Cardiovascular risk assessment in Portugal's primary health care system: SCORE vs. SCORE2.

INTRODUCTION AND OBJECTIVES: The 2021 European Society of Cardiology guidelines on cardiovascular disease (CVD) prevention introduced the more accurate SCORE2 risk model as a replacement for the earlier SCORE, which is still used in primary care software in Portugal. Our objective is to determine whether the difference between risk assessment using SCORE and SCORE2, in the same patient population, is statistically significant. METHODS: A total of 1642 patients aged 40-65 without previous CVD, from the medical records of two Family Health Units, were included in this cross-sectional study. SCORE and SCORE2 were calculated using the variables gender, age, smoking status, lipid profile and systolic blood pressure. A statistical analysis was performed on the results. RESULTS: Using SCORE, 98% of the patients were in the low-moderate risk categories and 2% in the high or very high risk categories. When using SCORE2, the corresponding percentages were 55% and 45%, respectively. Reclassification with SCORE2 into higher categories was more often observed in younger (under 50 years of age) and male patients. With SCORE, 38.61% of patients were within the LDL-C target range; this figure fell to 20.28% with SCORE2. These differences are statistically significant (p<0.0001). CONCLUSION: Our findings show that a significant number of patients in this cohort who were classified through SCORE at lower risk levels were reclassified into higher risk categories with SCORE2. Similarly, the number of patients within the LDL-C target range for LDL-C was also lower using SCORE2.

Use of Monoterpenes as Potential Therapeutics in Diabetes Mellitus: A Prospective Review.

Monoterpenes are secondary metabolites of plants belonging to the terpenoid class of natural products. They are the most abundant components of essential oils that are generally considered to have various pharmacological properties. These compounds are reported to have antidiabetic effects in recent years. Due to nature's complex biosynthetic machinery, they also exhibit a reasonable degree of structural complexity/diversity for further analysis in structure-activity studies. Therefore, monoterpenes as antidiabetic agents have been investigated by recent in vitro and in vivo studies extensively reported in the scientific literature and claimed by patent documents. The purpose of this survey is to provide a comprehensive and prospective review concerning the potential applications of monoterpenes in the treatment of diabetes. The data for this research were collected through the specialized databases PubMed, Scopus, Web of Science, and ScienceDirect between the years 2014 and 2022, as well as the patent databases EPO, WIPO, and USPTO. The research used 76 articles published in the leading journals in the field. The main effect observed was the antidiabetic activity of monoterpenes. This review showed that monoterpenes can be considered promising agents for prevention and/or treatment of diabetes as well as have a marked pharmaceutical potential for the development of bioproducts for therapeutics applications.

Reciprocal regulation between the molecular clock and kidney injury.

Tubulointerstitial fibrosis is the common pathological substrate for many etiologies leading to chronic kidney disease. Although perturbations in the circadian rhythm have been associated with renal disease, the role of the molecular clock in the pathogenesis of fibrosis remains incompletely understood. We investigated the relationship between the molecular clock and renal damage in experimental models of injury and fibrosis (unilateral ureteral obstruction, folic acid, and adenine nephrotoxicity), using genetically modified mice with selective deficiencies of the clock components Bmal1, Clock, and Cry We found that the molecular clock pathway was enriched in damaged tubular epithelial cells with marked metabolic alterations. In human tubular epithelial cells, TGFß significantly altered the expression of clock components. Although Clock played a role in the macrophage-mediated inflammatory response, the combined absence of Cry1 and Cry2 was critical for the recruitment of neutrophils, correlating with a worsening of fibrosis and with a major shift in the expression of metabolism-related genes. These results support that renal damage disrupts the kidney peripheral molecular clock, which in turn promotes metabolic derangement linked to inflammatory and fibrotic responses.

The impact of the COVID-19 pandemic on airlines' passenger satisfaction.

This study aims to understand airline passengers' satisfaction trends by analyzing the most influential factors on satisfaction before and during the COVID-19 pandemic. The sample consists of a dataset with 9745 passenger reviews published on airlinequality.com. The reviews were analyzed with a sentiment analysis tool calibrated for the aviation industry for accuracy. Machine learning algorithms were then implemented to predict review sentiment based on airline company, travelers' type and class, and country of origin. Findings show passengers were unhappy before the pandemic, aggravated after the COVID-19 outbreak. The staff's behavior is the main factor influencing passengers' satisfaction. Predictive modeling showed that it is possible to predict negative review sentiments with satisfactory performance rather than positive reviews. The main takeaway is that passengers, after the pandemic, are most worried about refunds and aircraft cabin cleanliness. From a managerial standpoint, airline companies can benefit from the created knowledge to adjust their strategies in agreement and meet their customers' expectations.

Pharmacokinetic and toxicological prediction of the chemical constituents of the essential oil of the leaves of Croton heliotropiifolius Kunth.

The development of new drugs through studies of candidate molecules is a complex undertaking; however, computational or in silico approaches aimed at optimizing molecules with greater development potential are being utilized for predictions of pharmacokinetic properties such as absorption, distribution, metabolism and excretion (ADME) as well as toxicological parameters. The objective of this study was to examine in silico and in vivo pharmacokinetic and toxicological properties of the chemical constituents present in the essential oil of Croton heliotropiifolius Kunth leaves. The following Pubchem platform as well as Software SwissADME and PreADMET software were employed for in silico studies while micronucleus (MN) testing for in vivo determination of mutagenicity, using Swiss adult male Mus musculus mice. In silico findings demonstrated that all chemical constituents presented (1) high oral absorption (2) medium cellular permeability and (3) high blood brain permeability. As for toxicity, these chemical constituents exhibited low to medium risk of occurrence of cytotoxicity. Regarding in vivo evaluation, peripheral blood samples obtained from animals tested with the oil showed no significant differences in number of MN compared to negative controls. Data indicate that further investigations are necessary to corroborate the findings of this study. Our data suggest that essential oil extracted from Croton heliotropiifolius Kunth leaves may serve as a candidate for new drug development.

Utility of CYP2D6 copy number variants as prognostic biomarker in localized anal squamous cell carcinoma.

BACKGROUND: Anal squamous cell carcinoma (ASCC) is an infrequent tumor whose treatment has not changed since the 1970s. The aim of this study is the identification of biomarkers allowing personalized treatments and improvement of therapeutic outcomes. METHODS: Forty-six paraffin tumor samples from ASCC patients were analyzed by whole-exome sequencing. Copy number variants (CNVs) were identified and their relation to disease-free survival (DFS) was studied and validated in an independent retrospective cohort of 101 ASCC patients from the Multidisciplinary Spanish Digestive Cancer Group (GEMCAD). GEMCAD cohort proteomics allowed assessing the biological features of these tumors. RESULTS: On the discovery cohort, the median age was 61 years old, 50% were males, stages I/II/III: 3 (7%)/16 (35%)/27 (58%), respectively, median DFS was 33 months, and overall survival was 45 months. Twenty-nine genes whose duplication was related to DFS were identified. The most representative was duplications of the CYP2D locus, including CYP2D6, CYP2D7P, and CYP2D8P genes. Patients with CYP2D6 CNV had worse DFS at 5 years than those with two CYP2D6 copies (21% vs. 84%; p < .0002, hazard ratio [HR], 5.8; 95% confidence interval [CI], 2.7-24.9). In the GEMCAD validation cohort, patients with CYP2D6 CNV also had worse DFS at 5 years (56% vs. 87%; p = .02, HR = 3.6; 95% CI, 1.1-5.7). Mitochondria and mitochondrial cell-cycle proteins were overexpressed in patients with CYP2D6 CNV. CONCLUSIONS: Tumor CYP2D6 CNV identified patients with a significantly worse DFS at 5 years among localized ASCC patients treated with 5-fluorouracil, mitomycin C, and radiotherapy. Proteomics pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets for these high-risk patients. PLAIN LANGUAGE SUMMARY: Anal squamous cell carcinoma is an infrequent tumor whose treatment has not been changed since the 1970s. However, disease-free survival in late staged tumors is between 40% and 70%. The presence of an alteration in the number of copies of CYP2D6 gene is a biomarker of worse disease-free survival. The analysis of the proteins in these high-risk patients pointed out mitochondria and mitochondrial cell-cycle genes as possible therapeutic targets. Therefore, the determination of the number of copies of CYP2D6 allows the identification of anal squamous carcinoma patients with a high-risk of relapse that could be redirected to a clinical trial. Additionally, this study may be useful to suggest new treatment strategies to increase current therapy efficacy.

Radiation Damage in Biomolecules and Cells 2.0.

It is well known that ionizing radiation, when it hits living cells, causes a plethora of different damage types at different levels [...].

A Mission to Mars: Prediction of GCR Doses and Comparison with Astronaut Dose Limits.

Long-term human space missions such as a future journey to Mars could be characterized by several hazards, among which radiation is one the highest-priority problems for astronaut health. In this work, exploiting a pre-existing interface between the BIANCA biophysical model and the FLUKA Monte Carlo transport code, a study was performed to calculate astronaut absorbed doses and equivalent doses following GCR exposure under different shielding conditions. More specifically, the interface with BIANCA allowed us to calculate both the RBE for cell survival, which is related to non-cancer effects, and that for chromosome aberrations, related to the induction of stochastic effects, including cancer. The results were then compared with cancer and non-cancer astronaut dose limits. Concerning the stochastic effects, the equivalent doses calculated by multiplying the absorbed dose by the RBE for chromosome aberrations ("high-dose method") were similar to those calculated using the Q-values recommended by ICRP. For a 650-day mission at solar minimum (representative of a possible Mars mission scenario), the obtained values are always lower than the career limit recommended by ICRP (1 Sv), but higher than the limit of 600 mSv recently adopted by NASA. The comparison with the JAXA limits is more complex, since they are age and sex dependent. Concerning the deterministic limits, even for a 650-day mission at solar minimum, the values obtained by multiplying the absorbed dose by the RBE for cell survival are largely below the limits established by the various space agencies. Following this work, BIANCA, interfaced with an MC transport code such as FLUKA, can now predict RBE values for cell death and chromosome aberrations following GCR exposure. More generally, both at solar minimum and at solar maximum, shielding of 10 g/cm2 Al seems to be a better choice than 20 g/cm2 for astronaut protection against GCR.

Sorting Transcriptomics Immune Information from Tumor Molecular Features Allows Prediction of Response to Anti-PD1 Therapy in Patients with Advanced Melanoma.

Immunotherapy based on anti-PD1 antibodies has improved the outcome of advanced melanoma. However, prediction of response to immunotherapy remains an unmet need in the field. Tumor PD-L1 expression, mutational burden, gene profiles and microbiome profiles have been proposed as potential markers but are not used in clinical practice. Probabilistic graphical models and classificatory algorithms were used to classify melanoma tumor samples from a TCGA cohort. A cohort of patients with advanced melanoma treated with PD-1 inhibitors was also analyzed. We established that gene expression data can be grouped in two different layers of information: immune and molecular. In the TCGA, the molecular classification provided information on processes such as epidermis development and keratinization, melanogenesis, and extracellular space and membrane. The immune layer classification was able to distinguish between responders and non-responders to immunotherapy in an independent series of patients with advanced melanoma treated with PD-1 inhibitors. We established that the immune information is independent than molecular features of the tumors in melanoma TCGA cohort, and an immune classification of these tumors was established. This immune classification was capable to determine what patients are going to respond to immunotherapy in a new cohort of patients with advanced melanoma treated with PD-1 inhibitors Therefore, this immune signature could be useful to the clinicians to identify those patients who will respond to immunotherapy.

Computational investigation of the alkaloids of Pilocarpus microphyllus species as phytopharmaceuticals for the inhibition of sterol 14α-demethylase protease of Trypanosoma cruzi.

Trypanosoma cruzi is a protozoan transmitted by the insect Triatoma infestans, popularly known as kissing bug. This protozoan causes the Chagas disease, a Neglected Tropical Disease. This study aimed to investigate, through DFT method and B3LYP hybrid functional, the physicochemical, pharmacokinetic, and pharmacodynamic properties of the alkaloids present in the leaves of the species Pilocarpus microphyllus (jaborandi) as a potential inhibitory activity on the protease sterol 14α-demethylase of T. cruzi associated with the techniques of molecular docking, molecular dynamics, MM-PBSA and ADMET predictions. The molecules of isopilosine, epiisopiloturine, epiisopilosine, and pilosine showed up the lowest binding energies by molecular docking, good human intestinal absorption, low penetration in the blood-brain barrier, antiprotozoal and anticarcinogenic activities in ADMET studies. It has been observed a better binding affinity of the sterol 14α-demethylase protease with isopilosine in molecular dynamics and MM-PBSA studies, which indicates it as a potential drug candidate for Chagas disease.Communicated by Ramaswamy H. Sarma.

Evaluation of the Effects of Gamma Radiation Sterilization on Rhein-Loaded Biodegradable Microparticles for the Treatment of Osteoarthritis.

In previous work, we reported on the design of biodegradable rhein-loaded PLGA microparticles for the treatment of osteoarthritis. Considering that a formulation designed for intra-articular administration must meet sterility requirements to guarantee its safety, in this study the effect of gamma radiation sterilization on these microparticles was evaluated. The size, morphology, and surface characteristics of the microparticles and the encapsulation efficiency of rhein were not affected by the sterilization process. Although DSC and PXRD analyses suggested otherwise, rhein release profiles were not altered by gamma radiation. The release of rhein from the microparticles was fitted to a Gompertz model. In conclusion, the results of this study suggest that gamma radiation is a suitable method for the sterilization of rhein-loaded PLGA microparticles to enable their intra-articular administration in order to provide a therapeutic solution to patients suffering from chronic joint diseases.

AmericasNLI: Machine translation and natural language inference systems for Indigenous languages of the Americas.

Little attention has been paid to the development of human language technology for truly low-resource languages-i.e., languages with limited amounts of digitally available text data, such as Indigenous languages. However, it has been shown that pretrained multilingual models are able to perform crosslingual transfer in a zero-shot setting even for low-resource languages which are unseen during pretraining. Yet, prior work evaluating performance on unseen languages has largely been limited to shallow token-level tasks. It remains unclear if zero-shot learning of deeper semantic tasks is possible for unseen languages. To explore this question, we present AmericasNLI, a natural language inference dataset covering 10 Indigenous languages of the Americas. We conduct experiments with pretrained models, exploring zero-shot learning in combination with model adaptation. Furthermore, as AmericasNLI is a multiway parallel dataset, we use it to benchmark the performance of different machine translation models for those languages. Finally, using a standard transformer model, we explore translation-based approaches for natural language inference. We find that the zero-shot performance of pretrained models without adaptation is poor for all languages in AmericasNLI, but model adaptation via continued pretraining results in improvements. All machine translation models are rather weak, but, surprisingly, translation-based approaches to natural language inference outperform all other models on that task.

High frequency of CD8 escape mutations in elite controllers as new obstacle for HIV cure.

Accumulation of mutations in epitopes of cytolytic-T-lymphocytes immune response (CTL) in HIV-reservoir seems to be one of the reasons for shock-and-kill strategy failure. Ten non-controller patients on successful cART (TX) and seven elite controllers (EC) were included. HIV-Gag gene from purified resting memory CD4+ T-cells was sequenced by Next-Generation-Sequencing. HLA class-I alleles were typed to predict optimal HIV-Gag CTL epitopes. For each subject, the frequency of mutated epitopes in the HIV-Gag gene, the proportion of them considered as CTL-escape variants as well as their effect on antigen recognition by HLA were assessed. The proportion (%) of mutated HIV-Gag CTL epitopes in the reservoir was high and similar in EC and TX (86%[50-100] and 57%[48-82] respectively, p=0.315). Many of them were predicted to negatively impact antigen recognition. Moreover, the proportion of mutated epitopes considered to be CTL-escape variants was also similar in TX and EC (77%[49-92] vs. 50%[33-75] respectively, p=0.117). Thus, the most relevant finding of our study was the high and similar proportions of HIV-Gag CTL-escape mutations in the reservoir of both HIV-noncontroller patients with cART (TX) and patients with spontaneous HIV-control (EC). Our findings suggest that escape mutations of CTL-response may be another obstacle to eliminate the HIV reservoir and constitute a proof of concept that challenges HIV cure strategies focused on the reactivation of reservoirs. Due to the small sample size that could impact the robustness of the study, further studies with larger cohorts of elite controller patients are needed to confirm these results.

Circulating tumor DNA tracking in patients with pancreatic cancer using next-generation sequencing / Evaluación de DNA circulante tumoral en paciente con Cáncer de páncreas empleando secuenciación de nueva generación

Background: Pancreatic cancer remains one of the most devastating malignancies due to the absence of techniques for early diagnosis and the lack of target therapeutic options for advanced disease. Next Generation Sequencing (NGS) generates high throughput and valuable genetic information when evaluating circulating tumor DNA (ctDNA); however clinical utility of liquid biopsy in pancreatic cancer has not been demonstrated yet. The aim of this study was to evaluate whether results from a Next Generation Sequencing panel on plasma samples from pancreatic cancer patients could have a clinical significance. Methods: From December 2016 to January 2020, plasma samples from 27 patients with pancreatic ductal adenocarcinoma at two different tertiary Spanish Hospitals underwent ctDNA testing using a commercial NGS panel of 65 genes. Clinical data were available for these patients. VarsSome Clinical software was used to analyse NGS data and establish pathogenicity. Results: Evaluable NGS results were obtained in 18 out of the 27 plasma samples. Somatic pathogenic mutations were found mainly in KRAS, BRCA2, FLT3 and HNF1A, genes. Pathogenic mutations were detected in 50% of plasma samples from patient diagnosed at stages III-IV samples. FLT3 mutations were observed in 22.22% of samples which constitute a novel result in the field. Conclusions: Liquid biopsy using NGS is a valuable tool but still not sensitive or specific enough to provide clinical utility in pancreatic cancer patients.(AU)

Introducción: El cáncer de páncreas es uno de los cánceres más devastadores debido a la falta de métodos que permitan un diagnóstico temprano y la ausencia de opciones terapéuticas en enfermedad avanzada. La técnica de secuenciación de nueva generación o Next Generation Sequencing (NGS) proporciona importantes resultados de alto rendimiento de información genética en muestras de DNA circulante tumoral (ctDNA); sin embargo, la utilidad clínica de la biopsia líquida en cáncer de páncreas no ha sido demostrado todavía. El objetivo de este estudio fue evaluar si los resultados de un panel de secuenciación de nueva generación en muestras de plasma de pacientes con cáncer de páncreas podría tener un significado clínico. Métodos: Empleando un panel comercial de NGS con 65 genes se evaluaron 27 muestras de plasma de pacientes con cáncer de páncreas recogidas entre diciembre del 2016 y enero del 2020 en 2 hospitales españoles. En el estudio se disponía de datos clínicos correspondientes a los pacientes. Se empleó el software VarSome Clinical para analizar resultados y establecer patogenicidad de las variantes. Resultados: Se obtuvieron resultados evaluables en 18 de las 27 muestras de plasma. Se encontraron mutaciones patogénicas en los genes KRAS, BRCA2, FLT3 y HNF1A. El 50% de los pacientes diagnosticados en estadios ii-iv presentaron alteraciones patogénicas en plasma. Se observaron mutaciones en FLT3 en el 22,22% de las muestras, lo cual es un resultado novedoso. Conclusiones: La NGS en biopsia líquida es una herramienta valiosa pero todavía no sensible ni específica para proporcionar utilidad clínica en pacientes con cáncer de páncreas.(AU)

Antiviral potential of diminazene aceturate against SARS-CoV-2 proteases using computational and in vitro approaches.

Diminazene aceturate (DIZE), an antiparasitic, is an ACE2 activator, and studies show that activators of this enzyme may be beneficial for COVID-19, disease caused by SARS-CoV-2. Thus, the objective was to evaluate the in silico and in vitro affinity of diminazene aceturate against molecular targets of SARS-CoV-2. 3D structures from DIZE and the proteases from SARS-CoV-2, obtained through the Protein Data Bank and Drug Database (Drubank), and processed in computer programs like AutodockTools, LigPlot, Pymol for molecular docking and visualization and GROMACS was used to perform molecular dynamics. The results demonstrate that DIZE could interact with all tested targets, and the best binding energies were obtained from the interaction of Protein S (closed conformation -7.87 kcal/mol) and Mpro (-6.23 kcal/mol), indicating that it can act both by preventing entry and viral replication. The results of molecular dynamics demonstrate that DIZE was able to promote a change in stability at the cleavage sites between S1 and S2, which could prevent binding to ACE2 and fusion with the membrane. In addition, in vitro tests confirm the in silico results showing that DIZE could inhibit the binding between the spike receptor-binding domain protein and ACE2, which could promote a reduction in the virus infection. However, tests in other experimental models with in vivo approaches are needed.

Assessment of fire resilience in subtropical wetlands using high spatial resolution images.

Resilience is the ability of a system to absorb disturbances, rearrange itself, and adapt in order to maintain its functionality, structure, identity, and feedback. Research involving fire resilience in subtropical wetlands (SW) allows us to understand the dynamics of these ecosystems, measure impacts on fauna and flora, and promote policies for the management and protection. The aim of the present study is to assess the fire resilience of SW. The study was divided into three steps: (i) burned area classification, (ii) vegetation pattern classification, and (iii) temporal analysis of SW fire resilience based on NDVI calculation. Our results show that (a) high resilience potential of emerging plants, which developed green leaves in less than 90 days after the fire; (b) poor recovery of peatlands with underground fire history. Daily coverage of high spatial resolution PlanetScope images has great potential for classification and monitoring of land use in areas where there are rapid changes, such as after a fire event, explosions, and dam ruptures with ore tailings, for example.

First application of the BIANCA biophysical model to carbon-ion patient cases.

Objective.The main objective of this work consists of applying, for the first time, the BIANCA (BIophysical ANalysis of Cell death and chromosome Aberrations) biophysical model to the RBE calculation for C-ion cancer patients, and comparing the outcomes with those obtained by the LEM I model, which is applied in clinics. Indeed, the continuous development of heavy-ion cancer therapy requires modelling of biological effects of ion beams on tumours and normal tissues. The relative biological effectiveness (RBE) of heavy ions is higher than that of protons, with a significant variation along the beam path. Therefore, it requires a precise modelling, especially for the pencil-beam scanning technique. Currently, two radiobiological models, LEM I and MKM, are in use for heavy ions in scanned pencil-beam facilities.Approach.Utilizing an interface with the FLUKA Particle Therapy Tool, BIANCA was applied to re-calculate the RBE-weighted dose distribution for carbon-ion treatment of three patients (chordoma, head-and-neck and prostate) previously irradiated at CNAO, where radiobiological optimization was based on LEM I. The predictions obtained by BIANCA were based either on chordoma cell survival (RBEsurv), or on dicentric aberrations in peripheral blood lymphocytes (RBEab), which are indicators of late normal tissue damage, including secondary tumours. The simulation outcomes were then compared with those provided by LEM I.Main results.While in the target and in the entrance channel BIANCA predictions were lower than those obtained by LEM I, the two models provided very similar results in the considered OAR. The observed differences betweenRBEsurvandRBEab(which were also dependent on fractional dose and LET) suggest that in normal tissues the information on cell survival should be integrated by information more closely related to the induction of late damage, such as chromosome aberrations.Significance.This work showed that BIANCA is suitable for treatment plan optimization in ion-beam therapy, especially considering that it can predict both cell survival and chromosome aberrations and has previously shown good agreement with carbon-ion experimental data.

Antileishmanial activity of Riparin structural analogs of Aniba riparia: Biological evaluation, in silico Adme-Tox, and molecular docking.

We performed a biological evaluation of antileishmanial activity, in silico ADME-Tox profile, and molecular docking of riparins A-F. The antileishmanial activity was evaluated in Leishmania major promastigotes, whereas the cytotoxic activity was tested on murine macrophages. Computational parameters were predicted by in silico analysis. Molecular docking was performed with 18 L. major molecular targets. Riparins, especially RipC and RipE, showed cytotoxic activity in vitro toward L. major promastigotes and a high selectivity index. Riparins showed small differences in their physicochemical properties, such as polarity and aqueous solubility. LogP was an important parameter for the differences in the antileishmanial activity between the molecules. In molecular docking, the ligands displayed Ki < 1 µM for LmNMT and LmLEI. Significant molecular interactions were observed with residues from the active site and adjacent regions of such enzymes. Thus, riparins have the potential for application in antileishmanial therapy.

Kidney microRNA Expression Pattern in Type 2 Diabetic Nephropathy in BTBR Ob/Ob Mice.

Diabetic nephropathy (DN) is the main leading cause of chronic kidney disease worldwide. Although remarkable therapeutic advances have been made during the last few years, there still exists a high residual risk of disease progression to end-stage renal failure. To further understand the pathogenesis of tissue injury in this disease, by means of the Next-Generation Sequencing, we have studied the microRNA (miRNA) differential expression pattern in kidneys of Black and Tan Brachyury (BTBR) ob/ob (leptin deficiency mutation) mouse. This experimental model of type 2 diabetes and obesity recapitulates the key histopathological features described in advanced human DN and therefore can provide potential useful translational information. The miRNA-seq analysis, performed in the renal cortex of 22-week-old BTBR ob/ob mice, pointed out a set of 99 miRNAs significantly increased compared to non-diabetic, non-obese control mice of the same age, whereas no miRNAs were significantly decreased. Among them, miR-802, miR-34a, miR-132, miR-101a, and mir-379 were the most upregulated ones in diabetic kidneys. The in silico prediction of potential targets for the 99 miRNAs highlighted inflammatory and immune processes, as the most relevant pathways, emphasizing the importance of inflammation in the pathogenesis of kidney damage associated to diabetes. Other identified top canonical pathways were adipogenesis (related with ectopic fatty accumulation), necroptosis (an inflammatory and regulated form of cell death), and epithelial-to-mesenchymal transition, the latter supporting the importance of tubular cell phenotype changes in the pathogenesis of DN. These findings could facilitate a better understanding of this complex disease and potentially open new avenues for the design of novel therapeutic approaches to DN.

Radiobiological damage by space radiation: extension of the BIANCA model to heavy ions up to iron, and pilot application to cosmic ray exposure.

Space research seems to be object of a renewed interest, also considering that human missions to the Moon, and possibly Mars, are being planned. Among the risks affecting such missions, astronauts' exposure to space radiation is a major concern. In this work, the question of the evaluation of biological damage by Galactic Cosmic Rays (GCR) was addressed by a biophysical model called BIophysical ANalysis of Cell death and chromosome Aberrations (BIANCA), which simulates the induction of cell death and chromosome aberrations by different ions. While previously BIANCA has been validated for calculating cell death along hadrontherapy beams up to oxygen, herein the approach was extended up to Fe ions. Specifically, experimental survival curves available in literature for V79 cells irradiated by Si-, Ne-, Ar- and Fe-ions were reproduced, and a reference radiobiological database describing V79 cell survival as a function of ion type (1 ⩽Z⩽ 26), energy and dose was constructed. Analogous databases were generated for Chinese hamster ovary hamster cells and human skin fibroblasts, finding good agreement between simulations and data. Concerning chromosome aberrations, which are regarded as radiation risk biomarkers, dicentric data in human lymphocytes irradiated by heavy ions up to iron were reproduced, and a radiobiological database allowing calculation of lymphocyte dicentric yields as a function of dose, ion type (1 ⩽Z⩽ 26) and energy was constructed. Following interface between BIANCA and the FLUKA Monte Carlo transport code, a feasibility study was performed to calculate the relative biological effectiveness (RBE) of different GCR spectrum components, for both dicentrics and cell death. Fe-ions, although representing only 10% of the total absorbed dose, were found to be responsible for about 35%-40% of the RBE-weighted dose. Interestingly, the RBE for dicentrics was higher than that for cell survival. More generally, this work shows that BIANCA can calculate RBE values for cell death and lymphocyte dicentrics not only for ion therapy, but also for space radiation.