Bacteriophages a bio sustainable solution to tackle Alzheimer´s disease

Introduction: Amyloid-beta (AB) is a prime suspect to cause Alzheimers disease (AD), an irreversible, progressive and age-dependent neurodegenerative disorder affecting millions of people worldwide. An accumulation of AB in the brain leads to its aggregation into soluble oligomeric and fibrillar clusters, which are the culprits to impair synaptic function and memory formation in mice models. Currently, we lack diagnostic tools to detect AB oligomers (ABOs) in the brain, all the methods used provide a late diagnosis when there are already symptoms. Moreover, the existence of the blood-brain-barrier (BBB) is the major bottleneck for reaching the brain. To overcome this, bacteriophages (phages: bacterial viruses) are a solution, once they posses the capacity to cross the BBB. Aims: Hence, our main goals were the development of a solution to 1) detect ABOs in the brain and monitor AD progression and 2) delay or prevent the onset of the symptoms. Methods: We resorted to phage engineering with AB-targeting peptides described to recognize ABOs and fibrils with high affinity. These were tested for their capacity to detect ABOs in tissues samples and their effect on AB aggregation. Results: The engineered phages are able to detect the early and toxic forms of AB in brain tissue of APP/PS1 transgenic mice and human donors. Moreover, these phages also possess a high therapeutic potential by inhibiting the aggregation process of AB. Conclusion: We provide a highly versatile bio-inspired solution based on phages displaying AB peptides to detect early soluble AB oligomers in the brain, and possibly prevent, or delay, the onset of the symptoms, consequently inhibiting AD progression.The authors thank the Project EARLY - Phage towards initial amyloid-beta funded by TecMinho through the iProof initiative, in the scope of the project UI-Transfer, co-financed by COMPETE 2020, through Fundo Europeu de Desenvolvimento Regional (FEDER). This study was supported by the Portuguese Foundation for Science and Technology (FCT) under the scope of the strategic funding of UIDB/04469/2020 unit, and by LABBELS – Associate Laboratory in Biotechnology, Bioengineering and Microelectromechanical Systems, LA/P/0029/2020, center grant UID/MULTI/04046/2020 (to BioISI), PhD fellowship SFRH/BD/101171/2014 (to J.S.C.), and by Alzheimer Nederland (H.W.K.).info:eu-repo/semantics/publishedVersio

M13 phage grafted with peptide motifs as a tool to detect amyloid- oligomers in brain tissue

Oligomeric clusters of amyloid- (A) are one of the major biomarkers for Alzheimers disease (AD). However, proficient methods to detect A-oligomers in brain tissue are lacking. Here we show that synthetic M13 bacteriophages displaying A-derived peptides on their surface preferentially interact with A-oligomers. When exposed to brain tissue isolated from APP/PS1-transgenic mice, these bacteriophages detect small-sized A-aggregates in hippocampus at an early age, prior to the occurrence of A-plaques. Similarly, the bacteriophages reveal the presence of such small A-aggregates in post-mortem hippocampus tissue of ADpatients. These results advocate bacteriophages displaying A-peptides as a convenient and low-cost tool to identify A-oligomers in post-mortem brain tissue of AD-model mice and AD patients.FCT -Fundação para a Ciência e a Tecnologia(SFRH/BD/101171/2014)info:eu-repo/semantics/publishedVersio

Risk factors for inadequate prenatal care use in the metropolitan area of Aracaju, Northeast Brazil

<p>Abstract</p> <p>Background</p> <p>The aim of prenatal care is to promote good maternal and foetal health and to identify risk factors for adverse pregnancy outcomes in an attempt to promptly manage and solve them. Although high prenatal care attendance is reported in most areas in Brazil, perinatal and neonatal mortalities are disproportionally high, raising doubts about the quality and performance of the care provided. The objective of the present study was to evaluate the adequacy of prenatal care use and the risk factors involved in inadequate prenatal care utilization in the metropolitan area of Aracaju, Northeast Brazil.</p> <p>Methods</p> <p>A survey was carried out with puerperal women who delivered singleton liveborns in all <b>four </b>maternity hospitals of Aracaju. A total of 4552 singleton liveborns were studied. The Adequacy of Prenatal Care Utilization Index, modified according to the guidelines of the Prenatal Care and Birth Humanization Programme, was applied. Socioeconomic, demographic, biological, life style and health service factors were evaluated by multiple logistic regression. Results: Prenatal care coverage in Aracaju was high (98.3%), with a mean number of 6.24 visits. Prenatal care was considered to be adequate or intensive in 66.1% of cases, while 33.9% were considered to have inadequate usage. Age < 18 to 34 years at delivery, low maternal schooling, low family income, two or more previous deliveries, maternal smoking during pregnancy, having no partner and prenatal care obtained outside Aracaju were associated with inadequate prenatal care use. In contrast, private service attendance protected from inadequate prenatal care use.</p> <p>Conclusion</p> <p>Prenatal care coverage was high. However, a significant number of women still had inadequate prenatal care use. Socioeconomic inequalities, demographic factors and behavioural risk factors are still important factors associated with inadequate prenatal care use.</p

Permanent vascular access in patients with end-stage renal disease, Brazil

OBJECTIVE: To assess factors associated with the establishment of permanent vascular access for patients with end-stage renal disease. METHODS: Cross-sectional study conducted in a nationally representative sample of Brazilian end-stage renal disease patients in dialysis and transplant centers during 2007. The sample comprised only patients who received hemodialysis as a primary therapy modality and reported the type of vascular access for their primary hemodialysis treatment (N=2,276). Data were from the TRS Project - "Economic and Epidemiologic Evaluation of Modalities of Renal Replacement Therapy in Brazil". Multiple logistic regression analysis was used to assess factors associated with the establishment of permanent vascular access in these patients. RESULTS: About 30% of the patients studied had an arteriovenous vascular access. The following factors were associated with a lower likelihood of having an arteriovenous vascular access as a primary type of access: time of hemodialysis start since the diagnosis of chronic renal failure < 1 year; shorter dialysis therapy; having no private health insurance; living in the central-western, northeastern and southeastern regions of Brazil; and living in the northern region plus having no private health insurance. In the final model there was found a positive association between the outcome and pre-dialysis care and no were association with socioeconomic and comorbidity variables. CONCLUSIONS: The study results showed that the focus should on pre-dialysis care to increase the establishment of an arteriovenous vascular access before starting hemodialysis in Brazil

Duration of temporary catheter use for hemodialysis: an observational, prospective evaluation of renal units in Brazil

<p>Abstract</p> <p>Background</p> <p>For chronic hemodialysis, the ideal permanent vascular access is the arteriovenous fistula (AVF). Temporary catheters should be reserved for acute dialysis needs. The AVF is associated with lower infection rates, better clinical results, and a higher quality of life and survival when compared to temporary catheters. In Brazil, the proportion of patients with temporary catheters for more than 3 months from the beginning of therapy is used as an evaluation of the quality of renal units. The aim of this study is to evaluate factors associated with the time between the beginning of hemodialysis with temporary catheters and the placement of the first arteriovenous fistula in Brazil.</p> <p>Methods</p> <p>This is an observational, prospective non-concurrent study using national administrative registries of all patients financed by the public health system who began renal replacement therapy (RRT) between 2000 and 2004 in Brazil. Incident patients were eligible who had hemodialysis for the first time. Patients were excluded who: had hemodialysis reportedly started after the date of death (inconsistent database); were younger than 18 years old; had HIV; had no record of the first dialysis unit; and were dialyzed in units with less than twenty patients. To evaluate individual and renal unit factors associated with the event of interest, the frailty model was used (N = 55,589).</p> <p>Results</p> <p>Among the 23,824 patients (42.9%) who underwent fistula placement in the period of the study, 18.2% maintained the temporary catheter for more than three months until the fistula creation. The analysis identified five statistically significant factors associated with longer time until first fistula: higher age (Hazard-risk - HR 0.99, 95% CI 0.99-1.00); having hypertension and cardiovascular diseases (HR 0.94, 95% CI 0.9-0.98) as the cause of chronic renal disease; residing in capitals cities (HR 0.92, 95% CI 0.9-0.95) and certain regions in Brazil - South (HR 0.83, 95% CI 0.8-0.87), Midwest (HR 0.88, 95% CI 0.83-0.94), Northeast (HR 0.91, 95% CI 0.88-0.94), or North (HR 0.88, 95% CI 0.83-0.94) and the type of renal unit (public or private).</p> <p>Conclusion</p> <p>Monitoring the provision of arteriovenous fistulas in renal units could improve the care given to patients with end stage renal disease.</p

Standardization of the NEO-PI-3 in the Greek general population

BACKGROUND: The revised NEO Personality Inventory (NEO-PI-3) includes 240 items corresponding to the Big Five personality traits (Extraversion, Agreeableness, Conscientiousness, Neuroticism, and Openness to Experience) and subordinate dimensions (facets). It is suitable for use with adolescents and adults (12 years or older). The aim of the current study was to validate the Greek translation of the NEO-PI-3 in the general Greek population. MATERIAL AND METHODS: The study sample included 734 subjects from the general Greek population of whom 59.4% were females and 40.6% males aged 40.80 +/- 11.48. The NEO-PI-3 was translated into Greek and back-translated into English, and the accuracy of the translation was confirmed and established. The statistical analysis included descriptive statistics, confirmatory factorial analysis (CFA), the calculation of Cronbach's alpha, and the calculation of Pearson product-moment correlations. Sociodemographics groups were compared by ANOVA. RESULTS: Most facets had Cronbach's alpha above 0.60. Confirmatory factor analysis showed acceptable loading of the facets on their own hypothesized factors and very good estimations of Cronbach's alphas for the hypothesized factors, so it was partially supportive of the five-factor structure of the NEO-PI-3.The factors extracted with Procrustes rotation analysis can be considered reasonably homologous to the factors of the American normative sample. Correlations between dimensions were as expected and similar to those reported in the literature. DISCUSSION: The literature suggests that overall, the psychometric properties of NEO-PI-3 scales have been found to generalize across ages, cultures, and methods of measurement. In accord with this, the results of the current study confirm the reliability of the Greek translation and adaptation of the NEO-PI-3. The inventory has comparable psychometric properties in its Greek version in comparison to the original and other national translations, and it is suitable for clinical as well as research use

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Global variation in diabetes diagnosis and prevalence based on fasting glucose and hemoglobin A1c

Fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c) are both used to diagnose diabetes, but these measurements can identify different people as having diabetes. We used data from 117 population-based studies and quantified, in different world regions, the prevalence of diagnosed diabetes, and whether those who were previously undiagnosed and detected as having diabetes in survey screening, had elevated FPG, HbA1c or both. We developed prediction equations for estimating the probability that a person without previously diagnosed diabetes, and at a specific level of FPG, had elevated HbA1c, and vice versa. The age-standardized proportion of diabetes that was previously undiagnosed and detected in survey screening ranged from 30% in the high-income western region to 66% in south Asia. Among those with screen-detected diabetes with either test, the age-standardized proportion who had elevated levels of both FPG and HbA1c was 29-39% across regions; the remainder had discordant elevation of FPG or HbA1c. In most low- and middle-income regions, isolated elevated HbA1c was more common than isolated elevated FPG. In these regions, the use of FPG alone may delay diabetes diagnosis and underestimate diabetes prevalence. Our prediction equations help allocate finite resources for measuring HbA1c to reduce the global shortfall in diabetes diagnosis and surveillance

Overexpression of the Cytokine BAFF and Autoimmunity Risk

$\textbf{BACKGROUND}$: Genomewide association studies of autoimmune diseases have mapped hundreds of susceptibility regions in the genome. However, only for a few association signals has the causal gene been identified, and for even fewer have the causal variant and underlying mechanism been defined. Coincident associations of DNA variants affecting both the risk of autoimmune disease and quantitative immune variables provide an informative route to explore disease mechanisms and drug-targetable pathways. $\textbf{METHODS}$: Using case-control samples from Sardinia, Italy, we performed a genomewide association study in multiple sclerosis followed by TNFSF13B locus-specific association testing in systemic lupus erythematosus (SLE). Extensive phenotyping of quantitative immune variables, sequence-based fine mapping, cross-population and cross-phenotype analyses, and gene-expression studies were used to identify the causal variant and elucidate its mechanism of action. Signatures of positive selection were also investigated. $\textbf{RESULTS}$: A variant in TNFSF13B, encoding the cytokine and drug target B-cell activating factor (BAFF), was associated with multiple sclerosis as well as SLE. The disease-risk allele was also associated with up-regulated humoral immunity through increased levels of soluble BAFF, B lymphocytes, and immunoglobulins. The causal variant was identified: an insertion-deletion variant, GCTGT→A (in which A is the risk allele), yielded a shorter transcript that escaped microRNA inhibition and increased production of soluble BAFF, which in turn up-regulated humoral immunity. Population genetic signatures indicated that this autoimmunity variant has been evolutionarily advantageous, most likely by augmenting resistance to malaria. $\textbf{CONCLUSIONS}$: A TNFSF13B variant was associated with multiple sclerosis and SLE, and its effects were clarified at the population, cellular, and molecular levels. (Funded by the Italian Foundation for Multiple Sclerosis and others.).Supported by grants (2011/R/13 and 2015/R/09, to Dr. Cucca) from the Italian Foundation for Multiple Sclerosis; contracts (N01-AG-1-2109 and HHSN271201100005C, to Dr. Cucca) from the Intramural Research Program of the National Institute on Aging, National Institutes of Health (NIH); a grant (FaReBio2011 “Farmaci e Reti Biotecnologiche di Qualità,” to Dr. Cucca) from the Italian Ministry of Economy and Finance; a grant (633964, to Dr. Cucca) from the Horizon 2020 Research and Innovation Program of the European Union; a grant (U1301.2015/AI.1157.BE Prat. 2015-1651, to Dr. Cucca) from Fondazione di Sardegna; grants (“Centro per la ricerca di nuovi farmaci per malattie rare, trascurate e della povertà” and “Progetto collezione di composti chimici ed attività di screening,” to Dr. Cucca) from Ministero dell’Istruzione, dell’Università e della Ricerca; grants (HG005581, HG005552, HG006513, and HG007022, to Dr. Abecasis) from the National Human Genome Research Institute; a grant (9-2011-253, to Dr. Todd) from JDRF; a grant (091157, to Dr. Todd) from the Wellcome Trust; a grant (to Dr. Todd) from the National Institute for Health Research (NIHR); and the NIHR Cambridge Biomedical Research Centre. Dr. Idda was a recipient of a Master and Back fellowship from the Autonomous Region of Sardinia