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Nature Aging Jun 2024Investigating the genetic underpinnings of human aging is essential for unraveling the etiology of and developing actionable therapies for chronic diseases. Here, we...
Investigating the genetic underpinnings of human aging is essential for unraveling the etiology of and developing actionable therapies for chronic diseases. Here, we characterize the genetic architecture of the biological age gap (BAG; the difference between machine learning-predicted age and chronological age) across nine human organ systems in 377,028 participants of European ancestry from the UK Biobank. The BAGs were computed using cross-validated support vector machines, incorporating imaging, physical traits and physiological measures. We identify 393 genomic loci-BAG pairs (P < 5 × 10) linked to the brain, eye, cardiovascular, hepatic, immune, metabolic, musculoskeletal, pulmonary and renal systems. Genetic variants associated with the nine BAGs are predominantly specific to the respective organ system (organ specificity) while exerting pleiotropic links with other organ systems (interorgan cross-talk). We find that genetic correlation between the nine BAGs mirrors their phenotypic correlation. Further, a multiorgan causal network established from two-sample Mendelian randomization and latent causal variance models revealed potential causality between chronic diseases (for example, Alzheimer's disease and diabetes), modifiable lifestyle factors (for example, sleep duration and body weight) and multiple BAGs. Our results illustrate the potential for improving human organ health via a multiorgan network, including lifestyle interventions and drug repurposing strategies.
PubMed: 38942983
DOI: 10.1038/s43587-024-00662-8 -
Radiography (London, England : 1995) Jun 2024Alzheimer's disease (AD), the most common cause of dementia, presents a global health crisis with its prevalence expected to triple worldwide by 2050, emphasizing the...
INTRODUCTION
Alzheimer's disease (AD), the most common cause of dementia, presents a global health crisis with its prevalence expected to triple worldwide by 2050, emphasizing the urgent need for early diagnosis to delay progression and improve patient quality of life. Our project aims to detect AD in its early phase by identifying subtle neuroanatomical changes with Radiomics features, offering a more accurate diagnosis.
METHODS
The AssemblyNet segmentation model was used to analyze brain changes by employing anonymized T1 MRI scans from 416 patients. For each segmented label we extracted Radiomic features. After preprocessing of Radiomic features we trained four models, Gradient Booster, Random Forest, Support Vector Classifier, and XGBoost, in a 70%/20%/10% train, validation and test split. All models were hyperparameter tuned with GridSearch, Cross validation and evaluated with accuracy on the test data.
RESULTS
208 T1-weighted MRI scans were segmented, with 132 segmentation labels per patient, 1130 Radiomic features per segmentation, totalling in over 31 million features. For all four models we achieved accuracies between 0.71 and 0.86, and the machine learning model with highest accuracy were XGBoost, achieving an accuracy at 0.86 on the segmentation of the left inferior lateral ventricle.
CONCLUSION
Our study's use of segmentation on T1-weighted MRI scans resulted promising accuracies for early AD diagnosis with the machine learning model XGBoost, peaking at 0.86 accuracy. Future research should aim to expand datasets and refine methodologies for broader applicability.
IMPLICATION FOR PRACTICE
Implementing Radiomics for early AD detection using T1-weighted MRI scans could substantially improve diagnostic accuracy, enabling earlier interventions that may delay disease progression and improve outcomes, thereby requiring radiographers to adopt more advanced imaging techniques and analysis tools, as well as additional training to effectively interpret complex Radiomic data.
PubMed: 38942647
DOI: 10.1016/j.radi.2024.06.016 -
Experimental Eye Research Jun 2024Over the past twenty years, ocular gene therapy has primarily focused on addressing diseases linked to various genetic factors. The eye is an ideal candidate for gene... (Review)
Review
Over the past twenty years, ocular gene therapy has primarily focused on addressing diseases linked to various genetic factors. The eye is an ideal candidate for gene therapy due to its unique characteristics, such as easy accessibility and the ability to target both corneal and retinal conditions, including retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), age-related macular degeneration (AMD), and Stargardt disease. Currently, literature documents 33 clinical trials in this field, with the most promising results emerging from trials focused on LCA. These successes have catalyzed further research into other ocular conditions such as glaucoma, AMD, RP, and choroideremia. The effectiveness of gene therapy relies on the efficient delivery of genetic material to specific cells, ensuring sustained and optimal gene expression over time. Viral vectors have been widely used for this purpose, although concerns about potential risks such as immune reactions and genetic mutations have led to the development of non-viral vector systems. Preliminary laboratory research and clinical investigations have shown a connection between vector dosage and the intensity of immune response and inflammation in the eye. The method of administration significantly influences these reactions, with subretinal delivery resulting in a milder humoral response compared to the intravitreal route. This review discusses various ophthalmic diseases, including both corneal and retinal conditions, and their underlying mechanisms, highlighting recent advances and applications in ocular gene therapies.
PubMed: 38942133
DOI: 10.1016/j.exer.2024.109983 -
Journal of Neurovirology Jun 2024The Rabies virus is a neurotropic virus that manipulates the natural cell death processes of its host to ensure its own survival and replication. Studies have shown that...
The Rabies virus is a neurotropic virus that manipulates the natural cell death processes of its host to ensure its own survival and replication. Studies have shown that the anti-apoptotic effect of the virus is mediated by one of its protein named, rabies glycoprotein (RVG). Alzheimer's disease (AD) is characterized by the loss of neural cells and memory impairment. We aim to examine whether expression of RVG in the hippocampal cells can shield the detrimental effects induced by Aβ. Oligomeric form of Aβ (oAβ) or vehicle was bilaterally microinjected into the dorsal hippocampus of male Wistar rats. One week later, two μl (10 T.U. /ml) of the lentiviral vector carrying RVG gene was injected into their dorsal hippocampus (post-treatment). In another experiment, the lentiviral vector was microinjected one week before Aβ injection (pre-treatment). One week later, the rat's brain was sliced into cross-sections, and the presence of RVG-expressing neuronal cells was confirmed using fluorescent microscopy. Rats were subjected to assessments of spatial learning and memory as well as passive avoidance using the Morris water maze (MWM) and the Shuttle box apparatuses, respectively. Protein expression of AMPA receptor subunit (GluA1) was determined using western blotting technique. In MWM, Aβ treated rats showed decelerated acquisition of the task and impairment of reference memory. RVG expression in the hippocampus prevented and restored the deficits in both pre- and post- treatment conditions, respectively. It also improved inhibitory memory in the oAβ treated rats. RVG increased the expression level of GluA1 level in the hippocampus. Based on our findings, the expression of RVG in the hippocampus has the potential to enhance both inhibitory and spatial learning abilities, ultimately improving memory performance in an AD rat model. This beneficial effect is likely attributed, at least in part, to the increased expression of GluA1-containing AMPA receptors.
PubMed: 38943023
DOI: 10.1007/s13365-024-01221-y -
PLoS Pathogens Jun 2024Plasmodium vivax serological exposure markers (SEMs) have emerged as promising tools for the actionable surveillance and implementation of targeted interventions to...
Plasmodium vivax serological exposure markers (SEMs) have emerged as promising tools for the actionable surveillance and implementation of targeted interventions to accelerate malaria elimination. To determine the dynamic profiles of SEMs in current and past P. vivax infections, we screened and selected 11 P. vivax proteins from 210 putative proteins using protein arrays, with a set of serum samples obtained from patients with acute P. vivax and documented past P. vivax infections. Then we used a murine protein immune model to initially investigate the humoral and memory B cell response involved in the generation of long-lived antibodies. We show that of the 11 proteins, especially C-terminal 42-kDa region of P. vivax merozoite surface protein 1 (PvMSP1-42) induced longer-lasting long-lived antibodies, as these antibodies were detected in individuals infected with P. vivax in the 1960-1970s who were not re-infected until 2012. In addition, we provide a potential mechanism for the maintenance of long-lived antibodies after the induction of PvMSP1-42. The results indicate that PvMSP1-42 induces more CD73+CD80+ memory B cells (MBCs) compared to P. vivax GPI-anchored micronemal antigen (PvGAMA), allowing IgG anti-PvMSP1-42 antibodies to be maintained for a long time.
PubMed: 38941356
DOI: 10.1371/journal.ppat.1012334 -
Journal of Medical Entomology Jun 2024Predicting the potential distribution and coexistence of suitable geographic areas for Chagas disease vectors in the Americas is a crucial task for understanding the...
Predicting the potential distribution and coexistence of suitable geographic areas for Chagas disease vectors in the Americas is a crucial task for understanding the eco-epidemiological dynamics of this disease. The potential distribution and coexistence of 3 species-Rhodnius prolixus (Hemiptera: Reduviidae), Cavernicola pilosa (Hemiptera: Reduviidae), and Rhodnius pictipes (Hemiptera: Reduviidae) were modeled. Presence records were obtained and environmental variables were selected based on correlation analysis, Jackknife analysis and knowledge of the biology and natural history of the species. The MaxEnt algorithm included in the kuenm package of R software was used for modeling the potential distribution, and various scenarios of the BAM diagram (Biotic, Abiotic, and Movement variables) were evaluated. The variables contributing to the final models were different for each species. Rhodnius pictipes showed a potential distribution in South America, particularly in Brazil, Bolivia, Peru, Colombia, Venezuela, Guyana, and Suriname. Areas with environmentally suitable conditions for R. prolixus were located in southern Brazil, Peru, Colombia, southern Mexico, Guatemala, El Salvador, and Honduras, whereas for C. pilosa they were in southeastern Brazil, southeastern Central America, Peru, Ecuador, Colombia, Venezuela, Guyana, Suriname, and French Guiana. Co-occurrence analysis revealed distinct patterns in the neotropical region, with some areas indicating the potential distribution of 1 or more species. In Brazil, occurrence and co-occurrence areas were concentrated in the northwest and southeast regions. Overall, this study provides valuable information on the potential distribution and coexistence of vectors, which can inform targeted vector control strategies and contribute to global efforts in combating Chagas disease.
PubMed: 38941237
DOI: 10.1093/jme/tjae077 -
Oncology Reports Aug 2024The prognosis of patients with human papillomavirus (HPV)‑negative cervical cancer is significantly worse than that of patients with HPV‑positive cervical cancer....
The prognosis of patients with human papillomavirus (HPV)‑negative cervical cancer is significantly worse than that of patients with HPV‑positive cervical cancer. Understanding the mechanisms of this is crucial for preventing disease evolution. In the present study, the GV367‑snail family transcriptional repressor 2 (SNAI2) lentiviral vector was constructed and transduced into C‑33A cells. Subsequently, the proliferation of tumor cells was detected using the Cell Counting Kit (CCK)‑8 method. Flow cytometry was used to analyze the cell cycle progression of tumor cells. The glucose consumption of tumor cells was detected using an oxidase assay, and the senescence of tumor cells was detected using beta‑galactosidase staining. The gene expression and the activity of p38 and ERK1/2 were detected using reverse transcription‑quantitative PCR and western blotting, respectively. The C‑33A‑SNAI2 cell line was successfully established. Compared with HeLa and C‑33A‑Wild cells, the proliferation and percentage of G0/G1‑phase cells in the C‑33A‑SNAI2 group were decreased, as detected by the CCK‑8 assay (100±0 vs. 239.1±58.3 vs. 39.7±20.1, P<0.01) and flow cytometry (34.0±7.1% vs. 46.2±10.6% vs. 61.3±5.3%, P<0.05). Compared with the HeLa group, the glucose consumption of the C‑33A‑Wild and C‑33A‑SNAI2 groups was significantly decreased (P<0.01). The results of beta‑galactosidase staining showed that the proportion of beta‑galactosidase‑positive cells in the C‑33A‑SNAI2 group was significantly decreased compared with the C‑33A‑Wild group (P<0.01). Upregulation of SNAI2 enhanced the increase in p21 expression, and the decrease in CDK1, urokinase plasminogen activator receptor (u‑PAR) and cyclin D1 expression in C‑33A cells compared with C‑33A‑Wild cells (P<0.05). In addition, the activities of p38, ERK1/2 and the phosphorylated (p)‑ERK1/2/p‑p38 ratio were decreased in the C‑33A‑SNAI2 group compared with the C‑33A‑Wild and HeLa groups (P<0.05). In conclusion, SNAI2 enhanced HPV‑negative cervical cancer C‑33A cell dormancy, which was characterized by G0/G1 arrest, by the downregulation of u‑PAR expression, and a decrease in the activity of the p‑ERK1/2 and p‑p38MAPK signaling pathways . Cancer recurrence and metastases are responsible for most cancer‑related deaths. Given that SNAI2 is required for enhancing HPV‑negative cervical cancer cell dormancy, regulating this process may promote cervical tumor cells to enter a continuous dormant state, which could be a potential approach for tumor therapy.
Topics: Humans; Uterine Cervical Neoplasms; Female; Snail Family Transcription Factors; Cell Proliferation; Gene Expression Regulation, Neoplastic; MAP Kinase Signaling System; HeLa Cells; Receptors, Urokinase Plasminogen Activator; Cell Line, Tumor; Papillomaviridae; Cellular Senescence; p38 Mitogen-Activated Protein Kinases; Cell Cycle
PubMed: 38940353
DOI: 10.3892/or.2024.8763 -
Expert Opinion on Biological Therapy Jun 2024Leber hereditary optic neuropathy (LHON) is among the most frequent inherited mitochondrial disease, causing a severe visual impairment, mostly in young-adult males. The... (Review)
Review
INTRODUCTION
Leber hereditary optic neuropathy (LHON) is among the most frequent inherited mitochondrial disease, causing a severe visual impairment, mostly in young-adult males. The causative mtDNA variants (the three common are m.11778 G>A/MT-ND4, m.3460 G>A/MT-ND1, and m.14484T>C/MT-ND6) by affecting complex I impair oxidative phosphorylation in retinal ganglion cells, ultimately leading to irreversible cell death and consequent functional loss. The gene therapy based on allotopic expression of a wild-type transgene carried by adeno-associated viral vectors (AVV-based) appears a promising approach in mitochondrial disease and its efficacy has been explored in several large clinical trials.
AREAS COVERED
The review work employed basic concepts in mitochondrial diseases, LHON, and gene therapy procedures. Reports from completed trials in LHON (i.e. RESCUE) were reviewed and critically compared.
EXPERT OPINION
New challenges, as the improvement of the contralateral untreated eye or the apparently better outcome in patients treated in later stages (6-12 months), were highlighted by the latest gene therapy trials. A better understanding of the pathogenetic mechanisms of the disease together with combined therapy (medical and gene therapy) and optimization in genetic correction approaches could improve the visual outcome of treated eyes.
PubMed: 38939999
DOI: 10.1080/14712598.2024.2359015 -
Journal of Extracellular Biology Feb 2024Colon cancer is one of the most commonly occurring tumours among both women and men, and over the past decades the incidence has been on the rise. As such, the need for...
Colon cancer is one of the most commonly occurring tumours among both women and men, and over the past decades the incidence has been on the rise. As such, the need for biomarker identification as well as an understanding of the underlying disease mechanism has never been greater. Extracellular vesicles are integral mediators of cell-to-cell communication and offer a unique opportunity to study the machinery that drives disease progression, and they also function as vectors for potential biomarkers. Tumour tissue and healthy mucosal tissue from the colons of ten patients were used to isolate tissue-resident EVs that were subsequently subjected to global quantitative proteomic analysis through LC-MS/MS. In total, more than 2000 proteins were identified, with most of the common EV markers being among them. Bioinformatics revealed a clear underrepresentation of proteins involved in energy production and cellular adhesion in tumour EVs, while proteins involved in protein biosynthesis were overrepresented. Additionally, 53 membrane proteins were found to be significantly upregulated in tumour EVs. Among them were several proteins with enzymatic functions that degrade the extracellular matrix, and three of these, Fibroblast activating factor (FAP), Cell surface hyaluronidase (CEMIP2), as well as Ephrin receptor B3 (EPHB3), were validated and found to be consistent with the global quantitative results. These stark differences in the proteomes between healthy and cancerous tissue emphasise the importance of the interstitial vesicle secretome as a major player of disease development.
PubMed: 38939898
DOI: 10.1002/jex2.127 -
Current Tropical Medicine Reports Dec 2023Human African Trypanosomiasis (HAT), also known as sleeping sickness, is a vector-borne parasitic neglected tropical disease (NTD) endemic in sub-Saharan Africa. This...
PURPOSE OF REVIEW
Human African Trypanosomiasis (HAT), also known as sleeping sickness, is a vector-borne parasitic neglected tropical disease (NTD) endemic in sub-Saharan Africa. This review aims to enhance our understanding of HAT and provide valuable insights to combat this significant public health issue by synthesizing the latest research and evidence.
RECENT FINDINGS
HAT has reached a historical < 1000 cases in 2018. In patients without neurologic symptoms and signs, the likelihood of a severe meningoencephalitic stage is deemed low, obviating the need for a lumbar puncture to guide treatment decisions using fexinidazole.
SUMMARY
Both forms of the disease, gambiense HAT (gHAT) and rhodesiense HAT (rHAT), have specific epidemiology, risk factors, diagnosis, and treatment. Disease management still requires a high index of suspicion, infectious disease expertise, and specialized medical care. Essential stakeholders in health policy are critical to accomplishing the elimination goals of the NTD roadmap for 2021-2030.
PubMed: 38939748
DOI: 10.1007/s40475-023-00304-w