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Supplementary Fig. S3 shows that mevalonate and estradiol prevent simvastatin inhibitory effects.

Supplementary Fig. S4 shows the apoptotic mechanism activated by statins in ACC cells

Supplementary Fig. S1 shows that statins affect ACC cell viability

Supplementary methods

Supplementary Fig. S2 shows Immunohistochemical staining of H295R xenograft samples.

S-adenosyl-L-methionine (SAM) is a coenzyme and the most commonly used methyl-group donor for the modification of metabolites, DNA, RNA and proteins. SAM biosynthesis and SAM regeneration from the methylation reaction product S-adenosyl-L-homocysteine (SAH) take place in the cytoplasm. Therefore, the intramitochondrial SAM-dependent methyltransferases require the import of SAM and export of SAH for recycling. Orthologous mitochondrial transporters belonging to the mitochondrial carrier family have been identified to catalyze this antiport transport step: Sam5p in yeast, SLC25A26 (SAMC) in humans, and SAMC1-2 in plants. In mitochondria SAM is used by a vast number of enzymes implicated in the following processes: the regulation of replication, transcription, translation, and enzymatic activities; the maturation and assembly of mitochondrial tRNAs, ribosomes and protein complexes; and the biosynthesis of cofactors, such as ubiquinone, lipoate, and molybdopterin. Mutations in SLC25A26 and mitochondrial SAM-dependent enzymes have been found to cause human diseases, which emphasizes the physiological importance of these proteins.

Mitochondrial carriers (MCs) belong to a eukaryotic protein family of transporters that in higher organisms is called the solute carrier family 25 (SLC25). All MCs have characteristic triplicated sequence repeats forming a 3-fold symmetrical structure of a six-transmembrane α-helix bundle with a centrally located substrate-binding site. Biochemical characterization has shown that MCs altogether transport a wide variety of substrates but can be divided into subfamilies, each transporting a few specific substrates. We have investigated the intron positions in the human MC genes and their orthologs of highly diversified organisms. The results demonstrate that several intron positions are present in numerous MC sequences at the same specific points, of which some are 3-fold symmetry related. Many of these frequent intron positions are also conserved in subfamilies or in groups of subfamilies transporting similar substrates. The analyses of the frequent and conserved intron positions in MCs suggest phylogenetic relationships not only between close but also distant homologs as well as a possible involvement of the intron positions in the evolution of the substrate specificity diversification of the MC family members.

The yeast mitochondrial transport of GTP and GDP is mediated by Ggc1p, a member of the mitochondrial carrier family. The physiological role of Ggc1p in

The human mitochondrial carrier family (MCF) consists of 53 members. Approximately one-fifth of them are still orphans of a function. Most mitochondrial transporters have been functionally characterized by reconstituting the bacterially expressed protein into liposomes and transport assays with radiolabeled compounds. The efficacy of this experimental approach is constrained to the commercial availability of the radiolabeled substrate to be used in the transport assays. A striking example is that of N-acetylglutamate (NAG), an essential regulator of the carbamoyl synthetase I activity and the entire urea cycle. Mammals cannot modulate mitochondrial NAG synthesis but can regulate the levels of NAG in the matrix by exporting it to the cytosol, where it is degraded. The mitochondrial NAG transporter is still unknown. Here, we report the generation of a yeast cell model suitable for identifying the putative mammalian mitochondrial NAG transporter. In yeast, the arginine biosynthesis starts in the mitochondria from NAG which is converted to ornithine that, once transported into cytosol, is metabolized to arginine. The deletion of ARG8 makes yeast cells unable to grow in the absence of arginine since they cannot synthetize ornithine but can still produce NAG. To make yeast cells dependent on a mitochondrial NAG exporter, we moved most of the yeast mitochondrial biosynthetic pathway to the cytosol by expressing four E. coli enzymes, argB-E, able to convert cytosolic NAG to ornithine. Although argB-E rescued the arginine auxotrophy of arg8∆ strain very poorly, the expression of the bacterial NAG synthase (argA), which would mimic the function of a putative NAG transporter increasing the cytosolic levels of NAG, fully rescued the growth defect of arg8∆ strain in the absence of arginine, demonstrating the potential suitability of the model generated.

Background Patients hospitalised for COVID-19 may present with or acquire bacterial or fungal infections that can affect the course of the disease. The aim of this study was to describe the microbiological characteristics of laboratory-confirmed infections in hospitalised patients with severe COVID-19. Methods We reviewed the hospital charts of a sample of patients deceased with COVID-19 from the Italian National COVID-19 Surveillance, who had laboratory-confirmed bacterial or fungal bloodstream infections (BSI) or lower respiratory tract infections (LRTI), evaluating the pathogens responsible for the infections and their antimicrobial susceptibility. Results Among 157 patients with infections hospitalised from February 2020 to April 2021, 28 (17.8%) had co-infections (≤ 48 h from admission) and 138 (87.9%) had secondary infections (> 48 h). Most infections were bacterial; LRTI were more frequent than BSI. The most common co-infection was pneumococcal LRTI. In secondary infections, Enterococci were the most frequently recovered pathogens in BSI (21.7% of patients), followed by Enterobacterales, mainly K. pneumoniae, while LRTI were mostly associated with Gram-negative bacteria, firstly Enterobacterales (27.4% of patients, K. pneumoniae 15.3%), followed by A. baumannii (19.1%). Fungal infections, both BSI and LRTI, were mostly due to C. albicans. Antibiotic resistance rates were extremely high in Gram-negative bacteria, with almost all A. baumannii isolates resistant to carbapenems (95.5%), and K. pneumoniae and P. aeruginosa showing carbapenem resistance rates of 59.5% and 34.6%, respectively. Conclusions In hospitalised patients with severe COVID-19, secondary infections are considerably more common than co-infections, and are mostly due to Gram-negative bacterial pathogens showing a very high rate of antibiotic resistance.

Robots operating with humans in highly dynamic environments need not only

In the past decade, hydrophilic interaction liquid chromatography (HILIC) has emerged as an efficient alternative to reversed-phase chromatography (RPC) for the analysis of phospholipid (PL) mixtures based on mass spectrometric detection. Since the separation of PL by HILIC is chiefly based on their headgroup, the mass spectrum of each class can be obtained by spectral averaging under the corresponding HILIC band. Using experimental m/z values resulting from high mass resolution/accuracy instruments, the sum compositions of PL in a specific class can be thus inferred but partial overlapping may occur between signals related to the M + 0 isotopologue of one species and the M + 2/M + 4 isotopologues of species having one/two more C═C bonds in their chemical structures. Here, an automated workflow, named LIPIC (lipid isotopic pattern interference correction), is proposed to account for such interferences. Starting from the experimentally verified assumption that peaks in isotope patterns are Gaussian, LIPIC predicts, as a function of m/z ratio, signal intensities due to M + 2 and M + 4 isotopologues of species with one or two more C = C bonds than the target one and calculates the corrected intensity for the M + 0 isotopologue of the latter. Thanks to an iterative procedure, the suggested algorithm compensates also for slight shifts occurring between experimental and theoretical m/z ratios related to isotopologue peaks. Examples of applications to simulated and experimental mass spectra of two PL classes, i.e., phosphatidylcholines (PC) and cardiolipins (CL), emphasize the increased extent of correction at the increase of molecular masses of involved species.

Background and aims Low potassium intake, in addition to high sodium, has been associated with higher risk of hypertension and CVD. The Study assessed habitual potassium intake and sodium/potassium ratio of the Italian adult population from 2008 to 2012 to 2018–2019 based on 24-h urine collection, in the framework of the CUORE Project/MINISAL-GIRCSI/MENO SALE PIU’ SALUTE national surveys. Methods and results Data were from cross-sectional surveys of randomly selected age-and-sex stratified samples of resident persons aged 35–74 years in 10 (out of 20) Italian regions. Urinary electrolyte and creatinine measurements were performed in a central laboratory. Analyses considered 942 men and 916 women, examined in 2008–2012, and 967 men and 1010 women, examined in 2018–2019. In 2008–2012, the age-standardized mean of potassium intake (urinary potassium accounts for 70% of potassium intake) was 3147 mg (95% CI 3086–3208) in men and 2784 mg (2727–2841) in women, whereas in 2018–2019, it was 3043 mg (2968–3118) and 2561 mg (2508–2614) respectively. In 2008–2012, age-adjusted prevalence of persons with an adequate potassium intake (i.e. ≥ 3510 mg/day) was 31% (95% CI 28–34%) for men and 18% (16–21%) for women; in 2018–2019, it was 26% (23–29%) and 12% (10–14%) respectively. The sodium/potassium ratio significantly decreased both in men and women. Conclusions The average daily potassium intake of the Italian general adult population remains lower than the WHO and EFSA recommended level. These results suggest the need of a revision to strengthen initiatives for the promotion of an adequate potassium intake at the population level.

Limited data are available on the prevalence and correlates of statin use for secondary cardiovascular (CV) prevention in the older adult population. We used data of older adults (65-79 years) with established atherosclerotic CV disease from the cross-sectional Italian Health Examination Survey 2008-2012 to address this issue. Lifestyles, CV risk factors, chronic diseases, and therapies were assessed using standardized procedures. A comprehensive geriatric assessment was performed to evaluate cognitive function, disability in basic activities of daily living/instrumental activities of daily living, mobility, and polypharmacy. Multiple regression analyses were performed to identify independent correlates of statin use. A total of 392 participants (mean age 72.1 ± 4.4 years, 61.5% men) were considered for this analysis. Coronary heart disease was identified in 67.1% of participants, cerebrovascular disease in 23.5%, and peripheral artery disease (PAD) in 18.1%. One hundred ninety (48.5%) were statin users. By multiple regression analysis, functional disability (odds ratio [OR] = 0.81; 95% confidence interval [CI] = 0.71-0.92

In Italy, the last 30 years witnessed the implementation of cross-sectional surveys providing baseline data on numerous risk factors collected from random samples of the adult general population. In order to support those groups who would like to implement an health examination survey (HES), according to the experience of the CUORE Project surveys, the objective of this paper is to describe some information related to the organization of a survey (examination sites and sampling, selection of analytic laboratory, coordination and personnel involved, sample selection, recruitment and appointment scheduling, informative notice and informed consent, participation rate, non-participation bias, quality assurance, survey data, long term storage of the samples, internal quality control, external quality assessment, feedback to participants, error checking, correction and documentation of the data, transfer and storage of the data, statistical analyses and interpretation of results, dissemination of results), usually shortly described in scientific papers but relevant when an HES is planned.

The assessment of data quality and suitability plays an important role in improving the validity and generalisability of the results of studies based on secondary use of health databases. The availability of more and more updated and valid information on data quality and suitability provides data users and researchers an useful tool to optimize their activities. In this paper, we have summarized and synthesized the main aspects of Data Quality Assessment (DQA) applied in the field of secondary use of healthcare databases, with the aim of drawing attention to the critical aspects having to be considered and developed for improving the correct and effective use of secondary sources. Four developing features are identified: standardizing DQA methods, reporting DQA methods and results, synergy between data managers and data users, role of Institutions. Interdisciplinarity, multi-professionality and connection between government institutions, regulatory bodies, universities and the scientific community will provide the "toolbox" for i) developing standardized and shared DQA methods for health databases, ii) defining the best strategies for disseminating DQA information and results.

Vaccines are among the most important public health achievements of the last century; however, vaccine awareness and uptake still face significant challenges and the COVID-19 pandemic has only exacerbated this phenomenon. Vaccine Literacy (VL) is the ability to find, understand and judge immunisation-related information to make appropriate immunisation decisions. A cross-sectional study on a sample of 3500 participants, representative of the Italian adult population aged 18+ years, was conducted in Italy in 2021. A validated questionnaire, including sections on health literacy (HL), sociodemographic characteristics, risk factors, and lifestyles of respondents, was used. VL was measured by four items (item 19, 22, 26 and 29) of the HL section. While 67.6% of the respondents had a “good” (47.5%) or “sufficient” (20.1%) level of VL, 32.4% had “limited” VL levels. Although the overall VL level was quite high, many participants reported difficulties in dealing with vaccination information, particularly those with a lower educational level, those living in southern and insular regions of Italy, those with greater financial deprivation and those with a migration background. Improving VL in Italy should be a top priority in the political agenda, with special regard to socially and geographically disadvantaged communities.

The COVID-19 pandemic has caused an overabundance of valid and invalid information to spread rapidly via traditional media as well as by internet and digital communication. Health literacy (HL) is the ability to access, understand, appraise, and apply health information, making it fundamental for finding, interpreting, and correctly using COVID-19 information. A cross-sectional study of a sample of 3500 participants representative of the Italian adult population aged 18+ years was conducted in Italy in 2021. A validated HL questionnaire was employed, including sections on coronavirus-related HL, general HL, sociodemographic characteristics, risk factors, and respondents’ lifestyle. Of our sample, 49.3% had “excellent” levels of coronavirus-related HL and 50.7% had “sufficient” (20.7%) or “limited” (30.0%) levels. Although the overall HL-COVID level was high, many participants reported difficulties dealing with COVID-19 information; in particular, participants older than 65 years, with a low education level, living in southern regions of Italy, and with high financial deprivation. Targeted public information campaigns and the promotion of HL are required for better navigation of health information environments. The COVID-19 pandemic has highlighted the need to improve HL and to prepare the general population for future emergency and non-emergency situations, confirming that HL can be considered a social vaccine.

Multiple mitochondrial matrix enzymes playing key roles in metabolism require cofactors for their action. Due to the high impermeability of the mitochondrial inner membrane, these cofactors need to be synthesized within the mitochondria or be imported, themselves or one of their precursors, into the organelles. Transporters belonging to the protein family of mitochondrial carriers have been identified to transport the coenzymes: thiamine pyrophosphate, coenzyme A, FAD and NAD

hondrial transporters for basic amino acids and phylogenetically related carriers belonging to the Slc25 family. The inhibitory effect of Pr3+ has been tested using mitochondrial transporters reconstituted into liposomes being effective in the micromolar range, acting as a competitive inhibitor of the human basic amino acids carrier (BAC, Slc25A29), the human carnitine/acylcarnitine carrier (CAC, Slc25A20). Furthermore, we provide computational evidence that the complete inhibition of the transport activity of the recombinant proteins is due to the Pr3+ coordination to key acidic residues of the matrix salt bridge network. Besides being used as a first choice stop inhibitor for functional studies in vitro of mitochondrial carriers reconstituted in proteoliposomes, Pr3+ might also represent a useful tool for structural studies of the mitochondrial carrier family.

Aims An exhaustive and updated estimation of cardiovascular disease burden and vascular risk factors is still lacking in European countries. This study aims to fill this gap assessing the global Italian cardiovascular disease burden and its changes from 1990 to 2017 and comparing the Italian situation with European countries. Methods All accessible data sources from the 2017 Global Burden of Disease study were used to estimate the cardiovascular disease prevalence, mortality and disability-adjusted life years and cardiovascular disease attributable risk factors burden in Italy from 1990 to 2017. Furthermore, we compared the cardiovascular disease burden within the 28 European Union countries. Results Since 1990, we observed a significant decrease of cardiovascular disease burden, particularly in the age-standardised prevalence (–12.7%), mortality rate (–53.8%), and disability-adjusted life years rate (–55.5%). Similar improvements were observed in the majority of European countries. However, we found an increase in all-ages prevalence of cardiovascular diseases from 5.75 m to 7.49 m Italian residents. Cardiovascular diseases still remain the first cause of death (34.8% of total mortality). More than 80% of the cardiovascular disease burden could be attributed to known modifiable risk factors such as high systolic blood pressure, dietary risks, high low density lipoprotein cholesterol, and impaired kidney function. Conclusions Our study shows a decline in cardiovascular mortality and disability-adjusted life years, which reflects the success in reducing disability, premature death and early incidence of cardiovascular diseases. However, the burden of cardiovascular diseases is still high. An approach that includes the cooperation and coordination of all stakeholders of the Italian National Health System is required to further reduce this burden.

With growing numbers of intelligent autonomous systems in human environments, the ability of such systems to perceive, understand and anticipate human behavior becomes increasingly important. Specifically, predicting future positions of dynamic agents and planning considering such predictions are key tasks for self-driving vehicles, service robots and advanced surveillance systems. This paper provides a survey of human motion trajectory prediction. We review, analyze and structure a large selection of work from different communities and propose a taxonomy that categorizes existing methods based on the motion modeling approach and level of contextual information used. We provide an overview of the existing datasets and performance metrics. We discuss limitations of the state of the art and outline directions for further research., Comment: Submitted to the International Journal of Robotics Research (IJRR), 37 pages

Background: To assess the association of antidepressant (AD) medication use with prevalence and control of cardiovascular (CV) risk factors. Methods: Data of older adults from the population-based ...

Robots have been operating in dynamic environments and shared workspaces for decades. Most optimization based motion planning methods, however, do not consider the movement of other agents, e.g. humans or other robots, and therefore do not guarantee collision avoidance in such scenarios. This paper builds upon the Convex Inner ApprOximation (CIAO) method and proposes a motion planning algorithm that guarantees collision avoidance in predictable dynamic environments. Furthermore, it generalizes CIAO’s free region concept to arbitrary norms and proposes a cost function to approximate time optimal motion planning. The proposed method, CIAO*, finds kinodynamically feasible and collision free trajectories for constrained single body robots using model predictive control (MPC). It optimizes the motion of one agent and accounts for the predicted movement of surrounding agents and obstacles. The experimental evaluation shows that CIAO* reaches close to time optimal behavior.

Patient-ventilator asynchronies (PVA) are associated to negative outcomes for patients: increased respiratory work, mechanical ventilation time and ICU length of stay, and mortality. Some studies described the positive impact of a training intervention on the knowledge and attitudes of nurses in detecting PVA. The aim of this study was to evaluate the efficacy of a training intervention focused on detection of PVA.A before-after design on a single group of nursing students was used. The training intervention about detection of the correct respiratory waveform through graphic monitoring was conducted in a single edition course of 2 hours, for 25 participants. Measurements of correct detection of PVA through specific competency assessment tool were performed before (T0), immediately after (T1) and at 1 month (T2) from the training intervention between January and February 2020.19 Nurse students completed the training. A total of 50 questionnaires were distributed (T0; n=19; T1; n=19; T2; n=12). PVA were correctly detected in 67.5% (77) of cases. Statistically significant difference There were differences in trainees performance between T0 and T1 [77,2% (CI95%: 68,7% - 85,8%; p=0.001)] and between T0 and T2 [75% (CI95%: 65,3% - 84,7%; p=0.001]. No significant difference was recorded between T1 and T2 (p=0.83) Conclusions: Nursing students increased their performance on analysis of the graphic monitoring of the respiratory waveforms and detection of asynchronies after a basic training intervention. These skills were retained after 1 month. Nurse student trained about PVA increased their competence potentially employed in critical care settings.

Background Health reporting shall provide up-to-date health-related data to inform policy-makers, researchers and the public. To this end, health reporting formats should be tailored to the needs and competencies of the target groups and provide comparable and high-quality information. Within the Joint Action on Health Information ‘InfAct’, we aimed at gaining an overview of health reporting practices in the EU Member States and associated countries, and developed quality criteria for the preparation of public health reports. The results are intended to facilitate making health information adequately available while reducing inequalities in health reporting across the EU. Methods A web-based desk research was conducted among EU Member States and associated countries to generate an overview of different formats of national health reporting and their respective target groups. To identify possible quality criteria for public health reports, an exploratory literature review was performed and earlier projects were analysed. The final set of criteria was developed in exchange with experts from the InfAct consortium. Results The web-based desk research showed that public health reports are the most frequently used format across countries (94%), most often addressed to scientists and researchers (51%), politicians and decision-makers (41%). However, across all reporting formats, the general public is the most frequently addressed target group. With regards to quality criteria for public health reports, the literature review has yielded few results. Therefore, two earlier projects served as main sources: the ‘Evaluation of National and Regional Public Health Reports’ and the guideline ‘Good Practice in Health Reporting‘from Germany. In collaboration with experts, quality criteria were identified and grouped into eight categories, ranging from topic selection to presentation of results, and compiled in a checklist for easy reference. Conclusion Health reporting practices in the EU are heterogeneous across Member States. The assembled quality criteria are intended to facilitate the preparation, dissemination and access to better comparable high-quality public health reports as a basis for evidence-based decision-making. A comprehensive conceptual and integrative approach that incorporates the policy perspective would be useful to investigate which dissemination strategies are the most suitable for specific requirements of the targeted groups.

ObjectivesTo assess in the Italian general adult population the trends of blood pressure (BP) and prevalence of raised BP (RBP), hypertension and its control in order to evaluate population health and care, and the achievement of an RBP 25% relative reduction as recommended by the WHO at population level.DesignResults comparison of health examination surveys, cross-sectional observational studies based on health examination of randomly selected age and sex stratified samples including residents aged 35–74 years. Data of the 2018/2019 survey were compared with the previous ones collected in 1998/2002 and 2008/2012.SettingHealth examination surveys conducted in Italy within the CUORE Project following standardised methodologies.Participants2985 men and 2955 women examined in 1998/2002, 2218 men and 2204 women examined in 2008/2012 and 1031 men and 1066 women examined in 2018/2019.Primary and secondary outcome measuresAge-standardised mean of BP, prevalence of RBP (systolic BP and/or diastolic BP ≥140/90 mm Hg), hypertension (presenting or being treated for RBP) and its awareness and control, according to sex, age class and educational level.ResultsIn 2018/2019, a significant reduction was observed in systolic BP and diastolic BP in men (1998/2002: 136/86 mm Hg; 2008/2012: 132/84 mm Hg; and 2018/2019: 132/78 mm Hg) and women (132/82 mm Hg, 126/78 mm Hg and 122/73 mm Hg), and in the prevalence of RBP (50%, 40% and 30% in men and 39%, 25% and 16% in women) and of hypertension (54%, 49% and 44% in men and 45%, 35% and 32% in women). Trends were consistent by age and education attainment. In 2018/2019, hypertensive men and women with controlled BP were only 27% and 41%, but a significant favourable trend was observed.ConclusionsData from 2018/2019 underlined that RBP is still commonly observed in the Italian population aged 35–74 years, however, the WHO RBP target at that time may be considered met.

Background/Objectives Obesity is associated with an increased risk of noncommunicable diseases, such as diabetes, coronary heart disease, stroke, cancers, and conditions, including obstructive sleep apnea and osteoarthritis. Obesity is largely preventable, and halting its rise is one of the World Health Organization Global Action Plan for the Prevention of Noncommunicable Diseases targets. This study aimed to assess trends of anthropometric measurements in Italy using the data collected within the CUORE Project health examination surveys (HESs) 1998, 2008, and 2018. Subjects/Methods Within the HESs 1998–2002, 2008–2012, and 2018–2019, anthropometric measurements were collected in random samples of the resident population aged 35–74 years, stratified by age and sex, from 10 Italian Regions in Northern, Central, and Southern Italy (2984 men and 2944 women, 2224 men and 2188 women, 1035 men and 1065 women, respectively). Weight, height, and waist and hip circumferences were measured using standardized methodologies. A standardized questionnaire was used to collect data on education. Indicators were age standardized. Results For both men and women, mean body mass index in 2018 was comparable with those in 1998 and 2008 (in 1998, 2008, and 2018—men: 26.7, 27.5, and 27.0 kg/m2; women: 26.2, 26.6, and 26.3 kg/m2). In 1998, 2008, 2018 prevalence of overweight resulted 49%, 47%, 46% in men and 33%, 32%, 28% in women respectively; prevalence of obesity resulted 17%, 24% 20% in men and 19%, 23%, 23% in women respectively. All indicators of excess weight worsen with increasing age and are more severe in persons with a lower educational level. Conclusions Although the overall trend of excess weight over the past two decades appeared to be substantially stable in the Italian adult population, the continuous strengthening of undertaken initiatives should continue since there remains a high proportion of overweight or obesity and a gap between educational levels.

The yeast mitochondrial transport of GTP and GDP is mediated by Ggc1p, a member of the mitochondrial carrier family. The physiological role of Ggc1p in S. cerevisiae is probably to transport GTP into mitochondria in exchange for GDP generated in the matrix. ggc1Δ cells exhibit lower levels of GTP and increased levels of GDP in mitochondria, are unable to grow on nonfermentable substrates and lose mtDNA. Because in yeast, succinyl-CoA ligase produces ATP instead of GTP, and the mitochondrial nucleoside diphosphate kinase is localized in the intermembrane space, Ggc1p is the only supplier of mitochondrial GTP required for the maturation of proteins containing Fe-S clusters, such as aconitase [4Fe-4S] and ferredoxin [2Fe-2S]. In this work, it was demonstrated that citrate is a regulator of purified and reconstituted Ggc1p by trans-activating unidirectional transport of GTP across the proteoliposomal membrane. It was also shown that the binding site of Ggc1p for citrate is different from the binding site for the substrate GTP. It is proposed that the citrate-induced GTP uniport (CIGU) mediated by Ggc1p is involved in the homeostasis of the guanine nucleotide pool in the mitochondrial matrix.

Background Health indicators are used to monitor the health status and determinants of health of the population and population sub-groups, identify existing or emerging health problems which would require prevention and health promotion activities, help to target health care resources in the most adequate way as well as for evaluation of the success of public health actions both at the national and international level. The quality and validity of the health indicator depends both on available data and used indicator definition. In this study we will evaluate existing knowledge about comparability of different data sources for definition of health indicators, compare how selected health indicators presented in different international databases possibly differ, and finally, present the results from a case study from Finland on comparability of health indicators derived from different data sources at national level. Methods For comparisons, four health indicators were selected that were commonly available in international databases and available for the Finnish case study. These were prevalence of obesity, hypertension, diabetes, and asthma in the adult populations. Our evaluation has three parts: 1) a scoping review of the latest literature, 2) comparison of the prevalences presented in different international databases, and 3) a case study using data from Finland. Results Literature shows that comparability of estimated outcomes for health indicators using different data sources such as self-reported questionnaire data from surveys, measured data from surveys or data from administrative health registers, varies between indicators. Also, the case study from Finland showed that diseases which require regular health care visits such as diabetes, comparability is high while for health outcomes which can remain asymptomatic for a long time such as hypertension, comparability is lower. In different international health related databases, country specific results differ due to variations in the used data sources but also due to differences in indicator definitions. Conclusions Reliable comparison of the health indicators over time and between regions within a country or across the countries requires common indicator definitions, similar data sources and standardized data collection methods.

Background Metabolic syndrome (MetS) is a public health problem in Europe, affecting all age groups. Several MetS definitions are available. The aim of this study was to compare four different MetS definitions in the Finnish adult population, to assess their agreement and to evaluate the impact of the choice of the definition on the prevalence of MetS. Methods Data from FinHealth 2017, a cross-sectional national population health survey, focusing on adults aged 25 years or older were used in the analysis (n=5687). Measured data on anthropometrics, blood pressure and biomarkers together with questionnaire data were used to classify the participants into the MetS categories according to the four definitions. The definitions chosen for the comparison were those by the World Health Organization (WHO) (1998), National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) (2004), International Diabetes Federation (IDF) (2005), and Joint Interim Statement (JIS) (2009). Results The four MetS definitions resulted in substantially different MetS prevalence: 17.7% by WHO, 33.3% by NCEP-ATP III, 41.5% by IDF, and 43.0% by JIS. Regardless of the definition used, the prevalence of MetS increased with age. The prevalence of the different components varied between the definitions, depending on the different cut-off points adopted. Out of all participants, only 13.6% were identified to have MetS according to all four definitions. Agreement between participants recognised by different MetS definitions, estimated through kappa coefficients, was almost perfect for IDF vs. JIS (0.97), strong for JIS vs. NCEP-ATP III (0.80), moderate for IDF vs. NCEP-ATP III (0.76) and weak for WHO vs. NCEP-ATP III (0.42), WHO vs. IDF (0.41) and WHO vs. JIS (0.40). Conclusions Differences between observed prevalence of MetS in Finnish men and women using different MetS definitions were large. For cross-country comparisons, as well as for trend analyses within a country, it is essential to use the same MetS definition to avoid discrepancies in classification due to differences in used definitions.

Mitochondrial citrate carrier plays a central role in exporting acetyl-CoA in the form of citrate from mitochondria to cytosol thereby connecting carbohydrate catabolism and lipogenesis. In this study, Yarrowia lipolytica mitochondrial citrate carrier was functionally defined and characterized. Firstly, deletion of Y. lipolytica YlCTP1 and YlYHM2 genes coding putative tricarboxylate mitochondrial carriers were performed. ΔYlctp1 strain did not differ significantly from wild type strain in terms of growth rate, organic acids and lipid production. In contrast, ΔYlyhm2 strain did not grow in liquid citrate-containing minimal medium. Moreover, in glucose-containing lipogenic medium YlYHM2 null mutant strain did not produce citric acid; the production of isocitric acid and lipids were decreased. Reintroduction of YlYHM2 gene as well as heterologous expression of Aspergillus niger gene AnYHM2 into ΔYlyhm2 strain restored the growth in minimal citrate medium and even enhanced citric acid production by 45% in both variants compared with wild type strain during test tube cultivation. Mitochondrial extracts isolated from YlYHM2 null mutant and wild type strain were incorporated into liposomes; citrate/citrate and α-ketoglutarate/α-ketoglutarate homoexchange activities were reduced by 87% and 40% in ΔYlyhm2 strain, respectively, compared with the wild type, whereas citratein/α-ketoglutarateout and α-ketoglutaratein/citrateout heteroexchanges were decreased by 87% and 95%, respectively. YlYhm2p was expressed in Escherichia coli, purified and reconstituted into liposomes. Besides high efficiency to citrate and α-ketoglutarate transport, YlYhm2p also transported oxaloacetate, succinate, fumarate, and to a much lesser extent, aconitate, malate, isocitrate, oxoadipate, and glutamate. The activity of reconstituted YlYhm2p was inhibited strongly by SH-blocking reagents, pyridoxal-5′-phosphate, and partly by N-ethylmaleimide. Co-expression of YlYHM2 and adenosine monophosphate deaminase YlAMPD genes resulted in the production of 49.7 g/L of citric acid during test tube cultivation, whereas wild type strain accumulated 30.1 g/L of citric acid. Large-scale cultivation in bioreactor of the engineered strain resulted in 97.1 g/L of citric acid production with a process selectivity of 94.2% and an overall citric acid yield of 0.5 g/g. The maximal specific rate of citric acid synthesis was 0.93 g/L/h. Therefore, the physiological role of YlYhm2p in glucose-containing medium is to catalyze both import of citrate into mitochondria for catabolic reactions and export of citrate as a source of acetyl-CoA from mitochondria. Possible shuttles for citrate exporting are discussed. Moreover, for the first time evidence has been given for the improvement of TCA cycle intermediate production by manipulation of a gene coding a mitochondrial carrier.

Background The Italian National Institute of Health (Istituto Superiore di Sanità, ISS) considers health inequalities (HI) an important area of activity. As the scientific and technical body of the Ministry of Health and the National Health Service, ISS may play a key role to reduce HI. In order to enable ISS in addressing the new and crucial HI challenge, a Research Positioning Exercise was designed and implemented. Methods The Exercise included: (i) workshop to strengthen the institutional interest in the field of HI; (ii) review and analysis of ISS publications (years 2000–2017) to identify HI research topics; (iii) survey among ISS researchers regarding main research challenges to address HI in the coming years; and (iv) analysis of input on research challenges from HI international experts. Results The results of this Exercise suggest that the following points should be included in the future ISS agenda planning: (i) themes which ISS should continue working on (e.g. migrants/vulnerable groups); (ii) themes to be improved: (a) relationship between social determinants and mechanism of HI generation and (b) relationship between risk factors exposure and social determinants; and (iii) new themes to be addressed: (a) mechanisms underlying the resilience observed in Italy; (b) new socioeconomic indicators for HI monitoring; and (c) evidence-based policies aimed at reducing HI. Conclusion Findings of this Exercise show that ISS researchers identified relevant areas, addressing inequalities in addressing the health. Because of ISS structural peculiarity that includes multidisciplinary expertise, the ISS could provide a significant contribution to HI research challenges and knowledge gaps.

Mitochondrial carriers, which transport metabolites, nucleotides, and cofactors across the mitochondrial inner membrane, have six transmembrane α-helices enclosing a translocation pore with a central substrate binding site whose access is controlled by a cytoplasmic and a matrix gate (M-gate). The salt bridges formed by the three PX[DE]XX[RK] motifs located on the odd-numbered transmembrane α-helices greatly contribute to closing the M-gate. We have measured the transport rates of cysteine mutants of the charged residue positions in the PX[DE]XX[RK] motifs of the bovine oxoglutarate carrier, the yeast GTP/GDP carrier, and the yeast NAD+ transporter, which all lack one of these charged residues. Most single substitutions, including those of the non-charged and unpaired charged residues, completely inactivated transport. Double mutations of charged pairs showed that all three carriers contain salt bridges non-essential for activity. Two double substitutions of these non-essential charge pairs exhibited higher transport rates than their corresponding single mutants, whereas swapping the charged residues in these positions did not increase activity. The results demonstrate that some of the residues in the charged residue positions of the PX[DE]XX[KR] motifs are important for reasons other than forming salt bridges, probably for playing specific roles related to the substrate interaction-mediated conformational changes leading to the M-gate opening/closing.

AimsTo investigate and compare changes in the rates of ischaemic heart disease (IHD) incidence and mortality between 1990 and 2019 in 20 high-income Western European countries with similar public health systems and low cardiovascular risk.Methods and resultsThe 2020 updated version of the Global Burden of Disease database was searched. Variability and differences in IHD incidence and mortality rates (per 100 000) between countries over time, were calculated. A piecewise linear (join point) regression model was used to identify the slopes of these trends and the points in time at which significant changes in the trends occur. Ischaemic heart disease incidence and mortality rates varied widely between countries but decreased for all between 1990 and 2019. The relative change was greater for mortality than for incidence. Ischaemic heart disease incidence rates declined by approximately 36% between 1990 and 2019, while mortality declined by approximately 60%. Breakpoint analysis showed that the largest decreases in incidence and mortality occurred between 1990 and 2009 (−32%, −52%, respectively), with a much slower decrease after that (−5.9%, −17.6%, respectively), and even a slight increase for some countries in recent years. The decline in both incidence and mortality was lower in the Mediterranean European countries compared to the Nordic and Central European regions.ConclusionsIn the Western European countries studied, the decline in age-standardized IHD incidence over three decades was slower than the decline in age-standardized IHD mortality. Decreasing trends of both IHD incidence and mortality has substantially slowed, and for some countries flattened, in more recent years.

Mitochondrial diseases result from inherited or spontaneous mutations in mitochondrial or nuclear DNA, leading to an impairment of the oxidative phosphorylation responsible for the synthesis of ATP. To date, there are no effective pharmacological therapies for these pathologies. We performed a yeast-based screening to search for therapeutic drugs to be used for treating mitochondrial diseases associated with dominant mutations in the nuclear ANT1 gene, which encodes for the mitochondrial ADP/ATP carrier. Dominant ANT1 mutations are involved in several degenerative mitochondrial pathologies characterized by the presence of multiple deletions or depletion of mitochondrial DNA in tissues of affected patients. Thanks to the presence in yeast of the AAC2 gene, orthologue of human ANT1, a yeast mutant strain carrying the M114P substitution equivalent to adPEO-associated L98P mutation was created. Five molecules were identified for their ability to suppress the defective respiratory growth phenotype of the haploid aac2M114P. Furthermore, these molecules rescued the mtDNA mutability in the heteroallelic AAC2/aac2M114P strain, which mimics the human heterozygous condition of adPEO patients. The drugs were effective in reducing mtDNA instability also in the heteroallelic strain carrying the R96H mutation equivalent to the more severe de novo dominant missense mutation R80H, suggesting a general therapeutic effect on diseases associated with dominant ANT1 mutations.

Understanding and anticipating human activity is an important capability for intelligent systems in mobile robotics, autonomous driving, and video surveillance. While learning from demonstrations with on-site collected trajectory data is a powerful approach to discover recurrent motion patterns, generalization to new environments, where sufficient motion data are not readily available, remains a challenge. In many cases, however, semantic information about the environment is a highly informative cue for the prediction of pedestrian motion or the estimation of collision risks. In this work, we infer occupancy priors of human motion using only semantic environment information as input. To this end we apply and discuss a traditional Inverse Optimal Control approach, and propose a novel one based on Convolutional Neural Networks (CNN) to predict future occupancy maps. Our CNN method produces flexible context-aware occupancy estimations for semantically uniform map regions and generalizes well already with small amounts of training data. Evaluated on synthetic and real-world data, it shows superior results compared to several baselines, marking a qualitative step-up in semantic environment assessment., Comment: 8 pages, final pre-print version of the IEEE RA-L letter

Background: In Italy, during the first epidemic wave of 2020, the peak of coronavirus disease 2019 (COVID-19) mortality was reached at the end of March. Afterward, a progressive reduction was observed until much lower figures were reached during the summer, resulting from the contained circulation of SARS-CoV-2. This study aimed to determine if and how the pathological patterns of the individuals deceased from COVID-19 changed during the phases of epidemic waves in terms of: (i) main cause of death, (ii) comorbidities, and (iii) complications related to death.Methods: Death certificates of persons who died and tested positive for SARS-CoV-2, provided by the National Surveillance system, were coded according to ICD rev10. Deaths due to COVID-19 were defined as those in which COVID-19 was the underlying cause of death.Results: The percentage of COVID-19 deaths varied over time. It decreased in the downward phase of the epidemic curve (76.6 vs. 88.7%). In February–April 2020, hypertensive heart disease was mentioned as a comorbidity in 18.5% of death certificates, followed by diabetes (15.9% of cases), ischemic heart disease (13.1%), and neoplasms (12.1%). In May–September, the most frequent comorbidity was neoplasms (17.3% of cases), followed by hypertensive heart disease (14.9%), diabetes (14.8%), and dementia/Alzheimer's disease (11.9%). The most mentioned complications in both periods were pneumonia and respiratory failure with a frequency far higher than any other condition (78.4% in February–April 2020 and 63.7% in May–September 2020).Discussion: The age of patients dying from COVID-19 and their disease burden increased in the May–September 2020 period. A more serious disease burden was observed in this period, with a significantly higher frequency of chronic pathologies. Our study suggests better control of the virus' lethality in the second phase of the epidemic, when the health system was less burdened. Moreover, COVID-19 care protocols had been created in hospitals, and knowledge about the diagnosis and treatment of COVID-19 had improved, potentially leading to more accurate diagnosis and better treatment. All these factors may have improved survival in patients with COVID-19 and led to a shift in mortality to older, more vulnerable, and complex patients.

Background Patients with severe mental illness (SMI), such as schizophrenia or bipolar disorders, are more frequently affected by metabolic syndrome and cardiovascular (CV) diseases than the general population, with a significant reduction in life expectancy. Beyond metabolic syndrome, quantifying the risk of CV morbidity in the long-term may help clinicians to put in place preventive strategies. In this study, we assessed 10-year CV risk in patients with SMI and healthy individuals using an algorithm validated on the Italian general population. Methods Patients aged 35–69 years diagnosed with SMI were consecutively recruited from psychiatric acute care units. Single CV risk factors were assessed, and 10-year CV risk calculated by means of the CUORE Project 10-year CV risk algorithm, based on the combination of the following risk factors: age, systolic blood pressure, total and high-density lipoprotein cholesterol, diabetes, smoking habit, and hypertensive treatment. Patients’ data were compared with those from the general population. The 10-year CV risk was log-transformed, and multivariable linear regression was used to estimate mean ratios, adjusting for age, and education. Results Three hundred patients and 3,052 controls were included in the analysis. Among men, the 10-year CV risk score was very similar between patients with SMI and the general population (mean ratio [MR]: 1.02; 95%CI 0.77–1.37), whereas a 39% increase in 10-year CV risk was observed in women with SMI compared to the general population (MR: 1.39; 95%CI 1.16–1.66). Conclusions In our study, women with SMI were consistently more at risk than the general population counterpart, even at younger age.

Abnormal sex hormone-binding globulin (SHBG) and sex hormone concentrations are the cause or the consequence of cardiometabolic diseases, however, the clinical correlates of SHBG is clearly less understood. In our study we investigate sex- and age-specific serum SHBG levels and their association with cardiovascular risk (CVR) factors and high-risk conditions in an adult cohort of Italian population. Data from 1176 men and 2236 women, aged 20–81 were analyzed and serum SHBG determined in stored samples using an immunoassay. SHBG concentrations, higher in women than in men in the younger age groups, exhibited a curvilinear increase with age in men and a U-shaped curve across the lifespan in women, with a decrease from the 2nd to the 6th decade of age and an increase after the 6th decade when SHBG concentrations were similar in both sexes. Low SHBG serum levels correlated with the traditional CVR factors diabetes, obesity, and hypertension, whereas high level of SHBG correlated with cholesterol HDL. These associations were more numerous in women than in men, in whom decreased with age. The sex- and age specific differences observed in our population-based cohort should be considered in establishing reference ranges and clinical cut-off points to improve CVR score charts and therapeutic approaches.

Uncoupling proteins (UCPs) form a distinct subfamily of the mitochondrial carrier family (MCF) SLC25. Four UCPs, DmUCP4A-C and DmUCP5, have been identified in Drosophila melanogaster on the basis of their sequence homology with mammalian UCP4 and UCP5. In a Parkinson’s disease model, DmUCP4A showed a protective role against mitochondrial dysfunction, by increasing mitochondrial membrane potential and ATP synthesis. To date, DmUCP4A is still an orphan of a biochemical function, although its possible involvement in mitochondrial uncoupling has been ruled out. Here, we show that DmUCP4A expressed in bacteria and reconstituted in phospholipid vesicles catalyzes a unidirectional transport of aspartate, which is saturable and inhibited by mercurials and other mitochondrial carrier inhibitors to various degrees. Swelling experiments carried out in yeast mitochondria have demonstrated that the unidirectional transport of aspartate catalyzed by DmUCP4 is not proton-coupled. The biochemical function of DmUCP4A has been further confirmed in a yeast cell model, in which growth has required an efflux of aspartate from mitochondria. Notably, DmUCP4A is the first UCP4 homolog from any species to be biochemically characterized. In Drosophila melanogaster, DmUCP4A could be involved in the transport of aspartate from mitochondria to the cytosol, in which it could be used for protein and nucleotide synthesis, as well as in the biosynthesis of ß-alanine and N-acetylaspartate, which play key roles in signal transmission in the central nervous system.