Stages Of Disease Development Research Articles

Identification of Molecular Profile of Cell Membrane via Magnetic Plasmonic Nanoprobe.

Cell membranes are primarily composed of lipids, membrane proteins, and carbohydrates, and the related studies of membrane components and structures at different stages of disease development, especially membrane proteins, are of great significance. Here, we investigate the chemical signature profiles of cell membranes as biomarkers for cancer cells via label-free surface-enhanced Raman scattering (SERS). A magnetic plasmonic nanoprobe was proposed by decorating magnetic beads with silver nanoparticles, allowing self-driven cell membrane-targeted accumulation within 5 min. SERS profiles of three types of breast cells were achieved under the plasmon enhancement effect of these nanoprobes. Membrane fingerprint spectra from breast cell lines were further classified with the convolutional neural network model, which perfectly distinguished between two breast cancer subtypes. We further tested various clinical samples using this method and obtained fingerprint spectra from primary cells and frozen slices. This study presents a practical, user-friendly approach for label-free and in situ analysis of cell membranes, which can work for early tumor screening and treatment assessment for tumors reliant on the Molecular profiles of cell membranes. Additionally, this method can be applied universally to explore cell membrane components of other cells, thus assisting Human Cell Atlas.

Importance of Shatkriya Kala in the Manifestation and Management of Amavata

“Ayurveda, the ancient Indian system of medicine, elucidates a comprehensive framework for understanding the pathogenesis and progression of diseases. A critical concept within this framework is the “Shatkriya kala”, explained by Acharya Sushruta which describes the six stages of disease development. These stages- Sanchaya, Prakopa, Prasara, Sthana Samshraya, Vyakta, Bheda- offer insight into the dynamic process of disease evaluation and guide timely intervention. It shows the stepwise progression of Dosha and Rogas. A clear understanding about the consecutive stages of disease, early diagnosis, prognosis, to adopt preventive and curative measures in Ayurvedic Pathology, the Shatkriya kala becomes essential. Likewise, understanding and inervening at the appropriate stages of Shatkriya Kala is crucial for the effective management and treatment of Amavata. In Ayurveda, Amavata is a debilitating condition compared to Rheumatoid Arthritis in modern, characterised by the accumulation of Ama(toxins) and the aggravation of Vata dosha. So, through this article, an attempt is made to highlight the importance of Shatkriya kala in the context of Amavata.

Automated system utilizing non-invasive technique mammograms for breast cancer detection

In order to increase the likelihood of obtaining treatment and achieving a complete recovery, early illness identification and diagnosis are crucial. Artificial intelligence is helpful with this process by allowing us to rapidly start the necessary protocol for treatment in the early stages of disease development. Artificial intelligence is a major contributor to the improvement of medical treatment for patients. In order to prevent and foresee this problem on the individual, family, and generational levels, Monitoring the patient's therapy and recovery is crucial. This study's objective is to outline a non-invasive method for using mammograms to detect breast abnormalities, classify breast disorders, and identify cancerous or benign tumor tissue in the breast. We used classification models on a dataset that has been pre-processed so that the number of samples is balanced, unlike previous work on the same dataset. Identifying cancerous or benign breast tissue requires the use of supervised learning techniques and algorithms, such as random forest (RF) and decision tree (DT) classifiers, to examine up to thirty features, such as breast size, mass, diameter, circumference, and the nature of the tumor (solid or cystic). To ascertain if the tissue is malignant or benign, the examination's findings are employed. These features are mostly what determines how effectively anything may be categorized. The DT classifier was able to get a score of 95.32%, while the RF satisfied a far higher 98.83 percent.

Symptom Cluster Assessment Tools for Gastric Cancer Care in China: A Comprehensive Review.

Gastric cancer is a common malignant tumor, and its incidence rate ranks first among malignant tumors of the digestive tract, seriously endangering human physical and mental health. Changes in the physiological state of gastric cancer patients can bring about many physical and psychological symptoms and have a serious impact on their quality of life. Symptom clusters are 2 or more concurrently occurring and interrelated symptoms, with the core symptoms within the cluster remaining stable over time and the symptoms in the cluster being independent of each other. The prerequisite for solving this problem is to screen out appropriate symptom assessment tools according to the clinical situation. The aim of this study was to provide a reference for the development of assessment tools suitable for symptom clusters of gastric cancer patients in China, and to provide evidence for the subsequent optimization of symptom management and some clinical decisions. The contents, application, advantages, and disadvantages of symptom cluster assessment tools for gastric cancer patients in China and abroad were reviewed, and the basic situation and contents of each assessment tool were compared. In China, most of the assessment tools used in domestic gastric cancer research institutes were imported from foreign scales, with a long time span and low specificity for symptoms in various stages of disease development at present. Scholars should be encouraged to develop time-specific assessment tools for the disease characteristics of gastric cancer patients in China, and actively explore the pathogenesis and influencing factors of symptom clusters in this population.

Artificial intelligence (AI) in mammographic screening in Norway

Artificial intelligence (AI) in mammographic screening in Norway BreastScreen Norway discusses how the results from their screening programme for early breast cancer detection can influence future artificial intelligence to streamline early breast cancer detection. Breast cancer is a significant global health concern, with more than 2 million new cases diagnosed and over half a million women dying from the disease annually.(1) Many countries, including Norway, have implemented mammographic screening to detect breast cancer in an early stage of disease development, as an early intervention has clear benefits on the disease outcome. In Norway, all women aged 50 to 69 years are invited to biennial mammographic screening through the national screening program, BreastScreen Norway.(2)

P-332 Decoding autophagy dynamics in adenomyosis: insights of a murine model

Abstract Study question This study aimed to highlight the role of autophagy in the pathogenesis of adenomyosis using a murine model of medically induced adenomyosis. Summary answer Autophagy seems to play a role in the early stages of the disease and is likely not the primary mechanism driving the progression of adenomyosis. What is known already Autophagy is an intracellular mechanism involved in the recycling of aging organelles and non-functional proteins. Initially described as a phenomenon activated under stress or fasting conditions (non-selective autophagy), it is now accepted that a basal level of autophagy is essential for several cellular functions to maintain cellular homeostasis (selective autophagy). Autophagy is essential for cell survival and tissue growth, and an alteration of the autophagic pathway has been described in endometrial pathologies such as endometrial hyperplasia and carcinoma, infertility, and endometriosis. The contribution of autophagy to adenomyosis is still unclear due to conflicting findings in the existing literature. Study design, size, duration This experimental study was conducted from October 2022 until January 2024. A total of 170 mice pups were treated (90 treated with tamoxifen – 80 with vehicle only). Participants/materials, setting, methods Female neonatal CD1 mice received oral doses of 2.7µmol/kg tamoxifen from days 2 to 5 after birth. Control mice received only the vehicle. After synchronizing their estrus cycle, the mice were euthanized at 1 month or 3 months old. The diagnostic and grading of adenomyosis were performed by histological examination (hematoxylin-eosin and immuno-fluorescence). RT-PCR and Western Blot were used to study the modulation of autophagy pathways between the uterus of the two groups. Main results and the role of chance Histological analysis of 3-month-old tamoxifen-treated group showed that 97% of the mice developed the disease. The grading method was defined by assessing the depth of lesions. After sensitivity enhancement through immunofluorescence staining (alpha-SMA, EpCAM and DAPI), grade 3 adenomyosis was diagnosed in up to 91% of our samples (vs 84% when analyzed by H&E only). Neonatal treatment of CD1 mice with tamoxifen reliably produces severe adenomyotic lesions. Immunofluorescence enhances sensitivity in histological examinations of myometrial lesions, combining alpha-SMA staining for smooth muscle detection with EpCAM for identifying epithelial cells. RTqPCR analysis of lc3b, akt, bcl2, bclxl, ulk2, ulk1, cxcr4, tnfs10, dapk1, igf1, atg9, pik3c3, and bid showed an up-regulation of autophagy in one-month-old adenomyosis mice. This was also indicated by a decrease in akt and bcl2, which are inhibitors of the pathway, along with an increase in lc3b, a marker for phagophore formation. However, the conflicting decrease in ulk2, a component of the induction complex, raises questions. Importantly, these changes in autophagy are not observed in 3-month-old mice, suggesting that autophagy may play a role in the early stages of disease development. There were no statistical differences in Protein expression of pakt/akt, lc3b, and bcl2 between the groups. Limitations, reasons for caution The analysis used protein or mRNA extracted from the whole uterus. Variations in results may arise if the endometrial and myometrial components are analyzed separately. Techniques like laser capture microdissection could prove valuable in this context. Continued research focusing on investigating the role of apoptosis in the study is essential. Wider implications of the findings Given the frequent association of adenomyosis with endometriosis and/or uterine fibroids, using an experimental model offers the advantage of eliminating bias from associated comorbidities. This approach presents a unique opportunity to unravel the molecular basis of adenomyosis, while enabling a translational analysis when juxtaposed with clinical studies. Trial registration number not applicable

Understanding the Pathogenesis of Infectious Diseases: Insights from Pathology

The pathogenesis of infectious diseases is essential for developing effective diagnostic, therapeutic, and preventive measures. Pathology, the study of disease mechanisms through the examination of tissues and organs, provides critical insights into how pathogens cause disease in their hosts. This paper presents a comprehensive framework for understanding the pathogenesis of infectious diseases, focusing on bacterial, viral, fungal, and parasitic infections. We explore the stages of disease development, including pathogen entry, colonization, immune evasion, tissue damage, and transmission. Key pathological techniques such as histopathology, gross pathology, and molecular pathology are discussed, highlighting their role in identifying and characterizing disease mechanisms. Through detailed case studies, we illustrate how pathological findings inform our understanding of specific infectious diseases, including tuberculosis, HIV/AIDS, and malaria. The significance of host factors, such as genetic variability and immune response, in disease pathogenesis is also examined. Furthermore, the paper addresses the therapeutic implications of these insights, including the development of targeted therapies and vaccines. Finally, we discuss future directions in the field, emphasizing the need for interdisciplinary collaboration and technological advancements to enhance our understanding of infectious disease pathogenesis. This paper aims to bridge the gap between basic pathological research and clinical applications, ultimately contributing to improved public health outcomes.

CD4+ T-cell Subsets and Cytokine Signature in Pemphigus Foliaceus Clinical Stratification beyond the th1/Th2 Paradigm.

T helper interplay and cytokines monitoring in auto-immune skin disorders such as Pemphigus Foliaceus [PF] may play a central role in predicting the clinical stratification of the pathology. In order to assess the CD4+ T cell imbalance, [i] this study aims to assess the related immune cells [Th1, Th2, Th17, and Treg cells] as well as the related cytokines [IL-1β, IFNγ, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, IL-17F, IL- 22, TNF-β, and TNFα] in peripheral blood, and [ii] their respective transcription factors in the lesioned skin of PF endemic patients during the clinical course. Peripheral blood of 22 PF patients was analyzed by flow cytometry to assess the functional associations of Th cell subpopulations and their characteristic cytokines by multiplex bead assay of 14-plex cytokines. Skin mRNA expression of their associated transcription factors was analyzed using the TaqMan detection system. Our findings revealed that the CD4+ T cell subtypes in PF patients compared to Healthy Controls [HC] were characterized by [i] a similar Th1/Th2 ratio and increased Th17/Treg ratio and [ii] significantly higher plasma levels of Th-17 specific cytokines; IL- 6, IL-8, IL-17A. Higher percentages in Th17 and Treg subtypes and a significant increase in plasma IL-17F levels were maintained in relapsing PF patients, arguing the pivotal role of Th17 cells in PF pathogenesis. Furthermore, our findings pointed out the major contribution of the pro-inflammatory cytokine IL-6. Indeed, in addition to being involved in the initial stages of disease development, IL-6 seems to also be involved in the maintenance of the pathophysiological process, probably through its effect on Th17 differentiation. The skin-relative mRNA expression levels of FOXP3 and TBET were significantly higher in relapsing PF patients compared to de novo PF patients. Our results highlight the central role played by Th17 lymphocytes and their related pro-inflammatory cytokines during the clinical course of the disease, reversing the Th1/Th2 dichotomy in PF.

Study of the Impact of the Parasitic Microalgae Coccomyxa parasitica on the Health of Bivalve Modiolus kurilensis

The invasion of bivalves by parasitic microalgae Coccomyxa is widespread and causes pathologies and dysfunctions of the organs, especially in the most valuable products: the mantle and the muscle. The pathogenesis of the disease remains completely unknown. In this study, based on a macroscopic examination of Modiolus kurilensis and microalgae count in each infected individual, four stages of disease development with characteristic pathognomonic symptoms were described. During the progression of the disease, the concentration of alkaline phosphatase, glucose, calcium, hemolytic and agglutinating activities, number of basophils, eosinophils, phagocytes, and cells with reactive oxygen species increased in the hemolymph, while number of agranulocytes, cells with lysosomes, dead hemocytes, total protein concentration, as well as the weight of mollusks decreased. In the nephridia and digestive gland, necrosis, invasion of Nematopsis sp., hemocyte infiltration, and fibrosis increased. The ratio of changed tubules and occurrence of granulocytomas increased in the digestive gland, while the base membrane, nephrocytes and concretions changed in the nephridia. This study helps establish the variability of these parameters under normal conditions and their alteration during the disease. Moreover, these findings can be used for veterinary monitoring of the state of bivalves in natural and aquaculture populations.

Advances in proteomics in diffuse large B‑cell lymphoma (Review).

Diffuse large B‑cell lymphoma (DLBCL) is the most common pathological type of non‑Hodgkin's lymphoma. Although the development of monoclonal antibodies, small‑molecule‑targeted drugs and novel chemotherapeutic agents, and the increased use of immunotherapy have markedly improved the outcomes of DLBCL, ~40% of patients cannot be cured following the use of standardized first‑line treatment. In addition, the specific mechanisms of drug resistance and potential factors associated with a poor prognosis in these patients remain unclear. Proteomics research is used to determine potential associations between changes in DLBCL protein expression levels and different stages of disease occurrence and development. Proteomics may aid in the identification of novel molecular mechanisms and drug resistance mechanisms, through identifying multiple associated proteins and monitoring changes in expression levels. Thus, proteomics research may exhibit potential in the development of therapeutic targets and in improving prognostic evaluation in patients with DLBCL. The present study aimed to review the use of proteomic methods for the investigation of DLBCL, including the mechanisms underlying disease progression and drug resistance in DLBCL, and the function of the tumor microenvironment in lymphoma growth. The present review also demonstrated the potential of proteomic‑guided therapeutic strategies for DLBCL and discussed the synergistic benefits of using proteomic methods in DLBCL research.

Comparative transcriptome revealed the molecular responses of Aconitum carmichaelii Debx. to downy mildew at different stages of disease development

BackgroundAconitum carmichaelii Debx. has been widely used as a traditional medicinal herb for a long history in China. It is highly susceptible to various dangerous diseases during the cultivation process. Downy mildew is the most serious leaf disease of A. carmichaelii, affecting plant growth and ultimately leading to a reduction in yield. To better understand the response mechanism of A. carmichaelii leaves subjected to downy mildew, the contents of endogenous plant hormones as well as transcriptome sequencing were analyzed at five different infected stages.ResultsThe content of 3-indoleacetic acid, abscisic acid, salicylic acid and jasmonic acid has changed significantly in A. carmichaelii leaves with the development of downy mildew, and related synthetic genes such as 9-cis-epoxycarotenoid dioxygenase and phenylalanine ammonia lyase were also significant for disease responses. The transcriptomic data indicated that the differentially expressed genes were primarily associated with plant hormone signal transduction, plant-pathogen interaction, the mitogen-activated protein kinase signaling pathway in plants, and phenylpropanoid biosynthesis. Many of these genes also showed potential functions for resisting downy mildew. Through weighted gene co-expression network analysis, the hub genes and genes that have high connectivity to them were identified, which could participate in plant immune responses.ConclusionsIn this study, we elucidated the response and potential genes of A. carmichaelii to downy mildew, and observed the changes of endogenous hormones content at different infection stages, so as to contribute to the further screening and identification of genes involved in the defense of downy mildew.

Evaluation of toothpastes for treating root carious lesions – a laboratory-based pilot study

BackgroundRoot caries is preventable and can be arrested at any stage of disease development. The aim of this study was to investigate the potential mineral exchange and fluorapatite formation within artificial root carious lesions (ARCLs) using different toothpastes containing 5,000 ppm F, 1,450 ppm F or bioactive glass (BG) with 540 ppm F.Materials and methodsThe crowns of each extracted sound tooth were removed. The remaining roots were divided into four parts (n = 12). Each sample was randomly allocated into one of four groups: Group 1 (Deionised water); Group 2 (BG with 540 ppm F); Group 3 (1,450 ppm F) and Group 4 (5,000 ppm F). ARCLs were developed using demineralisation solution (pH 4.8). The samples were then pH-cycled in 13 days using demineralisation solution (6 h) and remineralisation solution (pH 7) (16 h). Standard tooth brushing was carried out twice a day with the assigned toothpaste. X-ray Microtomography (XMT) was performed for each sample at baseline, following ARCL formation and after 13-day pH-cycling. Scanning Electron Microscope (SEM) and 19F Magic angle spinning nuclear magnetic resonance (19F-MAS-NMR) were also performed.ResultsXMT results showed that the highest mineral content increase (mean ± SD) was Group 4 (0.09 ± 0.05), whilst the mineral content decreased in Group 1 (-0.08 ± 0.06) after 13-day pH-cycling, however there was evidence of mineral loss within the subsurface for Groups 1, 3 and 4 (p < 0.05). SEM scans showed that mineral contents within the surface of dentine tubules were high in comparison to the subsurface in all toothpaste groups. There was evidence of dentine tubules being either partially or completely occluded in toothpaste groups. 19F-MAS-NMR showed peaks between − 103 and − 104ppm corresponding to fluorapatite formation in Groups 3 and 4.ConclusionWithin the limitation of this laboratory-based study, all toothpastes were potentially effective to increase the mineral density of artificial root caries on the surface, however there was evidence of mineral loss within the subsurface for Groups 1, 3 and 4.

Radiological methods for diagnosing temporomandibular joint diseases

The article provides a literature review of modern views on the application of radiological methods diagnosing temporomandibular joint diseases. This problem is one of the most current in dentistry. Correct choice of the method of radiological diagnosis of temporomandibular joint diseases is the key to their successful treatment. Computed tomography and magnetic resonance imaging make it possible to assess the severity of the pathological process in more detail than other radiological examination methods, systematize the results obtained and, based on them, distinguish the stages of disease development. However, the most complete assessment of the anatomical and functional state of the temporomandibular joint, including visualization of bone and soft tissue structures, is possible with the comprehensive application of radiological diagnostics methods.

Biomarkers in Ovarian Cancer: Towards Personalized Medicine.

Ovarian cancer is one of the deadliest cancers in women. The lack of specific symptoms, especially at the initial stages of disease development, together with the malignancy heterogeneity, lower the life expectancy of patients. Aiming to improve survival rates, diagnostic and prognostic biomarkers are increasingly employed in clinics, providing gynecologists and oncologists with new tools to guide their treatment decisions. Despite the vast number of investigations, there is still an urgent need to discover more ovarian cancer subtype-specific markers which could further improve patient classification. To this end, high-throughput screening technologies, like mass spectrometry, are applied to deepen the tumoral cellular landscape and describe the malignant phenotypes. As for disease treatment, new targeted therapies, such as those based on PARP inhibitors, have shown great efficacy in destroying the tumoral cells. Likewise, drug-nanocarrier systems targeting the tumoral cells have exhibited promising results. In this narrative review, we summarize the latest achievements in the pursuit of biomarkers for ovarian cancer and recent anti-tumoral therapies.

Machine learning framework to extract the biomarker potential of plasma IgG N-glycans towards disease risk stratification

Effective management of chronic diseases and cancer can greatly benefit from disease-specific biomarkers that enable informative screening and timely diagnosis. IgG N-glycans found in human plasma have the potential to be minimally invasive disease-specific biomarkers for all stages of disease development due to their plasticity in response to various genetic and environmental stimuli. Data analysis and machine learning (ML) approaches can assist in harnessing the potential of IgG glycomics towards biomarker discovery and the development of reliable predictive tools for disease screening. This study proposes an ML-based N-glycomic analysis framework that can be employed to build, optimise, and evaluate multiple ML pipelines to stratify patients based on disease risk in an interpretable manner. To design and test this framework, a published colorectal cancer (CRC) dataset from the Study of Colorectal Cancer in Scotland (SOCCS) cohort (1999–2006) was used. In particular, among the different pipelines tested, an XGBoost-based ML pipeline, which was tuned using multi-objective optimisation, calibrated using an inductive Venn-Abers predictor (IVAP), and evaluated via a nested cross-validation (NCV) scheme, achieved a mean area under the Receiver Operating Characteristic Curve (AUC-ROC) of 0.771 when classifying between age-, and sex-matched healthy controls and CRC patients. This performance suggests the potential of using the relative abundance of IgG N-glycans to define populations at elevated CRC risk who merit investigation or surveillance. Finally, the IgG N-glycans that highly impact CRC classification decisions were identified using a global model-agnostic interpretability technique, namely Accumulated Local Effects (ALE). We envision that open-source computational frameworks, such as the one presented herein, will be useful in supporting the translation of glycan-based biomarkers into clinical applications.

Multi-proteomic analyses of 5xFAD mice reveal new molecular signatures of early-stage Alzheimer's disease.

An early diagnosis of Alzheimer's disease is crucial as treatment efficacy is limited to the early stages. However, the current diagnostic methods are limited to mid or later stages of disease development owing to the limitations of clinical examinations and amyloid plaque imaging. Therefore, this study aimed to identify molecular signatures including blood plasma extracellular vesicle biomarker proteins associated with Alzheimer's disease to aid early-stage diagnosis. The hippocampus, cortex, and blood plasma extracellular vesicles of 3- and 6-month-old 5xFAD mice were analyzed using quantitative proteomics. Subsequent bioinformatics and biochemical analyses were performed to compare the molecular signatures between wild type and 5xFAD mice across different brain regions and age groups to elucidate disease pathology. There was a unique signature of significantly altered proteins in the hippocampal and cortical proteomes of 3- and 6-month-old mice. The plasma extracellular vesicle proteomes exhibited distinct informatic features compared with the other proteomes. Furthermore, the regulation of several canonical pathways (including phosphatidylinositol 3-kinase/protein kinase B signaling) differed between the hippocampus and cortex. Twelve potential biomarkers for the detection of early-stage Alzheimer's disease were identified and validated using plasma extracellular vesicles from stage-divided patients. Finally, integrin α-IIb, creatine kinase M-type, filamin C, glutamine γ-glutamyltransferase 2, and lysosomal α-mannosidase were selected as distinguishing biomarkers for healthy individuals and early-stage Alzheimer's disease patients using machine learning modeling with approximately 79% accuracy. Our study identified novel early-stage molecular signatures associated with the progression of Alzheimer's disease, thereby providing novel insights into its pathogenesis.

Does fungal infection increase the palatability of oilseed rape to insects?

Multiple and simultaneous attacks by pathogens and insect pests frequently occur in nature. Plants respond to biotic stresses by activating distinct defense mechanisms, but little is known about how plants cope with multiple stresses. The focus of this study was the combined interaction of fungal infection caused by Leptosphaeria maculans (synonym Plenodomus lingam) and arthropod infestation by the diamondback moth (Plutella xylostella) in oilseed rape (Brassica napus). We hypothesized that infection by the fungal pathogen L. maculans could alter oilseed rape palatability to P. xylostella-chewing caterpillars. Feeding preference tests were complemented with analyses of defense gene transcription, and levels of glucosinolates (GLSs) and volatile organic compounds (VOCs) in L. maculans-inoculated and non-inoculated (control) leaves to determine possible causes of larval choice. Caterpillars preferred true leaves to cotyledons, hence true leaves were used for further experiments. True leaves inoculated with L. maculans were more palatable to caterpillars over control leaves during the early stage of infection at 3 days post inoculation (dpi), but this preference disappeared in the later stages of infection at 7 dpi. In parallel, genes involved in the salicylic acid and ethylene pathways were up-regulated in L. maculans-inoculated leaves at 3 and 7 dpi; L. maculans increased the level of total aliphatic GLSs, specifically glucobrassicanapin, and decreased the level of glucoiberin at 3 dpi and altered the content of specific VOCs. A group of 55 VOCs with the highest variability between treatments was identified. We suggest that the P. xylostella preference for L. maculans-inoculated leaves in the early stage of disease development could be caused by the underlying mechanisms leading to changes in metabolic composition. Further research should pinpoint the compounds responsible for driving larval preference and evaluate whether the behavior of the adult moths, i.e. the stage that makes the first choice regarding host plant selection in field conditions, correlates with our results on larval host acceptance. © 2024 Society of Chemical Industry.

Identification of key regulatory molecules in the early development stage of Alzheimer's disease.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, the incidence of which increases with age, and the pathological changes in the brain are irreversible. Recent studies have highlighted the essential role of long noncoding RNAs (lncRNAs) in AD by acting as competing endogenous RNAs (ceRNAs). Our aim was to construct lncRNA-associated ceRNA regulatory networks composed of potential biomarkers for the early stage of AD. AD related datasets come from AlzData and GEO databases. The R package 'Limma' identifies differentially expressed genes (DEGs), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) databases for functional enrichment analysis. Protein-protein interactions (PPIs) in DEGs were constructed in the STRING database, and Cytoscape software identified DEGs. Convergent functional genomics (CFG) analysis of differentially expressed hub genes (referred to as early-DEGs) in the brain before the development of AD pathology. The AlzData database analyses the expression levels of early-DEGs in different nerve cells. The lncRNA-miRNA-mRNA regulatory network was established according to the ceRNA hypothesis. We identified four lncRNAs (XIST, NEAT1, KCNQ1OT1 and HCG18) and four miRNAs (hsa-let-7c-5p, hsa-miR-107, hsa-miR-129-2-3p and hsa-miR-214-3p) were preliminarily identified as potential biomarkers for early AD, competitively regulating Atp6v0b, Atp6v1e1 Atp6v1f and Syt1. This study indicates that NEAT1, XIST, HCG18 and KCNQ1OT1 act as ceRNAs in competitive binding with miRNAs to regulate the expression of Atp6v0b, Atp6v1e1, Atp6v1f and Syt1 before the occurrence of pathological changes in AD.

First report of branch dieback caused by Neoscytalidium dimidiatum on Styphnolobium japonicum (L.) Schott in China.

Styphnolobium japonicum (L.) Schott (family Fabaceae Juss.) also called pagoda tree, is widely planted in northern China in landscape plantings, for erosion control and forestry. In recent years, symptoms of branch dieback were observed on S. japonicum in the southern part of Xinjiang province, China. From 2019 to 2022, in total ca. 1000 ha area was surveyed in Korla (41.68°N, 86.06°E), Bohu (41.95°N, 86.53°E) and Alaer (41.15°N, 80.29°E). Typical symptoms were observed in 70% of the surveyed branches. To identify the cause, we collected 50 symptomatic branches. Symptoms were initially observed on green current-year twigs, which turned grayish white in color. In the later stages of disease development, a large number of nacked black conidia formed under epidermis of perennial branches, causing visible black protrusions (pycnidia) on branch surface. The disease occurred throughout the entire growing season of S. japonicum. Symptoms also occurred on the inflorescence, fruit, and twigs. In some cases, infection resulted in tree mortality. Isolations were made from the margin between healthy and diseased tissues. Small pieces were excised, surface disinfested (75% ethanol 30 s, 1% NaClO solution 5 mins), cut into pieces (5 to 10 mm2), and incubated on PDA medium at 28℃ for 3 days. A total of 16 isolates (GH01-GH16) with similar colony morphology were obtained. The colonies were initially white, gradually turning to olive-green on the surface and black on the underside after 7 days. Microscopically, the conidia were aseptate, 1-septate, two-septate, and muriform, 2.6-4.5 × 2.9-27.6 μm (n=50). Pycnidia ranged in size from 120.2 to 135.5 × 112.4 to 118.6 µm (n=20). Those morphological characters matched the descriptions of Neoscytalidium dimidiatum (previously N. novaehollandiae) (Alizadeh et al. 2022; Pavlic et al. 2008). For molecular identification, genomic DNA of GH01-GH16 were extracted from fresh mycelia. The internal transcribed spacer (ITS), large subunit ribosomal RNA gene (LSU), and translation elongation factor 1-alpha (EF1-α) gene were amplified using the primer sets ITS1/ITS4 (White 1990), LRoR/LR5 (Vilgalys and Hester 1990) and EF1-728F/EF1-986R (Carbone and Kohn 1999). The sequences were deposited in GenBank (accession No. OP379832, OQ096643-OQ096657 for ITS, OP389048, OQ127403-OQ127417 for LSU, and OQ136617, OQ586044-OQ586058 for EF1-α). The ITS sequence had 100% identity (505/505 bp) to MT362600. Similarly, the LSU and EF1-α sequences were found to be identical to MW883823 (100%, 821/821 bp) and KX464763(99%, 256/258 bp), respectively. Pathogenicity was tested on one-year-old healthy S. japonicum seedlings. Spores of representative isolate GH01 were produced on PDA by incubating for 7-days at 28℃. Conidia were washed with sterile water. Five trees were inoculated with 1 × 106 conidia/ml conidial suspensions and five trees were sprayed with sterile water. All trees were covered with plastic bags for 24 h and kept at 25°C in a greenhouse. Signs and symptoms were similar to those observed in field collections one month after inoculation, while no symptoms occurred on the controls. The original fungus was successfully reisolated from the inoculated trees and was identified as N. dimidiatum following the methods described above. N. dimidiatum has been reported in many Asian country such as Malaysia, India, Turkey, and Iran(Akgül et al. 2019; Alizadeh et al. 2022; Khoo et al. 2023; Salunkhe et al. 2023). To our knowledge, this is the first report of N. dimidiatum associated with branch dieback of S. japonicum in China. Our findings have expanded the host range of N. dimidiatum in China and provides a theoretical basis for the diagnosis and treatment of the disease.

Imaging Neuroinflammation: Quantification of Astrocytosis in a Multitracer PET Approach.

The recent progress in the development of in vivo biomarkers is rapidly changing how neurodegenerative diseases are conceptualized and diagnosed and how clinical trials are designed today. Alzheimer's disease (AD) - the most common neurodegenerative disorder - is characterized by a complex neuropathology involving the deposition of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) of hyperphosphorylated tau proteins, accompanied by the activation of glial cells, i.e., astrocytes and microglia, and neuroinflammatory response, leading to neurodegeneration and cognitive dysfunction. An increasing diversity of positron emission tomography (PET) imaging radiotracers is available to selectively target the different pathophysiological processes of AD. Along with the success of Aβ PET and the more recent tau PET imaging, there is a great interest to develop PET tracers to image glial reactivity and neuroinflammation. While most research to date has focused on imaging microgliosis, there is an upsurge of interest in imaging reactive astrocytes in the AD continuum. There is increasing evidence that reactive astrocytes are morphologically and functionally heterogeneous, with different subtypes that express different markers and display various homeostatic or detrimental roles across disease stages. Therefore, multiple biomarkers are desirable to unravel the complex phenomenon of reactive astrocytosis. In the field of in vivo PET imaging in AD, the research concerning reactive astrocytes has predominantly focused on targeting monoamine oxidase B (MAO-B), most often using either 11C-deuterium-L-deprenyl (11C-DED) or 18F-SMBT-1 PET tracers. Additionally, imidazoline2 binding (I2BS) sites have been imaged using 11C-BU99008 PET. Recent studies in our group using 11C-DED PET imaging suggest that astrocytosis may be present from the early stages of disease development in AD. This chapter provides a detailed description of the practical approach used for the analysis of 11C-DED PET imaging data in a multitracer PET paradigm including 11C-Pittsburgh compound B (11C-PiB) and 18F-fluorodeoxyglucose (18F-FDG). The multitracer PET approach allows investigating the comparative regional and temporal patterns of in vivo brain astrocytosis, fibrillar Aβ deposition, glucose metabolism, and brain structural changes. It may also contribute to understanding the potential role of novel plasma biomarkers of reactive astrocytes, in particular the glial fibrillary acidic protein (GFAP), at different stages of disease progression. This chapter attempts to stimulate further research in the field, including the development of novel PET tracers that may allow visualizing different aspects of the complex astrocytic and microglial response in neurodegenerative diseases. Progress in the field will contribute to the incorporation of PET imaging of glial reactivity and neuroinflammation as biomarkers with clinical application and motivate further investigation on glial cells as therapeutic targets in AD and other neurodegenerative diseases.