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Background: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. Methods: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun’s electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). Results: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01. Conclusion: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed. © 2021, The Author(s).

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of cancers and inflammation-related diseases. This phenomenon becomes common in persons aged >= 80 years, in whom the implications of CHIP are not well defined. We performed a mutational screening in 1794 persons aged >= 80 years and investigated the relationships between CHIP and associated pathologies. Mutations were observed in one-third of persons aged >= 80 years and were associated with reduced survival. Mutations in JAK2 and splicing genes, multiple mutations (DNMT3A, TET2, and ASXL1 with additional genetic lesions), and variant allele frequency >= 0.096 had positive predictive value for myeloid neoplasms. Combining mutation profiles with abnormalities in red blood cell indices improved the ability of myeloid neoplasm prediction. On this basis, we defined a predictive model that identifies 3 risk groups with different probabilities of developing myeloid neoplasms. Mutations in DNMT3A, TET2, ASXL1, or JAK2 were associated with coronary heart disease and rheumatoid arthritis. Cytopenia was common in persons aged >= 80 years, with the underlying cause remaining unexplained in 30% of cases. Among individuals with unexplained cytopenia, the presence of highly specific mutation patterns was associated with myelodysplastic-like phenotype and a probability of survival comparable to that of myeloid neoplasms. Accordingly, 7.5% of subjects aged >= 80 years with cytopenia had presumptive evidence of myeloid neoplasm. In summary, specific mutational patterns define different risk of developing myeloid neoplasms vs inflammatory-associated diseases in persons aged >= 80 years. In individuals with unexplained cytopenia, mutational status may identify those subjects with presumptive evidence of myeloid neoplasms.

Introduction: Domestic felids represent one of the main species in which amyloidosis occurs. The disease is caused by the presence of protein complexes, known as amyloids, which form insoluble deposits in different organs. However, little is known about the pathogenic pathway and the genetic of the disease is still under exploration. Among cat breeds, amyloidosis particularly affects Abyssinian/Somali and Siamese/Oriental cats, where the main target organs for the deposit are kidneys and liver, respectively. Objective: The aim of this study is i) to detect miRNAs expressed in amyloidosis affected and healthy Abyssinian kidneys ii) to evaluate their possible differential expression iii) to identify miRNAs potentially involved in the disease onset or in the regulation of its pathogenesis. Materials & Methods: miRNAs were extracted from Formalin Fixed Paraffin Embedded (FFPE) kidney slides collected from 6 affected and 4 healthy Abyssinians using the miRNeasy Mini Kit (Qiagen). The sequencing of miRNAs was carried out by smallRNA-seq kit (Illumina) and Illumina NextSeq500 platform, and its quality was assessed with FastQC. Cutadapter was used to remove the adapter sequences from the high-throughput sequencing reads. MiRDeep2 was then used to map reads against the cat reference genome (Felis catus, genome assembly version 9.0), identify putative miRNAs, quantify their expression and identify homologous human miRNAs. MiRNAs with less than 10 reads for each sample were filtered out. Raw counts were normalized with TMM method (Trimmed mean of M values) and expressed as log2 CPM (counts per million). Differential expression was assessed with a moderated t test (limma) and nominal p values were adjusted by Benjamini-Hochberg method. Results: A total of 854 miRNAs were detected, and 341 miRNAs were selected as representative after filtering. A total of 22 miRNAs showed significant expression difference between affected and healthy Abyssinians (p0.05), miR- 26a-5p (P-value 0.120) is one of the main miRNAs involved in the human immunoglobulin light chain (AL) amyloidosis onset. Conclusions: recent studies in humans have been focusing on disclosing the potential role of miRNAs in the accumulation of amyloid fibrils, especially in AD. It was shown that miRNAs dysregulation plays an important role in the disease alterations, although it cannot be considered the main trigger of the AD itself. Some of the identified miRNAs in the present study were already known to be associated with human AD. These results are encouraging and will help understanding the pathogenesis of feline amyloidosis. The genes directly regulated and involved in these pathways are under investigation and further evidences will be obtained with an integrative approach through a proteomic analysis.

In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p < 0.01). In summary, living in locations with large changes in solar insolation between winter and summer may be associated with increased suicide attempts in patients with bipolar disorder. Further investigation of the impacts of solar insolation on the course of bipolar disorder is needed. © 2019 Elsevier Ltd

Gene-environment interaction, through abnormal intestinal adsorption, has been proposed as possible mechanism for autism pathogenesis in those patients lacking of causative genetic variants. Haptoglobin (HP) is a haemoglobin binding and acute-phase plasma protein, encoded by two co-dominant alleles, HP-1 and HP-2, producing pre-HP-1 and pre-HP-2 proteins that mature in HP-1 and HP-2, respectively. Due to a 1.7Kb copy number variation in the HP gene, the HP-2 allele has two extra exons with respect to HP-1 (Fig. 1). Thus the HP protein is a dimer in homozygous subjects for HP-1 allele and is multimer in homozygous HP-2. Endogenous pre-HP-2 protein deregulates intestinal tight-junctions through EGFR and PAR2 activation, increases intestinal permeability and has been associated with autoimmune and inflammatory diseases as well as with psychiatric conditions (Fasano, 2011; Sturgeon and Fasano, 2016). Since the association between HP alleles and autism has just been investigated in a very small sample size of patients and controls (Rose et al., 2018), we genotyped, by PCR analysis, HP in a cohort of Italian patients with autism (n=406) and in controls (n=367). The aim was to evaluate the possible association of HP-2 and autism spectrum disorder (ASD). Contrary to what we expected, HP-1 allele distribution was different between patients and controls (36.3% and 29.4%, respectively) and significantly associated with autism (P=0.0041). Since a subgroup of patients and controls have already been genotyped by Illumina Human Omni-15-8 v.1.0 and Affy-6.0 chips, respectively, we are trying to impute HP alleles from flanking SNP haplotypes. HP alleles will therefore be predicted in publicly available large cohorts of patients with autism.

Tissues and organs are generated during development and repaired over the lifetime by stem cells with extensive self-renewal and differentiation potential. The characteristics and the identity of the stem and differentiated cells are determined by specific transcription factors that act together with chromatin regulators to stabilize expression patterns that maintain the cell identities. Disruption of the chromatin state or changes in the expression levels of chromatin regulators is associated with cellular reprogramming, disease and oncogenesis. While a large number of chromatin regulators have been identified, the epigenomic processes by which stem cells differentiate remains largely unknown for some somatic stem cell types. Three dimensional organoid cultures generated from patient derived single cells with stem cells properties, allow for investigating regulators of the chromatin state and gene expression patterns in mammary gland normal or tumor development. In this work by using cell lineage tracing and cell tracking, I characterized homogenous populations of cells derived from single mammary cells with organoid formation capacity. My findings suggest that chromatin changes in the histone state of mammary cells both initiate and stabilize gene expression patterns before the establishment of lineage specifying transcription factors.

Objective: To confirm prior findings that the larger the maximum monthly increase in solar insolation in springtime, the younger the age of onset of bipolar disorder. Method: Data were collected from 5536 patients at 50 sites in 32 countries on six continents. Onset occurred at 456 locations in 57 countries. Variables included solar insolation, birth-cohort, family history, polarity of first episode and country physician density. Results: There was a significant, inverse association between the maximum monthly increase in solar insolation at the onset location, and the age of onset. This effect was reduced in those without a family history of mood disorders and with a first episode of mania rather than depression. The maximum monthly increase occurred in springtime. The youngest birth-cohort had the youngest age of onset. All prior relationships were confirmed using both the entire sample, and only the youngest birth-cohort (all estimated coefficients P < 0.001). Conclusion: A large increase in springtime solar insolation may impact the onset of bipolar disorder, especially with a family history of mood disorders. Recent societal changes that affect light exposure (LED lighting, mobile devices backlit with LEDs) may influence adaptability to a springtime circadian challenge. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Studio e progetto di un sistema di profilometria laser per lo studio di difetti su materiali compositi in linea di produzione

Summary The identification of genes and SNPs involved in human diseases remains a challenge. Many public resources, databases and applications, collect biological data and perform annotations, increasing the global biological knowledge. The need of SNPs prioritization is emerging with the development of new high-throughput genotyping technologies, which allow to develop customized disease-oriented chips. Therefore, given a list of genes related to a specific biological process or disease as input, a crucial issue is finding the most relevant SNPs to analyse. The selection of these SNPs may rely on the relevant a-priori knowledge of biomolecular features characterising all the annotated SNPs and genes of the provided list. The bioinformatics approach described here allows to retrieve a ranked list of significant SNPs from a set of input genes, such as candidate genes associated with a specific disease. The system enriches the genes set by including other genes, associated to the original ones by ontological similarity evaluation. The proposed method relies on the integration of data from public resources in a vertical perspective (from genomics to systems biology data), the evaluation of features from biomolecular knowledge, the computation of partial scores for SNPs and finally their ranking, relying on their global score. Our approach has been implemented into a web based tool called SNPRanker, which is accessible through at the URL http://www.itb.cnr.it/snpranker. An interesting application of the presented system is the prioritisation of SNPs related to genes involved in specific pathologies, in order to produce custom arrays.