bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolution of Viviparity in Salamanders (Amphibia, Caudata)
Authors: Buckley David
Published: April 2013

Reproductive modes in salamanders (Amphibia, Caudata) are highly diverse. Viviparity, for instance, implies the retention of the developing embryos inside the females until the end of the gestation, at which point they deliver fully developed terrestrial juveniles. From an ecological point of view, the evolution of viviparity is highly significant, since it implies the semi‐independence of water for an amphibian. Nevertheless, viviparity is not very common among salamander. It has independently evolved only in a few species, all included within the family Salamandridae. Furthermore, the characteristics of viviparous strategies are different among species, although they all share some commonalities. The detailed study of these particular and common features in a phylogenetic context will reveal the genetic, physiological, developmental, morphological and historic factors that have triggered the evolution of this peculiar mode of reproduction in only one lineage among all the species of salamanders.

Key Concepts:

Viviparity entails the complete development of the progeny within the mother's genital tract, together with the maternal provisioning of nutrients to the embryos.

Since development occurs within the females, viviparity in amphibians implies that the aquatic phase of the standard amphibian life cycle is obviated in viviparous species.

Viviparity has independently evolved only in a few species of salamanders.
Osteoporosis: Genetics
Authors: Li Wen‐Feng , Hou Shu‐Xun , Férec Claude , Chen Jian‐Min
Published: April 2013

Osteoporosis is characterised by comprised bone strength predisposing to an increased risk of fracture. It is a complex trait that is influenced by many genetic variants and their interactions with environmental factors. In the past four to five years, we have witnessed an accelerated pace in identifying and validating osteoporosis susceptibility loci, which was largely attributable to the use of genome‐wide association studies (GWAS). At least 15 genes (i.e.

VDR

,

ESR1

,

ESR2

,

LRP5

,

LRP4

,

SOST

,

GRP177

,

OPG

,

RANK

,

RANKL

,

COLIA1

,

SPP1

,

ITGA1

,

SP7

and

SOX6

) may be reasonably assigned as confirmed osteoporosis genes; and new osteoporosis‐associated genes are being increasingly reported. Notably, confirmed and promising osteoporosis genes are clustered in three biological pathways, the estrogen endocrine pathway, the Wnt/β‐catenin signalling pathway and the
RANKL
/
RANK
/
OPG
pathway. The ultimate promise of osteoporosis genetics is not only to better understand the disease process, but more importantly, to lead better therapeutic and preventive interventions.

Key Concepts:

Osteoporosis is characterised by low bone mineral density (BMD) and structural deterioration of bone tissue, leading to an increased risk of fractures that occur mostly at the hip, spine and wrist.

Osteoporosis is the most common metabolic bone disorder worldwide.

The burden of osteoporosis on the healthcare system is extremely large.

Osteoporosis is a complex trait that is influenced by many genetic variants and their interactions with environmental factors.

An accelerated pace in identifying and validating osteoporosis susceptibility loci has been observed in the past four to five years, which was largely attributable to the use of genome‐wide association studies (GWAS).

At least 15 genes (i.e.
VDR
,
ESR1
,
ESR2
,
LRP5
,
LRP4
,
SOST
,
GRP177
,
OPG
,
RANK
,
RANKL
,
COLIA1
,
SPP1
,
ITGA1
,
SP7
and
SOX6
) have recently been assigned as confirmed osteoporosis genes.

The currently reported osteoporosis‐associated genes are clustered in three biological pathways, the estrogen endocrine pathway, the Wnt/β‐catenin signalling pathway and the RANKL/RANK/OPG pathway.

Some newly found genes may be classified into the aforementioned three biological pathways once a clearer picture of their functional roles is developed. New biological pathways may also emerge once more if association and functional data are available.

Both common and rare genetic variants are likely to contribute to osteoporosis.

The advances in the genetics of osteoporosis hold promise for personalised medicine.
Protein Degradation in Cell Cycle
Authors: Shaik Shavali , Liu Pengda , Fukushima Hidefumi , Wang Zhiwei , Wei Wenyi
Published: April 2013

Cell cycle is a series of events that take place within a cell, leading to its division and duplication. Protein degradation through ubiquitin‐mediated proteolysis plays an important role in the cell‐cycle regulation. Most importantly, the Anaphase Promoting Complex/Cyclosome (APC/C) and the Skp1‐Cullin‐1‐F‐box complex (SCF) are the two major E3 ubiquitin ligase complexes that regulate proper cell cycle transitions by timely degrading the various key cell cycle regulators. The SCF complex controls the G1/S and the G2/M transitions by degrading Cyclin D, Cyclin E, p27, CDC6 and Wee1, whereas the APC complex facilitates the transition from metaphase to anaphase by degrading Cyclin A, Cyclin B, Securin and many other substrates. The APC complex also plays an integral role in the maintenance of chromatin metabolism, particularly in G1 and G0 via destruction of the aurora A kinase. These cell cycle transitions are tightly regulated, and defective regulation of cell cycle leads to genomic instability and ultimately cancer development.

Key Concepts:

Cell cycle is an essential physiological process, which generates additional number of cells when the body needs them.

Cell cycle checkpoints are the built‐in control mechanisms that ensure the accuracy of cell division in eukaryotic cells.

The timely destruction of various cell cycle regulators by the APC/C and the SCF complexes is necessary for proper cell cycle progression.

The protein degradation pathways involve the ubiquitin‐mediated modification of substrates, which are subsequently targeted for degradation by the 26S proteasome.

Misregulation of the cell cycle processes leads to abnormal cell division, chromosomal instability and subsequently cancer development.
Baculovirus Expression Strategies for Protein Complex Production
Authors: Sumitra Vijayachandran Lakshmi , Viola Cristina , Berger Imre
Published: April 2013

Protein complexes often contain multiple subunits, and it is these complexes that are at the core of biological function in the cell. Inherently low quantities of protein complexes in eukaryotes can prohibit the extraction of these essential cellular machines from native source material, posing a considerable challenge for functional analysis at the molecular level. The baculovirus expression vector system (BEVS) is particularly useful for recombinantly producing eukaryotic proteins in the quality and quantity required for deciphering their structure and function. Recent efforts have focused on improving reagents and streamlining protocols to routinely express protein complexes by recombinant baculoviruses. The challenge of integration of baculovirus expression in high‐throughput production pipelines for proteins and their complexes is being addressed.

Key Concepts:

Protein complexes are a cornerstone of biological function in the cell.

Recombinant production is essential to study many multiprotein complexes.

Ongoing development of expression systems for producing multiprotein complexes.

BEVS as a method of choice for large‐scale production of complexes requires integration of all genes in a single multigene baculovirus rather than coinfecting insect cell cultures with many baculoviruses.

Creation of new reagents and streamlined protocols to address the challenge of generating multigene baculoviruses for routine laboratory use.

Engineering baculoviruses and new host cell lines to further enhance protein production by BEVS.

Multigene vector generation incorporated into automation pipelines to increase the throughput of protein complex expression by BEVS.
Cyclooxygenase‐2: Biology of Prostanoid Biosynthesis and Metabolism
Authors: Patrignani Paola , Maenthaisong Ratree , Tacconelli Stefania
Published: April 2013

Cyclooxygenase (COX)
‐2 is a key enzyme in the conversion of
arachidonic acid (AA)
to
prostanoids
. Inhibition of COX‐2‐dependent
prostanoids
by nonsteroidal anti‐inflammatory drugs (NSAIDs) (both traditional(t) and selective for COX‐2, named coxibs) is involved in their efficacy in affecting pain and inflammation and in reducing the recurrence of colorectal polyps. However, the use of tNSAIDs and coxibs is associated with a small but consistent increase of cardiovascular (CV) risk which is believed to be due to the reduction of the biosynthesis of endothelial

COX‐2‐dependent prostacyclin (PGI
2
)

. Novel knowledge on the biology of COX‐2 show that endocannabinoids may be the substrate for the COX‐isozyme. Endocannabinoids and endocannabinoid‐derived products of COX‐2‐mediated oxidative metabolism serve a variety of regulatory functions. Interference with endocannabinoid metabolism by NSAIDs might contribute to their pharmacological effects.

Key Concepts:

COX‐2 is overexpressed in inflammation and cancer mainly through posttranscriptional mechanisms involving stabilisation of its mRNA.

Enhanced cytoplasmic levels of RNA stability factors, such as HuR, and reduced levels of microRNAs govern COX‐2 mRNA stability and translational efficiency.

The constitutive expression of COX‐2 in endothelial cells plays an important role in cardiovascular homoeostasis through the generation of prostacyclin.

COX‐2 is the target of NSAIDs, traditional and coxibs, thus leading to therapeutic effects and cardiovascular hazard, in some individuals.

The major mechanism of action of NSAIDs is through the inhibition of the conversion of AA to biologically active prostanoids.

Novel knowledge on the biology of COX‐2 shows that the activity of the COX‐isozyme may be involved in the generation of novel biologically active lipid mediators through the metabolism of endocannabionids.

COX‐2 might affect endocannabinoid tone by contributing to its reduction.

Endocannabinoids activate cannabinoid receptors to serve a variety of regulatory functions.

These novel actions of COX‐2 may suggest their contribution to the therapeutic effects of NSAIDs.

The (R) enantiomers of ibuprofen, naproxen and flurbiprofen, which are inactive to inhibit the metabolism of AA by COX‐2, are potent substrate‐selective inhibitors of endocannabinoid oxygenation.

The discovery of these novel effects of (R) enantiomers of NSAIDs opens the way to develop novel analgesic drugs based on this mechanism of action.
Intrinsically Disordered Proteins
Authors: Rezaei‐Ghaleh Nasrollah , Zweckstetter Markus
Published: April 2013

Intrinsically disordered proteins (IDPs) represent a growing category of proteins, especially in the eukaryotic proteomes. They are linked to a wide variety of biological functions, including those which are commonly impaired in cancer and neurodegenerative diseases. Since IDPs by definition do not adopt a well‐defined native structure in solution but exist as an ensemble of rapidly interconverting conformations, their structural characterisation is highly challenging. However, a large body of evidence accumulated mainly through nuclear magnetic resonance spectroscopy and small‐angle X‐ray scattering techniques indicates that IDPs are far from the statistical random coil polypeptide chains such as chemically denatured proteins, but exhibit a rich diversity of transient local and long‐range structural propensities. Such structural preferences are likely to be of functional importance and may be considered as potential drug targets.

Key Concepts:

A large proportion of proteins, especially in eukaryotic proteomes, do not adopt a well‐ordered structure in near‐physiologic conditions.

The classical tenet of biochemistry, the so‐called ‘structure–function paradigm’, that proteins need to have a well‐ordered structure to be functional, presents a restricted view. Instead, a wide variety of proteins from highly structured to almost completely unstructured ones play functional roles in biological systems.

Intrinsically disordered proteins play crucial roles in cellular processes as diverse as signalling, cell cycle control, molecular recognition, transcription, replication and chaperoning. Accordingly, they are closely linked to pathologic states such as cancer and neurodegenerative disorders.

Biophysical techniques, in particular NMR spectroscopy, SAXS and single‐molecule fluorescence measurements, provide detailed insight into the conformations populated by intrinsically disordered proteins.

The intrinsically disordered proteins are not like statistical coil‐like polypeptide chains, but show local and even long‐range structural preferences.

The ‘ensemble view’ of intrinsically disordered proteins resolves the ‘reconciliation problem’, the apparent inconsistence between their coil‐like hydrodynamic behaviour and presence of secondary and even tertiary contacts.

A more‐detailed structural knowledge of intrinsically disordered proteins might provide a basis for rational drug design against them.
Virocell Concept, The
Authors: Patrick Forterre
Published: April 2013

Viruses have been historically defined as viral particles (virions). The virocell concept has been proposed to put instead emphasis on the intracellular cycle of virus reproduction. In that view, viral infection transforms the infected cells (either a bacterium, an archaeon or a eukaryote) into a novel type of cellular organism, a virocell, whose aim is to produce virions. The virocell concept has several implications for the question of the origin and nature of viruses. It emphasises that viruses originated after ribosome‐encoding cells (ribocells) and can be considered asbona fide, cellular, living organisms. Notably, the virocell concept helps to realise that novel proteins could originate in two different cellular contexts (either ribocell or virocell) during genome replication/recombination. Considering the diversity, ubiquity and abundance of viruses, a huge proportion of proteins in the biosphere have therefore probably abona fideviral origin. Many of them were later on transferred to genomes of ribocells by viral/plasmid integrations. The concept of virocell thus helps to understand the fundamental role that viruses have played in biological evolution.

Key Concepts:

Virocells correspond to infected cells producing virons.

Ribovirocell are Infected cells that produce virions but can still divide.

The virus is a living entity during the intracellular phase of its life cycle.

Different organisms (archaea, bacteria, eucaryote or virus) can share the same cell, each one being defined by its own evolutionary trajectory.

The ancestors of modern viruses appeared after the invention of the ribosome and modern proteins but before the divergence of modern cells from their last common ancestor.

Viruses are a huge source of new genes that originated during replication/recombination of viral genomes.
Protein Conservation in Virus Evolution
Authors: Krupovic Mart , Bamford Dennis H
Published: April 2013

Evolution of viruses is considerably more rapid than that of the cellular organisms that they infect. The reach of sequence‐based evolutionary studies on viruses is therefore rather limited. The tertiary protein structure is generally conserved over longer time periods than the primary one. Indeed, structural studies proved to be more informative for reconstructing deep evolutionary connections between distantly related viruses. It has become apparent that certain viruses infecting hosts from different domains of life are remarkably similar in their virion assembly and architecture, suggesting a common ancestry for these structurally related viruses. Furthermore, the presence of several distinct architectural principles employed by viruses suggested that the origin of the current virosphere has multiple evolutionary origins. Insights obtained from numerous structural studies may not only be successfully used to refine the existing virus classification scheme, but may also lead to a major shift in our understanding on the origin, evolution and organisation of the viral domain.

Key Concepts:

Tertiary protein structure is conserved over longer periods of time than the primary one and thus allows recognising deep evolutionary connections between viruses that have diverged in a distant past.

The ability to build virions (i.e., presence of capsid proteins) is a hallmark feature of viruses that distinguishes them from other mobile genetic elements, such as plasmids and transposons.

Structural studies suggest that certain viruses infecting bacteria, archaea and eukaryotes are evolutionarily related.

Viral lineage hypothesis predicts a common origin for structurally related viruses, infecting hosts from different domains of life.

There are several different viral lineages of structurally distinct viruses, suggesting that the contemporary virosphere has multiple evolutionary origins.

The molecular virion complexity shared by viruses in different domains of life suggests that at the time of the last universal cellular ancestor (LUCA) viruses were already very sophisticated.
Nucleo‐cytoplasmic Large
DNA
Viruses (
NCLDV
) of Eukaryotes
Authors: Koonin Eugene V , Yutin Natalya
Published: April 2013

A group of diverse viruses with large
deoxyribonucleic acid (DNA)
genomes that replicate in the cytoplasm and in some cases partly in the nucleus of eukaryotic cells share a set of conserved genes and probably have evolved from a common ancestral virus. Known as nucleo‐cytoplasmic large
DNA
viruses (NCLDV), this class of viruses encompasses seven families:
Poxviridae, Asfarviridae, Iridoviridae, Ascoviridae, Phycodnaviridae, Mimiviridae
, and a probable new family represented by Marseillevirus and Lausannevirus. The family
Mimiviridae
includes giant viruses that possess genomes of a million or more basepairs that are comparable in size and complexity with some bacterial genomes. Phylogenetic analysis of the conserved genes of the NCLDV and mapping of the resulting phylogeny of the NCLDV onto the phylogeny of their eukaryotic hosts suggest an early origin and primary radiation of the NCLDV, possibly concomitant with the primary radiation of eukaryotes.

Key Concepts:

Seven families of viruses with large double‐stranded DNA genomes together constitute a monophyletic class of viruses known as Nucleo‐Cytoplasmic Large DNA Viruses (NCLDV).

All NCLDV share several genes that encode essential proteins involved in viral genome replication and virion formation.

An evolutionary reconstruction using a maximum‐likelihood model assigns approximately 50 genes coding for most of the key virus functions to the common ancestor of all extant NCLDV.

Some of the NCLDV families infect many diverse eukaryotes whereas many groups of eukaryotes are infected by diverse NCLDV suggesting that the major radiation of the NCLDV occurred at an early stage of evolution, perhaps concomitantly with eukaryogenesis.

The NCLDV includes the largest known viruses: Mimiviruses which encode over 1000 genes and are comparable to bacteria in size and complexity.
MMR
Controversy
Authors: Fitzpatrick Michael
Published: April 2013

The measles, mumps and rubella (MMR) controversy erupted in 1998 when Andrew Wakefield, a medical researcher at a London teaching hospital, suggested that the MMR vaccine, given routinely in the second year of life, caused inflammatory bowel disease and autism. Though the MMR‐autism theory was scientifically discredited by studies in epidemiology and virology, the campaign against MMR was taken up by parents and lawyers, politicians and journalists. It resulted in a fall in the uptake of MMR and outbreaks of measles as well as imposing a new burden of guilt and blame on parents of children with autism. A decade later Wakefield was found guilty by the General Medical Council of serious professional misconduct in relation to the conduct and publication of his research and struck off the medical register. His work was subsequently shown to be fraudulent.

Key Concepts:

The Andrew Wakefield theory that the MMR vaccine caused inflammatory bowel disease and autism provoked a major controversy between 1998 and 2010.

Epidemiological studies in different populations, using different methods, failed to confirm a causal link between MMR and autism.

Virological studies failed to confirm persistent measles infection in children with autism.

The notion of a distinctive inflammatory bowel condition in children with autism – ‘autistic enterocolitis’ – has not been generally accepted by gastroenterologists.

Litigation based on claims of a link between MMR and autism collapsed in the UK in 2003, in the USA in 2009.

Influential journalists promoted Wakefield as a scientific maverick, as a champion of autistic children and as a victim of the medical establishment.

The exposure of ethical violations and other forms of malpractice in the Wakefield research by the journalist Brian Deer led to his disgrace.

In 2010 Wakefield was found guilty of serious professional misconduct and struck off the medical register.

In 2011 the
BMJ
concluded that the Wakefield campaign against MMR ‘was based not on bad science but on a deliberate fraud’.
CRISPR
/
Cas
System and Resistance to Bacteriophage Infection
Authors: Garneau Josiane E , Moineau Sylvain
Published: April 2013

Bacteria and phages co‐evolve in their environments through an arm‐race with bacteria developing strategies to combat infection by diverse phages, while phages finding ways to circumvent them. Clustered regularly interspaced short palindromic repeats (CRISPR) loci, along with several Cas (CRISPR‐associated) proteins, represents a form of immune system widespread in Bacteria and Archaea. The CRISPR loci evolve through the incorporation of short
deoxyribonucleic acid
(DNA) sequences (spacers), derived mostly from extrachromosomal DNA such as phage or plasmid sequences, between two partially palindromic repeats. A CRISPR transcript is produced and cleaved within the repeats by Cas protein(s) with or without other host proteins to produce smaller
ribonucleic acid
fragments (RNAs). These small mature RNAs and Cas proteins target and cleave through base complementarity the invading nucleic acids to ensure cell defence. Phages can also evade the CRISPR/Cas system through point mutations or deletions, forcing the host to adapt by either acquiring new spacers or relying on other defence systems. Hence, phage/host interactions can be appreciated at a microbial population‐wide level through the dynamism of CRISPR/Cas loci.

Key Concepts:

CRISPR/Cas loci are composed of multiple repeat‐spacer units associated with a group of specific genes (
cas
genes).

The spacers (short DNA sequences mainly from extrachromosomal elements including foreign DNA) are inserted into CRISPR loci and serve as a molecular directory and memory to prevent future invasion.

CRISPR/Cas system prevents bacteriophage infection and plasmid transfer.

Depending on the CRISPR/Cas system, the DNA (or RNA) target is cleaved within the proto‐spacer (homologous spacer sequence in the invading element).

The successful cleavage of the target relies on the identity between the bacterial spacer and the target (proto‐spacer).

CRISPR loci are highly variable and constantly respond to a phage/host or plasmid/host co‐evolution.

The CRISPR/Cas can inadvertently acquire self‐DNA and be responsible for some form of auto‐immunity, presumably leading to cell death. To survive this self‐attack, either the targeted genomic DNA is altered by mutation/deletion or the CRISPR/Cas locus is inactivated.

By preventing introduction of plasmid, the CRISPR/Cas system can be used to limit the spread of antibiotic resistance genes.

Natural
bacteriophage insensitive mutants
or
plasmid interfering mutants
can be generated to respectively increase the efficiency or the safety of industrial strains.
RNA
Viruses: Control, Mutagenesis and Extinction
Authors: Lázaro Ester
Published: April 2013

Ribonucleic acid (RNA)
viruses form populations with a high degree of genetic diversity, which facilitates adaptation to most changes in the environmental conditions. Therapeutic treatments are a type of change in the selective pressures to which RNA viruses also try to adapt. The selection of drug‐resistant mutants and escape mutants able to evade the immune response of the host are clear examples of the capacity of RNA viruses to maintain their infectivity in the presence of inhibitors. Therefore, it is increasingly evident that to find successful control measures for RNA viruses it is necessary to take into account the adaptive potential of these pathogens. Combination therapies and multiepitopic vaccines are antiviral strategies that have demonstrated their effectiveness. Another promising approach, referred to as lethal mutagenesis, exploits the high error rates of RNA viruses to push them above an error threshold incompatible with viability.

Key Concepts:

RNA viruses cause diseases that can be very difficult to treat.

RNA viruses replicate their genomes with a very high error rate, giving rise to populations that contain a large genetic diversity.

RNA viruses possess a great adaptive capacity that permits them to rapidly generate drug‐resistant mutants, as well as antibody or cytotoxic T lymphocyte escape mutants.

The development of strategies for the control of RNA viruses must take into account their adaptive potential.

One of the most successful strategies to control RNA viruses is the use of combination therapies.

Lethal mutagenesis is a new antiviral therapy, which consists in the artificial increase of the virus error rate above a limit that is incompatible with viability.
Clinical Chemistry in Paediatrics
Authors: Jones Patricia M
Published: April 2013

Clinical chemistry in the arena of paediatrics often involves some special concerns which are not commonly encountered in laboratories that perform testing on primarily adult populations. Being aware of these potential problems and the major differences between the two types of laboratories is important. A laboratory with an adult clientele will occasionally encounter specimens from paediatric patients and being conscious of possible issues allows the laboratory to respond correctly when they arise. The purpose of this article is to discuss basic day to day operational issues facing a chemistry laboratory in a paediatric setting, including several topics related to sample volume concerns and their effect on work flow. The article then describes the most noticeable differences in test menu and testing practices found between paediatric and adult institutions.

Key Concepts:

Paediatric patients have limited blood volume which restricts the sample volumes which are available for testing.

Test results from paediatric patients must be interpreted using age‐ and gender‐related reference intervals.

Testing for Inborn Errors of Metabolism is commonly performed in‐house in paediatric laboratories.

Sweat chloride testing is a common test in a paediatric laboratory and is still used to diagnose Cystic Fibrosis.
Molecular Genetics of Myeloproliferative Disorders
Authors: Finnegan Kathleen
Published: April 2013

The myeloproliferative neoplasms (MPNs) are a group of clonal stem cell disorders characterised by increased proliferation of one or more cell lines. The 2008 World Health Organization classification of the four major MPNs includes chronic myeloid leukaemia, polycythaemia vera, primary myelofibrosis and essential thrombocythemia. In recent years, the research and utilisation of molecular markers have been paving the way for a better understanding of the MPNs for pathophysiology, classification, prognosis and treatment. With the introduction of the BCR/ABL fusion 1 gene and the JAK 2 mutation involving the tyrosine kinase pathways, it is now used in evaluating patients for diagnosis, prognosis and enhancing current practices. More and more molecular markers (MPL, TET2, LNK, CBL, IDH1 and IDH2) are being identified with the hope of having a better understanding for clinical assessment and management of these neoplasms. The importance for patient care is about understanding the role of these molecular mutations in the MPNs and what the future is for prognosis and treatment of patients diagnosed with these disorders.

Key Concepts:

The myeloproliferative neoplasms are clonal stem cell disorders due to unregulated cell production.

The MPNs have increased tyrosine kinase involvement with an increase of cell proliferation and a loss of apoptosis.

The BCR/ABL fusion gene1 plays a critical role in the pathogenesis of chronic myeloid leukaemia.

The BCR/ABL fusion gene is the reciprocal translocation between the chromosomes 9 and 22.

The MPNs that do not present with the BCR/ABL mutation are referred to the BCR/ABL negative neoplasms.

Tyrosine kinase activation involves signal transduction in the proliferative pathways.

JAK kinase is involved in myeloid cell proliferation and differentiation.

JaK2 mutation results in a ‘gain of function’ for the signalling molecule of the tyrosine kinase pathway.

Jak2 is present in most patients with PV, ET and PMF.

MPL, LNK, TET2, CBL, ASX‐L1,IDH1/IDH2, EZH2, DNMT3 and IKZF1 are currently known mutations in BCR/ABL negative MPNs.
Genetic Epidemiology of Smoking Behaviour and Nicotine Dependence
Authors: Korhonen Tellervo , Kaprio Jaakko
Published: April 2013

The public health significance of sustained smoking is overwhelming. The genetic epidemiology and architecture of smoking behaviour and nicotine dependence have been studied for several decades. Twin, family and adoption studies show consistent evidence for genetic effects on many aspects of smoking behaviour and nicotine dependence. Gene–environment interactions have been detected, such as parental monitoring moderating genetic vulnerability for smoking initiation. Molecular genetic analyses have only recently identified few genes consistently associated with amount smoked and nicotine dependence, whereas large genome‐wide association studies have identified only a handful of genes associated with nicotine dependence. The nicotinic receptor alpha 5 gene (CHRNA5) variant associated with nicotine dependence in genetic association studies is functional. Further studies with more sophisticated phenotypes, larger sample sizes and better measures of the environment are needed.

Key Concepts:

Smoking behaviour and nicotine dependence aggregate in families.

Genetic liability underlies this familial aggregation.

The heritability of smoking behaviour is moderate, but varies between populations.

The genetic architecture of nicotine dependence is poorly known.

Large genome‐wide association studies have identified only a handful of genes associated with nicotine dependence.

The nicotinic receptor alpha 5 gene variant associated with nicotine dependence in genetic association studies is functional.

This functional variant affects nicotine intake in animal models.

Gene–environment interactions have been detected for smoking behaviours, such as parental monitoring moderating genetic vulnerability in youth.
Animal Personality
Authors: Réale Denis , Dingemanse Niels J
Published: April 2013

Personality represents individual behavioural differences that are consistent over time and across situations. In humans and many taxa of nonhuman animals, individuals differ in the way they react to novel and challenging situations, and these differences affect resource acquisition, social interactions, survival and reproduction. Researchers in fields like psychology, behaviour genetics or behavioural ecology have developed different methods to study and measure personality differences, each method being characterised by its own advantages and limitations. The results associated with each method provide different colours to the concept of personality. The main goal of students of animal personality is to understand why individuals differ in their behavioural responses to identical stimuli, and why they often show sets of correlated behaviour traits. Several adaptive theoretical hypotheses offer promising explanations for the maintenance of personality differences in wild populations, although empirical confirmation of their predictions is still needed.

Key Concepts:

Personality represents individual behavioural differences that are consistent over time and across situations.

The concept ‘individual consistency’ only makes sense with the population as a referent.

Individual differences define the evolutionary potential of a population.

Individual differences within a population, differences between populations and potentially between species, are all expressions of genetic/environmental differences at different levels of organisation.

Rating, coding and experimental manipulation, are the three approaches to study personality in animals: each approach has advantages and limitations.

Individual behavioural differences are key to understanding many ecological processes and patterns.

We distinguish five evolutionary mechanisms that can explain the maintenance of personality differences in wild populations: trade‐offs between life history traits; spatial‐temporal heterogeneity; frequency‐dependent selection; antagonistic selection; correlational selection.
Ecological Monitoring
Authors: Yoccoz Nigel Gilles
Published: April 2013

Ecological monitoring aims at inferring causes of ecosystem changes, by measuring ecosystem state variables in space and time. This is required for management, when different actions are possible and their consequences need to be assessed and compared, and for science, which aims at establishing the causes of observed patterns. The success of an ecological monitoring programme will heavily depend on having well‐articulated questions and objectives, formulated using a simple conceptual model. Future challenges lie in integrating monitoring programmes through questions and models that include both global and local scales, and adding the human dimension in order to achieve social‐ecological monitoring.

Key Concepts:

Many ecological monitoring programmes have been inefficient and passive.

Ecological monitoring should start with simple model(s) and questions.

The model(s) and questions should be frequently confronted with data, and changed if necessary.

Developments in statistics and other fields are crucial for accurate estimation of state variables.

Long‐term ecological research (LTER) sites are examples of successful monitoring, with major results.

More work is needed to integrate monitoring programmes in order to achieve local and global objectives.

Social and economic aspects, such as ecosystem services, need to be added to monitoring programmes.
Genetics of Congenital Tooth Agenesis
Authors: Vieira Alexandre R
Published: April 2013

Tooth agenesis is the most common congenital anomaly in humans. It has variable expression and most severe forms segregate in families, which allowed for the application of strategies for gene identification. A subset of those cases is caused by mutations inPAX9,MSX1,AXIN2,EDA,EDAR,EDARADD, andWNT10A. However, the vast majority of cases of tooth agenesis is less severe and may be the result of hypomorphic genetic variations in multiple genes. Of particular interest is the association of tooth agenesis with other conditions such as cleft lip and palate and cancer. Individuals born with oral clefts have a much higher chance to have tooth agenesis outside the cleft area. Cases of tooth agenesis caused by mutations inAXIN2can also develop colorectal cancer. These types of cases suggest the understanding of the aetiology of developmental disruptions of dental development can also impact other relevant fields of medicine.

Key Concepts:

Oligodontia (agenesis of six or more teeth excluding third molars) is not common in the population (0.3%).

Hypodontia (agenesis of less than six teeth excluding third molars) can be as common as 11% in the population.

Mutations in genes such asPAX9,MSX1, andAXIN2explain just a small percentage of oligodontia cases segregating in an autosomal dominant fashion.

Mutations in genes such asWNT10Aexplain just a small percentage of hypodontia cases segregating in an autosomal dominant fashion.

X‐linked inheritance of isolated oligodontia can be caused by mutations in ectodermal dysplasia genes.

Tooth agenesis is four times more common in individuals born with oral clefts, as well as in their relatives.

Individuals with oligodontia caused by mutations inAXIN2are at higher risk for colorectal cancer.
Molecular Genetics of Congenital Adrenal Hyperplasia
Authors: Parajes Silvia , Krone Nils
Published: April 2013

Congenital adrenal hyperplasia (CAH) is a group of autosomal recessive disorders causing an impairment of cortisol biosynthesis. The phenotypic expression of different CAH forms depends on the underlying enzymatic defect. Steroid 21‐hydroxylase (CYP21A2) and 11β‐hydroxylase (CYP11B1) deficiencies only affect adrenal steroidogenesis, whereas 17α‐hydroxylase (CYP17A1) and 3β‐hydroxysteroid dehydrogenase type 2 (HSD3B2) also impair gonadal steroid biosynthesis. P450 oxidoreductase deficiency (PORD) manifests with apparent combined CYP17A1–CYP21A2 deficiency. In contrast to other CAH forms, PORD also causes skeletal malformations and genital ambiguity in both sexes. Three additional enzymatic defects have been traditionally classified as CAH. Steroidogenic acute regulatory protein (StAR) deficiency results in congenital lipoid adrenal hyperplasia (CLAH), and has the unique feature of adrenal and gonadal lipid accumulation. P450 side‐chain cleavage (CYP11A1) deficiency resembles the CLAH phenotype, but patients have normal‐sized or absent adrenals. Aldosterone synthase (CYP11B2) deficiency manifests with isolated aldosterone deficiency and normal cortisol synthesis.

Key Concepts:

Congenital adrenal hyperplasia (CAH) is one of the most common inherited metabolic disorders and comprises a group of autosomal recessive conditions.

Molecular genetic analysis of the
CYP21A2
gene is challenging due to a high rate of conversions and a multitude of possible complex rearrangements.

Common mutations in
CYP21A2
account for the majority of cases including gene deletions, chimeric genes, seven single point mutations, an eight base‐pair deletions and a cluster of point mutations.

CYP21A2
gene duplications have to be considered in carriers of the p.Gln318X mutation to provide the correct molecular genetic diagnosis.

Other forms of CAH are less often caused by common mutations, which are only found in specific populations.

The genotype correlates overall well with the adrenal phenotype in all CAH forms, CLAH, CYP11A1 and CYP11B2 deficiencies.

Although a trend exists, correlation between genotype and genital development is weaker, and it is particularly poor in CYP11A1 or 3β‐hydroxysteroid dehydrogenase type 2 deficiencies.

Mutations in
POR
and
CYP17A1
genes can be associated with clinically isolated 17,20‐lyase deficiency.

CYP11A1 deficiency and CLAH due to StAR deficiency can manifest with a phenotype resembling familial glucocorticoid deficiency.

Molecular genetic diagnosis is essential to provide the correct diagnosis and allow for appropriate clinical and genetic counselling.
Genetic and Epigenetic Heterogeneity in Cancer
Authors: Stevens Joshua B , Abdallah Batoul Y , Horne Steven D , Liu Guo , Bremer Steven W , Heng Henry H
Published: April 2013

Cancer is commonly viewed as a disease of the stepwise accumulation of gene mutations. However, genetic and epigenetic heterogeneity (GEH) is pervasive in cancer, playing a key role in promoting cancer progression. GEH occurs at three primary levels, the genome, gene and epigenetic levels and increases during the aging process and during stress. GEH at the genome level plays the largest role of the three in cancer evolution, as genome level change creates new cellular systems whereas genetic and epigenetic level change mainly modify the existing system. This system replacement achieved by genome level change is essential for cancer evolution. GEH challenges traditional molecular‐based cancer research that focuses on common gene mutations in linear models of progression. Clinically, GEH must be monitored in order to determine the evolutionary potential of a tumour. Increased knowledge about GEH will benefit basic research and cancer treatment.

Key Concepts:

Cancer progression is a typical process of somatic evolution of which system heterogeneity is a key component.

Genetic and epigenetic heterogeneity occurs at three levels: the genome level, the gene level and the epigenetic level. The three levels of genetic and epigenetic heterogeneity are highly interactive. Genome level heterogeneity can influence gene and epigenetic level heterogeneity and vice versa.

Genetic and epigenetic heterogeneity, especially at the genome level is the key driver of somatic evolution.

Genome level change results in macroevolution, which creates new systems, whereas gene and epigenetic level changes result in microevolution which modifies the existing system.

The heterogeneity within cancer can lead to the identification of multiple driver pathways, however, each identified pathway reduces the relative contributions of the others to the cancer phenotype within patient populations. This leads to limitations of clinical predictions that are based on individual genes or pathways.

Monitoring heterogeneity rather than specific pathways will lead to a better understanding of the evolutionary potential of a tumour and will aid in treatment and diagnosis.
Biodiversity and Ecosystem Function of Decomposition
Authors: Swan Christopher M , Kominoski John S
Published: April 2013

Decomposition of organic matter derived from plants is an important ecosystem process in many environments, both aquatic and terrestrial. This process underlies soil formation and the liberalisation of energy to higher trophic levels. Since consumers do not influence the renewal rate of detritus, this donor‐controlled resource often serves to stabilise food web dynamics. How species loss influences decomposition rate involves different mechanisms than invoked for plant and consumer communities. In particular, loss of tree species in forests translates into loss of leaf litter species in the detrital pool. As there can exist high interspecific variation in leaf litter chemistry among tree species, how consumers (e.g. bacteria, fungi, invertebrates) respond to resource variability is often the focus of biodiversity–ecosystem function research in these ecosystems. Although competition and facilitation among microbial and invertebrate consumers might generate emergent effects of biodiversity on organic matter processing rates at the consumer level, the strong interactions between consumers and leaf litter species diversity comprise an important link as to how biodiversity in detritus‐based ecosystems influences decomposition.

Key Concepts:

Decomposition of senesced plant material is an important ecosystem process.

Loss of tree species translates in the loss of resource diversity from the detrital pool.

Interspecific variation in leaf litter quality drives nonadditive effects of biodiversity on decomposition via responses by microbial and invertebrate consumers.

Composition and dominance, more so than species richnessper se, drive the strength of nonadditive effects.
Parasites as Prey
Authors: Goedknegt Anouk , Welsh Jennifer , Thieltges David W
Published: April 2013

Parasites are usually considered to use their hosts as a resource for energy. However, there is increasing awareness that parasites can also become a resource themselves and serve as prey for other organisms. Here we describe various types of predation in which parasites act as prey for other organisms: (1) predation of nonhosts on infected hosts (concomitant predation), (2) predation on free‐living parasite life cycle stages, (3) predation on ectoparasites in form of grooming or cleaning and (4) predation or hyperparasitism by other parasites. In many cases, these types of predation significantly reduce the numbers of parasites and thus affect parasite population dynamics. In contrast, predation on parasites is often beneficial for the hosts as they are released from parasite burden. Finally, when parasites act as prey they may contribute to the nonhost predator's diet, in some cases constituting a significant proportion of energy intake.

Key Concepts:

There is increasing awareness that parasites can become a resource themselves by serving as prey for other organisms.

Predation on parasites can have significant effects on parasite population dynamics, for example, by interfering with the transmission of infective stages.

For hosts, parasite predation may result in a reduced parasite burden, the so‐called dilution effect.

When nonhosts prey on parasites or infected prey, this may have an effect on their energy uptake by mediating the energetic value of their prey.

Future studies on the levels of predation on parasites in food webs will increase our understanding of disease dynamics as well as the topology and functioning of food webs.
Ecology of Deep Oceans: Hadal Trenches
Authors: Jamieson Alan J
Published: April 2013

The majority of the Earth is covered by ocean which itself averages greater than 3500 m deep. It is comprised mainly of the vast deep ocean plains, which span a depth range of 2000–6000 m. The maximum depth of the ocean however is nearly 11 000 m deep. These extremely deep areas are a result of tectonic plate convergence where an oceanic plate is subducted beneath a neighbouring continental plate. This subduction forms extraordinarily deep trenches which comprise what is known as the ‘hadal zone’. The hadal zone (6000–11 000 m) is therefore encompassed by clusters of disjunct and often extremely isolated deep trenches and troughs. The morphology of these habitats had provided a setting where environmental conditions (hydrostatic pressure and food supply) differ greatly from the majority of the deep‐sea and has resulted in high levels of species endemism at the greatest depths.

Key Concepts:

The deepest biozone in the oceans is the hadal zone (6000–11 000 m deep).

The hadal zone is comprised mainly of deep trenches formed by tectonic convergence.

The trench environment is characterised by high hydrostatic pressure, low temperatures, the absence of light and a limited food supply.

Trench topography provides a unique setting with regard to food supply input because organic matter (food) is accumulated at the deepest trench axis.

High levels of species endemism are observed in trenches as a result of their geographical isolation.

Physiological adaptation to high pressure and low food supply is an essential prerequisite for survival in the trenches.

Most metazoan taxa are represented in these deep trenches.

Until recently, the technical challenges of studying the hadal zone were responsible for a dearth of information regarding the ecology at these depths.

Research into the ecology of the hadal zone is in its infancy relative to shallower biozones.