Candidate Genes and MiRNAs Linked to the Inverse Relationship Between Cancer and Alzheimer’s Disease: Insights From Data Mining and Enrichment Analysis

The incidence of cancer and Alzheimer\u2019s disease (AD) increases exponentially with age. A growing body of epidemiological evidence and molecular investigations inspired the hypothesis of an inverse relationship between these two pathologies. It has been proposed that the two diseases might utilize the same proteins and pathways that are, however, modulated differently and sometimes in opposite directions. Investigation of the common processes underlying these diseases may enhance the understanding of their pathogenesis and may also guide novel therapeutic strategies. Starting from a text-mining approach, our in silico study integrated the dispersed biological evidence by combining data mining, gene set enrichment, and protein-protein interaction (PPI) analyses while searching for common biological hallmarks linked to AD and cancer. We retrieved 138 genes (ALZCAN gene set), computed a significant number of enriched gene ontology clusters, and identified four PPI modules. The investigation confirmed the relevance of autophagy, ubiquitin proteasome system, and cell death as common biological hallmarks shared by cancer and AD. Then, from a closer investigation of the PPI modules and of the miRNAs enrichment data, several genes (SQSTM1, UCHL1, STUB1, BECN1, CDKN2A, TP53, EGFR, GSK3B, and HSPA9) and miRNAs (miR-146a-5p, MiR-34a-5p, miR-21-5p, miR-9-5p, and miR-16-5p) emerged as promising candidates. The integrative approach uncovered novel miRNA-gene networks (e.g., miR-146 and miR-34 regulating p62 and Beclin1 in autophagy) that might give new insights into the complex regulatory mechanisms of gene expression in AD and cancer

Influenza Vaccination Uptake in the General Italian Population during the 2020–2021 Flu Season: Data from the EPICOVID-19 Online Web-Based Survey

To assess influenza vaccine uptake during the 2020/2021 flu season and compare it with that of the 2019/2020 flu season among respondents to the second phase of the web-based EPICOVID-19 survey, we performed an observational web-based nationwide online survey (January–February 2021) in which respondents to the first survey (April–June 2020) were contacted and asked to complete a second questionnaire. Factors associated with vaccine uptake in the 2020/2021 flu season were assessed by applying a multivariable multinomial logistic regression model. Out of the 198,822 respondents to the first survey, 41,473 (20.9%) agreed to fill out the followup questionnaire; of these, 8339 (20.1%) were vaccinated only during the 2020/2021 season, 8828 (21.3%) were vaccinated during both seasons and 22,710 (54.8%) were vaccinated in neither season. Educational level (medium (aOR 1.33 95%CI 1.13–1.56) and high (aOR 1.69 95%CI 1.44–1.97) vs. low) and socio-economic deprivation according to SES scoring (1 point aOR 0.83 (95%CI 0.78–0.89), 2 aOR 0.68 (95%CI 0.60–0.77) points or ≥3 points aOR 0.42 (95%CI 0.28–0.45) vs. 0 points) were found to be associated with flu vaccine uptake. Our study shows that social determinants seemed to affect flu vaccination uptake and identifies specific categories of the population to target during future influenza vaccination campaigns

Epidemiology of SARS-CoV-2 Infection in Italy Using Real-World Data: Methodology and Cohort Description of the Second Phase of Web-Based EPICOVID19 Study

Digital technologies have been extensively employed in response to the SARS-CoV-2 pandemic worldwide. This study describes the methodology of the two-phase internet-based EPI-COVID19 survey, and the characteristics of the adult volunteer respondents who lived in Italy during the first (April–May 2020) and the second wave (January–February 2021) of the epidemic. Validated scales and ad hoc questionnaires were used to collect socio-demographic, medical and behavioural characteristics, as well as information on COVID-19. Among those who provided email addresses during phase I (105,355), 41,473 participated in phase II (mean age 50.7 years ± 13.5 SD, 60.6% females). After a median follow-up of ten months, 52.8% had undergone nasopharyngeal swab (NPS) testing and 13.2% had a positive result. More than 40% had undergone serological test (ST) and 11.9% were positive. Out of the 2073 participants with at least one positive ST, 72.8% had only negative results from NPS or never performed it. These results indicate that a large fraction of individuals remained undiagnosed, possibly contributing to the spread of the virus in the community. Participatory online surveys offer a unique opportunity to collect relevant data at individual level from large samples during confinement

HLA-A is a Predictor of Hepatitis B e Antigen Status in HIV-Positive African Adults

Outcomes of chronic infection with hepatitis B virus (HBV) are varied, with increased morbidity reported in the context of human immunodeficiency virus (HIV) coinfection. The factors driving different outcomes are not well understood, but there is increasing interest in an HLA class I effect. We therefore studied the influence of HLA class I on HBV in an African HIV-positive cohort. We demonstrated that virologic markers of HBV disease activity (hepatitis B e antigen status or HBV DNA level) are associated with HLA-A genotype. This finding supports the role of the CD8+ T-cell response in HBV control, and potentially informs future therapeutic T-cell vaccine strategies.Version of Recor

Rapid COVID-19 screening based on self-reported symptoms: Psychometric assessment and validation of the EPICOVID19 short diagnostic scale

Background: Confirmed COVID-19 cases have been registered in more than 200 countries, and as of July 28, 2020, over 16 million cases have been reported to the World Health Organization. This study was conducted during the epidemic peak of COVID-19 in Italy. The early identification of individuals with suspected COVID-19 is critical in immediately quarantining such individuals. Although surveys are widely used for identifying COVID-19 cases, outcomes, and associated risks, no validated epidemiological tool exists for surveying SARS-CoV-2 infection in the general population. Objective: We evaluated the capability of self-reported symptoms in discriminating COVID-19 to identify individuals who need to undergo instrumental measurements. We defined and validated a method for identifying a cutoff score. Methods: Our study is phase II of the EPICOVID19 Italian national survey, which launched in April 2020 and included a convenience sample of 201,121 adults who completed the EPICOVID19 questionnaire. The Phase II questionnaire, which focused on the results of nasopharyngeal swab (NPS) and serological tests, was mailed to all subjects who previously underwent NPS tests. Results: Of 2703 subjects who completed the Phase II questionnaire, 694 (25.7%) were NPS positive. Of the 472 subjects who underwent the immunoglobulin G (IgG) test and 421 who underwent the immunoglobulin M test, 22.9% (108/472) and 11.6% (49/421) tested positive, respectively. Compared to NPS-negative subjects, NPS-positive subjects had a higher incidence of fever (421/694, 60.7% vs 391/2009, 19.5%; P<.001), loss of taste and smell (365/694, 52.6% vs 239/2009, 11.9%; P<.001), and cough (352/694, 50.7% vs 580/2009, 28.9%; P<.001). With regard to subjects who underwent serological tests, IgG-positive subjects had a higher incidence of fever (65/108, 60.2% vs 43/364, 11.8%; P<.001) and pain in muscles/bones/joints (73/108, 67.6% vs 71/364, 19.5%; P<.001) than IgG-negative subjects. An analysis of self-reported COVID-19 symptom items revealed a 1-factor solution, the EPICOVID19 diagnostic scale. The following optimal scores were identified: 1.03 for respiratory problems, 1.07 for chest pain, 0.97 for loss of taste and smell 0.97, and 1.05 for tachycardia (ie, heart palpitations). These were the most important symptoms. For adults aged 18-84 years, the cutoff score was 2.56 (sensitivity: 76.56%; specificity: 68.24%) for NPS-positive subjects and 2.59 (sensitivity: 80.37%; specificity: 80.17%) for IgG-positive subjects. For subjects aged ≥60 years, the cutoff score was 1.28, and accuracy based on the presence of IgG antibodies improved (sensitivity: 88.00%; specificity: 89.58%). Conclusions: We developed a short diagnostic scale to detect subjects with symptoms that were potentially associated with COVID-19 from a wide population. Our results support the potential of self-reported symptoms in identifying individuals who require immediate clinical evaluations. Although these results come from the Italian pandemic period, this short diagnostic scale could be optimized and tested as a screening tool for future similar pandemics

Self-reported symptoms of SARS-CoV-2 infection in a non-hospitalized population : results from the large Italian web-based EPICOVID19 cross-sectional survey. (Preprint)

Background: Understanding the occurrence of Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2)-like symptoms in a large non-hospitalized population, when the epidemic peak was occurring in Italy, is of paramount importance but data are scarce. Objective: Aims of this study were to evaluate the association of self-reported symptoms with SARS-CoV-2 nasopharyngeal swab (NPS) test in non-hospitalized individuals and to estimate the occurrence of COVID-19-like symptoms in a larger non-tested population. Methods: This is an Italian countrywide self-administered cross-sectional web-based survey on voluntary adults who completed an anonymous questionnaire in the period 13-21 April 2020. The associations between symptoms potentially related to SARS-CoV-2 infection and NPS results were calculated as adjusted odds ratios with 95% confidence intervals (aOR, 95%CI) by means of multiple logistic regression analysis controlling for age, sex, education, smoking habits, and the number of co-morbidities. Thereafter, for each symptom and for their combination, we calculated sensitivity, specificity, accuracy and AUC in a ROC analysis to estimate the occurrence of COVID-19-like infections in the non-tested population. Results: A total of 171,310 responded to the survey (59.9% females, mean age 47.4 years). Out of the 4,785 respondents with known NPS test result, 4,392 were not hospitalized. Among them, the NPS positive respondents (n=856) most frequently reported myalgia (61.6%), olfactory and/or taste disorders (OTDs, 59.2%), cough (54.4%), and fever (51.9%) whereas 7.7% were asymptomatic. Multiple regression analysis showed that OTDs (aOR 10.3, [95%CI 8.4-12.7]), fever (2.5, 95%CI 2.0-3.1), myalgia (1.5, 95%CI 1.2-1.8), and cough (1.3, 95%CI 1.0-1.6) were associated with NPS positivity. Having two to four of these symptoms increased the aOR from 7.4 (95%CI, 5.6-9.7) to 35.5 (95%CI, 24.6-52.2). The combination of the four symptoms showed an AUC of 0.810 (95%CI 0.795-0.825) in classifying NPS-P, and was applied to the non-hospitalized and non-tested sample (n=165,782). We found that from 4.4% to 12.1% of respondents had experienced symptoms suggestive of COVID-19 infection. Conclusions: Our results suggest that self-reported symptoms may be reliable indicators of SARS-CoV-2 infection in a pandemic context. A not negligible part (up to 12.1%) of the symptomatic respondents were left undiagnosed and potentially contributed to the spread of the infection

Phenotypic effect of GBA1 variants in individuals with and without Parkinson's disease: The RAPSODI study

Background: Variants in the GBA1 gene cause the lysosomal storage disorder Gaucher disease (GD). They are also risk factors for Parkinson's disease (PD), and modify the expression of the PD phenotype. The penetrance of GBA1 variants in PD is incomplete, and the ability to determine who among GBA1 variant carriers are at higher risk of developing PD, would represent an advantage for prognostic and trial design purposes. Objectives: To compare the motor and non-motor phenotype of GBA1 carriers and non-carriers. Methods: We present the cross-sectional results of the baseline assessment from the RAPSODI study, an online assessment tool for PD patients and GBA1 variant carriers. The assessment includes clinically validated questionnaires, a tap-test, the University of Pennsyllvania Smell Identification Test and cognitive tests. Additional, homogeneous data from the PREDICT-PD cohort were included. Results: A total of 379 participants completed all parts of the RAPSODI assessment (89 GBA1-negative controls, 169 GBA1-negative PD, 47 GBA1-positive PD, 47 non-affected GBA1 carriers, 27 GD). Eighty-six participants were recruited through PREDICT-PD (43 non-affected GBA1 carriers and 43 GBA1-negative controls). GBA1-positive PD patients showed worse performance in visual cognitive tasks and olfaction compared to GBA1-negative PD patients. No differences were detected between non-affected GBA1 carriers carriers and GBA1-negative controls. No phenotypic differences were observed between any of the non-PD groups. Conclusions: Our results support previous evidence that GBA1-positive PD has a specific phenotype with more severe non-motor symptoms. However, we did not reproduce previous findings of more frequent prodromal PD signs in non-affected GBA1 carriers

GSK-3 Activity Is Critical for the Orientation of the Cortical Microtubules and the Dorsoventral Axis Determination in Zebrafish Embryos

The formation of dorsal-ventral (D–V) axis is the earliest event that breaks the radial symmetry and determines the bilateral body plan of a vertebrate embryo, however, the maternal control of this process is not fully understood. Here, we discovered a new dorsalizing window of acute lithium treatment, which covers only less than 10 minutes after fertilization. Lithium treatment in this window was not able to reverse the ventralized phenotype in tokkeabi (tkk) mutant embryos, and its dorsalizing activity on wild-type embryos was inhibited by nocodazole co-treatment. These evidences indicate that the underlying mechanism is independent of a direct activation of Wnt/β-catenin signaling, but depends on the upstream level of the microtubule mediated dorsal determinant transport. In order to identify the target of lithium in this newly discovered sensitive window, GSK-3 inhibitor IX as well as the IMPase inhibitor L690, 330 treatments were performed. We found that only GSK-3 inhibitor IX treatment mimicked the lithium treatment in the dorsalizing activity. Further study showed that the parallel pattern of cortical microtubules in the vegetal pole region and the directed migration of the Wnt8a mRNA were randomized by either lithium or GSK-3 inhibitor IX treatment. These results thus revealed an early and critical role of GSK-3 activity that regulates the orientation of the cortical microtubules and the directed transport of the dorsal determinants in zebrafish embryos

Deletion of the WD40 Domain of LRRK2 in Zebrafish Causes Parkinsonism-Like Loss of Neurons and Locomotive Defect

LRRK2 plays an important role in Parkinson's disease (PD), but its biological functions are largely unknown. Here, we cloned the homolog of human LRRK2, characterized its expression, and investigated its biological functions in zebrafish. The blockage of zebrafish LRRK2 (zLRRK2) protein by morpholinos caused embryonic lethality and severe developmental defects such as growth retardation and loss of neurons. In contrast, the deletion of the WD40 domain of zLRRK2 by morpholinos targeting splicing did not induce severe embryonic developmental defects; rather it caused Parkinsonism-like phenotypes, including loss of dopaminergic neurons in diencephalon and locomotion defects. These neurodegenerative and locomotion defects could be rescued by over-expressing zLRRK2 or hLRRK2 mRNA. The administration of L-dopa could also rescue the locomotion defects, but not the neurodegeneration. Taken together, our results demonstrate that zLRRK2 is an ortholog of hLRRK2 and that the deletion of WD40 domain of zLRRK2 provides a disease model for PD

Using fish models to investigate the links between microbiome and social behaviour: the next step for translational microbiome research?

Recent research has revealed surprisingly important connections between animals’ microbiome and social behaviour. Social interactions can affect the composition and function of the microbiome; conversely, the microbiome affects social communication by influencing the hosts’ central nervous system and peripheral chemical communication. These discoveries set the stage for novel research focusing on the evolution and physiology of animal social behaviour in relation to microbial transmission strategies. Here, we discuss the emerging roles of teleost fish models and their potential for advancing research fields, linked to sociality and microbial regulation. We argue that fish models, such as the zebrafish (Danio rerio, Cyprinidae), sticklebacks (‎Gasterosteidae), guppies (Poeciliidae) and cleaner–client dyads (e.g., obligate cleaner fish from the Labridae and Gobiidae families and their visiting clientele), will provide valuable insights into the roles of microbiome in shaping social behaviour and vice versa, while also being of direct relevance to the food and ornamental fish trades. The diversity of fish behaviour warrants more interdisciplinary research, including microbiome studies, which should have a strong ecological (field‐derived) approach, together with laboratory‐based cognitive and neurobiological experimentation. The implications of such integrated approaches may be of translational relevance, opening new avenues for future investigation using fish models