bluuebunny/crossref_metadata_2025 huggingface dataset:
History of Cortisone and Related Compounds
Authors: Patrick Graham
Published: April 2013

Steroidal hormones were isolated from the adrenal cortex in the 1930s and were synthesised a decade later. Several of these structures have highly effective anti‐inflammatory activity but also exhibit serious side effects. Chemical analogues have now been discovered with better activity and reduced side effects. Such agents are administered for the treatment of a wide range of inflammatory conditions, including rheumatoid arthritis and asthma. Anti‐inflammatory activity can be improved by introducing functional groups or substituents at key positions of the steroid structure. Similarly, substituents placed at key positions can reduce side effects and metabolic susceptibility. Nevertheless, there are still risks associated with the long‐term use of steroids, and research is currently looking at novel agents that will act locally at the site of administration and are rapidly metabolised to inactive compounds once they reach the blood supply.

Key Concepts:

Adrenocorticoids are released by the adrenal glands and can be classified as glucocorticoids or mineralocorticoids.

Cortisone, hydrocortisone and corticosterone are examples of glucocorticoids.

Cortisone was isolated in the late 1930s, and a synthesis was devised in 1948.

The beneficial anti‐inflammatory effects of cortisone on patients with rheumatoid arthritis were demonstrated in the late 1940s.

Glucocorticoids have important effects on cell metabolism and are released as a result of stress.

Several glucocorticoids have anti‐inflammatory activity making them useful in the treatment of conditions such as skin and mucosal inflammations, rheumatoid arthritis and asthma.

Endogenous glucocorticoids such as cortisol and cortisone are used in the clinic but suffer from side effects.

Analogues of cortisone and cortisol have been developed that have improved anti‐inflammatory activity and reduced side effects.

Key structural features have been identified that can be introduced to the steroid structure in order to increase anti‐inflammatory activity and absorption, while decreasing side effects and metabolism.

Soft drugs have been developed since the 1970s, which act locally at the site of administration and are rapidly metabolised should they reach the blood supply.
Brugada Syndrome
Authors: Campuzano Oscar , Sarquella‐Brugada Georgia , Brugada Ramon , Brugada Josep , Brugada Pedro
Published: April 2013

Brugada syndrome (BrS) is characterised by right bundle branch block and persistent ST‐segment elevation in right precordial leads. It is responsible for 4–12% of total sudden cardiac death cases and 20% of sudden cardiac death in healthy individuals with structurally normal hearts. The prevalence is difficult to estimate because the pattern is not always recognised or because it may transiently normalise. BrS is more common in males approximately 40 years of age. In individuals with a history of syncope or cardiac arrest, the only effective treatment is the implantable defibrillator. BrS is a familial disease with an autosomal dominant pattern of transmission and variable penetrance. Currently, several mutations have been described in 13 genes being all together responsible for 30–35% of total BrS cases. Identification of relatives at risk using electrocardiogram or molecular genetic testing enables use of preventive measures and avoidance of medications that can induce ventricular arrhythmias.

Key Concepts:

The electrocardiographic pattern is thesine qua nonof Brugada syndrome diagnosis.

The diagnosis of Brugada syndrome is difficult because of incomplete penetrance and dynamic electrocardiographic manifestations.

Cardiac events typically occur in men approximately 40 years old, mainly at rest, during sleep.

Patients with the typical electrocardiographic pattern who present with cardiac arrest or syncope of suspected cardiac origin should be protected with a defibrillator.

The controversy still remains as what to do with asymptomatic patients.

The Brugada syndrome is a familial disease inherited with an autosomal dominant pattern of transmission and variable penetrance.

Only 30–35% of patients with the clinical phenotype currently have a causative mutation identified.
Ecological Integrity: Evaluating Success in National Parks and Protected Areas
Authors: Cafaro Philip , Primack Richard
Published: April 2013

National parks and protected areas have been established for a variety of purposes, but preserving wild nature is certainly one of the most important. Three concepts are particularly useful in defining what we want to protect within these areas. First,wilderness: unmanaged nature, free to be and to evolve into what it will. Second,biodiversity: the totality of natural life, including natural species, their genetic diversity and the diversity of wild communities they form. Third,ecological integrity: defined as the combination of biodiversity and wildness. Over the past two decades, land managers around the world have refined and applied the concept of ecological integrity to assess the status and evaluate management options for a wide range of landscapes. This article explores some of the main challenges and complexities of pursuing ecological integrity in parks management and in environmental policy more generally.

Key Concepts:

Over the past century, parks and natural areas managers have come to realise the value of maintaining all the natural processes and all the native species on the landscapes they manage.

Ecological integrity involves preserving the full complement of native biodiversity in an area, while limiting human manipulation and control of nature.

Preserving (and where possible restoring) ecological integrity is the primary goal in natural areas management, to which other goals are properly subordinate.

Good progress has been made in developing measurements of ecological integrity for a variety of natural and managed landscapes.

Climate change and global ecological degradation will make it increasingly difficult to maintain ecological integrity in coming decades.

Preserving ecological integrity in the long‐term demands restricting inappropriate human uses within protected areas, while reining in human overpopulation and overconsumption outside them.

Ecological integrity will continue to decline worldwide, until humanity accepts limits to growth and acts accordingly.
Gnetales
Authors: Carmichael Jeffrey
Published: April 2013

The Gnetales (Ephedra,GnetumandWelwitschia) represent a fascinating group of nonflowering seed plants (gymnosperms). This group of plants has intrigued plant biologists for well over a century due, in part, to their interesting growth habits, medicinal properties, unusual reproductive features, and status a potential link between flowering and other nonflowering seed plants. Indeed, the reproductive biology of Gnetales has increased our understanding of the origin of angiosperms including the process of double fertilisation. The phylogenetic position of Gnetales has been highly debated over the years. Early studies, based largely on structural data, concluded that the Gnetales are monopyletic and represent the sister group to angiosperms (‘anthophyte’ hypothesis). More recent studies provide evidence that the Gnetales represent the sister group to conifers (‘Gnetifer’ hypothesis) or are embedded within conifers and represent the sister group to Pinaceae (‘Gnepine’ hypothesis). Regardless of their phylogenetic position, various structural features of Gnetales have a strong bearing on our understanding of evolutionary trends in seed plants.

Key Concepts:

Members of the Gnetales are gymnosperms that possess some angiosperm‐like features.

A modified form of double fertilisation occurs in Gnetales.

Ephedrais a shrub that produces ephedrine, a stimulant and decongestant found in certain weight‐loss and energy‐boosting products.

Welwitschiais endemic to the Namib desert in Africa and is considered by many to be one of the most bizarre plants on Earth.
Eudicots
Authors: Ronse De Craene Louis P
Published: April 2013

Eudicots represent the largest clade of flowering plants, comprising approximately 75% of all species and characterised by pollen having three apertures. Eudicots consist of a basal grade and a large (core eudicot) clade, which comprises the majority of species. Evolution of flowers in core eudicots is highly diverse and is driven by repeated diversifications of pollination mechanisms. Two major clades, the Asterids and Rosids, have evolved separately and have attained a high level of diversity. Eudicots are a highly successful group of plants, occupying almost all habitats on earth. Apart from Poaceae in the monocots, the major food crops are found in the core eudicots. Flowers of eudicots are mostly with parts in five and with a differentiated perianth of sepals and petals. Specific pollination mechanisms have led to groups with specialised animal‐pollinated zygomorphic flowers (Leguminosae and Lamiales) or wind‐pollinated apetalous flowers (Fagales and Caryophyllales). Dispersal mechanisms are also highly diverse.

Key Concepts:

Eudicots contain the highest concentration of economic plants outside the grasses.

Molecular phylogenies have almost resolved the relationships within eudicots.

Eudicots occupy almost all habitats on earth and range from the smallest to the largest flowering plants.

Eudicots represent the most successful plant group with the highest number of species in the flowering plants.

Eudicots are composed of a basal grade of early diverging eudicots and a clade of core eudicots.

Petals have evolved several times from stamens or from bracts.

The origin of the core eudicot flower remains controversial.

Floral evolution in eudicots is mainly dependent on diversity of pollination systems.

Flowers of core eudicots have undergone opposing trends of reduction and increased complexity.

The distinction dicot–monocot should be abandoned, as it does not represent a natural division.
Zea Mays(Maize, Corn)
Authors: Vincent P Leszek D
Published: April 2013

Zea maysL. (maize, corn) is a member of the grass family (Poaceae). It has been an important food crop since ancient times, especially among the peoples of Central and South America. Although most grasses have bisexual florets the mature florets ofZ. maysare functionally unisexual on the sample plant, a condition referred to as monoecy. The functionally male florets are borne on the tassel whereas the functionally female florets are borne on the ear. All of the components of the adultZ. maysplant are initiated within the first 4 weeks after germination. Research on maize genetics has led to some exciting discoveries (some associated with the award of a Nobel prize). These discoveries have clarified the putative origin and biology ofZ. maysand have also provided significant insights for plant biology as a whole. An overview of the taxonomy ofZ. maysis provided.

Key Concepts:

The species,Zea maysL. (maize/corn), is a member of the grass family (Poaceae) and a member of the genusZea. Taxonomically and nomenclaturally maize is known asZ. maysL. ssp.mays.

Maize is considered to have evolved from the Mexican annual teosintes (Z. maysssp.parviglumisand ssp.mexicana).

A large number of exciting genetic discoveries originated from the research on maize. One of these discoveries, the phenomenon of transposable elements, resulted in the awarding of a Nobel prize.

The flowers ofZ. mays, typically referred to as florets, are initially bisexual but before the florets are reproductively functional they become unisexual, resulting in monoecy.

The functionally male florets are borne terminally on the plant in the tassel. The functionally female florets are borne laterally on the plant in one or more ears.

The occurrence of separate male and female florets in separate flowering structures (inflorescences) on theZ. maysplant (monoecy) has enabled the genetics of this species to be extensively studied because controlled pollinations are relatively easily performed.

The morphological structure of the very young florets inZ. maysis typical of the florets in the grass family (Poaceae) in that each floret is subtended by a lemma and a palea. Pairs of florets form spikelets.

In the tassel, both florets in each spikelet are functionally male and produce pollen. In the ear one of the two florets in each spikelet aborts. The remaining floret results in a kernel following successful pollination and fertilisation.
Brassicaceae (Mustard Family)
Authors: Al‐Shehbaz Ihsan A
Published: April 2013

The Brassicaceae (Cruciferae) or mustard family is a well‐defined group of about 310 genera and some 3500 species distributed primarily in the temperate and alpine areas of all continents except Antarctia. It is most highly diversified in central and western Asia, Mediterranean Europe and western North America. This article discusses the economic importance of the family (food, oils, condiments, ornamentals and weeds) and role played by one of its weedy member, the model organismArabidopsis thaliana, in the advancement of modern experimental biology. Here we also review the morphology, biogeography, ecology and phylogenetic relationship within Brassicaceae and to other families. We also cover the significance of molecular data in dividing the family into 48 monophyletic tribes and in determining its major lineages. Finally, a brief discussion is presented on the whole‐genome duplication events and their possible role in the radiation and diversification of the family.

Key Concepts:

Model organisms, such as the mustardArabidopsis thaliana, should always be used to understand complex biological phenomena in other organisms.

Owing to extensive morphological convergence, molecular data alone provide the most reliable and solid phylogenetic classification within the Brassicaceae.

Invasive weeds of the mustard family can only be understood by closer studies of their immediate wild relatives.

Germplasm conservation centres of the economically important Brassicaceae should substantially increase their efforts to save their rapidly disappearing wild relatives.

Vegetable crops ofBrassicashould be thoroughly tested to determine their medicinal values in combating cancer and other diseases.
Laurales
Authors: Renner Susanne S
Published: April 2013

The Laurales are an order of flowering plants comprising seven families that contain some 2500–2800 species in 100 genera. Most Laurales are tropical trees or shrubs, often with scented wood of great durability. Besides being a source of high quality timber, the Laurales also include the avocado tree (

Persea americana

), a native of Mexico and Central America, the cinnamon tree and the camphor tree (
Cinnamomum
species), native in Southeast Asia, and the bay laurel (

Laurus nobilis

), native in the Mediterranean region. The earliest lauraceous fossils are from the early Cretaceous, and within flowering plants, the order is among the oldest groups to diversify. The presently accepted classification of the seven families is based on molecular sequence data.

Key Concepts:

Many ancient groups of flowering plants are tropical trees.

Flowering plants came to dominate the World's flora during the Early Cretaceous.

Most tropical tree species have minute flowers, pollinated by bees, flies, or beetles.

Biogeographic studies of ancient tropical plant groups today usually rely on molecular clock‐based estimates of divergence times.
Dioscoreales (Yams and Allies)
Authors: Geeta R
Published: April 2013

Dioscoreales, the ‘true’ yams and allies, are a group whose current circumscription is dictated by results of molecular phylogenetic analyses. Consisting as it does of several nontraditional members, the group is made up of a heterogeneous set of taxa: unremarkable liliaceous plants, minute chlorophyll‐less plants that live off their associated fungal partners, and large, robust, green plants of the tropics, some of which store starch in large underground tubers (

Dioscorea

yams) that are important human food across the world, especially in Africa and the Pacific Islands. Some species are important sources of folk medicines and pharmaceuticals; the original birth pills were manufactured from relatives of the edible yams.

Dioscorea

is remarkable in the ‘dicot’‐like appearance of its stalked, net‐veined leaves borne on vines. Dioscoreales occur across the world and may existed by about 120 million years ago.

Key Concepts:

Dioscoreales are herbaceous monocots of northern temperate regions and the tropics.

Dioscoreales contain five families: Burmanniaceae, Dioscoreaceae, Nartheciaceae, Taccaceae and Thismiaceae, with 24 genera and 643 species; new species of Burmanniaceae and Thismiaceae are still being discovered.

The flower has an inferior ovary, short style and branched stigma, anthers often with apical extension. Many species contain steroidal saponins.

The order includes heterotrophs that depend on associated fungi for their nutrition (Burmannicaeae and Thismiaceae) and autotrophic tuberous plants that are a food source for other organisms including humans (Dioscoreaceae).

Dioscorea
, the genus of ‘true’ yams, contains about 10 cultivated species.

Dioscoreales are at least 123 million years old according to molecular clock estimates.
Parasitism: Life Cycle and Host Defences against Parasites
Authors: Stephen Phillips R
Published: April 2013

Parasites must reach new hosts and have evolved a variety of strategies to achieve this. For some there is a direct life cycle, with the parasite passing from one member of the host species to another via the infective stage of the life cycle. Other parasite species have more complex life cycles, known indirect life cycles, involving intermediate host species, before final transmission to the definitive host. The host's defence against parasitisation broadly takes two forms. First there are nonimmune mechanisms such as the protection given to infection with the human malaria parasitePlasmodium falciparumby the presence of the abnormal ‘sickle’ haemoglobin. Secondly, parasites can be attacked by the full panoply of the host's acquired immune defence system. A feature of most host/parasite relationships is survival of the host but equally survival of the parasite: parasites have evolved a variety of mechanisms for evading or down‐regulating the host's immune response to their advantage. The pathological consequences to the host of parasitic attack include physical damage from the host's activities to indirect consequences of the host's immune response. The problems of developing antiparasite vaccines are discussed.

Key Concepts:

Finding a new host is a formidable challenge for a parasite: variety of strategies evolved to achieve this end.

A detailed understanding of parasite life cycles facilitates development of strategies for control of parasites of medical and veterinary importance.

Host species can be very restricted for some parasites, but for some parasites many host species can be infected.

Some parasites have direct simple life cycles whereas others have indirect complex lifecycles involving a vector or intermediate host.

In complex life cycles the parasite's development and progression through the life cycle is adapted to the physiology and behaviour of the host.

Prevalence of parasites in the host population is often over dispersed – that is most individuals have a few parasites but a few have many.

In general the higher the parasite load the greater the severity of disease in the host.

Defence to parasitic infection involves both nonimmune and acquired immune mechanisms.

In many host/parasite relationships the host defences reduces the parasite load to low levels but fails to eliminate the parasite completely and transmission continues.

Parasites have evolved a variety of strategies to survive or evade the host's defence mechanisms.
Protein–Ligand Interactions: Computational Docking
Authors: Dhanik Ankur , Kavraki Lydia E
Published: April 2013

A pharmaceutical drug compound is usually a small organic molecule, also termed as ligand, that binds to the target protein and alters the natural activity of the protein, thus, leading to a therapeutic effect. Computational docking or computer‐aided docking is an extremely useful tool to gain an understanding of protein–ligand interactions which is important for the drug discovery. Computational docking is the process of computationally predicting the placement and binding affinity of the ligand in the binding pocket of the protein. Docking methods rely on a search algorithm which computes the placement of the ligand in the binding pocket and a scoring function which estimates the binding affinity, that is, how strongly the ligand interacts with the protein. A variety of methods have been developed to solve the computational docking problems that range from simple point‐matching algorithms to explicit physical simulation methods.

Key Concepts:

Computational docking methods play an important role in the drug discovery process.

A docking method computes the placement of a ligand in the binding pocket of a protein and estimates the binding affinity.

Rigid‐body docking methods treat both the protein and ligand as rigid bodies.

Flexible ligand methods treat the ligand as a flexible molecule and flexible receptor methods treat both the ligand and the protein as flexible molecules.

Two main features of computational docking techniques are a conformation search algorithm and a scoring function that estimates binding affinity.

Most of the computational docking programs treat the protein as a rigid molecule and the ligand as a flexible molecule.

Protein flexibility is an important determinant of the accuracy of docking programs.

Efforts have been made to account for protein flexibility in docking methods, but more needs to be done.
Isochores
Authors: Bernardi Giorgio
Published: April 2013

Chromosomes of warm‐blooded vertebrates are mosaics of isochores, megabase
deoxyribonucleic acid
(DNA) stretches that are fairly homogeneous in base composition. In the human genome, isochores can be assigned to five families that cover a very broad range of guanine+cytosine (30–60% GC; this range is narrower in cold‐blooded vertebrates). The isochore structure of the genome led to new insights into a number of important genome features such as (1) the distribution of genes, (2) the structure of chromatin, and (3) the localisation of insertions/deletions and of the integration of proviral sequences. Moreover it also led to (1) the discovery of a set of correlations (collectively called the genomic code) linking coding sequences and extended flanking noncoding sequences, as well as other genome features, (2) the visualisation of the isochore patterns of the genomes as genome phenotypes, that may be conserved or change in evolution, like the classical phenotypes, and (3) the development of the neoselectionist theory of evolution, which explains the two modes, conservative and shifting, of genome evolution.

Key Concepts:

Isochores are the structural, functional and evolutionary units of the genomes of vertebrates and other eukaryotes.

Structurally, isochores correspond to the highest resolution bands of chromosomes.

Functionally, isochores from different families are characterised by different frequencies of short oligonucleotides, not only in the extended inter‐ and intragenic noncoding sequences, but also in short regulatory sequences upstream and downstream of coding sequences. Moreover, different categories of genes have a different distribution in isochore families.

Evolutionarily, the isochore patterns change in different classes of vertebrates, from the relatively simple (low‐heterogeneity) patterns of cold‐blooded vertebrates to the complex (high‐heterogeneity) of warm‐blooded vertebrates.
Titin Gene (

TTN

)
Authors: Labeit Siegfried , Bogomolovas Julius , Labeit Dietmar , Granzier Henk
Published: April 2013

The titin locus located on chromosome 2q24 in the human genome expresses about 100 kb full‐length mRNAs, that are translated into giant up to 34.350‐residue large polypeptides. Therefore, titin is by far the largest known protein. The titin protein is abundant in vertebrate muscles, where it spans half of the sarcomere.

In situ

, 1–2 μm long titin polypeptides establish a sarcomeric filament system that is critical for myofibrillar integrity and elasticity. Biomechanically, titin's intrinsic elasticity is fine‐tuned in the different muscle tissues through alternative splicing, post‐translational modifications and protein–protein interactions. Moreover, a plethora of molecular interactions with stress‐regulated ligands positions titin centrally in stretch‐dependent signalling in muscle. Therefore, mutations in this filament system are important causes of hereditary cardiomyopathies and muscular dystrophies.

Key Concepts:

Sarcomeres consist of precisely assembled proteins that together form the basic functional units of striated muscle and give rise to efficient and finely tuned contraction.

In muscle tissues, 1–2 μm single titin polypeptide chains span half of the sarcomere.

The intrasarcomeric filamentous titin protein provides sarcomeres with intrinsic elasticity and couples stretch‐dependent signalling together with muscle remodelling.

Titin molecule is tailored to physiological requirements of different muscles through alternative splicing, post‐translational modifications and protein–protein interactions.

Mutations in the titin gene are associated with different heart and skeletal muscle diseases.
Alternative Processing: Neuronal Nitric Oxide Synthase
Authors: Marsden Philip A , Newton Derek C , Tsui Albert K Y
Published: April 2013

The humanneuronal nitric oxide synthase(nNOS) gene is expressed from multiple promoters and is subject to alternate messengerribonucleic acid(mRNA) processing. These complex molecular mechanisms contribute to regulating gene expression and function in multiple tissues and cell types. In the case of nNOS, these distinct promoters give rise to mRNA transcripts with untranslated leader sequences that have differing lengths, nucleotide composition and three‐dimensional structure. These distinct leader sequences have robust effects on translational efficiency. In disease settings, these have functional relevance. For example, in settings of low oxygen content, a unique promoter becomes trancriptionally active. In contrast to basally expressed transcripts, this hypoxia‐induced mRNA is very efficiently translated. To accommodate diverse biological roles, multiple mechanisms have evolved to produce a diverse range of nNOS mRNA transcripts from a single genetic locus.

Key Concepts:

Mammalian genes can have more than one promoter.

Having more than one promoter implies that the gene has more than one version of exon 1.

Initiation of transcription in different regions of genomic DNA imparts different nucleotide sequences to the leader regions of messenger ribonucleic acid transcripts, also known as the 5′‐untranslated region (5′‐UTR).

Different leader sequences may, or may not, affect protein structure depending on whether the initiator AUG codon for translation of the protein lies in exon 1 or downstream.

If multiple versions of exon 1 all have their own initiator AUG codon, then the encoded protein will exist if different forms, each with a uniqueN‐terminal peptide sequence.

Different 5′‐UTRs of messenger ribonucleic acid transcripts can have functional effects on expression of the encoded protein.

The 5′‐UTRs of messenger ribonucleic acid transcripts can affect translational efficiency.

The 5′‐UTRs of messenger ribonucleic acid transcripts can affect subcellular messenger ribonucleic acid transcript localisation.

The 5′‐UTRs of messenger ribonucleic acid transcripts can affect messenger ribonucleic acid transcript stability.
t
RNA
and the Human Genome
Authors: Goldman Emanuel
Published: April 2013

Transfer
ribonucleic acid
(tRNAs) decode the genetic code and carry attached amino acids to the growing protein chain on the ribosome. With the availability of the complete sequence of the human genome, at least 497 tRNA genes have been identified (which include some gene duplications). With the exception of the UGA‐decoding tRNA that inserts selenocysteine into protein under special circumstances, no tRNAs were found that decode stop codons. This opens up the possibility of using nonsense codons for insertion of nonnatural amino acids into selected proteins, to facilitate structural and functional analyses of these proteins. This has been accomplished by evolving tRNA:aminoacyl‐tRNA synthetase pairs in which the synthetase recognises a nonnatural amino acid and attaches it to its partner nonsense‐suppressor tRNA and no other tRNAs.

Key Concepts:

tRNAs are grouped into families of isoacceptors, with each family recognised by a single cognate aminoacyl‐tRNA synthetase.

All tRNAs conform to a secondary structure described as a ‘cloverleaf’, and fold in three‐dimensional space into an ‘L‐shaped’ molecule, in which the amino acid and the anticodon are at opposite ends of the molecule.

The 3′ end of all tRNAs have the sequence CCA, with the amino acid attached by the tRNA synthetase to the terminal adenosine residue. In eukaryotic cells, the 3′ terminal CCA is not encoded but is enzymatically added posttranscriptionally.

The anticodon of the tRNA decodes a complementary codon on mRNA in an antiparallel fashion.

Wobble between the third codon position in an mRNA and the first anticodon position in the tRNA extends allowable base‐pairing.

There are extensive modifications of the bases in tRNAs, with functional importance.

During protein synthesis, tRNAs interact with the ribosomal ‘A’ (aminoacyl), ‘P’ (peptidyl) and ‘E’ (exit) sites.

All organisms exhibit preferred ‘codon bias’, in which certain synonymous codons are preferred over others, generally corresponding to cognate tRNA abundance.

The human genome has 497 identified tRNA genes and 324 putative tRNA pseudogenes. There are no tRNAs that decode stop codons.

Dedicated, unique tRNA: aminoacyl‐tRNA synthetase pairs have been developed for insertion of nonnatural amino acids into protein.
Transmembrane Domains
Authors: Ramasarma T , Joshi NV , Sekar K , Uthayakumar M , Sherlin D
Published: April 2013

Stretches of approximately 25 hydrophobic residues with an occasional polar residue of integral proteins that pass across membrane are known as transmembrane (TM) domains. Besides anchoring to the membrane they participate in the functions of these proteins in some unspecified way. A variety of membrane proteins with spans in the range 1–17 are present in human genome and those with 1, 4 and 7 spans are more common. Impacting a variety of cellular functions, these include receptors for growth factors, hormones and other ligands, two‐way membrane transporters, selective enzymes, channel proteins, energy‐transducing tiny molecular motor, molecular facilitators in signalling, adhesion, differentiation and proliferation. Highly variable sequences of these short stretches of hydrophobic residues of TM domains, with hardly any repetition, arise out of repeating XTX/XCX triplets in theircomplementary deoxyribonucleic acid (cDNA). They are encoded by a random exon make‐up, one exon coding for one or more domains and one domain coded by two exons with the junction between triplets and in some cases within a triplet.

Key Concepts:

Cell membrane is composed of hydrophobic phospholipid bilayer that separates two aqueous phases.

The selective permeability endows the membrane two‐way transport of desired materials.

Proteins attached to the membrane facilitate this exchange process.

Proteins that span across the bilayer in one or multiple passes are known as integral proteins or transmembrane (TM) proteins.

TM domains, composed of largely hydrophobic residues, anchor these proteins firmly to the membrane and also participate in the functions.

Topology of TM domains facilitates transfer of signals, channelling ions and transporting material.

The amino acid sequences of TM domains are highly variable and are not repeated.

Some of these short stretches of TM domains are encoded by two exons with junction between triplet or within triplet.
Centromeric Sequences and Sequence Structures
Authors: Koch Jørn , Andersen Anni
Published: April 2013

Centromere function is essential for the faithful passing on of the parental genome to daughter cells in cell division. This function is carried by specialised noncoding
deoxyribonucleic acid
(DNA), centromere DNA. The functional DNA element in human centromeres is the α‐satellite DNA, which we share with all other primates, but not with nonprimate species. This DNA acts through timed interactions with proteins belonging to the cell‐cycle machinery, such as topoisomerase II, which cuts the interconnecting bridges between sister‐chromatids to allow and enable the completion of mitotic and second state meiotic cell divisions. To orchestrate these interactions, centromere DNA has the ability to fold into complex three‐dimensional shapes, which are the form of the DNA recognised by its protein partners.

Key Concepts:

Unlike genes coding for proteins, noncoding DNA is not coded in a triplet code where each triplet can be translated into a specific amino acid.

Noncoding DNA is instead coded in the form of spatial structures capable of governing specific interactions with DNA, RNA and proteins in ways that are more reminiscent of antigen–antibody reactions than of the triplet coding.

For this reason scientists have had a hard time understanding what noncoding DNA is good for, at some point even leading to the misconception that it served no good function, but merely was ‘selfish DNA’.

With the discovery of the noncoding RNAs, which are very important for gene regulation, a very different picture is now dawning, and we trust that it will end in the understanding that genes are nothing more than ‘stupid’ data files, whereas the rest of the genome is ‘the software’ reading those data files to produce ‘the hardware’ in the form of gene products.

Centromere DNA is one species of noncoding DNA. It serves its functions through interactions with a whole range of DNA‐binding proteins, and to enable the interactions to be ‘on’ or ‘off’ as appropriate, the DNA must be able to turn into different shapes and forms, which are recognised, or not recognised by the various proteins.
Polyploid Origin of the Human Genome
Authors: Kasahara Masanori
Published: April 2013

Accumulated evidence indicates strongly that two rounds of whole‐genome duplication (2R‐WGD) took place in the vertebrate lineage after its separation from invertebrate chordates; hence, the human genome can be regarded as paleooctoploid. The vertebrate genome often contains closely linked sets of paralogous genes (paralogues) on typically four different chromosomes. This genome architecture is widely believed to reflect the remnants of 2R‐WGD. In honour of Susumu Ohno, who initially proposed that the vertebrate genome underwent one or two rounds of tetraploidisation, paralogues that arose by 2R‐WGD are called ohnologues. Only 15% to 30% of human genes are members of the ohnologue families, indicating that most of the duplicated copies generated by 2R‐WGD were lost. Preferentially retained after WGD are dosage‐sensitive genes such as those encoding components of the complex biological machines or cascades.

Key Concepts:

2R‐WGD took place in the vertebrate lineage after its separation from invertebrate chordates.

The strong evidence supporting 2R‐WGD is the occurrence of closely linked sets of paralogues on typically four different chromosomes.

WGD enabled duplicated genes to coevolve efficiently, thus leading to the formation of gene networks required for biological innovations.

After gene duplication, one of the duplicated copies becomes redundant and usually begins to accumulate deleterious mutations, resulting in its eventual loss.

An important requisite for the retention of duplicated genes is their divergence to acquire new functions or to partition the functions of their ancestral gene.

Dosage‐sensitive genes tend to be preferentially retained after WGD.
Exons and Protein Modules
Authors: Patthy László
Published: April 2013

Modules are versatile protein domains that are frequently used as building blocks in the construction of diverse multidomain proteins. The degree of versatility or promiscuity of protein modules is usually defined as the number of distinct domain architectures in which they are present or the number of domain types with which they are associated in diverse multidomain proteins. The assembly of multidomain proteins from modules is facilitated by recombination in introns flanking the exons that encode the modules, but it may also occur by recombination in exons or through cotranscription and fusion of tandem genes. Protein modules that frequently participate in domain‐shuffling events (that is, moved from one genomic location to the other) are usually referred to as mobile domains.

Key Concepts:

Domain types that are frequently used as building blocks of multidomain proteins are usually referred to as protein modules.

The degree of versatility or promiscuity of protein modules may be defined as the number of distinct domain architectures in which it is present or the number of domain types with which it is associated in diverse proteins.

Protein modules that frequently participate in domain‐shuffling events (that is, moved from one genomic location to the other) are usually referred to as mobile domains.

Protein modules flanked by introns of identical phase are exceptionally mobile because their shuffling is facilitated by intronic recombination.

Although assembly of multidomain proteins from modules is facilitated by recombination in introns it may also occur by recombination in exons.
Children in Genetic Research
Authors: Alderson Priscilla
Published: April 2013

Genetic research offers potential benefits and harms to children. Respect for children's individual and collective best interests, and for their human rights and worth and dignity includes keeping them informed, and involving competent children as much as possible in making decisions about genetic research that affects them. Their privacy and identity must be respected, as well as the consent or refusal of parents and of competent children. The article reviews theDeclaration of Helsinkiand other ethical guidance, as well as differing standards for research with children between Britain and the USA. The term ‘therapeutic research’ is critically analysed, and also questions of justice and who bears the burdens or enjoys the benefits of genetic research in richer and in poorer countries. Research with children about dominant and recessive, autosomal and sex‐linked genetic conditions, about multigenetic predisposition meaning causally heterogeneous and often complex in origin, genomics and epigenetics, gene therapy and nature versus nurture, attention deficit hyperactivity disorder (ADHD) and economic influences is discussed.

Key Concepts:

Genetic research includes investigation into how children's traits, anomalies, behaviour or disease might be influenced by genomics, or by epigenetics, how this knowledge can be applied and shared, and how interventions to detect, treat and prevent adverse genetic conditions can be developed.

Research ranges from the study of conditions associated with single genes in closed predictable systems, to multigenetic predispositions interacting with many environmental influences.

The differing influences of genes and environment and their complex overlapping and interactions are debated, particularly regarding behavioural conditions.

When exploring connections between genotypes and phenotypes (ways in which genes are expressed) researchers also need to know about children's social contexts.

There are risks that genetic researchers overstate the value and influence of their knowledge on health, and confuse giving information with providing therapy.

Children and adults tend not to accept advice to alter their life‐style significantly in order to reduce or prevent symptoms of a genetic condition.

Research about gene therapy incurs risks and has not yet provided tested or proven effective treatments.

Children should be involved in genetic research only if the findings are intended to benefit them and cannot be obtained from an older age group.

Economics crucially influences all stages of genetic research in the selection of topics, the funding and scale of projects, promotion of reports and implementation of findings.

Social justice requires that the groups of children who take part in research, including those in poorer countries, should also be able to benefit from the findings.
deCODEand Iceland: A Critique
Authors: Árnason Einar , Andersen Bogi
Published: April 2013

deCODE Genetics Inc. was a for‐profit American corporation built around the idea of cloning and characterising the genes of Icelanders and marketing the information so obtained through a central database containing health information, genetic information and genealogy. deCODE's database plan in Iceland brought into focus business practices of the genomics industry and a number of ethical issues. The company promoted and sold its shares to the public in Iceland through a ‘grey market’ before its initial public offering, leading to large investment losses for common Icelanders with little investment experience. The law permitting the health sector database was found unconstitutional and the company never built the controversial database. Instead it pursued traditional genome‐wide association studies attempting to identify genetic changes contributing to common diseases. Through this work, the company created a large database and contributed a large number of scientific papers, but was a commercial failure going bankrupt in 2009. After a stalking‐horse sale it rose from the ashes and continued operation as a private company under almost the same name, focusing on whole genome sequencing data to understand common diseases and human variation. At the end of 2012, Amgen announced that it would pay $415 million to acquire deCODE. The sale price was based on a product derived from an Icelandic resource but no compensation was given to the Icelandic people.

Key Concepts:

deCODE was founded on the belief that unifactorial methods of searching for identity by descent in extensive pedigrees, so important in searching for Mendelian traits, would yield the genetics of common disease.

The genetic variants in most current GWA studies only explain a portion of the heritability.

Multiple variants, each with a small effect, seem to contribute to common diseases.

Rare genetic variant conferring a larger effect may also contribute to common diseases.

As a foundation for a commercial company, the identification of genetic variants in common disease was a failure for deCODE Genetics.

deCODE lays claim to a number of scientific papers but turning the science into a profitable busienss failed.

deCODE Genetics Inc. employed questionable business practices when raising funds from the public in Iceland.

The health sector database law in Iceland was found to be unconstitutional and deCODE Genetics never built the database on which its initial public offering was based.

deCODE Genetics Inc. declared bankruptcy but rose from the ashes after a stalking‐horse sale to a company partly owned by some of initial investors and by sequencing giant Illumina. It now operates under the name deCODE Genetics ehf. In December 2012 deCODE was purchased by Amgen and is now operated as a wholly owned Amgen subsidiary.
Patenting of Genes: Discoveries or Inventions?
Authors: Gold E Richard
Published: April 2013

Since the 1980s, patent offices in most developed countries (with some exceptions, particularly in Latin America) have been granting patents over both genomic and modified
deoxyribonucleic acid (DNA)
sequences based on the legal understanding of the difference between invention and discovery, which does not necessarily accord with the same concepts among scientists. Recent litigation in USA has, however, cast uncertainty over this conclusion, particularly with respect to genomic DNA sequences. Patents over the process of using these sequences to identify the risk of contracting a disease is even more uncertain. Controversy continues over the role that both DNA sequence and associated method patents play in encouraging innovation. This is particularly true in clinical genetics in which the patent holder is rarely the first to make a genetic test available to patients.

Key Concepts:

The legal understanding of the difference between an ‘invention’ and a ‘discovery’ does not correspond to how scientists appreciate the difference.

Patent offices in most developed countries have been granting patents over both DNA sequences (in both genomic and modified form such as cDNA) and methods of using them since the 1980s.

Only recently have these been challenged in court in USA with uncertain results.
China: The Maternal and Infant Health Care Law
Authors: Guo Sun‐Wei
Published: April 2013

The Law of the People's Republic of China on the Maternal and Infant Health Care (MIHCL), enacted in 1995, sparked widespread concerns, criticisms and in some cases fierce outcries in the Western scientific community. This article describes the background in drafting the law, chronicles reactions to its release and its subsequent development, attempts to provide a balanced presentation on perspectives of the West and of Chinese side, draws up a list of questions surrounding this controversy and its subsequent development, and, finally, argues that the entire process holds several lessons to future legislature in China when drafting health‐related laws.

Key Concepts:

The Law of the People's Republic of China on the Maternal and Infant Health Care (MIHCL) was enacted in 1995.

The law was drafted apparently in response to enormous population pressure, the heavy burden of people with disability, and questionable local practices that restrict reproductive freedom on people with mental and putative hereditary diseases.

The law sparked widespread concerns, criticisms, and in some cases fierce outcries in the Western scientific community, yet experts in China defended the law.

The most contentious articles in the law include ones that propel physicians to provide medical advice on long‐term contraception or sterilisation to couples who have been diagnosed with unspecified genetic disease of a serious nature after a mandatory pre‐marital medical examination (PMME).

In 2001, the Implementation Methods of MIHCL went effective, in which articles in the MIHCL that aroused controversies were written in a manner that is more ‘politically correct’ by Western standards.

In 2003, the Ministry of Civil Affairs issued The Marriage Registration Code, which effectively abolished the mandatory requirement for PMME as a prerequisite for marriage registration.

This dramatic change, viewed by many as inconsistent with the MIHCL, received warm welcome from the public, many of them unhappy with the mandatory requirement for PMME, but it also raised concern that the abolishment may have resulted in increased incidence of birth defects.

In 2005, a special Task Force reached conclusions that there is no credible evidence that suggests that the rising incidence of birth defects in some areas can be attributable to the abolishment of compulsive PMME and that the PMME has limited value in preventing birth defects.

The enactment of MIHCL and the subsequent, somewhat dramatic reverse in course beg for many questions regarding the scientific basis, if any, for the legislature.

The controversy surrounding the MIHCL and its subsequent development hold several lessons for people who attempt to solve complex health‐related problems through judiciary means.