochemistry demonstrated that Ab42 increases VCAM-1 expression through the Src/p38/MEK signaling pathway specifically within the blood-brain barrier (BBB) endothelium. In summary, these results demonstrate that Ab42 augments cerebrovascular inflammation by elevating VCAM-1 expression via Src/MEK/p38 pathway. Hence, targeting VCAM-1 at the BBB as a diagnostic and therapeutic marker may hold potential for detecting and mitigating cerebrovascular inflammation in Alzheimer's disease. Significance Statement While considered a core pathological feature of Alzheimer's disease, molecular pathways leading to cerebrovascular inflammation remain partially understood. Moreover, clinical diagnostic methods for detecting cerebrovascular inflammation are underdeveloped. In this study, we demonstrated VCAM-1 detection using radio-iodinated VCAM-1 antibody and SPECT/CT imaging. The study demonstrated that the exposure to Aβ42 increases VCAM-1 expression on the BBB endothelium via Src/p38/MEK pathway. These findings are expected to aid in the development of diagnostic and therapeutic approaches for addressing cerebrovascular inflammation in AD.

Inhibiting mtDNA transcript translation alters Alzheimer's disease-associated biology.

Alzheimer's disease (AD) features changes in mitochondrial structure and function. Investigators debate where to position mitochondrial pathology within the chronology and context of other AD features. To address whether mitochondrial dysfunction alters AD-implicated genes and proteins, we treated SH-SY5Y cells and induced pluripotent stem cell (iPSC)-derived neurons with chloramphenicol, an antibiotic that inhibits mtDNA-generated transcript translation. We characterized adaptive, AD-associated gene, and AD-associated protein responses. SH-SY5Y cells and iPSC neurons responded to mtDNA transcript translation inhibition by increasing mtDNA copy number and transcription. Nuclear-expressed respiratory chain mRNA and protein levels also changed. There were AD-consistent concordant and model-specific changes in amyloid precursor protein, beta amyloid, apolipoprotein E, tau, and α-synuclein biology. Primary mitochondrial dysfunction induces compensatory organelle responses, changes nuclear gene expression, and alters the biology of AD-associated genes and proteins in ways that may recapitulate brain aging and AD molecular phenomena. In AD, mitochondrial dysfunction could represent a disease cause or consequence. We inhibited mitochondrial translation in human neuronal cells and neurons. Mitochondrial and nuclear gene expression shifted in adaptive-consistent patterns. APP, Aβ, APOE, tau, and α-synuclein biology changed in AD-consistent patterns. Mitochondrial stress creates an environment that promotes AD pathology.

An effective unsupervised domain adaptation for in-field potato disease recognition

Accurate disease recognition through computer vision is crucial for the intelligent management of potato production. Popular data-driven classification methods face challenges including limited labelled data and poor model portability. Unsupervised Domain Adaptation (UDA) addresses these challenges with a novel learning strategy. However, the complex field environment introduces a significant domain shift problem due to varying conditions. Existing UDA methods usually concentrate on aligning global data distribution and employ a single structure for disease feature extraction, thereby limiting their efficacy in true field environment. To tackle this challenge of potato disease recognition, the Multi-Representation Adaptive Network (MRSAN) based on subdomain alignment is presented. MRSAN effectively aligns feature distributions across diverse data by minimising distribution differences among relevant subdomains. Simultaneously, the multi-representation extraction method captures finer details from various perspectives in the disease images. The combination of these two approaches efficiently mitigates the adverse effects caused by various interference factors in field environment. Based on the acquisition conditions of light variation and disease progression, two field potato disease image datasets are created, containing five and six kinds of potato leaf disease, respectively. Extensive transfer experiments are conducted on the two datasets. MRSAN achieves average classification accuracies of 87.03% and 80.06% on the datasets for the corresponding transfer tasks, outperforming the other compared methods. This not only validates the effectiveness of MRSAN but also demonstrates its robust ability to generalise across changes in regard to light variation and disease progression.

Investigation of the chemical composition and biological activities of Eremurus spectabilis M. Bieb through antioxidant, enzyme inhibition, COX-2 and iNOS assessment.

Eremurus spectabilis is widespread and used primarily for medicinal and culinary purposes. This study aimed to evaluate the chemical composition, antiradical and antioxidant activities, enzyme inhibitory activities, and anti-inflammatory properties of various extracts from the aerial parts of E. spectabilis. Various assays were used to investigate the antioxidant and enzyme inhibitory properties. The chemical composition of the tested extracts was analyzed using High-Performance Liquid Chromatography-Electrospray Ionization Tandem Mass Spectrometry (HPLC-ESI-MS/MS). Additionally, the extracts were tested on isolated mouse colon tissue challenged with E. coli lipopolysaccharide (LPS) to replicate the inflammation and oxidative stress burden characteristic of inflammatory bowel diseases. In the chemical composition, vanillic, ferulic, 4-hydroxybenzoic acids were the prominent compounds. The greatest antioxidant activity was observed in the methanol and water extracts from the aerial parts. Enzyme inhibition tests showed that the ethyl acetate extract had the highest anti-acetylcholinesterase activity. The gene expression of pro-inflammatory cyclooxygenase-2 (COX-2) and pro-oxidant inducible nitric oxide synthase (iNOS) biomarkers were assayed. Among the extracts, the methanol extract was the most effective in blunting LPS-induced gene expression of COX-2. E. spectabilis may serve as a valuable source of phytochemicals for combating oxidative stress and inflammation-driven diseases, with a particular emphasis on colon inflammatory condition.

Molecular characterization and immunopathological investigation of Avian reticuloendotheliosis virus in breeder flocks in Egypt

BackgroundReticuloendotheliosis virus (REV) is an oncogenic immunosuppressive retrovirus that infects different kinds of avian species; posing significant economic losses to the poultry industry worldwide.MethodsIn Egypt, there is an unidentified disease associated with the runting-stunting syndrome with neoplasia, suspected to be REV, that has been continuously monitored in several breeder flocks. To diagnose and analyze REV by cell cultures, enzyme-linked immunosorbent assay (ELISA), histopathological investigation, the polymerase chain reaction (PCR) test, and sequencing analysis, 200 blood samples, and 50 tissue specimens were collected. The current study targets the occurrence and genetic characteristics of a viral neoplastic disease, resembling REV infection, circulating in breeder flocks from 2022 to 2023 in the Ismailia, El-Sharqia, and El-Dakahliya governorates.ResultHere, REV was isolated on chicken embryo fibroblast cell culture; exhibiting cell aggregation, rounding, and cell detachments. Collectively, only 70 serum samples were positive for anti‐REV antibodies with seroprevalence rates of 35% based on the ELISA test. The histopathological observation demonstrated lymphoreticular tumors in the liver, spleen, and other examined organs. The immunohistochemical staining method confirmed the REV-positive signals in all examined organs (liver, kidney, spleen, bursa, ovaries) except for the heart. The PCR assay of the LTR gene assessed 370 base pairs with only 5 positive samples with a percentage of 16.6%. Three positive samples were further sequenced and submitted to the Genbank under accession numbers (PP763709, PP763710, PP763711). Phylogenetic analysis of the REV-LTR gene showed that our three isolates (Sharquia-1-REV, Ismilia-2-REV, Mansoura-3-REV) are REV subtype III which predominantly circulated in breeders in Egypt. These three isolates are highest similar to American, Chinese, and Taiwanese REV reference strains, and other Egyptian strains with nucleotide identity percentages of 100%, 99%, and 99%; respectively, and on the amino acid identity level were with (99–100%), (98%, 99%), (99%, 100%); respectively.ConclusionsThis study established that REV infection was extensively distributed in the breeders and became one of the causes of the clinical outbreaks of tumors, raising awareness of REV as the causative agent of avian oncogenic disease in Egypt.

Longitudinal Micro-Computed Tomography Detects Onset and Progression of Pulmonary Fibrosis in Conditional Nedd4-2 Deficient Mice.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease which is usually diagnosed late in advanced stages. Little is known about the subclinical development of IPF. We previously generated a mouse model with conditional Nedd4-2 deficiency (Nedd4-2-/-) that develops IPF-like lung disease. The aim of this study was to characterize the onset and progression of IPF-like lung disease in conditional Nedd4-2-/- mice by longitudinal micro-computed tomography (CT). In vivo micro-CT was performed longitudinally in control and conditional Nedd4-2-/- mice at 1, 2, 3, 4 and 5 months after doxycycline induction. Further, terminal in vivo micro-CT followed by pulmonary function testing and post mortem micro-CT was performed in age-matched mice. Micro-CT images were evaluated for pulmonary fibrosis using an adapted fibrosis scoring system. Histological assessment of lung collagen content was conducted as well. Micro-CT is sensitive to detect onset and progression of pulmonary fibrosis in vivo and to quantify distinct radiological IPF-like features along disease development in conditional Nedd4-2-/- mice. Nonspecific interstitial alterations were detected from 3 months, whereas key features such as honeycombing-like lesions were detected from 4 months onwards. Pulmonary function correlated well with in vivo (r=-0.738) and post mortem (r=-0.633) micro-CT fibrosis scores and collagen content. Longitudinal micro-CT enables in vivo monitoring of onset and progression and detects radiologic key features of IPF-like lung disease in conditional Nedd4-2-/- mice. Our data support micro-CT as sensitive quantitative endpoint for preclinical evaluation of novel antifibrotic strategies.

The role of IL-17 family cytokines in cardiac fibrosis.

Myocardial fibrosis is a common pathological feature in various cardiovascular diseases including myocardial infarction, heart failure, and myocarditis. Generally, persistent myocardial fibrosis correlates with poor prognosis and ranks among the leading causes of death globally. Currently, there is no effective treatment for myocardial fibrosis, partly due to its unclear pathogenic mechanism. Increasing studies have shown IL-17 family cytokines are strongly associated with the initiation and propagation of myocardial fibrosis. This review summarizes the expression, action, and signal transduction mechanisms of IL-17, focusing on its role in fibrosis associated with cardiovascular diseases such as myocardial infarction, heart failure, hypertension, diabetes, and myocarditis. It also discusses its potential as a therapeutic target, offering new insights for the clinical treatment of myocardial fibrosis.

Transforming Care in SEA: Evidence and Considerations for Evolution of the Current Treatment Paradigm

This article reviews an industry symposium held on 8 September 2024 as part of the European Respiratory Society (ERS) Congress 2024 in Vienna, Austria, which brought together four experts to discuss the current treatment paradigm for severe eosinophilic asthma (SEA), including the role of biologics and background medication tapering. Katrin Milger-Kneidinger, Professor of Respiratory Medicine at the University Hospital of the Ludwig Maximilian University Munich (LMU), in Germany, and the MedUni Graz, in Austria, explored the critical role eosinophils play in SEA pathology and how biologic therapies targeting eosinophils can address key disease features, including airway remodelling, airway hyperresponsiveness (AHR), and mucus production. Felix Herth, Professor of Pulmonary and Critical Care Medicine at Thoraxklinik Heidelberg, Heidelberg University Hospital, in Germany, discussed persistent airflow obstruction (PAO) in patients with SEA, focusing on a typical patient profile to understand the clinical manifestation and opportunities for management. Stephanie Korn, Professor of Pulmonary and Respiratory Medicine at Thoraxklinik Heidelberg, Heidelberg University Hospital, in Germany, and Head of the Clinical Research Centre, Institute für Klinische Forschung (IKP) Pneumologie in Mainz, Germany, presented on remission as a clinical target in SEA, focusing on how biologics can help achieve remission in some patients. Lastly, in a discussion led by symposium chair Stefano Del Giacco, Professor of Medicine, Allergy, and Clinical Immunology, at the University of Cagliari, Sardinia, in Italy, the experts agreed that a positive practice change would be to get more patients with relevant clinical manifestations on biologics, and that background medication tapering, when appropriate, could lead to improved patient outcomes and quality of life (QoL) in SEA.

Factors Associated with Axial Spondyloarthritis Remission in a Cohort of Saudi Patients with Longstanding Disease: A Multicenter Prospective Cohort Study.

Earlier treatment in axial spondyloarthritis (axSpA) was proposed to alter disease prognosis in this often-challenging condition. We aimed to assess the proportion of patients and prognostic factors associated with axSpA remission. The aim was to determine the number of patients with Ankylosing Spondylitis Disease Activity Score with C-reactive protein (ASDAS-CRP) of <2.1 (inactive/moderate disease activity). We also evaluated global functioning and health using the Assessment of Spondyloarthritis International Society-Health Index (ASAS-HI). Patients with axSpA who were receiving targeted synthetic/biological disease- modifying anti-rheumatic drug (ts/bDMARDs) treatments and visited the rheumatology units at two tertiary-care centers between December 2021 and December 2022 were prospectively interviewed. Data regarding patient demographics, disease features, active and previous ts/bDMARDs treatments, and disease activity scores were obtained. Patients were assessed using the ASDAS- CRP, ASDAS-erythrocyte sedimentation rate (ASDAS-ESR), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and ASAS-HI. Overall, 60 patients with axSpA were included in this study (women, n = 35); 25 (41.7%) and 36 (62.1%) achieved an ASDAS-CRP of <2.1 and an ASAS-HI of ≤5 (good health), respectively. Out of the 60 patients, 75% (n = 45) were treated with anti-tumor necrosis factor. Factors associated with achieving the target ASDAS-CRP included age (p = 0.019), sex (p = 0.015), employment status (p = 0.015), education level (p = 0.030), and the number of previous ts/bDMARDs treatments (p = 0.019). Additionally, the ASDAS-CRP strongly correlated with spinal pain and moderately correlated with the ASAS-HI, BASDAI, and the number of previous ts/bDMARDs treatments. Remission was observed in 41.7% of patients, indicating a challenge in achieving target disease activity. However, 62.1% attained good health. Achieving remission was associated with younger age, male sex, a higher level of education, lower level of spinal pain, better global function by ASAS-HI, employment, and receiving their first ts/bDMARDs treatment. Our findings may potentially improve disease prognosis with the earlier use of ts/bDMARDs in those without favorable features by implementing an early axSpA intervention strategy.

Hippo signaling cooperates with p53 to regulate lung airway mucous cell metaplasia.

Airway mucous cell metaplasia is a significant feature of many chronic airway diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis, and asthma. However, the mechanisms underlying this process remain poorly understood. Here, we employ in vivo mouse genetic models to demonstrate that Hippo and p53 cooperate to modulate the differentiation of club cells into goblet cells. We reveal that ablation of Mst1 and Mst1 (Mst1/2), the core components of Hippo signaling, significantly reduces mucous metaplasia in the lung airways in a lipopolysaccharide (LPS)-induced lung inflammation murine model while promoting club cell proliferation in a Yap-dependent manner. Additionally, we show that deleting Mst1/2 is sufficient to suppress p53 deficiency-mediated goblet cell metaplasia. Finally, single-cell RNA analysis reveals a downregulation of Yap and p53 signaling in goblet cells in the human airways. These findings underscore the important role of Hippo and p53 signaling in regulating airway mucous metaplasia.

Update on Inherited Pediatric Motor Neuron Diseases: Clinical Features and Outcome.

Inherited pediatric motor neuron diseases (MNDs) are a group of neurodegenerative disorders characterized by the degeneration of motor neurons in the brain and the spinal cord. These diseases can manifest as early as infancy and originate from inherited pathogenic mutations in known genes. Key clinical features of MNDs include muscle weakness, hypotonia, and atrophy due to the degeneration of lower motor neurons or spasticity, hypertonia, and hyperreflexia caused by upper motor neuron dysfunction. The course of the disease varies among individuals and is influenced by the specific subtype. We performed a non-systematic, narrative clinical review, employing a systematic methodology for the literature search and article selection to delineate the features of hereditary pediatric motor neuron diseases. The growing availability of advanced molecular testing, such as whole-exome sequencing (WES) and whole-genome sequencing (WGS), has expanded the range of identified genetic factors. These advancements provide insights into the genetic complexity and underlying mechanisms of these disorders. As more MND-related genes are discovered, the accumulating genetic data will help prioritize promising candidate genes for future research. In some cases, targeted treatments based on specific genetic mechanisms have already emerged, underscoring the critical role of early and timely diagnosis in improving patient outcomes. Common MNDs include amyotrophic lateral sclerosis, spinal muscular atrophy, and bulbar spinal muscular atrophy. This narrative clinical review covers the clinical presentation, genetics, molecular features, and pathophysiology of inherited pediatric MNDs.

Clinical characteristics of ABCB4 gene variant-associated cholestatic liver disease in adults

Objective: To investigate the clinical manifestations, pathological, and gene mutation characteristics of ABCB4 gene variant-associated cholestatic liver disease in adults. Methods: Eight adult cases of ABCB4 gene variant-associated cholestatic liver disease who were hospitalized in the Department of Hepatology, Fifth Medical Center of the People's Liberation Army General Hospital from May 2010 to December 2022 were enrolled in this study. The clinical manifestations, pathological features, gene variant features, and prognostic conditions were analyzed. Patient gene testing and biological information analysis were performed using whole-exome next-generation sequencing. SPSS 19.0 software was used to conduct descriptive analysis. Results: Among the eight adult cases of the ABCB4 gene variant, there were three males and five females, with a median age of onset of 24 (20, 37) years. There were three cases with a compound heterozygous variant in ABCB4, and the clinical phenotypes included two cases of progressive familial intrahepatic cholestasis type 3 and one case of intrahepatic cholestasis of pregnancy overlapping with low-phospholipid-associated cholelithiasis syndrome. There were five cases with a single heterozygous variant in ABCB4, and the clinical phenotypes included two cases of intrahepatic cholestasis of pregnancy overlapping with drug-induced liver injury and three cases of low-phospholipid-associated cholelithiasis syndrome. Imaging of all eight cases showed liver fibrosis, and six cases already had cirrhosis. All patients underwent liver histopathological examination, which mainly showed cholestasis and portal fibrosis in eight cases, small bile duct hyperplasia in seven cases, copper deposition in three cases, and cirrhosis in five cases. ABCB4 screening revealed 11 different mutations, including eight new mutations. The pathogenicity assessment showed that c.2394+82C>T (intron) was a benign mutation, and the rest were deleterious mutations. Ursodeoxycholic acid was the treatment for all patients, with a follow-up time of 7.5 (0.5, 12.7) years. One case died of end-stage liver disease, two cases developed cholestatic cirrhosis, and five cases were in stable condition. Conclusion: The adult ABCB4 gene variant-associated cholestatic liver disease are mostly single heterozygous mutations, the clinical phenotypes are diverse and overlapping, the disease is more severe in those who carried non-functional mutations.

Oxygen control in bioreactor drives high yield production of functional hiPSC-like hepatocytes for advanced liver disease modelling

Hepatocytes-like cells (HLC) derived from human induced pluripotent stem cells show great promise for cell-based liver therapies and disease modelling. However, their application is currently hindered by the low production yields of existing protocols. We aim to develop a bioprocess able to generate high numbers of HLC. We used stirred-tank bioreactors with a rational control of dissolved oxygen concentration (DO) for the optimization of HLC production as 3D aggregates. We evaluated the impact of controlling DO at physiological levels (4%O2) during hepatic progenitors’ stage on cell proliferation and differentiation efficiency. Whole transcriptome analysis and biochemical assays were performed to provide a detailed characterization of HLC quality attributes. When DO was controlled at 4%O2 during the hepatic progenitors’ stage, cells presented an upregulation of genes associated with hypoxia-inducible factor pathway and a downregulation of oxidative stress genes. This condition promoted higher HLC production (maximum cell concentration: 2 × 106 cell/mL) and improved differentiation efficiencies (80% Albumin-positive cells) when compared to the bioreactor operated under atmospheric oxygen levels (21%O2, 0.6 × 106 cell/mL, 43% Albumin positive cells). These HLC exhibited functional characteristics of hepatocytes: capacity to metabolize drugs, ability to synthesize hepatic metabolites, and inducible cytochrome P450 activity. Bioprocess robustness was confirmed with HLC derived from different donors, including a primary hyperoxaluria type 1 (PH1) patient. The generated PH1.HLC showed metabolic features of PH1 disease with higher secretion of oxalate compared with HLC generated from healthy individuals. This work reports a reproducible bioprocess, that shows the importance of controlling DO at physiological levels to increase HLC production, and the HLC capability to display PH1 disease features.

Targeting Metals in Alzheimer's Disease: An Update.

One pathological feature of Alzheimer's disease (AD) is the dysregulated metal ions, e.g., zinc, copper, and iron in the affected brain regions. The dysregulation of metal homeostasis may cause neurotoxicity and directly addressing these dysregulated metals through metal chelation or mitigating the downstream neurotoxicity stands as a pivotal strategy for AD therapy. This review aims to provide an up-to-date comprehensive overview of the application of metal chelators and drugs targeting metal-related neurotoxicity, such as antioxidants (ferroptotic inhibitors), in the context of AD treatment. It encompasses an exploration of their pharmacological effects, clinical research progress, and potential underlying mechanisms.

An Orai1 gain-of-function tubular aggregate myopathy mouse model phenocopies key features of the human disease.

Tubular aggregate myopathy (TAM) is a heritable myopathy primarily characterized by progressive muscle weakness, elevated levels of creatine kinase (CK), hypocalcemia, exercise intolerance, and the presence of tubular aggregates (TAs). Here, we generated a knock-in mouse model based on a human gain-of-function mutation which results in a severe, early-onset form of TAM, by inducing a glycine-to-serine point mutation in the ORAI1 pore (Orai1G100S/+ or GS mice). By 8 months of age, GS mice exhibited significant muscle weakness, exercise intolerance, elevated CK levels, hypocalcemia, and robust TA presence. Unexpectedly, constitutive Ca2+ entry in mutant mice was observed in muscle only during early development and was abolished in adult skeletal muscle, partly due to reduced ORAI1 expression. Consistent with proteomic results, significant mitochondrial damage and dysfunction was observed in skeletal muscle of GS mice. Thus, GS mice represent a powerful model for investigation of the pathophysiological mechanisms that underlie key TAM symptoms, as well as those compensatory responses that limit the damaging effects of uncontrolled ORAI1-mediated Ca2+ influx.

New Method for Tomato Disease Detection Based on Image Segmentation and Cycle-GAN Enhancement

A major concern in data-driven deep learning (DL) is how to maximize the capability of a model for limited datasets. The lack of high-performance datasets limits intelligent agriculture development. Recent studies have shown that image enhancement techniques can alleviate the limitations of datasets on model performance. Existing image enhancement algorithms mainly perform in the same category and generate highly correlated samples. Directly using authentic images to expand the dataset, the environmental noise in the image will seriously affect the model’s accuracy. Hence, this paper designs an automatic leaf segmentation algorithm (AISG) based on the EISeg segmentation method, separating the leaf information with disease spot characteristics from the background noise in the picture. This algorithm enhances the network model’s ability to extract disease features. In addition, the Cycle-GAN network is used for minor sample data enhancement to realize cross-category image transformation. Then, MobileNet was trained by transfer learning on an enhanced dataset. The experimental results reveal that the proposed method achieves a classification accuracy of 98.61% for the ten types of tomato diseases, surpassing the performance of other existing methods. Our method is beneficial in solving the problems of low accuracy and insufficient training data in tomato disease detection. This method can also provide a reference for the detection of other types of plant diseases.