A Neuropathology Case Report of a Woman with Down Syndrome who Remained Cognitively Stable.

In this neuropathology case report, we present findings from an individual with Down syndrome (DS) who remained cognitively stable despite Alzheimer's disease (AD) neuropathology. Clinical assessments, fluid biomarkers, neuroimaging, and neuropathological examinations were conducted to characterize her condition. Notably, her ApoE genotype was E2/3, which is associated with a decreased risk of dementia. Neuroimaging revealed stable yet elevated amyloid profiles and moderately elevated tau levels, while neuropathology indicated intermediate AD neuropathologic change with Lewy body pathology and cerebrovascular pathology. Despite the presence of AD pathology, the participant demonstrated intact cognitive functioning, potentially attributed to factors such as genetic variations, cognitive resilience, and environmental enrichment. The findings suggest a dissociation between clinical symptoms and neuropathological changes, emphasizing the complexity of AD progression in DS. Further investigation into factors influencing cognitive resilience in individuals with DS, including comorbidities and social functioning, is warranted. Understanding the mechanisms underlying cognitive stability in DS could offer insights into resilience to AD neuropathology in people with DS and in the general population and inform future interventions.

Alzheimer's polygenic risk scores are associated with cognitive phenotypes in Down syndrome.

INTRODUCTION: This study aimed to investigate the influence of the overall Alzheimer's disease (AD) genetic architecture on Down syndrome (DS) status, cognitive measures, and cerebrospinal fluid (CSF) biomarkers. METHODS: AD polygenic risk scores (PRS) were tested for association with DS-related traits. RESULTS: The AD risk PRS was associated with disease status in several cohorts of sporadic late- and early-onset and familial late-onset AD, but not in familial early-onset AD or DS. On the other hand, lower DS Mental Status Examination memory scores were associated with higher PRS, independent of intellectual disability and APOE (PRS including APOE, PRSAPOE , p = 2.84 × 10-4 ; PRS excluding APOE, PRSnonAPOE , p = 1.60 × 10-2 ). PRSAPOE exhibited significant associations with Aß42, tTau, pTau, and Aß42/40 ratio in DS. DISCUSSION: These data indicate that the AD genetic architecture influences cognitive and CSF phenotypes in DS adults, supporting common pathways that influence memory decline in both traits. HIGHLIGHTS: Examination of the polygenic risk of AD in DS presented here is the first of its kind. AD PRS influences memory aspects in DS individuals, independently of APOE genotype. These results point to an overlap between the genes and pathways that leads to AD and those that influence dementia and memory decline in the DS population. APOE ε4 is linked to DS cognitive decline, expanding cognitive insights in adults.

Assessing surface water pollution in Hanoi, Vietnam, using remote sensing and machine learning algorithms.

Rapid urbanization led to significant land-use changes and posed threats to surface water bodies worldwide, especially in the Global South. Hanoi, the capital city of Vietnam, has been facing chronic surface water pollution for more than a decade. Developing a methodology to better track and analyze pollutants using available technologies to manage the problem has been imperative. Advancement of machine learning and earth observation systems offers opportunities for tracking water quality indicators, especially the increasing pollutants in the surface water bodies. This study introduces machine learning with the cubist model (ML-CB), which combines optical and RADAR data, and a machine learning algorithm to estimate surface water pollutants including total suspended sediments (TSS), chemical oxygen demand (COD), and biological oxygen demand (BOD). The model was trained using optical (Sentinel-2A and Sentinel-1A) and RADAR satellite images. Results were compared with field survey data using regression models. Results show that the predictive estimates of pollutants based on ML-CB provide significant results. The study offers an alternative water quality monitoring method for managers and urban planners, which could be instrumental in protecting and sustaining the use of surface water resources in Hanoi and other cities of the Global South.

Triplication of Synaptojanin 1 in Alzheimer's Disease Pathology in Down Syndrome.

Down Syndrome (DS), caused by triplication of human chromosome 21 (Hsa21) is the most common form of intellectual disability worldwide. Recent progress in healthcare has resulted in a dramatic increase in the lifespan of individuals with DS. Unfortunately, most will develop Alzheimer's disease like dementia (DS-AD) as they age. Understanding similarities and differences between DS-AD and the other forms of the disease - i.e., late-onset AD (LOAD) and autosomal dominant AD (ADAD) - will provide important clues for the treatment of DS-AD. In addition to the APP gene that codes the precursor of the main component of amyloid plaques found in the brain of AD patients, other genes on Hsa21 are likely to contribute to disease initiation and progression. This review focuses on SYNJ1, coding the phosphoinositide phosphatase synaptojanin 1 (SYNJ1). First, we highlight the function of SYNJ1 in the brain. We then summarize the involvement of SYNJ1 in the different forms of AD at the genetic, transcriptomic, proteomic and neuropathology levels in humans. We further examine whether results in humans correlate with what has been described in murine and cellular models of the disease and report possible mechanistic links between SYNJ1 and the progression of the disease. Finally, we propose a set of questions that would further strengthen and clarify the role of SYNJ1 in the different forms of AD.

Correlation between conduction velocity and frequency analysis in patients with atrial fibrillation using high-density charge mapping.

Spectral analysis of atrial signals has been used to identify regions of interest in atrial fibrillation (AF). However, the relationship to the atrial substrate is unclear. In this study, we compare regions with dominant frequency (DF), simultaneously determined in the left atrium (LA) by a novel noncontact mapping system using unipolar charge density signals, to the zones of slow conduction (SZ) during AF.In 19 AF patients the conduction during AF was assessed by a validated algorithm and SZ compared to the DF and the DF ratio between the DF peak and the area under the total spectrum (DFR). The results were compared in five different regions of the LA. The reproducibility of SZ location at different time measurements was higher than for DF or DFR. The SZs are mainly confined at the anterior and posterior wall of the LA. There was no statistically significant correlation between SZ and DF or DFR across the atrium.

Molecular Gatekeeper Discovery: Workflow for Linking Multiple Exposure Biomarkers to Metabolomics.

The exposome reflects multiple exposures across the life-course that can affect health. Metabolomics can reveal the underlying molecular basis linking exposures to health conditions. Here, we explore the concept and general data analysis framework of "molecular gatekeepers"─key metabolites that link single or multiple exposure biomarkers with correlated clusters of endogenous metabolites─to inform health-relevant biological targets. We performed untargeted metabolomics on plasma from 152 adolescent girls participating in the Growing Up Healthy Study in New York City. We then performed network analysis to link metabolites to exposure biomarkers including five trace elements (Cd, Mn, Pb, Se, and Hg) and five perfluorinated chemicals (PFCs; n-PFOS, Sm-PFOS, n-PFOA, PFHxS, and PFNA). We found 144 molecular gatekeepers and annotated 22 of them. Lysophosphatidylcholine (16:0) and taurodeoxycholate were correlated with both n-PFOA and n-PFOS, suggesting a shared dysregulation from multiple xenobiotic exposures. Sphingomyelin (d18:2/14:0) was significantly associated with age at menarche; yet, no direct association was detected between any exposure biomarkers and age at menarche. Thus, molecular gatekeepers can also discover molecular linkages between exposure biomarkers and health outcomes that may otherwise be obscured by complex interactions in direct measurements.

A community-powered search of machine learning strategy space to find NMR property prediction models.

The rise of machine learning (ML) has created an explosion in the potential strategies for using data to make scientific predictions. For physical scientists wishing to apply ML strategies to a particular domain, it can be difficult to assess in advance what strategy to adopt within a vast space of possibilities. Here we outline the results of an online community-powered effort to swarm search the space of ML strategies and develop algorithms for predicting atomic-pairwise nuclear magnetic resonance (NMR) properties in molecules. Using an open-source dataset, we worked with Kaggle to design and host a 3-month competition which received 47,800 ML model predictions from 2,700 teams in 84 countries. Within 3 weeks, the Kaggle community produced models with comparable accuracy to our best previously published 'in-house' efforts. A meta-ensemble model constructed as a linear combination of the top predictions has a prediction accuracy which exceeds that of any individual model, 7-19x better than our previous state-of-the-art. The results highlight the potential of transformer architectures for predicting quantum mechanical (QM) molecular properties.

An Elite Hybrid Particle Swarm Optimization for Solving Minimal Exposure Path Problem in Mobile Wireless Sensor Networks.

Mobile wireless sensor networks (MWSNs), a sub-class of wireless sensor networks (WSNs), have recently been a growing concern among the academic community. MWSNs can improve network coverage quality which reflects how well a region of interest is monitored or tracked by sensors. To evaluate the coverage quality of WSNs, we frequently use the minimal exposure path (MEP) in the sensing field as an effective measurement. MEP refers to the worst covered path along which an intruder can go through the sensor network with the lowest possibility of being detected. It is greatly valuable for network designers to recognize the vulnerabilities of WSNs and to make necessary improvements. Most prior studies focused on this problem under a static sensor network, which may suffer from several drawbacks; i.e., failure in sensor position causes coverage holes in the network. This paper investigates the problem of finding the minimal exposure paths in MWSNs (hereinafter MMEP). First, we formulate the MMEP problem. Then the MMEP problem is converted into a numerical functional extreme problem with high dimensionality, non-differentiation and non-linearity. To efficiently cope with these characteristics, we propose HPSO-MMEP algorithm, which is an integration of genetic algorithm into particle swarm optimization. Besides, we also create a variety of custom-made topologies of MWSNs for experimental simulations. The experimental results indicate that HPSO-MMEP is suitable for the converted MMEP problem and performs much better than existing algorithms.

Image-guided ablation of scar-related ventricular tachycardia: towards a shorter and more predictable procedure.

PURPOSE: The aim of this study was to analyze the feasibility and reproducibility of using image integration software at a remote setting over the MUSIC network to perform image-guided VT ablation. Furthermore, we analyzed the efficacy of a focused workflow with electroanatomical mapping (EAM) limited to imaging-defined scar. METHODS: In a prospective two-centre study, consecutive patients undergoing image integration-guided VT ablation (magnetic resonance [DE-MRI] and/or multidetector computed tomography [MDCT]) were included. Patients were divided into two groups (Group 1, complete EAM; Group 2, EAM limited to imaging-defined substrate). RESULTS: Forty-nine patients (62 ± 15 years; 90% male; LVEF 41 ± 14%; ischemic 69%) who underwent image integration-guided VT ablation were included (MDCT 98%; DE-MRI in 35%). Total procedure time was 172 ± 48 min (ablation 31 ± 17 min; fluoroscopy 23 ± 13 min). Procedure time was shorter in Group 2 as compared to Group 1 (Group 2 [n = 26] vs. Group 1 [n = 23]; procedure time: 151 ± 33 vs. 180 ± 53 min, P = 0.01). Non-inducibility of all VT was achieved in 37 (76%), with no difference between Group 1 and 2 (Group 2 vs. Group 1; VT non-inducibility 71 vs. 74%, P = 0.8). During a follow-up period of 19 ± 8 months, 13 patients (27%) had a VT recurrence. Two patients (4%) died during follow-up. There were no differences in VT-free survival between Group 1 and Group 2 (p = 0.77). CONCLUSION: Image-integrated VT ablation is feasible through a network between highly experienced centers and remotely located centers. Focused image integration-guided VT ablation is associated with short and predictable procedure duration, achieving high-long term success rates.

High-resolution noncontact charge-density mapping of endocardial activation.

BACKGROUND: Spatial resolution in cardiac activation maps based on voltage measurement is limited by far-field interference. Precise characterization of electrical sources would resolve this limitation; however, practical charge-based cardiac mapping has not been achieved. METHODS: A prototype algorithm, developed from first principles of electrostatic field theory, derives charge density (CD) as a spatial representation of the true sources of the cardiac field. The algorithm processes multiple, simultaneous, noncontact voltage measurements within the cardiac chamber to inversely derive the global distribution of CD sources across the endocardial surface. RESULTS: Comparison of CD to an established computer-simulated model of atrial conduction demonstrated feasibility in terms of spatial, temporal, and morphologic metrics. Inverse reconstruction matched simulation with median spatial errors of 1.73 mm and 2.41 mm for CD and voltage, respectively. Median temporal error was less than 0.96 ms and morphologic correlation was greater than 0.90 for both CD and voltage. Activation patterns observed in human atrial flutter reproduced those established through contact maps, with a 4-fold improvement in resolution noted for CD over voltage. Global activation maps (charge density-based) are reported in atrial fibrillation with confirmed reduction of far-field interference. Arrhythmia cycle-length slowing and termination achieved through ablation of critical points demonstrated in the maps indicates both mechanistic and pathophysiological relevance. CONCLUSION: Global maps of cardiac activation based on CD enable classification of conduction patterns and localized nonpulmonary vein therapeutic targets in atrial fibrillation. The measurement capabilities of the approach have roles spanning deep phenotyping to therapeutic application. TRIAL REGISTRATION: ClinicalTrials.gov NCT01875614. FUNDING: The National Institute for Health Research (NIHR) Translational Research Program at Royal Papworth Hospital and Acutus Medical.

Author Correction: ZSCAN10 expression corrects the genomic instability of iPSCs from aged donors.

In the version of this Article originally published, Supplementary Fig. 6j showed incorrect values for the LS and AG4 glutathione samples, and Fig. 5c and Supplementary Fig. 6j did not include all n = 6 samples for the hESC, Y-hiPSC and AG4-ZSCAN10 groups as was stated in the legend. In addition, the bars for hESC, Y-hiPSC, AG4-ZCNAN10, AG4 and LS in Supplementary Fig. 6i and j have been reproduced from Fig. 5b and c, respectively. Fig. 6e was also reproduced in the lower panel of Supplementary Fig. 6h, to enable direct comparison of the data, however this was not explained in the original figure legends. The correct versions of these figures and their legends are shown below, and Supplementary Table 5 has been updated with the source data for all numerical data in the manuscript.

ZSCAN10 expression corrects the genomic instability of iPSCs from aged donors.

Induced pluripotent stem cells (iPSCs), which are used to produce transplantable tissues, may particularly benefit older patients, who are more likely to suffer from degenerative diseases. However, iPSCs generated from aged donors (A-iPSCs) exhibit higher genomic instability, defects in apoptosis and a blunted DNA damage response compared with iPSCs generated from younger donors. We demonstrated that A-iPSCs exhibit excessive glutathione-mediated reactive oxygen species (ROS) scavenging activity, which blocks the DNA damage response and apoptosis and permits survival of cells with genomic instability. We found that the pluripotency factor ZSCAN10 is poorly expressed in A-iPSCs and addition of ZSCAN10 to the four Yamanaka factors (OCT4, SOX2, KLF4 and c-MYC) during A-iPSC reprogramming normalizes ROS-glutathione homeostasis and the DNA damage response, and recovers genomic stability. Correcting the genomic instability of A-iPSCs will ultimately enhance our ability to produce histocompatible functional tissues from older patients' own cells that are safe for transplantation.

Candidate gene analysis for Alzheimer's disease in adults with Down syndrome.

Individuals with Down syndrome (DS) overexpress many genes on chromosome 21 due to trisomy and have high risk of dementia due to the Alzheimer's disease (AD) neuropathology. However, there is a wide range of phenotypic differences (e.g., age at onset of AD, amyloid ß levels) among adults with DS, suggesting the importance of factors that modify risk within this particularly vulnerable population, including genotypic variability. Previous genetic studies in the general population have identified multiple genes that are associated with AD. This study examined the contribution of polymorphisms in these genes to the risk of AD in adults with DS ranging from 30 to 78 years of age at study entry (N = 320). We used multiple logistic regressions to estimate the likelihood of AD using single-nucleotide polymorphisms (SNPs) in candidate genes, adjusting for age, sex, race/ethnicity, level of intellectual disability and APOE genotype. This study identified multiple SNPs in APP and CST3 that were associated with AD at a gene-wise level empirical p-value of 0.05, with odds ratios in the range of 1.5-2. SNPs in MARK4 were marginally associated with AD. CST3 and MARK4 may contribute to our understanding of potential mechanisms where CST3 may contribute to the amyloid pathway by inhibiting plaque formation, and MARK4 may contribute to the regulation of the transition between stable and dynamic microtubules.

Canonical microRNAs Enable Differentiation, Protect Against DNA Damage, and Promote Cholesterol Biosynthesis in Neural Stem Cells.

Neural stem cells (NSCs) have the capacity to differentiate into neurons, astrocytes, and oligodendrocytes, and therefore represent a promising donor tissue source for treating neurodegenerative diseases and repairing injuries of the nervous system. However, it remains unclear how canonical microRNAs (miRNAs), the subset of miRNAs requiring the Drosha-Dgcr8 microprocessor and the type III RNase Dicer for biogenesis, regulate NSCs. In this study, we established and characterized Dgcr8-/- NSCs from conditionally Dgcr8-disrupted mouse embryonic brain. RNA-seq analysis demonstrated that disruption of Dgcr8 in NSCs causes a complete loss of canonical miRNAs and an accumulation of pri-miRNAs. Dgcr8-/- NSCs can be stably propagated in vitro, but progress through the cell cycle at reduced rates. When induced for differentiation, Dgcr8-/- NSCs failed to differentiate into neurons, astrocytes, or oligodendrocytes under permissive conditions. Compared to Dgcr8+/- NSCs, Dgcr8-/- NSCs exhibit significantly increased DNA damage. Comparative RNA-seq analysis and gene set enrichment analysis (GSEA) revealed that Dgcr8-/- NSCs significantly downregulate genes associated with neuronal differentiation, cell cycle progression, DNA replication, protein translation, and DNA damage repair. Furthermore, we discovered that Dgcr8-/- NSCs significantly downregulate genes responsible for cholesterol biosynthesis and demonstrated that Dgcr8-/- NSCs contain lower levels of cholesterol. Together, our data demonstrate that canonical miRNAs play essential roles in enabling lineage specification, protecting DNA against damage, and promoting cholesterol biosynthesis in NSCs.

Safety and efficacy of the nMARQ catheter for paroxysmal and persistent atrial fibrillation.

AIMS: Circular irrigated radiofrequency ablation using the nMARQ catheter has recently been introduced for the treatment of atrial fibrillation (AF). The aim of this study is to report the safety and efficacy of catheter ablation using this technology in patients with paroxysmal and persistent AF. METHODS AND RESULTS: The data of a prospective registry describing the experience of a single operator using this technology on 327 consecutive patients were analysed. The mean procedure time was 69 ± 22 min for paroxysmal AF (n = 228) and 75 ± 23 min for persistent AF (n = 97). Follow-up was available for 206 (63%) patients for 6 ± 5 months (range 1-23, median 3.3). Single procedure success off antiarrhythmic drugs was 75% in paroxysmal AF and 52% in persistent AF. Including the 5% redo cases and those on antiarrhythmic medication, freedom from AF was documented in 90 and 83% of paroxysmal and persistent AF patients, respectively. There were no serious complications in the first 325 patients, but the last two consecutive patients (0.6%) developed atrio-oesophageal fistulas and had a fatal outcome. The catheter has been recalled from market. CONCLUSION: The nMARQ catheter is a highly effective tool for treatment of paroxysmal and persistent AF. Nevertheless, the occurrence of life-threatening oesophageal fistulas is of major concern and requires further investigation.

Candidate genes for Alzheimer's disease are associated with individual differences in plasma levels of beta amyloid peptides in adults with Down syndrome.

We examined the contribution of candidates genes for Alzheimer's disease (AD) to individual differences in levels of beta amyloid peptides in adults with Down syndrom, a population at high risk for AD. Participants were 254 non-demented adults with Down syndrome, 30-78 years of age. Genomic deoxyribonucleic acid was genotyped using an Illumina GoldenGate custom array. We used linear regression to examine differences in levels of Aß peptides associated with the number of risk alleles, adjusting for age, sex, level of intellectual disability, race and/or ethnicity, and the presence of the APOE ε4 allele. For Aß42 levels, the strongest gene-wise association was found for a single nucleotide polymorphism (SNP) on CAHLM1; for Aß40 levels, the strongest gene-wise associations were found for SNPs in IDE and SOD1, while the strongest gene-wise associations with levels of the Aß42/Aß40 ratio were found for SNPs in SORCS1. Broadly classified, variants in these genes may influence amyloid precursor protein processing (CALHM1, IDE), vesicular trafficking (SORCS1), and response to oxidative stress (SOD1).

Genetic architecture of variation in the lateral line sensory system of threespine sticklebacks.

Vertebrate sensory systems have evolved remarkable diversity, but little is known about the underlying genetic mechanisms. The lateral line sensory system of aquatic vertebrates is a promising model for genetic investigations of sensory evolution because there is extensive variation within and between species, and this variation is easily quantified. In the present study, we compare the lateral line sensory system of threespine sticklebacks (Gasterosteus aculeatus) from an ancestral marine and a derived benthic lake population. We show that lab-raised individuals from these populations display differences in sensory neuromast number, neuromast patterning, and groove morphology. Using genetic linkage mapping, we identify regions of the genome that influence different aspects of lateral line morphology. Distinct loci independently affect neuromast number on different body regions, suggesting that a modular genetic structure underlies the evolution of peripheral receptor number in this sensory system. Pleiotropy and/or tight linkage are also important, as we identify a region on linkage group 21 that affects multiple aspects of lateral line morphology. Finally, we detect epistasis between a locus on linkage group 4 and a locus on linkage group 21; interactions between these loci contribute to variation in neuromast pattern. Our results reveal a complex genetic architecture underlying the evolution of the stickleback lateral line sensory system. This study further uncovers a genetic relationship between sensory morphology and non-neural traits (bony lateral plates), creating an opportunity to investigate morphological constraints on sensory evolution in a vertebrate model system.

Duty-cycled unipolar/bipolar versus conventional radiofrequency ablation in paroxysmal and persistent atrial fibrillation.

BACKGROUND: Duty-cycled (DC) radiofrequency ablation (RFA) for atrial fibrillation (AF) has been introduced, however, data on large patient series and comparison to conventional RFA are scarce. METHODS: Between 2006 and 2008 DC RFA was performed in 209 consecutive patients (143 (68%) paroxysmal and 66 (32%) persistent AF). As controls served 211 patients, 155 (73%) with paroxysmal and 56 (27%) with persistent AF (p=0.3). In DC RFA, the pulmonary veins (PV) were isolated followed by ablation at the septum and left atrium, if AF persisted. Conventional PV isolation was followed by anatomical lines at the roof and mitral isthmus. RESULTS: Freedom of paroxysmal AF was demonstrated after 1.08 DC RFA procedures per patient in 82% and after 1.19 conventional procedures in 87% after 8.5 ± 6.5 months (ns). In persistent AF, success rates were 79% after 1.35 DC RFA procedures and 80% after 1.34 conventional procedures after 11.5 ± 8.5 months (ns). The subgroup analysis of 119 patients with follow-up ≥ 12 months (17.5 [14.1-23.6] months) showed similar results. Left atrial flutter occurred in 3% and 8% after paroxysmal AF ablation (p < 0.05) and in 12% and 23% after persistent AF ablation (p=0.1). Multivariate predictors for success in both groups were age, left atrial size, presence of persistent vs. paroxysmal AF and previous pacemaker implantation, but not the ablation technique used. Non-fatal complications were seen in 2.8% with no differences between the groups. CONCLUSION: Outcome in DC RFA is similar to conventional RFA with a final success rate exceeding 80% in both paroxysmal and persistent AF in the absence of fatal complications.