FSMD-Based Hardware Accelerators for FPGAs

Current VLSI technology allows the design of sophisticated digital systems with escalated demands in performance and power/energy consumption. The annual increase of chip complexity is 58%, while human designers productivity increase is limited to 21 % per annum (ITRS, 2011). The growing technology-productivity gap is probably the most importan

1,2-Αnnulated Adamantane Heterocyclic Derivatives as Anti-Influenza Α Virus Agents

In this report we review our results on the development of 1,2-annulated adamantane heterocyclic derivatives and we discuss the structure-activity relationships obtained from their biological evaluation against influenza A virus. We have designed and synthesized numerous potent 1,2-annulated adamantane analogues of amantadine and rimantadine against influenza A targeting M2 protein the last 20 years. For their synthesis we utilized the key intermediates 2-(2-oxoadamantan-1-yl)acetic acid and 3-(2-oxoadamantan-1-yl)propanoic acid, which were obtained by a simple, fast and efficient synthetic protocol. The latter involved the treatment of protoadamantanone with different electrophiles and a carbon-skeleton rearrangement. These ketoesters offered a new pathway to the synthesis of 1,2-disubstituted adamantanes, which constitute starting materials for many molecules with pharmacological potential, such as the 1,2-annulated adamantane heterocyclic derivatives. To obtain additional insight for their binding to M2 protein three structurally similar 1,2-annulated adamantane piperidines, differing in nitrogen position, were studied using molecular dynamics (MD) simulations in palmitoyl-oleoyl-phosphatidyl-choline (POPC) hydrated bilayers. This work is licensed under a Creative Commons Attribution 4.0 International License

Environmental Barriers and Facilitators to Participation of People with Autism Spectrum Disorders: stakeholders’ perspective

Introduction: Social participation is a vital construct in inclusive philosophies and practices across communities. People with Autism Spectrum Disorders have been facing autism-related and environmental participation restrictions, placing them at risk of social exclusion and institutionalization. A multinational project has been developed in order to identify vital facilitating factors and establish PCP system for persons with ASD and tools for facilitators, as well as a ‘master class’ course for facilitators in several south-eastern European countries. The aim of the study is to identify the most common barriers to participation faced by individuals with ASD and to highlight facilitating factors that can be utilised in development of an autism specific PCP approach. Methodology: a mixed methodology employing concurrent qualitative-quantitative triangulation design was used. The participants consisted of four groups of stakeholders: young people with ASD, parents & family members of children/young people with ASD, teachers, and professionals. The data was collected via interviews and questionnaires with participants from the mentioned groups, using closed-ended and open-ended questions. Results: thematic analysis of the information gathered from the interviews and questionnaires was detailed by topics. Each topic was viewed with regards to barriers and facilitators to social participation. Conclusions: people with ASD have unique support needs that are qualitatively different from other special needs and communities are lacking specific understanding and approaches in meeting those needs. Insights from key stakeholders’ view point represents indispensable considerations in Person-Centred support for overcoming barriers to social participation and promoting health, equity and well-being of persons with ASD

Novel Lipophilic Hydroxamates Based on Spirocarbocyclic Hydantoin Scaffolds with Potent Antiviral and Trypanocidal Activity

Flaviviridae infections, such as those caused by hepatitis C (HCV) and dengue viruses (DENVs), represent global health risks. Infected people are in danger of developing chronic liver failure or hemorrhagic fever, both of which can be fatal if not treated. The tropical parasites Trypanosoma brucei and Trypanosoma cruzi cause enormous socioeconomic burdens in Sub-Saharan Africa and Latin America. Anti-HCV chemotherapy has severe adverse effects and is expensive, whereas dengue has no clinically authorized treatment. Antiparasitic medicines are often toxic and difficult to administer, and treatment failures are widely reported. There is an urgent need for new chemotherapies. Based on our previous research, we have undertaken structural modification of lead compound V with the goal of producing derivatives with both antiviral and trypanocidal activity. The novel spirocarbocyclic-substituted hydantoin analogs were designed, synthesized, and tested for antiviral activity against three HCV genotypes (1b, 3a, 4a), DENV, yellow fever virus (YFV), and two trypanosome species (T. brucei, T. cruzi). The optimization was successful and led to compounds with significant antiviral and trypanocidal activity and exceptional selectivity. Several modifications were made to further investigate the structure-activity relationships (SARs) and confirm the critical role of lipophilicity and conformational degrees of freedom

Lipophilic Guanylhydrazone Analogues as Promising Trypanocidal Agents: An Extended SAR Study.

In this report, we extend the SAR analysis of a number of lipophilic guanylhydrazone analogues with respect to in vitro growth inhibition of Trypanosoma brucei and Trypanosoma cruzi. Sleeping sickness and Chagas disease, caused by the tropical parasites T. brucei and T. cruzi, constitute a significant socioeconomic burden in low-income countries of sub-Saharan Africa and Latin America, respectively. Drug development is underfunded. Moreover, current treatments are outdated and difficult to administer, while drug resistance is an emerging concern. The synthesis of adamantane-based compounds that have potential as antitrypanosomal agents is extensively reviewed. The critical role of the adamantane ring was further investigated by synthesizing and testing a number of novel lipophilic guanylhydrazones. The introduction of hydrophobic bulky substituents onto the adamantane ring generated the most active analogues, illustrating the synergistic effect of the lipophilic character of the C1 side chain and guanylhydrazone moiety on trypanocidal activity. The n-decyl C1-substituted compound G8 proved to be the most potent adamantane derivative against T. brucei with activity in the nanomolar range (EC50=90 nM). Molecular simulations were also performed to better understand the structure-activity relationships between the studied guanylhydrazone analogues and their potential enzyme target

Scaffold hybridization strategy towards potent hydroxamate-based inhibitors of Flaviviridae viruses and Trypanosoma species.

Infections with Flaviviridae viruses, such as hepatitis C virus (HCV) and dengue virus (DENV) pose global health threats. Infected individuals are at risk of developing chronic liver failure or haemorrhagic fever respectively, often with a fatal outcome if left untreated. Diseases caused by tropical parasites of the Trypanosoma species, T. brucei and T. cruzi, constitute significant socioeconomic burden in sub-Saharan Africa and continental Latin America, yet drug development is under-funded. Anti-HCV chemotherapy is associated with severe side effects and high cost, while dengue has no clinically approved therapy and antiparasitic drugs are outdated and difficult to administer. Moreover, drug resistance is an emerging concern. Consequently, the need for new revolutionary chemotherapies is urgent. By utilizing a molecular framework combination approach, we combined two distinct chemical entities with proven antiviral and trypanocidal activity into a novel hybrid scaffold attached by an acetohydroxamic acid group (CH2CONHOH), aiming at derivatives with dual activity. The novel spiro-carbocyclic substituted hydantoin analogues were rationally designed, synthesized and evaluated for their potency against three HCV genotypes (1b, 3a, 4a), DENV and two Trypanosoma species (T. brucei, T. cruzi). They exhibited significant EC50 values and remarkable selectivity indices. Several modifications were undertaken to further explore the structure activity relationships (SARs) and confirm the pivotal role of the acetohydroxamic acid metal binding group

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Publisher Copyright: © 2022, The Author(s).Background: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.Peer reviewe

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Abstract Background Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. Results To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3–5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. Conclusions Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk

Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis

Funding GMP, PN, and CW are supported by NHLBI R01HL127564. GMP and PN are supported by R01HL142711. AG acknowledge support from the Wellcome Trust (201543/B/16/Z), European Union Seventh Framework Programme FP7/2007–2013 under grant agreement no. HEALTH-F2-2013–601456 (CVGenes@Target) & the TriPartite Immunometabolism Consortium [TrIC]-Novo Nordisk Foundation’s Grant number NNF15CC0018486. JMM is supported by American Diabetes Association Innovative and Clinical Translational Award 1–19-ICTS-068. SR was supported by the Academy of Finland Center of Excellence in Complex Disease Genetics (Grant No 312062), the Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, and University of Helsinki HiLIFE Fellow and Grand Challenge grants. EW was supported by the Finnish innovation fund Sitra (EW) and Finska Läkaresällskapet. CNS was supported by American Heart Association Postdoctoral Fellowships 15POST24470131 and 17POST33650016. Charles N Rotimi is supported by Z01HG200362. Zhe Wang, Michael H Preuss, and Ruth JF Loos are supported by R01HL142302. NJT is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC & WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215–2001) and the MRC Integrative Epidemiology Unit (MC_UU_00011), and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A19169). Ruth E Mitchell is a member of the MRC Integrative Epidemiology Unit at the University of Bristol funded by the MRC (MC_UU_00011/1). Simon Haworth is supported by the UK National Institute for Health Research Academic Clinical Fellowship. Paul S. de Vries was supported by American Heart Association grant number 18CDA34110116. Julia Ramierz acknowledges support by the People Programme of the European Union’s Seventh Framework Programme grant n° 608765 and Marie Sklodowska-Curie grant n° 786833. Maria Sabater-Lleal is supported by a Miguel Servet contract from the ISCIII Spanish Health Institute (CP17/00142) and co-financed by the European Social Fund. Jian Yang is funded by the Westlake Education Foundation. Olga Giannakopoulou has received funding from the British Heart Foundation (BHF) (FS/14/66/3129). CHARGE Consortium cohorts were supported by R01HL105756. Study-specific acknowledgements are available in the Additional file 32: Supplementary Note. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute; the National Institutes of Health; or the U.S. Department of Health and Human Services.Peer reviewedPublisher PD