Heart in anatomy history, radiology, anthropology and art

Background: Anthropologic, artistic and medical significance of heart inspired usto undertake this multidisciplinary study.Materials and methods: Amongst the 24 obtained echocardiograms and phonograms, 1 was used for a Photoshop processing. In addition, over 20,000 art work reproductions were examined in this study.Results: Artistic and symbolic presentation of heart started some 15,000 years ago. First heart models were made by the Egyptian and Olmec civilisations. Ancient cultures regarded heart as the seat of the soul, spirit and intelligence. First anatomical and artistic images of heart were created by Leonardo da Vinci in the15th century, and first wax models by the Italian anatomists in the 17th century. Mediaeval religious symbolism of heart was replaced in the Renaissance and later on mainly by its role in the romantic love. Anatomical heart art continued in the 18th and 19th centuries through the works of Sénac, Cloquet, Hirschfeldand Bourgery. Some modern artists, such as Dalí, Kahlo, Rivera, Warhol, Ivanjicki, Vital, Kober and Mastrlova, created the anatomical heart images or sculptures, whereas some others, such as Duchamp, Klee, Miró, Matisse and Dine, presented heart symbol in their artworks. New radiologic technologies produce fine images of heart, some of which are similar to the works of modern artists.Conclusions: Heart biology and symbolism have had a tremendous influence on our culture, including art and medical sciences. New radiologic techniques and computer technology have produced such images of heart, which substantially improved diagnosis, but also enhanced the heart aesthetics

Brain and art: illustrations of the cerebral convolutions. A review

Background: Aesthetics and functional significance of the cerebral cortical relief gave us the idea to find out how often the convolutions are presented in fine art, and in which techniques, conceptual meaning and pathophysiological aspect.Materials and methods: We examined 27,614 art works created by 2,856 authors and presented in art literature, and in Google images search.Results: The cerebral gyri were shown in 0.85% of the art works created by 2.35% of the authors. The concept of the brain was first mentioned in ancient Egypt some 3,700 years ago. The first artistic drawing of the convolutions was made by Leonardo da Vinci, and the first colour picture by an unknown Italian author. Rembrandt van Rijn was the first to paint the gyri. Dozens of modern authors, who are professional artists, medical experts or designers, presented the cerebralc onvolutions in drawings, paintings, digital works or sculptures, with various aesthetic, symbolic and metaphorical connotation. Some artistic compositions and natural forms show a gyral pattern. The convolutions, whose cortical layers enable the cognitive functions, can be affected by various disorders. Some artists suffered from those disorders, and some others presented them in their artworks.Conclusions: The cerebral convolutions or gyri, thanks to their extensive cortical mantle, are the specific morphological basis for the human mind, but also the structures with their own aesthetics. Contemporary authors relatively often depictor model the cerebral convolutions, either from the aesthetic or conceptual aspect. In this way, they make a connection between the neuroscience and fineart

In silico Design of "Un-Natural" Natural Products

Poliketidi i neribosomski sintetizirani peptidi su vrlo važne kemijske supstancije za farmaceutsku industriju i agroindustriju. Njihov biosintetski put obuhvaća spajanje jednostavnih građevnih jedinica u složene kemijske strukture katalitičkim djelovanjem enzimskih kompleksa poliketid-sintaza ili sintetaza neribosomskih peptida. U posljednjem desetljeću u znanstvenoj javnosti postoji osobito zanimanje za oblikovanje novih supstancija u proizvodnji novih lijekova manipulacijom genskih nakupina tih enzimskih kompleksa u uvjetima in vitro, postupcima kombinatorne biosinteze. Međutim, značajna je prepreka napretku na tom području što većina promjena u uvjetima in vitro ne dovodi do sinteze produkta ili su mu prinosi vrlo mali. Jedno od mogućih rješenja toga problema bilo bi oblikovanje novih genskih nakupina homolognom rekombinacijom u uvjetima in vivo jer bi se tako omogućilo spajanje identičnih sekvencija i smanjile poteškoće zbog pojave nefunkcionalnih čvorišta te opće nedovoljne identičnosti različitih modula. Osim toga, homolognom bi se rekombinacijom povećala učestalost rekombinacije te potaknula kombinatorna raznolikost rekombinanata. U tijeku je razvoj integralnih računalnih programskih paketa, CompGen i ClustScan, za modeliranje tih procesa u uvjetima in silico. Okosnica je programskog paketa CompGen specifično strukturirana baza podataka koja povezuje biosintetski put sinteze sa sekvencijama DNA genskih nakupina. Povezanost sekvencija DNA s biosintetskim putem omogućuje njezinu povezanost sa strukturom produkta. Jedna je od funkcija računalnoga programskog paketa, temeljena na toj povezanosti, sposobnost oblikovanja virtualnih rekombinanata između genskih nakupina. To se obavlja pomoću modela rekombinacije da bi se in silicopredvidjele sekvencije DNA u kojima dolazi do homologne rekombinacije. CompGen iz tih podataka predviđa kemijsku strukturu nove supstancije i sprema je u bazu podataka virtualnih kemijskih struktura radi daljnjega molekulskog modeliranja. Računalni programski paket omogućuje i analizu tzv. "obrnutom genetikom". Naime, ako se pretpostavi poželjna kemijska struktura, program može predvidjeti kako bi trebala izgledati genska nakupina poliketid-sintazâ ili sintetaza neribosomskih peptida, koja bi sintetizirala takvu strukturu na temelju građevnih jedinica genskih nakupina u bazi podataka. U cjelini, CompGen će omogućiti oblikovanje baze podataka novih prirodnih kemijskih entiteta u uvjetima in silico, koja se zatim može upotrijebiti za istraživanja na području tehnologije računalnoga dizajna novih lijekova. Drugi će integralni generički računalni programski paket, ClustScan, moći prepoznati i anotirati nove genske nakupine iz sekvencija cjelovitih mikrobnih genoma ili genskih nakupina u metagenomima mikroorganizama koji žive u tlu ili u simbiozi s morskim organizmima.Polyketides and non-ribosomal peptides represent a large class of structurally diverse natural products much studied over recent years because the enzymes that synthesise them, the modular polyketide synthases (PKSs) and the non-ribosomal peptide synthetases (NRPSs), share striking architectural similarities that can be exploited to generate "un-natural" natural products. PKS and NRPS proteins are multifunctional, composed of a co-linear arrangement of discrete protein domains representing each enzymic activity needed for chain elongation using either carboxylic acid or amino acid building blocks. Each domain is housed within larger modules which form the complex. Polyketide and peptide antibiotics, antifungals, antivirals, cytostatics, immunosuppressants, antihypertensives, antidiabetics, antimalarials and anticholesterolemics are in clinical use. Of commercial importance are also polyketide and peptide antiparasitics, coccidiostatics, animal growth promoters and natural insecticides. Polyketides are assembled through serial condensations of activated coenzyme-A thioester monomers derived from simple organic acids such as acetate, propionate and butyrate. The choice of organic acid allows the introduction of different chiral centres into the polyketide backbone. The active sites required for condensation include an acyltransferase (AT), an acyl carrier protein (ACP) and a ß-ketoacylsynthase (KS). Each condensation results in a ß-keto group that undergoes all, some or none of a series of processing steps. Active sites that perform these reactions are contained within the following domains; ketoreductase (KR), dehydratase (DH) and an enoylreductase (ER). The absence of any ß-keto processing results in the incorporation of a ketone group into the growing polyketide chain, a KR alone gives rise to a hydroxyl moiety, a KR and DH produce an alkene, while the combination of KR, DH and ER domains lead to complete reduction to an alkane. Most often, the last module contains the thioesterase domain (TE) responsible for the release of linear polyketide chain from the enzyme and final cyclisation. After assembly, the polyketide backbone typically undergoes post-PKS modifications such as hydroxylation(s), methylation(s) and glycosylation(s) to give the final active compound. Non-ribosomal peptides are assembled by the so-called "multiple carrier thio-template mechanism". Three domains are necessary for an elongation module: an adenylation (A) domain that selects the substrate amino acid, analogous to a polyketide AT domain, and activates it as an amino acyl adenylate; a peptidyl carrier protein (PCP) that binds the co-factor 4-phosphopantetheine to which the activated amino acid is covalently attached, analogous to the ACP of a PKS; and a condensation (C) domain that catalyzes peptide bond formation, again analogous to the KS in modular PKSs. The NRPSs also contain a (Te) domain located at the C-terminal of the protein which is essential for release of linear, cyclic or branched cyclic peptides. Auxiliary activities can further enlarge the structural diversity of the peptide especially common are epimerization domains (Epim) that convert the thioester-bound amino acid from an L- to D- configuration. There has been a lot of interest in the last few years in generating new compounds for the production of novel drugs by manipulating the programming of such clusters in vitro (e.g. the idea of combinatorial biosynthesis). However, an important barrier to the progress is the fact that most changes made by in vitro methods result in very low yields or no detectable product. A possible solution to the yield problem would be the generation of novel clusters by homologous recombination in vivo, because this would favour more closely related sequences and should reduce problems caused by non-functional incompatible junctions. The Unified Modeling Language (UML) was used to define the platform independent integral generic program packages, CompGen and ClustScan, which are under development to model these processes in silico. The heart of CompGen is a specially structured database, based on BioSQL v1.29, which connects the biosynthetic order of synthase/synthetase enzymes to the sequences of the component polypeptides. The additional linkage to the gene sequences allows the integration of DNA sequence with product structure. The database contains sequences of the well-characterised PKS/NRPS clusters, and non-annotated sequenced clusters whose structure and function is yet unknown, to act as building blocks for the production of novel products. It is easy to add custom sequences to the database and to annotate them by the use of propriety protein profiles designed by Pfam database and HMMER. One function of the program is the ability to generate virtual recombinants between clusters. This can be done using a recombination model (with optional parameters) to predict sites for homologous recombination or by user defined recombination sites (e.g. to model in vitro genetic manipulation such as module replacement). The program predicts the linear polyketide structure of the resulting "un-natural" natural products with a chemical description using isomeric SMILES. Molecular modelling of the subsequent spontaneous cyclisation process produces structures for a virtual compound database for further molecular modelling studies using PASS and CDD technology. An optional "reverse genetics" module analyses a given chemical structure to see if it could be produced by a novel PKS/NRPS synthesis cluster and suggests the DNA sequence of a suitable cluster based on building blocks derived from clusters contained in the database. Overall, the CompGen allows in silico generation of the database of novel "un-natural" natural chemical compounds that can be used for in silico screening using PASS or CDD technology. The other integral generic program package, ClustScan, will recognise and annotate new gene clusters from microbial genome sequencing projects or in metagenomes of soil and/or marine microorganisms

Pharmacokinetic modelling of the anti-malarial drug artesunate and its active metabolite dihydroartemisinin

A four compartment mechanistic mathematical model is developed for the pharmacokinetics of the commonly used anti-malarial drug artesunate and its principle metabolite dihydroartemisinin following oral administration of artesunate. The model is structurally unidentifiable unless additional constraints are imposed. Combinations of mechanistically derived constraints are considered to assess their effects on structural identifiability and on model fits. Certain combinations of the constraints give rise to locally or globally identifiable model structures. Initial validation of the model under various combinations of the constraints leading to identifiable model structures was performed against a dataset of artesunate and dihydroartemisinin concentration–time profiles of 19 malaria patients. When all the discussed constraints were imposed on the model, the resulting globally identifiable model structure was found to fit reasonably well to those patients with normal drug absorption profiles. However, there is wide variability in the fitted parameters and further investigation is warranted

Hydroxybenzothiazoles as New Nonsteroidal Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1 (17β-HSD1)

17β-estradiol (E2), the most potent estrogen in humans, known to be involved in the development and progession of estrogen-dependent diseases (EDD) like breast cancer and endometriosis. 17β-HSD1, which catalyses the reduction of the weak estrogen estrone (E1) to E2, is often overexpressed in breast cancer and endometriotic tissues. An inhibition of 17β-HSD1 could selectively reduce the local E2-level thus allowing for a novel, targeted approach in the treatment of EDD. Continuing our search for new nonsteroidal 17β-HSD1 inhibitors, a novel pharmacophore model was derived from crystallographic data and used for the virtual screening of a small library of compounds. Subsequent experimental verification of the virtual hits led to the identification of the moderately active compound 5. Rigidification and further structure modifications resulted in the discovery of a novel class of 17β-HSD1 inhibitors bearing a benzothiazole-scaffold linked to a phenyl ring via keto- or amide-bridge. Their putative binding modes were investigated by correlating their biological data with features of the pharmacophore model. The most active keto-derivative 6 shows IC50-values in the nanomolar range for the transformation of E1 to E2 by 17β-HSD1, reasonable selectivity against 17β-HSD2 but pronounced affinity to the estrogen receptors (ERs). On the other hand, the best amide-derivative 21 shows only medium 17β-HSD1 inhibitory activity at the target enzyme as well as fair selectivity against 17β-HSD2 and ERs. The compounds 6 and 21 can be regarded as first benzothiazole-type 17β-HSD1 inhibitors for the development of potential therapeutics

Abdominal aortic aneurysm – computer modelling and numerical solution

The main purpose of this study was to reconstruct 3D aorta models based on a series of 2D CT images of two patients suffering from an aneurysm. After the 3D models had been made, a numerical solution of the problem of the abdominal aortic aneurysm was obtained. The numerical solution incorporated mathematical models of biomechanical systems. Various parameters such as shear stress, pressure, and velocity of fluid through blood vessel could be calculated using these methods. The first part of the paper introduces the abdominal aorta and aneurysm. The second part of this paper describes the process of getting 3D model geometries of the aortic aneurysms. Finally, the results obtained from the models are discussed with the aim of predicting a rupture of an abdominal aortic aneurysm and selecting the right treatment for this disease

'It's all the same, only he's not here'?: popular music and political change in post-Tuđman Croatia

While Franjo Tuđman was the president of Croatia (1990–99), popular music and other forms of entertainment were heavily structured around the key presidential narratives: Croatia’s political and cultural independence from Yugoslavia, and the idea that Croatia’s war effort had been purely defensive. After Tuđman, the Croatian music industry had to cope with media pluralism and the transnational challenges of the digital era. Patriotic popular music expressed an oppositional narrative of Euroscepticism and resistance to the Hague Tribunal, yet Croatia retained and expanded its position in the transnational post-Yugoslav entertainment framework, undermining a key element of Tuđman’s ideology

Self-compassion and empathy as predictors of happiness among late adolescents

Happiness is a fundamental characteristic of life, helping individuals to become healthy and productive members of society. Pakistan has been ranked as the 67th happiest country out of 156 countries in the world. Self-compassion (SC) and empathy are considered some of the finest emotions and moral values of human beings leading to a happier life. This is the first study in South Asia that examined self-compassion as a moderator between empathy and happiness. Furthermore, we also determined self-compassion and empathy as predictors of happiness among late adolescents. Data collected from 566 students, selected randomly from different educational institutions in Lahore, suggested that self-compassion (r = 0.273) and empathy (r = 0.131) had a significant positive relationship with happiness. Self-compassion and empathy both significantly predicted happiness. Male adolescents had slightly higher self-compassion and mindfulness than females. Self-compassion (F (3, 562) = 29.74, p = 0.000) was found to significantly moderate the relationship between empathy and happiness. Self-compassion can be highly beneficial to relate to oneself, specifically for adolescents who are involved in developing their identities and self-worth, and it makes their transition from adolescence to adulthood easy