Region-specific changes in gene expression are associated with cognitive deficits in the alpha-synuclein-induced model of Parkinson's disease: A transcriptomic profiling study

Mild cognitive impairment (MCI) is a common trait of Parkinson's disease (PD), often associated with early motor deficits, eventually evolving to PD with dementia in later disease stages. The neuropathological substrate of MCI is poorly understood, which weakens the development and administration of proper therapies. In an alpha-synuclein (alpha Syn)-based model of PD featuring early motor and cognitive impairments, we investigated the transcriptome profile of brain regions involved in PD with cognitive deficits, via a transcriptomic analysis based on RNA sequencing (RNA-seq) technology.Rats infused in the substantia nigra with human alpha-synuclein oligomers (H-SynOs) developed mild cognitive deficits after three months, as measured by the two-trial recognition test in a Y-maze and the novel object recognition test. RNA-seq analysis showed that 17,436 genes were expressed in the anterior cingulate cortex (ACC) and 17,216 genes in the hippocampus (HC). In the ACC, 51 genes were differentially expressed between vehicle and H-alpha SynOs treated samples, which showed N= 21 upregulated and N = 30 downregulated genes. In the HC, 104 genes were differentially expressed, the majority of them not overlapping with DEGs in the ACC, with N = 41 upregulated and N = 63 downregulated in H-alpha SynOs-treated samples. The Gene Ontology (GO) and the Kyoto Encyclopedia of Gene and Genomes (KEGG) analysis, followed by the protein-protein interaction (PPI) network inspection of DEGs, revealed that in the ACC most enriched terms were related with immune functions, specifically with antigen processing/presentation via the major histocompatibility complex (MHC) class II and phagocytosis via CD68, supporting a role for dysregulated immune responses in early PD cognitive dysfunction. Immunofluorescence analysis confirmed the decreased expression of CD68 within microglial cells. In contrast, the most significantly enriched terms in the HC were mainly involved in mitochondrial homeostasis, potassium voltage-gated channel, cytoskeleton and fiber organisation, suggesting that the gene expression in the neuronal population was mostly affected in this region in early disease stages.Altogether results show that H-alpha SynOs trigger a region-specific dysregulation of gene expression in ACC and HC, providing a pathological substrate for MCI associated with early PD

Modeling Parkinson’s disease neuropathology and symptoms by intranigral inoculation of preformed human α-synuclein oligomers

The accumulation of aggregated α-synuclein (αSyn) is a hallmark of Parkinson’s disease (PD). Current evidence indicates that small soluble αSyn oligomers (αSynOs) are the most toxic species among the forms of αSyn aggregates, and that size and topological structural properties are crucial factors for αSynOs-mediated toxicity, involving the interaction with either neurons or glial cells. We previously characterized a human αSynO (H-αSynO) with specific structural properties promoting toxicity against neuronal membranes. Here, we tested the neurotoxic potential of these H-αSynOs in vivo, in relation to the neuropathological and symptomatic features of PD. The H-αSynOs were unilaterally infused into the rat substantia nigra pars compacta (SNpc). Phosphorylated αSyn (p129-αSyn), reactive microglia, and cytokine levels were measured at progressive time points. Additionally, a phagocytosis assay in vitro was performed after microglia pre-exposure to αsynOs. Dopaminergic loss, motor, and cognitive performances were assessed. H-αSynOs triggered p129-αSyn deposition in SNpc neurons and microglia and spread to the striatum. Early and persistent neuroinflammatory responses were induced in the SNpc. In vitro, H-αSynOs inhibited the phagocytic function of microglia. H-αsynOs-infused rats displayed early mitochondrial loss and abnormalities in SNpc neurons, followed by a gradual nigrostriatal dopaminergic loss, associated with motor and cognitive impairment. The intracerebral inoculation of structurally characterized H-αSynOs provides a model of progressive PD neuropathology in rats, which will be helpful for testing neuroprotective therapies

Resolvin D2 Attenuates Cardiovascular Damage in Angiotensin II-Induced Hypertension.

Background: Resolution of inflammation is orchestrated by specialized proresolving lipid mediators (SPMs), and this would be impaired in some cardiovascular diseases. Among SPMs, resolvins (Rv) have beneficial effects in cardiovascular pathologies, but little is known about their effect on cardiovascular damage in hypertension. Methods: Aorta, small mesenteric arteries, heart, and peritoneal macrophages were taken from C57BL/6J mice, infused or not with angiotensin II (AngII; 1.44 mg/kg/day, 14 days) in presence or absence of resolvin D2 (RvD2) (100 ng/mice, every second day) starting 1 day before or 7 days after AngII infusion. Results: Enzymes and receptors involved in SPMs biosynthesis and signaling were increased in aorta or heart from AngII-infused mice. We also observed a differential regulation of SPMs in heart from these mice. Preventive treatment with RvD2 partially avoided AngII-induced hypertension and protected the heart and large and small vessels against functional and structural alterations induced by AngII. RvD2 increased the availability of vasoprotective factors, modified SPMs profile, decreased cardiovascular fibrosis, and increased the infiltration of pro-resolving macrophages. When administered in hypertensive animals with established cardiovascular damage, RvD2 partially improved cardiovascular function and structure, decreased fibrosis, reduced the infiltration of neutrophils, and shifted macrophage phenotype toward a pro-resolving phenotype. Conclusions: There is a disbalance between proinflammatory and resolution mediators in hypertension. RvD2 protects cardiovascular function and structure when administered before and after the development of hypertension by modulating vascular factors, fibrosis and inflammation. Activating resolution mechanisms by treatment with RvD2 may represent a novel therapeutic strategy for the treatment of hypertensive cardiovascular disease.pre-print362 K

Climbing walls, making bridges: children of immigrants’ identity negotiations through capoeira and parkour in Turin.

Capoeira and parkour are two different body practices which have gained worldwide attention in urban settings in the last few decades. The following paper will explore how capoeira and parkour relate to the construction of identity paths amongst children of immigrants between 12 and 20 in Turin, Italy. It will do so by looking at how such practices are used by young men of migrant origin to negotiate and perform narratives of self-worth, belonging and recognition within marginalising and excluding urban environments. This study acknowledges that social identifications are created, negotiated and (re)produced through bodily and spatial means and within networks of power relations. Following this premise, the insights proposed in this paper suggest that the ambivalent and fluid use of bodies and spaces implied by capoeira and parkour can represent a meaningful lens to understand the embodied and spatial identity negotiations enacted by participants in their daily lives. This theoretical perspective will illuminate the place that active bodies, spaces and leisure practices take in the negotiation of social identities, and dynamics of inclusion/exclusion, enacted by youth of migrant origin within early twenty-first century Turin cityscape

Nocturnal blood pressure fall as predictor of diabetic nephropathy in hypertensive patients with type 2 diabetes

<p>Abstract</p> <p>Background</p> <p>Hypertensive patients with reduced blood pressure fall (BPF) at night are at higher risk of cardiovascular events (CVE).</p> <p>Methods</p> <p>We evaluated in hypertensive diabetic patients, if a reduced nocturnal BPF can precedes the development of diabetic nephropathy (DN). We followed 70 patients with normal urinary albumin excretion (UAE) for two years. We performed 24-hours ambulatory BP monitoring in baseline and at the end of the study.</p> <p>Results</p> <p>Fourteen (20%) patients (GI) developed DN (N = 11) and/or CVE (n = 4). Compared to the remaining 56 patients (GII) in baseline, GI had similar diurnal systolic (SBP) and diastolic BP (DBP), but higher nocturnal SBP (138 ± 15 vs 129 ± 16 mmHg; p < 0.05) and DBP (83 ± 12 vs 75 ± 11 mmHg; p < 0,05). Basal nocturnal SBP correlated with occurrence of DN and CVE (R = 0.26; P < 0.05) and with UAE at the end of the study (r = 0.3; p < 0.05). Basal BPF (%) correlated with final UAE (r = -0.31; p < 0.05). In patients who developed DN, reductions occurred in nocturnal systolic BPF (12 ± 5 vs 3 ± 6%, p < 0,01) and diastolic BPF (15 ± 8 vs 4 ± 10%, p < 0,01) while no changes were observed in diurnal SBP (153 ± 17 vs 156 ± 16 mmHg, NS) and DBP (91 ± 9 vs 90 ± 7 mmHg, NS). Patients with final UAE < 20 μg/min, had no changes in nocturnal and diurnal BP.</p> <p>Conclusions</p> <p>Our results suggests that elevations in nocturnal BP precedes DN and increases the risk to develop CVE in hypertensive patients with T2DM.</p

Cancer mortality in a cohort of asbestos textile workers

A cohort of 889 men and 1077 women employed for at least 1 month between 1946 and 1984 by a former Italian leading asbestos (mainly textile) company, characterised by extremely heavy exposures often for short durations, was followed up to 1996, for a total of 53 024 person-years of observation. Employment data were obtained from factory personnel records, while vital status and causes of death were ascertained through municipality registers and local health units. We observed 222 cancer deaths compared with 116.4 expected (standardized mortality ratio, SMR=191). The highest ratios were found for pleural (SMR=4105), peritoneal (SMR=1817) and lung (SMR=282) cancers. We observed direct relationships with duration of employment for lung and peritoneal cancer, and with time since first employment for lung cancer and mesothelioma. Pleural cancer risk was independent from duration (SMR=3428 for employment <1 year, 7659 for 1–4 years, 2979 for 5–9 years and 2130 for ⩾10 years). Corresponding SMRs for lung cancer were 139, 251, 233 and 531. Nonsignificantly increased ratios were found for ovarian (SMR=261), laryngeal (SMR=238) and oro-pharyngeal (SMR=226) cancers. This study confirms and further quantifies the central role of latency in pleural mesothelioma and of cumulative exposure in lung cancer

Population Structure of Hispanics in the United States: The Multi-Ethnic Study of Atherosclerosis

Using ∼60,000 SNPs selected for minimal linkage disequilibrium, we perform population structure analysis of 1,374 unrelated Hispanic individuals from the Multi-Ethnic Study of Atherosclerosis (MESA), with self-identification corresponding to Central America (n = 93), Cuba (n = 50), the Dominican Republic (n = 203), Mexico (n = 708), Puerto Rico (n = 192), and South America (n = 111). By projection of principal components (PCs) of ancestry to samples from the HapMap phase III and the Human Genome Diversity Panel (HGDP), we show the first two PCs quantify the Caucasian, African, and Native American origins, while the third and fourth PCs bring out an axis that aligns with known South-to-North geographic location of HGDP Native American samples and further separates MESA Mexican versus Central/South American samples along the same axis. Using k-means clustering computed from the first four PCs, we define four subgroups of the MESA Hispanic cohort that show close agreement with self-identification, labeling the clusters as primarily Dominican/Cuban, Mexican, Central/South American, and Puerto Rican. To demonstrate our recommendations for genetic analysis in the MESA Hispanic cohort, we present pooled and stratified association analysis of triglycerides for selected SNPs in the LPL and TRIB1 gene regions, previously reported in GWAS of triglycerides in Caucasians but as yet unconfirmed in Hispanic populations. We report statistically significant evidence for genetic association in both genes, and we further demonstrate the importance of considering population substructure and genetic heterogeneity in genetic association studies performed in the United States Hispanic population

The bank lending channel: an empirical assessment of measures to stimulate bank lending in the European Union

This thesis first examines the role of banks in the transmission mechanism of monetary policy by focusing on the eight European new member States of Central and Eastern Europe over the 2004-2013 period. We specifically investigate the influence of monetary policy changes on bank lending activity and if this potential influence is contingent on bank characteristics, such as banks’ size, capital, liquidity, risk factor and market power. Moreover, we focus on the prospective role of banks in the monetary policy transmission mechanism in order to reveal any clear trends in banks’ lending behaviour during the 2008-2011 financial crisis. Secondly, we investigate the impact of a protracted period of low monetary policy rates on loosening of banks’ credit standards regarding enterprises, households and consumer loans through concentrating on the nine Eurozone countries involved since the initiation of the Euro area Bank Lending Survey in the three distinct time frames of pre- (2002Q4-2008Q3), mid- (2008Q4-2010Q4) and post- (2011Q1-2014:Q4) financial crisis. Furthermore, we test the fundamental concept of the risk taking channel by examining excessive risk-taking behaviour by banks in stressed vs. non-stressed countries of the Eurozone. In an additional analysis, the efficacy of the European Central Bank’s 3 year Long-Term Refinancing Operations is evaluated in great depth in order to determine whether banks’ credit standards have been softened and the degree to which demand for loans has increased. Thirdly, we explore the financing structure of bank lending constrained Small and Medium Sized Enterprises in the eleven Eurozone countries by utilising firm-level data over the period of 2009 to 2014. We estimate if bank lending constrained firms demonstrate relatively more usage or requests for alternative financing. Additionally, a comprehensive investigation is presented by unveiling the impact and determinants of various financing constraints including credit lines, bank loans, trade credit and other lending on Eurozone firms. Furthermore, the notion of discouraged borrowers originally formulated by Kon and Storey (2003) is empirically evaluated. Finally, we present the conclusion of our research by further outlining its limitations and prospective scope for future studie

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals

Correction: Volume53, Issue5 Page 762-762 DOI: 10.1038/s41588-021-00832-z Published MAY 2021Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequencyPeer reviewe