Validation of the Medonic CA620/530 Vet 20-ml microcapillary sampler system for hematology testing of feline blood

The aim of the current study was to compare feline hematologic variables in blood collected in microcapillary tubes (20 ml) and conventional blood tubes with the Medonic CA620/530 Vet in-house hematologic analyzer. A comparison of results obtained in 60 cats presented at the clinics of the veterinary school showed that the correlations between the 2 methods were 0.97 for white blood cell, 0.95 for red blood cell, and 0.93 for platelet counts; 0.92 for hemoglobin concentration; and 0.99 for mean corpuscular volume. No clinically relevant differences between the 2 blood sampling techniques were observed for any variable, which suggests that both techniques are interchangeable in cats. Moreover, microcapillary tubes would allow easier repeated sampling in the same cat and would likely be useful in other small species

Feline herpesvirus infection

Genomic and antigenic variations of feline herpesvirus type 1 (FHV1) are relatively limited. The virus is not particularly resistant in the environment, but it is able to remain latent inside infected organisms. FHV1 tends to reactivate under circumstances propitious to its transmission to new hosts. Acute infections lead to a rather severe upper respiratory and ocular inflammation. Mortality is uncommon but the sequelae of the infection may be irreversible. Acute lesions are necrotic and severe whereas eosinophilic infiltration is generally associated with subacute and chronic forms of the disease. Diagnosis is mainly based on clinical signs. Treatment is predominantly non-specific, but antiviral therapy is gaining more and more attention. Disease control is based on vaccination and prevention of viral spreading from latent carriers during reactivation episodes.L'herpèsvirus félin de type 1 montre une faible variabilité génomique et antigénique. Il s'agit d'un virus peu résistant dans le milieu extérieur mais capable de persister dans l'organisme infecté à l'état latent. Le phénomène de réactivation virale chez les porteurs latents se produit en particulier dans des conditions favorables à sa dissémination. L'infection aiguë entraîne une inflammation respiratoire et oculaire plutôt sévère. La mortalité est exceptionnelle mais les séquelles de l'infection peuvent être irréversibles. Les lésions aiguës sont nécrotiques et sévères alors que l'infiltration éosinophilique est plus caractéristiques des infections subaiguës et chroniques. Le diagnostic est avant tout clinique. La prise en charge des malades est essentiellement non spécifique mais l'amélioration de la connaissance des traitements antiviraux mérite d'être mise à profit. La prophylaxie repose sur la vaccination et la prévention de la dissémination du virus dans les phases de réactivation

Carbon dynamics of the Weddell Gyre, Southern Ocean

The accumulation of carbon within the Weddell Gyre and its exchanges across the gyre boundaries are investigated with three recent full-depth oceanographic sections enclosing this climatically important region. The combination of carbonmeasurements with ocean circulation transport estimates from a box inverse analysis reveals that deepwater transports associated with Warm Deep Water (WDW) and Weddell Sea Deep Water dominate the gyre’s carbon budget, while a dual-cell vertical overturning circulation leads to both upwelling and the delivery of large quantities of carbon to the deep ocean. Historical sea surface pCO2 observations, interpolated using a neural network technique, confirm the net summertime sink of 0.044 to 0.058 ± 0.010 Pg C / yr derived from the inversion. However, a wintertime outgassing signal similar in size results in a statistically insignificant annual air-to-sea CO2 flux of 0.002± 0.007 Pg C / yr (mean 1998–2011) to 0.012 ± 0.024 Pg C/ yr (mean 2008–2010) to be diagnosed for the Weddell Gyre. A surface layer carbon balance, independently derived fromin situ biogeochemical measurements, reveals that freshwater inputs and biological drawdown decrease surface ocean inorganic carbon levels more than they are increased by WDW entrainment, resulting in an estimated annual carbon sink of 0.033 ± 0.021 Pg C / yr. Although relatively less efficient for carbon uptake than the global oceans, the summertime Weddell Gyre suppresses the winter outgassing signal, while its biological pump and deepwater formation act as key conduits for transporting natural and anthropogenic carbon to the deep ocean where they can reside for long time scales

Genome-wide determinants of mortality and motor progression in Parkinson’s disease

\ua9 The Author(s) 2024.There are 90 independent genome-wide significant genetic risk variants for Parkinson’s disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. We studied 6766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out genome-wide survival studies for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality). There was a robust effect of the APOE ε4 allele on mortality in PD. We also identified a locus within the TBXAS1 gene encoding thromboxane A synthase 1 associated with mortality in PD. We also report 4 independent loci associated with motor progression in or near MORN1, ASNS, PDE5A, and XPO1. Only the non-Gaucher disease causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, these may represent new candidates for disease modification in PD

Association between the LRP1B and APOE loci in the development of Parkinson’s disease dementia

Parkinson’s disease is one of the most common age-related neurodegenerative disorders. Although predominantly a motor disorder, cognitive impairment and dementia are important features of Parkinson’s disease, particularly in the later stages of the disease. However, the rate of cognitive decline varies among Parkinson’s disease patients, and the genetic basis for this heterogeneity is incompletely understood. To explore the genetic factors associated with rate of progression to Parkinson’s disease dementia, we performed a genome-wide survival meta-analysis of 3923 clinically diagnosed Parkinson’s disease cases of European ancestry from four longitudinal cohorts. In total, 6.7% of individuals with Parkinson’s disease developed dementia during study follow-up, on average 4.4 ± 2.4 years from disease diagnosis. We have identified the APOE ε4 allele as a major risk factor for the conversion to Parkinson’s disease dementia [hazard ratio = 2.41 (1.94–3.00), P = 2.32 × 10−15], as well as a new locus within the ApoE and APP receptor LRP1B gene [hazard ratio = 3.23 (2.17–4.81), P = 7.07 × 10−09]. In a candidate gene analysis, GBA variants were also identified to be associated with higher risk of progression to dementia [hazard ratio = 2.02 (1.21–3.32), P = 0.007]. CSF biomarker analysis also implicated the amyloid pathway in Parkinson’s disease dementia, with significantly reduced levels of amyloid β42 (P = 0.0012) in Parkinson’s disease dementia compared to Parkinson’s disease without dementia. These results identify a new candidate gene associated with faster conversion to dementia in Parkinson's disease and suggest that amyloid-targeting therapy may have a role in preventing Parkinson’s disease dementia

Investigation of the genetic aetiology of Lewy body diseases with and without dementia

\ua9 The Author(s) 2024.Up to 80% of Parkinson\u27s disease patients develop dementia, but time to dementia varies widely from motor symptom onset. Dementia with Lewy bodies presents with clinical features similar to Parkinson\u27s disease dementia, but cognitive impairment precedes or coincides with motor onset. It remains controversial whether dementia with Lewy bodies and Parkinson\u27s disease dementia are distinct conditions or represent part of a disease spectrum. The biological mechanisms underlying disease heterogeneity, in particular the development of dementia, remain poorly understood, but will likely be the key to understanding disease pathways and, ultimately, therapy development. Previous genome-wide association studies in Parkinson\u27s disease and dementia with Lewy bodies/Parkinson\u27s disease dementia have identified risk loci differentiating patients from controls. We collated data for 7804 patients of European ancestry from Tracking Parkinson\u27s, The Oxford Discovery Cohort, and Accelerating Medicine Partnership-Parkinson\u27s Disease Initiative. We conducted a discrete phenotype genome-wide association study comparing Lewy body diseases with and without dementia to decode disease heterogeneity by investigating the genetic drivers of dementia in Lewy body diseases. We found that risk allele rs429358 tagging APOEe4 increases the odds of developing dementia, and that rs7668531 near the MMRN1 and SNCA-AS1 genes and an intronic variant rs17442721 tagging LRRK2 G2019S on chromosome 12 are protective against dementia. These results should be validated in autopsy-confirmed cases in future studies

Mitochondria function associated genes contribute to Parkinson's Disease risk and later age at onset

Mitochondrial dysfunction has been implicated in the etiology of monogenic Parkinson’s disease (PD). Yet the role that mitochondrial processes play in the most common form of the disease; sporadic PD, is yet to be fully established. Here, we comprehensively assessed the role of mitochondrial function-associated genes in sporadic PD by leveraging improvements in the scale and analysis of PD GWAS data with recent advances in our understanding of the genetics of mitochondrial disease. We calculated a mitochondrial-specific polygenic risk score (PRS) and showed that cumulative small effect variants within both our primary and secondary gene lists are significantly associated with increased PD risk. We further reported that the PRS of the secondary mitochondrial gene list was significantly associated with later age at onset. Finally, to identify possible functional genomic associations we implemented Mendelian randomization, which showed that 14 of these mitochondrial functionassociated genes showed functional consequence associated with PD risk. Further analysis suggested that the 14 identified genes are not only involved in mitophagy, but implicate new mitochondrial processes. Our data suggests that therapeutics targeting mitochondrial bioenergetics and proteostasis pathways distinct from mitophagy could be beneficial to treating the early stage of PD

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition

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

Regulatory sites for splicing in human basal ganglia are enriched for disease-relevant information

Genome-wide association studies have generated an increasing number of common genetic variants associated with neurological and psychiatric disease risk. An improved understanding of the genetic control of gene expression in human brain is vital considering this is the likely modus operandum for many causal variants. However, human brain sampling complexities limit the explanatory power of brain-related expression quantitative trait loci (eQTL) and allele-specific expression (ASE) signals. We address this, using paired genomic and transcriptomic data from putamen and substantia nigra from 117 human brains, interrogating regulation at different RNA processing stages and uncovering novel transcripts. We identify disease-relevant regulatory loci, find that splicing eQTLs are enriched for regulatory information of neuron-specific genes, that ASEs provide cell-specific regulatory information with evidence for cellular specificity, and that incomplete annotation of the brain transcriptome limits interpretation of risk loci for neuropsychiatric disease. This resource of regulatory data is accessible through our web server, http://braineacv2.inf.um.es/