Disease Research Research Articles

Intravascular delivery of an ultraflexible neural electrode array for recordings of cortical spiking activity

Although intracranial neural electrodes have significantly contributed to both fundamental research and clinical treatment of neurological diseases, their implantation requires invasive surgery to open craniotomies, which can introduce brain damage and disrupt normal brain functions. Recent emergence of endovascular neural devices offers minimally invasive approaches for neural recording and stimulation. However, existing endovascular neural devices are unable to resolve single-unit activity in large animal models or human patients, impeding a broader application as neural interfaces in clinical practice. Here, we present the ultraflexible implantable neural electrode as an intravascular device (uFINE-I) for recording brain activity at single-unit resolution. We successfully implanted uFINE-Is into the sheep occipital lobe by penetrating through the confluence of sinuses and recorded both local field potentials (LFPs) and multi-channel single-unit spiking activity under spontaneous and visually evoked conditions. Imaging and histological analysis revealed minimal tissue damage and immune response. The uFINE-I provides a practical solution for achieving high-resolution neural recording with minimal invasiveness and can be readily transferred to clinical settings for future neural interface applications such as brain-machine interfaces (BMIs) and the treatment of neurological diseases.

What Is the Recipe for Success in Science?

This article narrates the life journey of a woman in science, drawing parallels between her grandmother’s improvisational apple pie making and her own path to success. Unlike a recipe, her career was shaped by unique, personal ingredients: a fervent love for learning from her parents; the importance of financial independence instilled by her mother; and a supportive network that facilitated both her family and career decisions. Through anecdotes, she emphasizes key life lessons: success is personal and varied; plans can change; guilt over work-life balance is self-imposed; and one should not be confined by traditional career paths. Her story highlights the importance of resilience, adaptability, and the pursuit of meaningful causes over conventional career milestones. Her transformative work in rare disease research underscores her commitment to leveraging her career for the greater good, embodying a blend of scientific curiosity and business acumen. The article concludes with a call to embrace learning, face failures, and build a trustworthy support network.

Advancing Parkinson's Disease Research in Africa: A Strategic Training Framework of the Global Parkinson's Genetics Program.

Advancing Parkinson's Disease Research in Africa: A Strategic Training Framework of the Global Parkinson's Genetics Program.

Unraveling the redox code to improve physiological research in human health and disease.

Redox reactions, involving electron transfer, are critical to human physiology. However, progress in understanding redox metabolism is hindered by flawed analytical methods. This review highlights emerging techniques that promise to revolutionize redox research, enhancing our comprehension of human health and disease. Oxygen, vital for aerobic metabolism, also produces reactive oxygen species (ROS), such as superoxide and hydrogen peroxide. While historically seen as harmful, ROS at low concentrations are now recognized as key regulators of cell signaling. A balance between ROS and antioxidants, known as redox balance, is crucial, and deviations can lead to oxidative stress. Recent studies have distinguished beneficial "oxidative eustress" from harmful "oxidative distress." New techniques, such as advanced mass spectrometry and high-throughput immunoassays, offer improved accuracy in measuring redox states and oxidative damage. These advancements are pivotal for understanding redox signaling, cysteine oxidation, and their implications for disease. Looking ahead, the development of precision redox medicine could lead to better treatments for oxidative stress-related diseases and foster interventions promoting health.

Changes in Gene Expression Profile with Age in SAMP8: Identifying Transcripts Involved in Cognitive Decline and Sporadic Alzheimer’s Disease

Background: The senescence-accelerated mouse 8 (SAMP8) represents a model for Alzheimer’s disease (AD) research because it exhibits age-related learning and memory impairments consistent with early onset and rapid progression of senescence. To identify transcriptional changes during AD progression, in this study, we analyzed and compared the gene expression profiles involved in molecular pathways of neurodegeneration and cognitive impairment in senescence-accelerated resistant 1 (SAMR1) and SAMP8 mice. Methods: In total, 48 female SAMR1 and SAMP8 mice were randomly divided into six groups (SAMR1 and SAMP8 at 3, 7, and 9 months of age). Microarray analysis of 22,000 genes was performed, followed by functional analysis using Gene Ontology (NCBI) and examination of altered molecular pathways using the KEGG (Kyoto Encyclopedia of Genes and Genomes). Results: SAMP8 mice had 2516 dysregulated transcripts at 3 months, 2549 transcripts at 7 months, and 2453 genes at 9 months compared to SAMR1 mice of the same age. These accounted for 11.3% of the total number. This showed that with age, the gene expression of downregulated transcripts increases, and that of over-expressed transcripts decreases. Most of these genes were involved in neurodegenerative metabolic pathways associated with Alzheimer’s disease: apoptosis, inflammatory response, oxidative stress, and mitochondria. The qPCR results indicated that Ndufs4, TST/Rhodanese, Wnt3, and Sema6a expression was differentially expressed during aging. Conclusions: These results further revealed significant differences in gene expression profiles at different ages between SAMR1 and SAMP8 and showed alteration in genes involved in age-related cognitive decline and mitochondrial processes, demonstrating the relevance of the SAMP8 model as a model for sporadic AD.

Recent advances in brain organoids: a comprehensive review of the last eight years

Organoids are three-dimensional cellular structures grown in vitro that can self-organize and differentiate into cell types with organ-specific functions, closely mimicking the biological properties of tissues and organs in vivo. Brain organoids, which differentiate into structures resembling brain function, serve as valuable models for medical research, including disease microenvironment simulation, brain mechanism exploration, and drug evaluation. In this review, we analyzed 808 articles retrieved from PubMed, CNKI, and Wanfang databases using the keyword "brain organoids," of which 180 were included. We summarized the research progress of brain organoids over the past eight years by categorizing and refining the findings. Our analysis shows that brain organoids have achieved significant success in simulating brain development in vitro, leading to the establishment and refinement of 3D brain organoid models for disease research. Brain organoids have been widely applied to explore disease-related mechanisms, yielding promising results and opening avenues for further research on the human brain. In this review, we summarize the progress of brain organoids in three areas: culture methods, disease-related research, and brain exploration.

Enhancing emerging technology discovery in nanomedicine by integrating innovative sentences using BERT and NLDA

Abstract Purpose Nanomedicine has significant potential to revolutionize biomedicine and healthcare through innovations in diagnostics, therapeutics, and regenerative medicine. This study aims to develop a novel framework that integrates advanced natural language processing, noise-free topic modeling, and multidimensional bibliometrics to systematically identify emerging nanomedicine technology topics from scientific literature. Design/methodology/approach The framework involves collecting full-text articles from PubMed Central and nanomedicine-related metrics from the Web of Science for the period 2013–2023. A fine-tuned BERT model is employed to extract key informative sentences. Noiseless Latent Dirichlet Allocation (NLDA) is applied to model interpretable topics from the cleaned corpus. Additionally, we develop and apply metrics for novelty, innovation, growth, impact, and intensity to quantify the emergence of novel technological topics. Findings By applying this methodology to nanomedical publications, we identify an increasing emphasis on research aligned with global health priorities, particularly inflammation and biomaterial interactions in disease research. This methodology provides deeper insights through full-text analysis and leading to a more robust discovery of emerging technologies. Research limitations One limitation of this study is its reliance on the existing scientific literature, which may introduce publication biases and language constraints. Additionally, manual annotation of the dataset, while thorough, is subject to subjectivity and can be time-consuming. Future research could address these limitations by incorporating more diverse data sources, and automating the annotation process. Practical implications The methodology presented can be adapted to explore emerging technologies in other scientific domains. It allows for tailored assessment criteria based on specific contexts and objectives, enabling more precise analysis and decision-making in various fields. Originality/value This study offers a comprehensive framework for identifying emerging technologies in nanomedicine, combining theoretical insights and practical applications. Its potential for adaptation across scientific disciplines enhances its value for future research and decision-making in technology discovery.

Biomarkers and Alzheimer’s disease: a bibliometric analysis

ObjectiveThe diagnosis and treatment of biomarkers in Alzheimer’s disease has emerged as a prominent topic within Alzheimer’s disease research. In this paper, we conducted a bibliometric analysis of data from a wide range of literature in this field to enhance the in-depth understanding of this area.MethodThe core collection of the Science Citation Index database (web of science) was used to search for relevant literature in the above fields from 1 January 2006 to 14 November 2022 and Citespace software was used to visualize and analyze the literature data.ResultsA total of 1,138 papers were included, of which the United States ranked first with 607 papers and China ranked 6th in the world with 84 papers. The value of mediational centrality is 0.49 in the United States and 0.05 in China. In terms of the number of articles published by the research authors, the Swedish scholar Blennow Kaj ranks first with 82 articles published, and the scholars who rank second and third are Zetterberg Henrik (78 articles) and Morris John C (64 articles), respectively; in terms of the mediational centrality, the American scholar Trojanowski John Q ranked first in the world with 0.1, and the second and third ranked scholars were Blennow Kaj (0.09) and Zetterberg Henrik (0.06) respectively. Scholar JACK CR ranked first with 377 citation frequency. The journal NEUROLOGY is ranked first with 943 citations.ConclusionIn recent years, global research in the field of biomarkers related to Alzheimer’s disease has shown signs of softening, and the momentum of research has slightly diminished. However, this trend does not imply a decline in the quality of research. It is essential to enhance collaboration among countries, major research institutions, and scholars, with a particular emphasis on fostering international partnerships in the future.

Concomitant primary and secondary syphilis: a case series from a reference center in Mexico

Primary syphilis is characterized by the presence of a chancre and secondary syphilis by the presence of syphilis. The presence of chancres within secondary syphilis have been reported, however, this form of presentation is rare. Patients with synchronous diagnosis of primary and secondary syphilis were included. They underwent a reverse sequence algorithm for syphilis diagnosis with a rapid syphilis test, if positive, a rapid plasma reagin (RPR) or venereal disease research laboratory (VDRL) tests were performed. A total of 15 patients were included. All were men. In primary syphilis, penile chancre predominated in 13 patients (86.6%), and one (6.7%) was in the tongue. In secondary syphilis syphilitic roseola was the most common type of presentation in 10 patients (66.6%), followed by the palmoplantar plaques in 6 patients (40%) and condyloma lata in 2 patients (13.3%). One patient presented alopecia in a “moth-eaten” pattern and this presentation coexisted with a condyloma lata and the palmoplantar plaques. Other patient presented with syphilitic roseola, palmoplantar plaques and condyloma lata. Clinical presentation as coexistent primary-secondary syphilis will become more frequent. First contact physicians and dermatologists would have to take more in consideration infrequent and atypical clinical forms of this disease.

Cryo-X-Ray Phase Contrast Imaging Enables Combined 3D Structural Quantification and Nucleic Acid Analysis of Myocardial Biopsies.

Snap-frozen biopsies serve as a valuable clinical resource of archival material for disease research, as they enable a comprehensive array of downstream analyses to be performed, including extraction and sequencing of nucleic acids. Obtaining three-dimensional (3D) structural information before multi-omics is more challenging but can potentially allow for better characterization of tissues and targeting of clinically relevant cells. Conventional histological techniques are limited in this regard due to their destructive nature and the reconstruction artifacts produced by sectioning, dehydration, and chemical processing. These limitations are particularly notable in soft tissues such as the heart. In this study, the feasibility of using synchrotron-based cryo-X-ray phase contrast imaging (cryo-X-PCI) of snap-frozen myocardial biopsies is assessed and 3D structure tensor analysis of aggregated myocytes, followed by nucleic acid (DNA and RNA) extraction and analysis. It is shown that optimal sample preparation is the key driver for successful structural and nucleic acid preservation which is unaffected by the process of cryo-X-PCI. It is proposed that cryo-X-PCI has clinical value for 3D tissue analysis of cardiac and potentially non-cardiac soft tissue biopsies before nucleic acid investigation.

Recent Developments in Infectious Disease Research

The field of infectious disease research is rapidly evolving and advancing, driven by the demand to address both current and emerging threats to global health. The recent COVID-19 pandemic underscored the criticality of infectious disease outbreak preparedness and response, while factors such as climate change, migration, and globalization continue to influence disease transmission dynamics. Innovative approaches to infectious disease research are more essential than ever to prevent future pandemics and the spread of vectorborne diseases. This comprehensive review article investigates some recent pertinent developments in infectious disease research, including the development of a novel serosurveillance platform, modeled after the one designed during the COVID-19 pandemic, aimed at tackling the growing global threat of arboviruses. Also investigated in this article is the repurposing and application of mRNA vaccine technology, initially developed during the pandemic, to address the complex challenge of tick-borne Lyme disease. Finally, we outline several novel and cutting-edge strategies aimed at tackling the ever-mounting crisis of antimicrobial resistance (AMR). Each of these innovations marks a significant step forward in global health security and preparedness, offering promising solutions to the challenges of a rapidly evolving world, while drawing on the lessons learned from past outbreaks and epidemics.

Review of national rare disease strategies: innovation driving change

Abstract Background A rare disease affects fewer than 5 in 10,000 people. More than 6,000 known rare diseases affect up to 6% of the European population. A national rare disease strategy sets out a country’s plan to reduce disease burden and improve quality of care for people with rare diseases. This review, requested by the Department of Health in Ireland to inform a new national strategy, described national rare disease strategies in 13 selected countries. Methods Strategies published from 2013 to 2023 were identified via online searches for Austria, Australia, Denmark, England, Finland, France, Germany, Ireland, the Netherlands, Northern Ireland, Portugal, Scotland and Wales. National representatives were contacted to confirm the identified resources. Data were extracted for the domains of: aims, priorities, implementation, governance and funding models. Descriptive analysis and narrative synthesis was undertaken. Results Improving treatment and coordination of care was a common overall aim. Priorities noted in all strategies were: screening and diagnosis; access to healthcare and coordination of services; rare disease research; and patient representation and empowerment. Implementation details varied to reflect the national context and time of strategy development. More recently-developed strategies included more precise actions and greater emphasis on innovations in genomics than older strategies. Strategies were developed, implemented, monitored and evaluated via combinations of newly-established bodies and or existing health authorities. Six countries did not specify a funding model or dedicated budget for strategy implementation. Conclusions National rare disease strategy contents and implementation approaches varied between countries and reflected innovations over time. This review will inform the development of Ireland’s new national rare disease strategy. Key messages • This review provided insights into national rare disease strategies over a 10-year period. • The findings will inform strategy development in Ireland, and are relevant to other countries.

GBNSS: A Method Based on Graph Neural Networks (GNNs) for Global Biological Network Similarity Search

Biological network similarity search plays a crucial role in the analysis of biological networks for human disease research and drug discovery. A biological network similarity search aims to efficiently identify novel networks biologically homologous to the query networks. Great progress has been achieved in biological network similarity searches. However, it remains a challenge to mine the biological network information fully to improve the accuracy of query results without increasing time overheads. In this study, we propose a biological network similarity search method based on graph neural networks named GBNSS, which combines topological and biological information (GO annotations) of biological networks into graph neural networks to find topologically and biologically similar biological networks in the database. Additionally, GBNSS is a topology-free biological network similarity search method with an arbitrary network structure. The experimental results on four benchmark datasets show that GBNSS outperforms the existing methods in terms of computational efficiency and search accuracy. Case studies further demonstrate that GBNSS is capable of searching similar networks in real-world biological networks.

Examining the Measurement Equivalence of Alzheimer Disease Research Centers' Neuropsychological Test Battery (Version 3) Between Singapore and US Samples.

Standardization of neuropsychological tests is crucial for consistency in cognitive assessment, as well as for validity and comparability of results across different populations. We examined the applicability and measurement equivalence of the Alzheimer Disease Research Centers' Neuropsychological Test Battery (version 3) (ADRC-NTB3) in Singapore. The ADRC-NTB3 was administered to 978 older persons with normal cognition in Singapore. To provide comparison between Singapore and US samples, a US sample with similar profile was retrieved from the National Alzheimer Coordinating Center (NACC) database. Scores were compared with 1853 participants with similar profile from the United States. Score-difference between the populations was computed using multiple linear regression (adjusted for covariates), with equivalent score considered present when 90% CI of the score-difference fell within the predefined margin of equivalence. Tasks assessing for memory, processing speed, and executive functioning showed equivalence in scores between US and Singapore samples (adjusted-score difference=-0.94 to 0.09). Singapore sample performed marginally better on the visuospatial task (adjusted-score difference=0.50), but poorer on the language task (adjusted-score difference=-3.22). Nonequivalence of visuospatial and language tasks, which may increase potential misinterpretation of cognitive profiles and misdiagnosis, are related to educational and cultural differences. This highlights the need for different normative data for more accurate diagnostic accuracy as well as research priorities.

Informant characteristics influence Clinical Dementia Rating Sum of Boxes scores-based staging of Alzheimer's disease.

The Clinical Dementia Rating Sum of Boxes (CDR-SB) is a staging scale for Alzheimer's disease (AD)1 and is commonly used as an outcome in clinical trials2. It relies on information provided by the patient and an informant3. The CDR-SB should reflect only the patient's disease severity. However, we explored whether informant characteristics were associated with CDR-SB scores because that association might introduce bias in Alzheimer's disease research. We found that the CDR-SB was 0.20 higher when informants were female, 0.39 higher when the informant was a patient's child and 0.18 lower if the relationship was other than spouse or children. Regarding the frequency of contact, CDR-SB scores were 0.38 higher when contact was at least once a week, 0.65 higher when daily and 0.57 higher when living with the patient. Our analysis results suggest that informant characteristics can modify the CDR-SB scores and might introduce bias into Alzheimer's disease trials and research.

Advances in bacterial artificial chromosome (BAC) transgenic mice for gene analysis and disease research.

Transgenic mice, including those created using Bacterial Artificial Chromosomes (BACs), are artificial manipulations that have become critical tools for studying gene function. While conventional transgenic techniques face challenges in achieving precise expression of foreign genes in specific cells and tissues, BAC transgenic mice offer a solution by incorporating large DNA segments that can include entire expression units with tissue-specific enhancers. This review provides a thorough examination of BAC transgenic mouse technology, encompassing both traditional and humanized models. We explore the benefits and drawbacks of BAC transgenesis compared to other techniques such as knock-in and CRISPR/Cas9 technologies. The review emphasizes the applications of BAC transgenic mice in various disciplines, including neuroscience, immunology, drug metabolism, and disease modeling. Additionally, we address crucial aspects of generating and analyzing BAC transgenic mice, such as position effects, copy number variations, and strategies to mitigate these challenges. Despite certain limitations, humanized BAC transgenic mice have proven to be invaluable tools for studying the pathogenesis of human diseases, drug development, and understanding intricate gene regulatory mechanisms. This review discusses current topics on BAC transgenic mice and their evolving significance in biomedical research.

DNA methylation stability in cardiac tissues kept at different temperatures and time intervals

Investigating DNA methylation (DNAm) in cardiac tissues is vital for epigenetic research in cardiovascular diseases (CVDs). During cardiac surgery, biopsies may not be immediately stored due to a lack of human or technical resources at the collection site. Assessing DNAm stability in cardiac samples left in suboptimal conditions is crucial for applying DNAm analysis. We investigated the stability of DNAm in human cardiac tissues kept at 4 °C and 22 °C for periods of 1, 7, 14, and 28 days (exposed samples) using the Illumina Infinium MethylationEPIC v1.0 BeadChip Array. We observed high correlations between samples analysed immediately after tissue collection and exposed ones (R2 > 0.992). Methylation levels were measured as β-values and median absolute β-value differences (|∆β|) ranged from 0.0093 to 0.0119 in all exposed samples. Pairwise differentially methylated position (DMP) analysis revealed no DMPs under 4 °C (fridge temperature) exposure for up to 28 days and 22 °C (room temperature) exposure for one day, while 3,437, 6,918, and 3,824 DMPs were observed for 22 °C samples at 7, 14, and 28 days, respectively. This study provides insights into the stability of genome-wide DNAm, showing that cardiac tissue can be used for reliable DNAm analysis even when stored suboptimally after surgery.

Functionalized Nanodiamonds for Targeted Neuronal Electromagnetic Signal Detection.

Intracellular sensing technologies necessitate a delicate balance of spatial resolution, sensitivity, biocompatibility, and stability. While existing methods partially fulfill these criteria, none offer a comprehensive solution. Nanodiamonds (NDs) harboring nitrogen-vacancy (NV) centers have emerged as promising candidates due to their sensing capabilities under biological conditions and their ability to meet all aforementioned requirements. This study focuses on expanding the application of NDs and NV center-based sensing to neuronal contexts by investigating their functionalization and subsequent effects on three distinct cell lines relevant to neurodegenerative disease research. Our study concentrates on positioning fluorescent NDs (FNDs) with NV center point defects onto neuronal cell surfaces. Achieving this through specific antibody attachment enhances the proximity of FND to neurites, facilitating the detection of local action potentials. Targeting voltage-dependent calcium channels (Cav2.2) with biotin-streptavidin-bound antibodies enables the precise positioning of FNDs. The functionalized FNDs (f-FNDs) show increased size and zeta potential, confirming the antibody presence without compromising cell viability. Two-color confocal imaging and co-localization algorithms are employed to further attest to the success of the functionalization. The f-FNDs are applied to cell cultures of three cell lines: SH-SY5Y, differentiated dopaminergic neurons, and hippocampal rat neurons; their biocompatibility and effects on synaptic activity are explored. Moreover, preliminary total internal reflection fluorescence - optically detected magnetic resonance (TIRF-ODMR) experiments across cellular sites demonstrate the magnetic field sensitivity of our sensor network. The successful establishment of this sensor network provides a platform for characterizing neuronal signaling in healthy models and conditions mimicking Parkinson's disease.

Enzyme Activity-Based Optical Probe: Imaging Aminopeptidases N in Vulnerable Plaque and Serum.

Cardiovascular disease, a chronic and progressive arterial wall disease, is increasingly recognized for its clinical significance. Aminopeptidases N (APN), crucial in the pathophysiological processes of vulnerable plaque, have been linked to endothelial dysfunction, oxidative stress, and plaque formation, thus highlighting their potential as biomarkers for disease progression. However, current detection methods for APN in body fluids and in vivo have limitations, including insufficient sensitivity and specificity, time delays, and the inability to directly reflect enzyme activity in plaques. To address these challenges, we developed an optical probe, HD-APN, for in vivo imaging of aminopeptidases, providing a potential implementation in cardiovascular disease. Our work demonstrated the applicability of HD-APN for specific monitoring of aminopeptidase levels in plaques and serum, shedding light on its potential for further research in cardiovascular disease.

The Alzheimer's Disease Neuroimaging Initiative-4 (ADNI-4) Engagement Core: A culturally informed, community-engaged research (CI-CER) model to advance brain health equity.

The Alzheimer's Disease Neuroimaging Initiative-4 (ADNI-4) Engagement Core was launched to advance Alzheimer's disease (AD) and AD-related dementia (ADRD) health equity research in underrepresented populations (URPs). We describe our evidence-based, scalable culturally informed, community-engaged research (CI-CER) model and demonstrate its preliminary success in increasing URP enrollment. URPs include ethnoculturally minoritized, lower education (≤ 12 years), and rural populations. The CI-CER model includes: (1) culturally informed methodology (e.g., less restrictive inclusion/exclusion criteria, sociocultural measures, financial compensation, results disclosure, Spanish Language Capacity Workgroup) and (2) inclusive engagement methods (e.g., the Engagement Core team; Hub Sites; Community-Science Partnership Board). As of April 2024, 60% of ADNI-4 new in-clinic enrollees were from ethnoculturally or educationally URPs. This exceeds ADNI-4's≥50% URP representation goal for new enrollees but may not represent final enrollment. Findings show a CI-CER model increases URP enrollment in AD/ADRD clinical research and has important implications for clinical trials to advance health equity. The Alzheimer's Disease Neuroimaging Initiative-4 (ADNI-4) uses a culturally informed, community-engaged research (CI-CER) approach. The CI-CER approach is scalable and sustainable for broad, multisite implementation. ADNI-4 is currently exceeding its inclusion goals for underrepresented populations.