Carbon isotope budget indicates biological disequilibrium dominated ocean carbon storage at the Last Glacial Maximum.

Understanding the causes of the  ~90 ppmv atmospheric CO2 swings between glacial and interglacial climates is an important open challenge in paleoclimate research. Although the regularity of the glacial-interglacial cycles hints at a single driving mechanism, Earth System models require many independent physical and biological processes to explain the full observed CO2 signal. Here we show that biologically sequestered carbon in the ocean can explain an atmospheric CO2 change of 75 ± 40 ppmv, based on a mass balance calculation using published carbon isotopic measurements. An analysis of the carbon isotopic signatures of different water masses indicates similar regenerated carbon inventories at the Last Glacial Maximum and during the Holocene, requiring that the change in carbon storage was dominated by disequilibrium. We attribute the inferred change in carbon disequilibrium to expansion of sea-ice or change in the overturning circulation.

Genome-wide analyses reveal a potential role for the MAPT, MOBP, and APOE loci in sporadic frontotemporal dementia.

Frontotemporal dementia (FTD) is the second most common cause of early-onset dementia after Alzheimer disease (AD). Efforts in the field mainly focus on familial forms of disease (fFTDs), while studies of the genetic etiology of sporadic FTD (sFTD) have been less common. In the current work, we analyzed 4,685 sFTD cases and 15,308 controls looking for common genetic determinants for sFTD. We found a cluster of variants at the MAPT (rs199443; p = 2.5 × 10-12, OR = 1.27) and APOE (rs6857; p = 1.31 × 10-12, OR = 1.27) loci and a candidate locus on chromosome 3 (rs1009966; p = 2.41 × 10-8, OR = 1.16) in the intergenic region between RPSA and MOBP, contributing to increased risk for sFTD through effects on expression and/or splicing in brain cortex of functionally relevant in-cis genes at the MAPT and RPSA-MOBP loci. The association with the MAPT (H1c clade) and RPSA-MOBP loci may suggest common genetic pleiotropy across FTD and progressive supranuclear palsy (PSP) (MAPT and RPSA-MOBP loci) and across FTD, AD, Parkinson disease (PD), and cortico-basal degeneration (CBD) (MAPT locus). Our data also suggest population specificity of the risk signals, with MAPT and APOE loci associations mainly driven by Central/Nordic and Mediterranean Europeans, respectively. This study lays the foundations for future work aimed at further characterizing population-specific features of potential FTD-discriminant APOE haplotype(s) and the functional involvement and contribution of the MAPT H1c haplotype and RPSA-MOBP loci to pathogenesis of sporadic forms of FTD in brain cortex.

Observations of diapycnal upwelling within a sloping submarine canyon.

Small-scale turbulent mixing drives the upwelling of deep water masses in the abyssal ocean as part of the global overturning circulation1. However, the processes leading to mixing and the pathways through which this upwelling occurs remain insufficiently understood. Recent observational and theoretical work2-5 has suggested that deep-water upwelling may occur along the ocean's sloping seafloor; however, evidence has, so far, been indirect. Here we show vigorous near-bottom upwelling across isopycnals at a rate of the order of 100 metres per day, coupled with adiabatic exchange of near-boundary and interior fluid. These observations were made using a dye released close to the seafloor within a sloping submarine canyon, and they provide direct evidence of strong, bottom-focused diapycnal upwelling in the deep ocean. This supports previous suggestions that mixing at topographic features, such as canyons, leads to globally significant upwelling3,6-8. The upwelling rates observed were approximately 10,000 times higher than the global average value required for approximately 30 × 106 m3 s-1 of net upwelling globally9.

Epidemic management and control through risk-dependent individual contact interventions.

Testing, contact tracing, and isolation (TTI) is an epidemic management and control approach that is difficult to implement at scale because it relies on manual tracing of contacts. Exposure notification apps have been developed to digitally scale up TTI by harnessing contact data obtained from mobile devices; however, exposure notification apps provide users only with limited binary information when they have been directly exposed to a known infection source. Here we demonstrate a scalable improvement to TTI and exposure notification apps that uses data assimilation (DA) on a contact network. Network DA exploits diverse sources of health data together with the proximity data from mobile devices that exposure notification apps rely upon. It provides users with continuously assessed individual risks of exposure and infection, which can form the basis for targeting individual contact interventions. Simulations of the early COVID-19 epidemic in New York City are used to establish proof-of-concept. In the simulations, network DA identifies up to a factor 2 more infections than contact tracing when both harness the same contact data and diagnostic test data. This remains true even when only a relatively small fraction of the population uses network DA. When a sufficiently large fraction of the population (≳ 75%) uses network DA and complies with individual contact interventions, targeting contact interventions with network DA reduces deaths by up to a factor 4 relative to TTI. Network DA can be implemented by expanding the computational backend of existing exposure notification apps, thus greatly enhancing their capabilities. Implemented at scale, it has the potential to precisely and effectively control future epidemics while minimizing economic disruption.

Protein interaction network analysis reveals genetic enrichment of immune system genes in frontotemporal dementia.

Interactors of protein products of known genes for frontotemporal dementia (FTD) are likely to be involved in the molecular pathways towards disease. We therefore applied protein interaction network (PIN) analysis to prioritize candidate genes for rare variant association analysis. We created an FTD-PIN starting from known FTD genes downloading their physical interactors and performed functional enrichment analyses. We identified overrepresented processes in FTD and selected genes (n = 440) belonging to these processes for rare variant analysis in a Belgian cohort of 228 FTD patients and 345 controls. SKAT-O analysis suggested TNFAIP3 as the top gene (p = 0.7 × 10-3) reaching near test-wide significance (p = 2.5 × 10-4). We then analyzed the TNFAIP3-subnetwork within the FTD-PIN which indicated enrichment of several immune signaling networks, suggesting that disrupted immune signaling may be implicated in TNFAIP3-related FTD. Our study demonstrates that integration of PINs with genetic data is a useful approach to increase the power for rare variant association analysis. Furthermore, we present a computational pipeline for identifying potential novel therapeutic targets and risk-modifying variants.

SLITRK2, an X-linked modifier of the age at onset in C9orf72 frontotemporal lobar degeneration.

The G4C2-repeat expansion in C9orf72 is the most common cause of frontotemporal dementia and of amyotrophic lateral sclerosis. The variability of age at onset and phenotypic presentations is a hallmark of C9orf72 disease. In this study, we aimed to identify modifying factors of disease onset in C9orf72 carriers using a family-based approach, in pairs of C9orf72 carrier relatives with concordant or discordant age at onset. Linkage and association analyses provided converging evidence for a locus on chromosome Xq27.3. The minor allele A of rs1009776 was associated with an earlier onset (P = 1 × 10-5). The association with onset of dementia was replicated in an independent cohort of unrelated C9orf72 patients (P = 0.009). The protective major allele delayed the onset of dementia from 5 to 13 years on average depending on the cohort considered. The same trend was observed in an independent cohort of C9orf72 patients with extreme deviation of the age at onset (P = 0.055). No association of rs1009776 was detected in GRN patients, suggesting that the effect of rs1009776 was restricted to the onset of dementia due to C9orf72. The minor allele A is associated with a higher SLITRK2 expression based on both expression quantitative trait loci (eQTL) databases and in-house expression studies performed on C9orf72 brain tissues. SLITRK2 encodes for a post-synaptic adhesion protein. We further show that synaptic vesicle glycoprotein 2 and synaptophysin, two synaptic vesicle proteins, were decreased in frontal cortex of C9orf72 patients carrying the minor allele. Upregulation of SLITRK2 might be associated with synaptic dysfunctions and drives adverse effects in C9orf72 patients that could be modulated in those carrying the protective allele. How the modulation of SLITRK2 expression affects synaptic functions and influences the disease onset of dementia in C9orf72 carriers will require further investigations. In summary, this study describes an original approach to detect modifier genes in rare diseases and reinforces rising links between C9orf72 and synaptic dysfunctions that might directly influence the occurrence of first symptoms.

MIR-NATs repress MAPT translation and aid proteostasis in neurodegeneration.

The human genome expresses thousands of natural antisense transcripts (NAT) that can regulate epigenetic state, transcription, RNA stability or translation of their overlapping genes1,2. Here we describe MAPT-AS1, a brain-enriched NAT that is conserved in primates and contains an embedded mammalian-wide interspersed repeat (MIR), which represses tau translation by competing for ribosomal RNA pairing with the MAPT mRNA internal ribosome entry site3. MAPT encodes tau, a neuronal intrinsically disordered protein (IDP) that stabilizes axonal microtubules. Hyperphosphorylated, aggregation-prone tau forms the hallmark inclusions of tauopathies4. Mutations in MAPT cause familial frontotemporal dementia, and common variations forming the MAPT H1 haplotype are a significant risk factor in many tauopathies5 and Parkinson's disease. Notably, expression of MAPT-AS1 or minimal essential sequences from MAPT-AS1 (including MIR) reduces-whereas silencing MAPT-AS1 expression increases-neuronal tau levels, and correlate with tau pathology in human brain. Moreover, we identified many additional NATs with embedded MIRs (MIR-NATs), which are overrepresented at coding genes linked to neurodegeneration and/or encoding IDPs, and confirmed MIR-NAT-mediated translational control of one such gene, PLCG1. These results demonstrate a key role for MAPT-AS1 in tauopathies and reveal a potentially broad contribution of MIR-NATs to the tightly controlled translation of IDPs6, with particular relevance for proteostasis in neurodegeneration.

Dementia in Latin America: Paving the way toward a regional action plan.

Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking, and translational research) and align them to current global strategies to translate regional knowledge into transformative actions. Then we characterize key sources of complexity (genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions), map them to the above challenges, and provide the basic mosaics of knowledge toward a KtAF. Finally, we describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF.

Identification of Candidate Parkinson Disease Genes by Integrating Genome-Wide Association Study, Expression, and Epigenetic Data Sets.

Importance: Substantial genome-wide association study (GWAS) work in Parkinson disease (PD) has led to the discovery of an increasing number of loci shown reliably to be associated with increased risk of disease. Improved understanding of the underlying genes and mechanisms at these loci will be key to understanding the pathogenesis of PD. Objective: To investigate what genes and genomic processes underlie the risk of sporadic PD. Design and Setting: This genetic association study used the bioinformatic tools Coloc and transcriptome-wide association study (TWAS) to integrate PD case-control GWAS data published in 2017 with expression data (from Braineac, the Genotype-Tissue Expression [GTEx], and CommonMind) and methylation data (derived from UK Parkinson brain samples) to uncover putative gene expression and splicing mechanisms associated with PD GWAS signals. Candidate genes were further characterized using cell-type specificity, weighted gene coexpression networks, and weighted protein-protein interaction networks. Main Outcomes and Measures: It was hypothesized a priori that some genes underlying PD loci would alter PD risk through changes to expression, splicing, or methylation. Candidate genes are presented whose change in expression, splicing, or methylation are associated with risk of PD as well as the functional pathways and cell types in which these genes have an important role. Results: Gene-level analysis of expression revealed 5 genes (WDR6 [OMIM 606031], CD38 [OMIM 107270], GPNMB [OMIM 604368], RAB29 [OMIM 603949], and TMEM163 [OMIM 618978]) that replicated using both Coloc and TWAS analyses in both the GTEx and Braineac expression data sets. A further 6 genes (ZRANB3 [OMIM 615655], PCGF3 [OMIM 617543], NEK1 [OMIM 604588], NUPL2 [NCBI 11097], GALC [OMIM 606890], and CTSB [OMIM 116810]) showed evidence of disease-associated splicing effects. Cell-type specificity analysis revealed that gene expression was overall more prevalent in glial cell types compared with neurons. The weighted gene coexpression performed on the GTEx data set showed that NUPL2 is a key gene in 3 modules implicated in catabolic processes associated with protein ubiquitination and in the ubiquitin-dependent protein catabolic process in the nucleus accumbens, caudate, and putamen. TMEM163 and ZRANB3 were both important in modules in the frontal cortex and caudate, respectively, indicating regulation of signaling and cell communication. Protein interactor analysis and simulations using random networks demonstrated that the candidate genes interact significantly more with known mendelian PD and parkinsonism proteins than would be expected by chance. Conclusions and Relevance: Together, these results suggest that several candidate genes and pathways are associated with the findings observed in PD GWAS studies.

Mendelian and Sporadic FTD: Disease Risk and Avenues from Genetics to Disease Pathways Through In Silico Modelling.

Frontotemporal dementia (FTD) is regarded as the second most common form of young-onset dementia after Alzheimer's disease (AD).FTD is a complex neurodegenerative condition characterised by heterogeneous clinical, pathological and genetic features. No efficient measures for early diagnosis and therapy are available.Familial (Mendelian) forms of disease have been studied over the past 20 years. Conversely, the genetics of sporadic forms of FTD (up to 70% of all cases) is understudied and still poorly understood. All this taken together suggests that more powerful and in-depth studies to tackle missing heritability and define the genetic architecture of sporadic FTD, with particular focus on the different subtypes (i.e. clinical and pathological diagnoses), are warranted.In parallel, it will be critical to translate the genetic findings into functional understanding of disease, i.e. moving from the identification of risk genes to the definition of risk pathways. It will be necessary to implement a paradigm shift - from reductionist to holistic approaches - to better interpret genetics and assist functional studies aimed at modelling and validating such risk pathways.In this chapter, we focus on the heterogeneous features of FTD touching upon its complex genetic landscape and discuss how novel approaches (e.g. computationally driven systems biology) promise to revolutionise the translation of genetic information into functional understanding of disease pathogenesis.

Genetic variation in APOE, GRN, and TP53 are phenotype modifiers in frontotemporal dementia.

Frontotemporal dementia (FTD) is a clinical, genetic, and pathologic heterogeneous group of neurodegenerative diseases. In this study, we investigated the role of APOƐ4, rs5848 in GRN, and rs1042522 in TP53 gene as disease risk factors and/or phenotype modifiers in 440 FTD patients, including 175 C9orf72 expansion carriers. We found that the C9orf72 expansion carriers showing an earlier age at onset (p < 0.001). Among the clinical groups, the FTD-MND (motoneuron disease) showed the lowest survival (hazard ratio [HR] = 4.12), and the progressive nonfluent aphasia group showed the highest onset age (p = 0.03). In our cohort, the rs1042522 in TP53 was associated with disease onset (p = 0.02) and survival (HR = 1.73) and rs5848 GRN with a significantly shorter survival in CC homozygous patients (HR = 1.98). The frequency of APOƐ4 carriers was significantly increased in the C9orf72 noncarriers (p = 0.022). Although validation of our findings is necessary, our results suggest that TP53, GRN, and APOE genes may act as phenotype modifiers in FTD and should be considered in future clinical trials.

Genetic determinants of survival in progressive supranuclear palsy: a genome-wide association study.

BACKGROUND: The genetic basis of variation in the progression of primary tauopathies has not been determined. We aimed to identify genetic determinants of survival in progressive supranuclear palsy (PSP). METHODS: In stage one of this two stage genome-wide association study (GWAS), we included individuals with PSP, diagnosed according to pathological and clinical criteria, from two separate cohorts: the 2011 PSP GWAS cohort, from brain banks based at the Mayo Clinic (Jacksonville, FL, USA) and in Munich (Germany), and the University College London PSP cohort, from brain banks and the PROSPECT study, a UK-wide longitudinal study of patients with atypical parkinsonian syndromes. Individuals were included if they had clinical data available on sex, age at motor symptom onset, disease duration (from motor symptom onset to death or to the date of censoring, Dec 1, 2019, if individuals were alive), and PSP phenotype (with reference to the 2017 Movement Disorder Society criteria). Genotype data were used to do a survival GWAS using a Cox proportional hazards model. In stage two, data from additional individuals from the Mayo Clinic brain bank, which were obtained after the 2011 PSP GWAS, were used for a pooled analysis. We assessed the expression quantitative trait loci (eQTL) profile of variants that passed genome-wide significance in our GWAS using the Functional Mapping and Annotation of GWAS platform, and did colocalisation analyses using the eQTLGen and PsychENCODE datasets. FINDINGS: Data were collected and analysed between Aug 1, 2016, and Feb 1, 2020. Data were available for 1001 individuals of white European ancestry with PSP in stage one. We found a genome-wide significant association with survival at chromosome 12 (lead single nucleotide polymorphism rs2242367, p=7·5 × 10-10, hazard ratio 1·42 [95% CI 1·22-1·67]). rs2242367 was associated with survival in the individuals added in stage two (n=238; p=0·049, 1·22 [1·00-1·48]) and in the pooled analysis of both stages (n=1239; p=1·3 × 10-10, 1·37 [1·25-1·51]). An eQTL database screen revealed that rs2242367 is associated with increased expression of LRRK2 and two long intergenic non-coding RNAs (lncRNAs), LINC02555 and AC079630.4, in whole blood. Although we did not detect a colocalisation signal for LRRK2, analysis of the PSP survival signal and eQTLs for LINC02555 in the eQTLGen blood dataset revealed a posterior probability of hypothesis 4 of 0·77, suggesting colocalisation due to a single shared causal variant. INTERPRETATION: Genetic variation at the LRRK2 locus was associated with survival in PSP. The mechanism of this association might be through a lncRNA-regulated effect on LRRK2 expression because LINC02555 has previously been shown to regulate LRRK2 expression. LRRK2 has been associated with sporadic and familial forms of Parkinson's disease, and our finding suggests a genetic overlap with PSP. Further functional studies will be important to assess the potential of LRRK2 modulation as a disease-modifying therapy for PSP and related tauopathies. FUNDING: PSP Association, CBD Solutions, Medical Research Council (UK).

Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.

We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.

CD33 and SIGLECL1 Immunoglobulin Superfamily Involved in Dementia.

Sialic acid-binding immunoglobulin-type lectins, which are predominantly expressed in immune cells, represent a family of immunomodulatory receptors with inhibitory and activating signals, in both healthy and disease states. Genetic factors are important in all forms of dementia, especially in early onset dementia. CD33 was recently recognized as a genetic risk factor for Alzheimer disease (AD). Here, we present a 2-generation family with 4 members, the father and the 3 siblings, characterized by an early form of unusual dementia exhibiting a behavioral variant close to behavioral variant frontotemporal dementia phenotype and severe forms of memory loss suggestive of AD. We analyzed the CD33 gene in this family and identified 10 single nucleotide polymorphisms (SNPs) in a linkage disequilibrium block associated with the disease. We also identified a tag SNP, rs2455069-A>G, in CD33 exon 2 that could be involved with dementia risk. Additionally, we excluded the presence of C9orf72 expansion mutations and other mutations previously associated with sporadic FTD and AD. The tag SNP association was also analyzed in selected sporadic AD patients from the same Southern Italy region. We demonstrate that CD33 and SIGLECL1 have a significantly increased level of expression in these patients.

PINOT: an intuitive resource for integrating protein-protein interactions.

BACKGROUND: The past decade has seen the rise of omics data for the understanding of biological systems in health and disease. This wealth of information includes protein-protein interaction (PPI) data derived from both low- and high-throughput assays, which are curated into multiple databases that capture the extent of available information from the peer-reviewed literature. Although these curation efforts are extremely useful, reliably downloading and integrating PPI data from the variety of available repositories is challenging and time consuming. METHODS: We here present a novel user-friendly web-resource called PINOT (Protein Interaction Network Online Tool; available at http://www.reading.ac.uk/bioinf/PINOT/PINOT_form.html) to optimise the collection and processing of PPI data from IMEx consortium associated repositories (members and observers) and WormBase, for constructing, respectively, human and Caenorhabditis elegans PPI networks. RESULTS: Users submit a query containing a list of proteins of interest for which PINOT extracts data describing PPIs. At every query submission PPI data are downloaded, merged and quality assessed. Then each PPI is confidence scored based on the number of distinct methods used for interaction detection and the number of publications that report the specific interaction. Examples of how PINOT can be applied are provided to highlight the performance, ease of use and potential utility of this tool. CONCLUSIONS: PINOT is a tool that allows users to survey the curated literature, extracting PPI data in relation to a list of proteins of interest. PINOT extracts a similar numbers of PPIs as other, analogous, tools and incorporates a set of innovative features. PINOT is able to process large queries, it downloads human PPIs live through PSICQUIC and it applies quality control filters on the downloaded PPI data (i.e. removing the need for manual inspection by the user). PINOT provides the user with information on detection methods and publication history for each downloaded interaction data entry and outputs the results in a table format that can be straightforwardly further customised and/or directly uploaded into network visualization software. Video abstract.

Concentration of Polymer Nanoparticles Through Dialysis: Efficacy and Comparison With Lyophilization for PEGylated and Zwitterionic Systems.

Biodegradable polymeric nanoparticles (NPs) are attracting increasing attention as carriers for drug delivery. However, one of the main factors limiting their transition to the market is their premature degradation and release of the payload during the storage. Therefore, for increasing the formulation shelf-life, the removal of water is of paramount importance. In this work, we synthesized both polyethylene glycol (PEG)-stabilized and zwitterionic NPs via Reversible Addition Fragmentation Chain Transfer (RAFT) Polymerization. We demonstrated that lyophilization leads the PEGylated NPs to irreversible aggregation, while the stability of the zwitterionic NPs was preserved only using a cryoprotectant. Therefore, we developed an alternative method for the NP concentration, based on the dialysis against a concentrated PEG solution. This method was optimized in terms of concentration factor (Fc), the ratio between the final and initial NP concentration, by acting on the PEG concentration in the dialysis medium, on its volume and on the initial NP concentration. With this approach, Fc up to 40 can be achieved in less than 10 h, preserving the possibility of redispersing the NPs to their original particle size distribution. Therefore, the dialysis proposed herein is a valuable alternative to lyophilization for the concentration of polymer NPs preserving their stability.

The vortex gas scaling regime of baroclinic turbulence.

The mean state of the atmosphere and ocean is set through a balance between external forcing (radiation, winds, heat and freshwater fluxes) and the emergent turbulence, which transfers energy to dissipative structures. The forcing gives rise to jets in the atmosphere and currents in the ocean, which spontaneously develop turbulent eddies through the baroclinic instability. A critical step in the development of a theory of climate is to properly include the eddy-induced turbulent transport of properties like heat, moisture, and carbon. In the linear stages, baroclinic instability generates flow structures at the Rossby deformation radius, a length scale of order 1,000 km in the atmosphere and 100 km in the ocean, smaller than the planetary scale and the typical extent of ocean basins, respectively. There is, therefore, a separation of scales between the large-scale gradient of properties like temperature and the smaller eddies that advect it randomly, inducing effective diffusion. Numerical solutions show that such scale separation remains in the strongly nonlinear turbulent regime, provided there is sufficient drag at the bottom of the atmosphere and ocean. We compute the scaling laws governing the eddy-driven transport associated with baroclinic turbulence. First, we provide a theoretical underpinning for empirical scaling laws reported in previous studies, for different formulations of the bottom drag law. Second, these scaling laws are shown to provide an important first step toward an accurate local closure to predict the impact of baroclinic turbulence in setting the large-scale temperature profiles in the atmosphere and ocean.

Role for ATXN1, ATXN2, and HTT intermediate repeats in frontotemporal dementia and Alzheimer's disease.

We analyzed the frequency of intermediate alleles (IAs) in the ATXN1, ATXN2, and HTT genes in several neurodegenerative diseases. The study included 1126 patients with Alzheimer's disease (AD), 440 patients with frontotemporal dementia (FTD), and 610 patients with Parkinson's disease. In all cohorts, we genotyped ATXN1 and ATXN2 CAG repeats. In addition, in the FTD cohort, we determined the number of HTT CAG repeats. The frequency of HTT IAs was higher in patients with FTD (6.9%) versus controls (2.9%) and in the C9orf72 expansion noncarriers (7.2%) versus controls (2.9%), although the difference was nonsignificant after correction for multiple testing. Compared with controls, progressive nonfluent aphasia (PNFA) groups showed a significantly higher frequency of HTT IAs (13.6% vs. 2.9% controls). For the ATXN2 gene, we observed an increase in IA frequency in AD cases (AD 4.1% vs. controls 1.8%) and in the behavioral FTD group (4.8% vs. 1.8%). For the ATXN1 gene, we found a significant increase of IAs in patients with PNFA (18.6%) versus controls (6.7%). In conclusion, our work suggests that the HTT and ATXN1 IAS may contribute to PNFA pathogenesis and point to a link between ATXN2 IAS and AD.

Recovery of Mineral Oil from Underground Electrical Cables.

To remove the mineral oil impregnating the insulating paper present in old, disconnected, underground electrical cables, which represents a threat to the environment, two approaches are investigated at laboratory (1 m) and pilot (10 m) scales. The first one involves in situ polymerization to clog the inner channel of the cables and to enable the washing of the outer paper region impregnated by the oil by axial flow of a displacing fluid (water). The second approach leaves the inner channel open and employs repeated cycles of pressurization and rest to displace the oil contained in the paper by radially pushing the water from the inner channel into the outer layers. The pressurization and rest times were optimized to obtain the highest oil extraction rate. While the first approach showed limitations in terms of required pressures and operating time, which increase with the length of the cables, the second one was effective at removing 97% of the oil impregnating the paper layers within 25 cycles. Even more relevant, this second solution, in contrast to the first one, can be easily scaled up as it does not depend on the length of the cable, and was successfully tested on a 10 m cable, showing 98% oil recovery.

Genetic variation across RNA metabolism and cell death gene networks is implicated in the semantic variant of primary progressive aphasia.

The semantic variant of primary progressive aphasia (svPPA) is a clinical syndrome characterized by neurodegeneration and progressive loss of semantic knowledge. Unlike many other forms of frontotemporal lobar degeneration (FTLD), svPPA has a highly consistent underlying pathology composed of TDP-43 (a regulator of RNA and DNA transcription metabolism). Previous genetic studies of svPPA are limited by small sample sizes and a paucity of common risk variants. Despite this, svPPA's relatively homogenous clinicopathologic phenotype makes it an ideal investigative model to examine genetic processes that may drive neurodegenerative disease. In this study, we used GWAS metadata, tissue samples from pathologically confirmed frontotemporal lobar degeneration, and in silico techniques to identify and characterize protein interaction networks associated with svPPA risk. We identified 64 svPPA risk genes that interact at the protein level. The protein pathways represented in this svPPA gene network are critical regulators of RNA metabolism and cell death, such as SMAD proteins and NOTCH1. Many of the genes in this network are involved in TDP-43 metabolism. Contrary to the conventional notion that svPPA is a clinical syndrome with few genetic risk factors, our analyses show that svPPA risk is complex and polygenic in nature. Risk for svPPA is likely driven by multiple common variants in genes interacting with TDP-43, along with cell death,x` working in combination to promote neurodegeneration.