bluuebunny/crossref_metadata_2025 huggingface dataset:
Racism, Ethnicity, Health and Society
Authors: Bradby Hannah
Published: April 2013

Racialised thinking about human diversity underlies some infamous medical and scientific abuses, although in some cases the form of discrimination is cloaked in the language of ethnicity. A central dilemma of measuring equity along the lines of ethnicity is that categories of difference are inevitably reinforced. Although measuring iniquity may facilitate its redress, it may also reify and reinforce categories which are the basis of discrimination. The role of historical manifestations of racism in the case of rickets and sickle cell disease are discussed. The compounding of racialised disadvantage with other forms of marginalisation is discussed in terms of individual and institutional discrimination with regard to the origins of the HeLa cell line.
Heredity and the Novel
Authors: Davis Lennard J , Jarman Michelle
Published: April 2013

The concept of heredity, as represented throughout the history of the novel, may be further illuminated by certain discoveries of the modern science of genetics. Since the novel's origin, authors have explored cultural beliefs and anxieties around heredity, nobility, bloodlines, birthrights and ‘tainted’ lineages. As modern genetics grows increasingly sophisticated, novelists engage in more complex ethical questions ranging from genetic selection and manipulation to reproductive choice and hereditary ‘rights’. In science fiction genres, themes can expand into human enhancement, species destruction and creation. Yet even as contemporary works engage in the complex new science and bioethical questions that grow out of genetic research, contemporary writers remain fundamentally interested in exploring what genetic knowledge and technology means within the context of intimate human relationships.

Key Concepts:

Since the origin of the novel, authors have engaged with hereditary themes.

Changing historic notions about heredity are reflected in novels of those periods.

Works of literature are important sites of investigation into public perceptions of emergent scientific ideas about heredity.
Deaf Community and Genetics
Authors: Middleton Anna , Emery Steve , Palmer Christina , Boudreault Patrick
Published: April 2013

The Deaf community consists of a group of like minded people sharing a common sign language and culture. This community has a positive attitude toward being deaf. Typically, deafness is considered a strong part of linguistic and cultural identity and Deaf individuals do not wish to have treatments or a cure.Deaf people have concerns that a hearing society, with little knowledge or experience of their rich culture and language, would encourage the use of pre‐implantation genetic diagnosis and prenatal genetic testing for deafness with the ultimate aim of having hearing children. They feel strongly that deafness is a source of human variation that does not warrant the use of genetic technology in this way. Deaf (written with an uppercase 'D') refers to people who belong to the Deaf community. Deaf people use sign language (e.g. British Sign Language, American Sign Language, Auslan, etc.) as their first or preferred language. They also have a positive identity attached to being Deaf. People who consider themselves deaf (written with a lowercase 'd') or hard of hearing tend to use speech as their preferred form of communication, and may experience being deaf as a medical disability that needs to be treated. These groups often have very differing attitudes towards the use of genetic technology.

Key Concepts:

Deaf people often do not mind if their children are deaf or hearing; whereas hearing or hard of hearing people typically prefer to have hearing children.

Genetic technology can be used to reduce the number of deaf children born, for example, via the use of preimplantation genetic diagnosis with a selection of embryos that contain the genes for hearing or via the use of prenatal genetic diagnosis where a termination of pregnancy is offered if the baby is found to have the genes for deafness.

There is a serious concern amongst the Deaf community that genetic technology will be ‘misused’ by hearing people to select against deafness. If significant number of people choose to use genetic technologies to facilitate the selection of hearing children then they fear that this will result in decline of the Deaf community.

If fewer deaf babies are born, Deaf people recognise that this may result in a decimation of their language and culture, and an increasing disregard for the rights of self‐determination of deaf individuals.

Being deaf can arise as a result of different factors, genetics is only one of these. It is likely that there will always be environmental causes, newly arising genetic causes, and people who do not use genetic technology for diagnostic purposes, and so there will always be D/deaf people in society.
Personal Identity: Genetics and Determinism
Authors: Chadwick Ruth
Published: April 2013

Traditional theories that locate the identity of the human person in physical or psychological attributes are subject to reinterpretation in the light of advances in genetics. A person's genome may be regarded as the ‘essence’ of the person, or as the foundation of specific characteristics that are central to a person's identity. A view that there is no such thing as ‘essence’ may still give genes an important role to play in constructing a person's biography, both as regards the past (ancestry tracing) and the future (e.g. future health status). Collective identity is also an issue, in terms of common origin or disease groupings. Developments in direct to consumer testing and whole genome sequencing have the potential to reinforce both the importance accorded to the genome, and genetic determinism.

Key Concepts:

There is a wide range of views about the importance of genes to personal identity.

In a physical account of identity, genes offer a consistent basis for identity throughout many changes to an individual, but present problems in the case of division.

In a psychological account of the person, while genes may be relevant in setting the parameters within which a person develops, this should not be taken to justify a reductionist view of genes and identity.

On a constructivist account, individuals’ self‐perceptions may be influenced by genetic information. This is likely to grow in importance as personalised genetic information becomes more widely accessible.

If personal identity is tied up with genes, questions of identity will come to the fore in discussions of gene therapy.

Developments in direct to consumer testing and whole genome sequencing have the potential to reinforce both the importance accorded to the genome, and genetic determinism.

Although genetic determinism was claimed to be dead upon the completion of the human genome project, current developments such as genetic ancestry testing hint at a resurgence of a popular belief in a meaningful identity buried deep within the genetic code.
Addiction and Genes: Animal Models
Authors: Phillips Tamara J , Gubner Noah R
Published: April 2013

Genes influence susceptibility to alcohol and drug dependence. The sequence of a gene may differ among individuals, and each gene form (or allele) may produce a different product (i.e. a different form of a protein, such as an enzyme, receptor or hormone). Differences in gene sequence or polymorphisms are one source of individual differences in risk for addiction. In addition, individuals with the same form of a gene may express the gene product in different amounts, and this may be another source of differential risk. Genetic animal models are used to study genetic influence and identify addiction‐relevant genes. These include classical genetic models, such as standard inbred strains and selected lines, and newer era genetic models and techniques such as transgenics, knockouts, microarray analysis, next generation sequencing and optogenetics. These genetic models are important tools used to identify factors that influence risk for addiction and mechanisms that could lead to novel treatments.

Key Concepts:

Addiction is not a single gene trait (also known as a Mendelian trait) like Huntington's disease or sickle‐cell anaemia.

Each gene that influences addiction may have a relatively small influence but together can account for a significant amount of the variation among people in risk for addiction.

The newest tools used to explore the genetics of addiction have benefited from the complete sequencing of the human genome and the genome of several other species.

Successful selective breeding indicates that there is genetic influence on the measured trait.

Bidirectional genetic research occurs when animal studies lead to investigation of similar genetic factors in humans and vice versa.

Optogenetics is a relatively new and exciting procedure for controlling brain activity with light using specific genetic manipulations.
Mitosis and Meiosis: Molecular Control of Chromosome Separation
Authors: Nagasaka Kota , Gallego‐Paez Lina M , Hirota Toru
Published: April 2013

Accurate chromosome segregation during both mitosis and meiosis is governed by an intricate and synchronised cascade of events. These are controlled by the molecular networks that ensure the proper assembly of sister
deoxyribonucleic acid
(DNA) molecules produced during DNA replication, followed by the action of the spindle that pulls the sister chromatids apart. Mistakes in these processes would lead to chromosome transmission defects and subsequent aneuploidy, a common hallmark of many tumour cells. Herein, we review recent progresses in the molecular illustration of the chromosome architecture and function specially those depending on the structural maintenance of chromosome family of protein complexes, in conjunction with the spatio‐temporal regulation of cell‐cycle progression.

Key Concepts:

Cohesin is the glue that entraps duplicated sister DNA.

DNA replication is coupled to the establishment of sister‐chromatid cohesion through cohesin acetylation.

The bulk of cohesin is removed from chromosome arms by phosphorylation in early stages of mitosis, whereas centromeric cohesin is removed by separase‐mediated cleavage at the metaphase anaphase transition.

Condensin is required for a proper mitotic chromosome assembly.

Smc family of protein complex determine chromosomal structure and function throughout the cell cycle.

Separase is tightly regulated in cell cycle and become active exclusively at the onset anaphase.

SAC monitors the presence of unattached kinetochores.

Protein degradation mediated by the APC/C drives anaphase onset.

Back‐to‐back orientation of kinetochores is required for Meiosis II and mitosis, whereas, side‐by‐side orientation of kinetochores is required for meiosis I.

Shugoshin protects precocious dissociation of cehesin.

Bi‐orientation of chromosomes depends on the correction mechanisms and spindle assembly checkpoint.
Severe Combined Immune Deficiency (
SCID
): Genetics
Authors: Fischer A
Published: April 2013

Severe combined immunodeficiency consists of an array of genetically determined blocks in T‐lymphocyte development. Characterisation of genetic defects contributes to a better understanding of lymphocyte differentiation pathways. Seventeen distinct defects have now been characterised that affect multiple steps of T lymphocytes ontogenesis, from defective survival of several haematopoietic lineage precursors, premature cell death of lymphocyte precursors, defective interleukin‐7‐dependent survival/proliferation of T‐lymphocyte precursors, defective recombination of T‐cell receptor (TCR) genes, defective (pre) TCR signalling and defective egress of the thymus. These disorders are life threatening because of the early onset of various infections notably caused by opportunistic agents, hence stressing the importance of T cell adaptive immunity in longevity. These disorders can be cured by allogeneic haematopoietic stem cell transplantation, some by gene therapy while neonatal screening is being developed.

Key Concepts:

Severe combined immunodeficiencies are rare inherited diseases caused by defective development of the T lymphocyte lineage.

Clinical consequences are devastating leading to death within the first year of life in the absence of treatment.

Allogeneic transplantation of haematopoietic stem cells or in some cases gene therapy can be life saving by restoring T‐cell development.

Seventeen different genetic defects have been found to cause SCID, they are classed in six groups as based on pathophysiology.

SCID variants – defined by the presence of residual T cells – are relatively frequent as a consequence of hypomorphic mutation or reversion.
Public Health Genomics
Authors: Zimmern Ronald L
Published: April 2013

Public health genomics is a subspecialty within public health that deals with the application of genetics, genomics and molecular science to the promotion of health and the prevention of disease. Its subject matter is multidisciplinary in scope and requires an understanding not just of scientific advances, but also the population sciences, biostatistics and epidemiology, and the humanities and social sciences. Its fundamental concept is that genetic variation is an important determinant of health, and that all human traits and pathology come about as a consequence of the combined effects of genetic and environmental factors. These considerations have important implications for the future practice of public health across all its roles: health protection, health promotion and the development and organisation of health services. Its impact is not only just on inherited disorders, but also across the entire range of infectious and noncommunicable diseases. Public policy and regulatory frameworks will need to be adapted to ensure the responsible implementation of genome‐based knowledge and technologies within society.

Key Concepts:

Public health genomics is multidisciplinary, with its knowledge base deriving from not just genetic and molecular science, but also from the population sciences, the humanities and social sciences.

Public health genomics relies on understanding that genetic variation is an important determinant of health, and that all human traits and pathology comes about as a consequence of the combined effects of genetic and environmental factors.

The mission of public health genomics is to improve population health through the use of knowledge and technologies in an effective and responsible manner.

Public health professionals must ensure that they understand the part played by genetic variation and other molecular and cellular processes, and how that understanding can be used to contribute to the health of individuals and populations.

Training and education, improving the utility and efficiency of research, ensuring safe and effective services and technologies, supporting the development of relevant public policy and of health service provisions are all essential activities within public health genomics.
Spinal Muscular Atrophy
Authors: Farrar Michelle A , Kiernan Matthew C
Published: April 2013

Spinal muscular atrophy (SMA) is a relatively common neurodegenerative disease marked by muscle weakness and atrophy due to degeneration of motor neurons of the spinal cord and lower brain stem. The most common form of SMA is caused by homozygous disruption of the survival motor neuron 1 (
SMN1
) gene on chromosome 5q and results in insufficient levels of SMN protein in motor neurons. There is a broad spectrum of clinical severity, which inversely relates to the number of copies of the
SMN2
gene. Although advances in the understanding of the disease biology have provided therapeutic targets, no effective disease modifying treatment is currently available. Promising therapeutic strategies include utilising the unique genomic structure of the
SMN
genes to increase SMN protein transcripts, neuroprotective agents, gene therapy and stem cell transplantation.

Key Concepts:

The most common form of SMA is secondary to homozygous disruption of the
survival motor neuron 1 gene
(
SMN1
) located on chromosome 5q13 and results in insufficient levels of survival motor neuron (SMN) protein in motor neurons.

SMA is classified into three common types based on age of onset and maximal motor milestones attained (Munsat and Davies, 1992): SMA type 1 has onset within the first 6 months and patients do not sit without support; SMA type 2 patients manifest weakness after 6 months of age and the maximum motor milestone is the ability to sit; SMA type 3 patients attain the ability to walk.

The clinical spectrum of SMA is broad, ranging from early infant death to normal adult life with minimal weakness.

The diagnosis of SMA is based on molecular genetic testing. Approximately 95% of individuals with SMA are homozygous for a deletion of
SMN1
and 5% may reflect compound heterozygotes.

In humans there is an almost identical copy of the gene,
SMN2
, which predominantly encodes a truncated form of the SMN protein that is rapidly degraded. Functional ability inversely relates to
SMN2
copy number.

Current management incorporates multidisciplinary care and focuses on preventing and addressing the complications of weakness and promoting quality of life.

Advances in the understanding of molecular pathogenesis of SMA have provided novel therapeutic targets, however translation has held limited success to date.
Parkinson Disease
Authors: Hatano Taku , Hattori Nobutaka
Published: April 2013

Parkinson's disease (PD) is a common movement disorder caused by loss of dopaminergic neuronal cells. The molecular mechanisms underlying neuronal degeneration in PD remain unknown; however, it is clear that genetic factors contribute to its pathogenesis. Over 15 loci and 11 causative genes have been identified so far, and many studies examine their effects on monogenic and sporadic forms of PD.
Parkin
mutations are the most common cause of autosomal recessive early onset PD. Parkin functions as an E3 ubiquitin ligase, which monoubiquitinates and polyubiquitinates the target proteins. Consequently, parkin participates in multiple cellular processes, such as protein degradation, mitochondrial function, endoplasmic reticulum stress, and membrane trafficking. Parkin could interact with other familial PD‐associated proteins and may share a common pathway that leads to nigral degeneration. There is evidence of a PINK1/Parkin pathway involving autophagic mitochondrial degradation. We review how parkin is associated with the pathogenesis of PD.

Key Concepts:

Parkinson's disease is the second most frequent neurodegenerative disease after Alzheimer's disease.

Approximately 5% of patients with Parkinson's disease have a clear familial aetiology, exhibiting a classical recessive or dominant Mendelian mode of inheritance.

Parkin is the most prevalent gene associated with early onset Parkinsonism, accounting for around 50% of recessive familial patients with an onset under 45 years of age.

Parkin functions as an E3 ubiquitin ligase, which participates in the ubiquitin–proteasome (Ub–Pr) system.

The collaboration between parkin and PINK1 promotes the autophagic degradation of damaged mitochondria.

Parkin could participate in several pathways which lead to dopaminergic neuronal degeneration, such as the Ub–Pr system, autophagic protein degradation, the mitochondrial quality control system, the membrane trafficking system, and endoplasmic reticulum stress.
Phenylketonuria
Authors: Güttler Flemming , Guldberg Per
Published: April 2013

Phenylketonuria (PKU) is an autosomal recessive disorder caused by deficiency of phenylalanine hydroxylase (PAH). Demonstration of mutations in the
PAH
gene establishes PAH deficiency as the cause of hyperphenylalaninaemia in the newborn and provides a basis for predicting the metabolic phenotype and anticipating the dietary requirements of the patient. Mutations in the
PAH
gene are well archived in the PAH Locus Knowledgebase. Loss of PAH protein is a consequence of misfolding, aggregation and accelerated degradation of the enzyme. BH
4
rescues the activity of mutant PAH enzymes by functioning as a chaperone to stabilise enzyme structure or by overcoming defects that alter the
K
m
for BH
4
. Defects in BH
4
metabolism can be divided into those associated with hyperphenylalaninaemia and those presenting without hyperphenylalaninaemia. The diagnosis of BH
4
deficiencies has to be considered for all conditions with hyperphenylalaninaemia. The measurement of pteridines in urine discriminates BH
4
synthesis deficiency from PKU children. Therapy is aimed at normalising Phe levels and brain neurotransmitters (Matalon
et al.
, 2006). Treatment includes a special diet and/or BH
4
supplements.

Key Concepts:

Deficiency of phenylalanine hydroxylase (PAH; E.C. 1.14.16.1.) is caused by mutations in the PAH gene.

PAH is inherited in an autosomal recessive pattern (MIM #
261600
).

PAH deficiency is a highly heterogeneous disorder that has been divided into four arbitrary phenotype categories: classic, moderate and mild PKU, and mild hyperphenylalninaemia (MHP).

More than 450 mutated versions of PAH have been reported worldwide, each producing a protein with partial or total loss of enzyme activity.

A clear correlation between genotype and phenylalanine tolerance has been documented and genotype/phenotype correlations are established on the basis of patient data.
Tumour Formation: Number of Mutations Required
Authors: Butcher Lindsay D , Boland C Richard
Published: April 2013

Cancer is a genetic disease, and occurs through the progressive accumulation of activating alterations to growth‐promoting oncogenes, and inactivating alterations to tumour suppressor genes. The rate of accumulation of these alterations may be accelerated by a variety of processes that cause genetic instability. There are several key ‘pathways’ involved in the evolution of a tumour, and the alterations may occur at any point in each pathway. Each tumour develops its own unique constellation of genetic alterations, and tumours are genetically distinct between tumour types, and within individual tumours of one type. The focus of this review is on colorectal cancer, but the concepts are broadly applicable to many types of tumours.

Key Concepts:

Cancer is a disease caused by genetic alterations.

Oncogenes are normal cellular genes altered by point mutations, amplification or changes in the regulation of gene expression that result in an increase cell growth, survival, ability to invade, or other tumour‐related cell behaviours.

Tumour suppressor genes normally restrain a cell's ability to grow or invade, and inactivation is involved in tumourigenesis.

Epigenetic alterations, such as deoxyribonucleic acid (DNA) methylation, play a role in carcinogenesis.

Most solid tumours evolve through progressive multistep carcinogenesis that is mediated by the accumulation of altered genes. This is why tumours may be found at various stages of development.

The genes involved in tumour formation are tissue‐specific.

The landscape of altered genes is heterogeneous among a group of tumours from one specific tissue or organ.

Genetic alterations may be heterogeneous throughout individual tumours.

Some tumours have a very large number of genetic alterations (chromosomal rearrangements, point mutations and DNA methylation), and others have many fewer alterations.
Thyroid Cancer: Molecular Genetics
Authors: Son Eun Ju , Nosé Vania
Published: April 2013

Thyroid cancer is the most common malignancy of endocrine organs. The thyroid comprises two specialised cell types, follicular thyrocytes and C cells. Most thyroid cancers arise from thyroid follicular cells. These cancers include well‐differentiated papillary carcinoma and follicular carcinoma, poorly differentiated carcinoma and anaplastic carcinoma, whereas medullary carcinomas arise from the calcitonin‐producing C cells. Papillary and follicular carcinomas are the two most common types of thyroid cancer. Genetic alterations, includingBRAFandRASpoint mutations, andRET/PTCandPAX8/PPARγ rearrangements, andp53inactivation underlines the molecular mechanisms resulting in thyroid cancer. These genetic alterations are found in more than 70% of papillary and follicular thyroid carcinomas. The use of molecular markers is expected to improve the accuracy of diagnosis of thyroid cancers and inform the prognosis of each cancer. We review common genetic alterations in thyroid carcinomas and discuss the diagnostic and prognostic significance.

Key Concepts:

The thyroid cancers are subdivided into well‐differentiated papillary carcinoma and follicular carcinoma, poorly differentiated carcinoma, and anaplastic carcinoma.

Papillary carcinomas carry point mutations of theBRAFandRASgenes as well asRET/PTCandTRKrearrangement.

Follicular carcinomas carry either RAS mutations orPAX8/PPARγ rearrangement.

The knowledge of molecular genetics of thyroid cancer eventually getting the clinical impact, such as improvement of diagnostic accuracy, management of thyroid cancer, and surgical planning and can be a prognostic markers.
Mass Spectrometry Instrumentation in Proteomics
Authors: Sprenger Richard R , Roepstorff Peter
Published: April 2013

Mass spectrometry has evolved into a crucial technology for the field of proteomics, enabling the comprehensive study of proteins in biological systems. Innovative developments have yielded flexible and versatile mass spectrometric tools, including quadrupole time‐of‐flight, linear ion trap, Orbitrap and ion mobility instruments. Together they offer various and complementary capabilities in terms of ionisation, sensitivity, speed, resolution, mass accuracy, dynamic range and methods of fragmentation. Mass spectrometers can acquire qualitative and quantitative information on a large scale to study protein expression, protein interactions and modifications, in complexes, organelles, cells and tissues. The currently available technological platforms and approaches offer a wide selection for proteomics experiments from low to high throughput, from shotgun discovery to targeted validation. In terms of desired outcome, cost and time, choosing between available instrumentation and methodologies is key to find the best analytical strategy suiting a particular proteomics experiment.

Key Concepts:

The basic elements of a mass spectrometer are an ionisation source, mass analyser and detector.

Mass spectrometers central to proteomics‐based research are mostly ‘hybrid’ instruments combining the capabilities of different types of mass analysers.

Key properties of MS instruments for proteomics are sensitivity, speed, resolution, mass accuracy, dynamic range and methods of fragmentation.

Bottom‐up LC–MS‐based shotgun approaches have become the dominant form of analysing complex samples in various proteomics approaches

Mass spectrometry is a crucial tool in proteomics research, but proper experimental design and sample preparation remains key; garbage in–garbage out.

The choice for a particular instrument is dependant on the chosen workflow, ranging from low throughput to shotgun discovery and targeted validation strategies.
Galactolipids in Plant Membranes
Authors: Dörmann Peter
Published: April 2013

Photosynthetic membranes of plants contain high amounts of galactolipids (monogalactosyldiacylglycerol (MGDG) and digalactosyldiacylglycerol (DGDG)) that are indispensable for the efficiency of photosynthetic light reactions. Galactolipids make up the bulk of the thylakoid membranes, and they are also found as integral constituents of the photosystems I and II. The presence of galactolipids is conserved from cyanobacteria and green algae to plants, in accordance with the endosymbiont theory. However, cyanobacteria and plants use different pathways for the synthesis of galactolipids. The ratio of MGDG to DGDG in the thylakoids is crucial for the stabilisation of the membrane bilayer. Under freezing and drought stress, a certain proportion of MGDG is converted into DGDG and oligogalactolipids to prevent fissions and fusions of chloroplast membranes. When plants are grown under phosphate‐limiting conditions, phospholipids are partially replaced by galactolipids in plastidial and extraplastidial membranes, thereby releasing phosphate for other essential cellular processes.

Key Concepts:

Galactolipids are phosphorous‐free glycoglycerolipids in plants.

Galactolipids make up the bulk of photosynthetic membranes.

Oxygenic photosynthesis in cyanobacteria and plants depends on the presence of galactolipids.

The ratio of the two galactolipids carrying one or two galactoses in the head group is crucial for the maintenance of membrane integrity during stress.

Phospholipids in plants are replaced by galactolipids during phosphate deprivation.
Evolution of the Mammalian
X
Chromosome
Authors: Waters Paul D , Robinson Terence J
Published: April 2013

The mammalian X chromosome has a fascinating evolutionary history, which is intimately linked to that of the Y chromosome because both evolved in concert from identical chromosomes. Teasing apart the events of this evolution has been helped greatly by identifying similarities and differences between the X and Y and by comparing the sex chromosomes of different mammalian species. Comparison of the human X and Y with the sex chromosomes of exotic basal eutherian mammals (in particular, afrotherian representatives such as the elephant) has revealed extraordinary conservation of gross X gene order. Comparison with the sex chromosomes of the distantly related marsupial and monotreme mammals has proved remarkably valuable for identifying features of the X that are unique to eutherian mammals along with characteristics that have been conserved since before the marsupial/eutherian split approximately 150 Ma.

Key Concepts:

Therian (eutherian and marsupial) sex chromosomes evolved from a homologous pair of autosomes via a process of Y degradation after recombination with the X was suppressed.

The therian sex chromosomes arose after divergence of monotremes but before the eutherian/marsupial split.

Dosage compensation evolved in response to the loss of functional Y genes, which ultimately restored the balance of gene dosage from the single X in males and two X chromosomes in females.

Because the Y is male specific, it bears genes important to male development and reproduction.

Alleles on the single X in males are instantly open to selection, which is hypothesised to have resulted from an accumulation of testis genes on the X.
The Mouse Genome as a Rodent Model in Evolutionary Studies
Authors: Vamathevan Jessica , Holbrook Joanna D , Emes Richard D
Published: April 2013

The recently updated and complete genome of the C57BL/6J mouse strain provides a model mammalian system for genetics, comparative genomics and evolutionary studies. The extensive freely available resources of mouse genetics and breeds and similarity between mouse and much of human biology makes the mouse genome the primary choice to enable discernment of the biological function of human and other mammalian genes. Of huge importance is that along with human, mouse is currently the only mammalian genome to be sequenced to completeness allowing the investigation of lineage specific biology. In particular the mouse genome sequence provides an unrivalled resource for medical bioscience, in encouraging a deeper understanding of the shared mammalian evolutionary history of potential drug targets.

Key Concepts:

The availability of high quality genome sequence is the cornerstone of comparative genomics.

Although many mammalian genomes have been sequenced with high coverage they are considered ‘drafts’. Only the mouse and human genomes are characterised as ‘complete’ and do not contain gaps in their genome coverage. The comparison of genes and genomes allows the investigation of evolutionary history of species.

The availability of multiple animal genomes provides the raw material for the discipline of genome zoology.
Introns Evolution in Duplicated Human Genes
Authors: Jabbari Kamel
Published: April 2013

The material covered herein touches on the recent understanding of the fate of introns in human duplicated genes. A structural genomics framework has been provided to account for the functional asymmetry of sister copies after the duplication event(s). Structural shift between duplicated copies are very remarkable. Indeed, translocation/transposition of newly born copies to other chromosomal areas are accompanied not only by aminoacid substitutions but also by dramatic changes in introns size, composition and splicing patterns, as well as the emergence of intronic CpG‐island and other regulatory DNA elements.

As an evolutionary working hypothesis, for the short‐term evolution (within mammalian orders), interchromosomal translocations may be followed by accelerated evolution (relaxed constraints) and consequently alteration in expression patterns of the displaced copy, with major changes in introns constitution. For the long term, namely at the compositional transition that characterises fish/amphibian and mammalian regional genome patterns (isochores), the translocated copies (gene copies of the gene‐dense ‘ancestral genome core’) underwent a strong guanine+cytosine (GC) enrichment to become the genes of the actual ‘genome core’ (actual open chromatin). Introns from these copies, in concert with their genomic surrounding, had accumulated major structural changes and their host genes acquired different functions and/or regulations.

Key Concepts:

Noncoding DNA; open chromatin; negative selection; recombination hot spots.

Noncoding DNA: DNA sequences that do not encode for protein sequences and was therefore sometimes referred to as ‘junk DNA’, but for which there is now ample evidence for functionality (e.g. micro RNAs, ribozymes and long ncRNA).

Open chromatin: It forms euchromatin, which contains regions harbouring promoters, enhancers and actively transcribed genes.

Recombination hot spots: Regions of the chromosome that have frequent recombination events.

Negative selection: Selection acting to eliminate emerging deleterious mutations that reduces carriers fitness. It is also called purifying selection.
Cancer Stem Cells
Authors: Cobaleda C , Vicente‐Dueñas C , Romero‐Camarero I , Sánchez‐García I
Published: April 2013

Cancer stem cells (CSCs) are the pathological counterpart of normal somatic tissue stem cells. They possess the capacities to self‐renew and to generate a more differentiated, rapidly dividing and expanding tumour progeny. Although they constitute just a small percentage of the tumour mass, they are responsible for its maintenance and, therefore, they should be the target of anticancer treatments. The existence of CSCs is still a matter of controversy for certain tumour types – some of which are actually frequent and clinically relevant – but it is confirmed in many others. Moreover, CSCs are predictably genetically diverse, and their frequency and phenotype can vary in the course of the disease. However, CSCs have nowadays been identified in almost all the frequent types of tumours, and recent findings have shown that CSC gene expression signatures can be predictive of adverse clinical outcome, therefore maintaining the study of CSCs at the forefront of cancer research.

Key Concepts:

Not all the cells within the tumour are equally capable of regenerating the tumour, either in transplantation experiments or in patient's relapse after surgery and treatment.

Cancer stem cells (CSCs) are the only cells within the tumour with the capacity to maintain and regenerate the tumour, and are responsible for cancer relapse.

Tumours are therefore stem cell‐maintained tissues, like many other tissues in the organism.

Understanding the biology of CSCs, their origin, evolution and molecular characteristics, should help us to design CSC‐specific therapies that should complement current anticancer treatments, mainly aimed at the reduction of the tumour mass composed, for the most part, of nonself‐renewing cells.
Facioscapulohumeral Muscular Dystrophy
Authors: Rabi Tawil , Van der Maarel Silvere
Published: April 2013

Facioscapulohumeral muscular dystrophy (FSHD) is a common, dominantly inherited, muscle disease with a distinctive clinical presentation and a wide spectrum of disease severity. In greater than 95% of individuals with FSHD, the genetic defect is a loss of a critical number of D4Z4 macrosatellite repeats on chromosome 4q35. However, D4Z4 contractions are only pathogenic on specific, permissive chromosomal backgrounds. Recent evidence demonstrates that this permissive background facilitates the stable transcription of

DUX4

, a retrogene sequence within D4Z4 that codes for a double homeodomain protein of unknown function. These findings implicate

DUX4

in the pathophysiology of FSHD and for the first time, offer a target for therapeutic development in FSHD.

Key Concepts:

Epigenetic modifications can lead to gene derepression.

FSHD results from reactivation of a retrogene.
Molecular Genetics of Sarcoidosis
Authors: Paul Manju , Iannuzzi Michael
Published: April 2013

Sarcoidosis is a systemic inflammatory disorder characterised by the presence of noncaseating granulomas. The aetiology of sarcoidosis remains unknown. Although any organ system can be involved, the common cause of morbidity and mortality occurs from involvement of the lung, heart and nervous system. There has been extensive research, directed on the identification of candidate genes (both HLA and non‐HLA) that lead to dysregulation of the T‐cell response in sarcoidosis. However, most of these reported associations between these genes and susceptibility to sarcoidosis have not been replicated. Advances in genomics and proteomics, in concert with emerging technologies, are expected to provide further insight into pathogenesis and disease risk.

Key Concepts:

Sarcoidosis is a systemic inflammatory disorder characterised by the presence of noncaseating granulomas of unknown aetiology.

Studies have revealed many candidate genes (both HLA and non‐HLA) that lead to dysregulation of the T‐cell response in sarcoidosis.

A new strategy is to subgroup patients into distinct clinical phenotypes to help identify genes of importance for the disease.

Gene expression profiling in BAL fluid and blood performed at the time of presentation may help to better predict disease resolution or progression.

Advances in genomics and proteomics, in concert with emerging technologies, are expected to provide further insight into pathogenesis and disease risk.
Mitochondrial Dynamics: Mechanisms and Pathologies
Authors: Lee Hakjoo , Yoon Yisang
Published: April 2013

Mitochondrial dynamics, a cellular process describing continuous change of shape and location of mitochondria, has drawn much attention recently due to its involvement in cell injury and human pathologies. Mitochondrial fission and fusion are the major processes that alter mitochondrial morphology. Molecular machineries for mitochondrial fission and fusion include proteins of dynamin family large GTPases that remodel biological membranes. Mutations in these proteins cause hereditary diseases or death in human, indicating that mitochondrial fission and fusion are important cellular processes. Identification of additional factors participating in mitochondrial fission and fusion still continues. Recent studies demonstrate that mitochondrial fission/fusion process is under tight regulation through cellular signalling networks and functional states of mitochondria. This information suggests that cellular cues both extrinsic and intrinsic to mitochondria regulate mitochondrial fission and fusion, indicating an important role of mitochondrial fission and fusion in controlling mitochondrial functionality. Many additional pathologies are associated with aberrant mitochondrial fission and fusion, and defining the form–function relationship of mitochondria will be the key for understanding disease aetiology and therapeutic application.

Key Concepts:

Mitochondria take a variety of shapes depending on cell types and activities.

Fission and fusion of mitochondria are the main processes changing their morphology.

Dynamin‐related proteins (DRPs) remodel mitochondrial membranes for fission and fusion.

Additional proteins and factors including signal‐induced protein modifications participate in mitochondrial fission and fusion.

Mutations in genes in mitochondrial fission and fusion are detrimental to human health.

Many diseases such as neurodegeneration, metabolic diseases, ischemia‐reperfusion injury, heart diseases, and aging are directly and indirectly associated with dysregulation of mitochondrial fission and fusion.
Viral Transneuronal Tracing Technology: Defining the Synaptic Organisation of Neural Circuits
Authors: Strick Peter L , Card J Patrick
Published: April 2013

Viral transneuronal tracing is a powerful approach that has been widely used to define the cellular organisation of functionally defined systems that underlie brain function. The method exploits the ability of neurotropic viruses to infect neurons and produce infectious progeny that pass through the intimate synaptic connections among neurons to infect polysynaptic pathways. A number of important technological advances in recent years have dramatically improved the ability of this experimental approach to define the synaptology of complex neural circuits. In this chapter we provide an overview of the method as well as mechanisms that contribute to its effectiveness for circuit analysis. We focus on alpha herpesviruses and rabies virus as these pathogens have been most widely applied in transneuronal tracing studies.

Key Concepts:

Viral transneuronal tracing exploits the invasive properties of neurotropic viruses.

Knowledge of the functional organisation of the viral genome is fundamental to an informed application of the viral transneuronal tracing method.

Circuit architecture is influential in determining the progression of viral infection through a neural circuit.

Isogenic recombinant viruses expressing unique reporters permit analysis of collateralisation of projections within complex neural circuits.

Colocalisation of reporters of infection with neurotransmitters and peptides permits neurochemical phenotyping of neurons within labelled circuits.
Molecular Genetics of Pulmonary Hypertension
Authors: Southgate Laura , Machado Rajiv D
Published: April 2013

Pulmonary arterial hypertension (PAH) is a progressive vascular disorder with high levels of mortality and morbidity. Approximately 10% of PAH patients have a family history of disease in which the disease segregates as an autosomal dominant trait. Employing a classical positional cloning approach comprising microsatellite linkage analysis and candidate gene screening, the causal gene for PAH in families was identified as
BMPR2
, encoding a type II receptor of the transforming growth factor beta (TGF‐β) signalling network. Subsequent functional investigation has revealed the molecular mechanisms of disease and together with protein–protein interaction studies underpinned key factors in disease progression. Taken together with the recent discovery of rare mutations in additional members of the TGF‐β family these data have served to underline the central importance of this pathway in the development and maintenance of the pulmonary vasculature.

Key Concepts:

Pulmonary arterial hypertension specifically constricts and obstructs the small arteries of the lung.

Vasoconstriction and arteriole occlusion is caused by the uncontrolled proliferation of pulmonary vascular endothelial and smooth muscle cells.

In the absence of treatment death occurs as a result of right heart failure.

Twice as many females as males are affected.

The major genetic factor underlying disease is heterozygous mutations of
BMPR2.

The predominant molecular mechanism of disease is haploinsufficiency.

BMPR2
mutations have been identified in nonfamilial PAH and, on rare occasions, PAH associated with other disorders and risk factors.

The identification of rare mutations in additional members of the TGF‐β pathway point to the importance of this signalling system in the maintenance of the pulmonary vascular bed.

The genetic architecture of pulmonary hypertension remains to be fully elucidated.
Mitotic Spindle Assembly: The Role of Motor Proteins
Authors: Titus Janel , Wadsworth Patricia
Published: April 2013

The mitotic spindle, a microtubule‐based structure, is required for chromosome segregation during cell division. Motor proteins are molecular machines that utilise the energy of
adenosine triphosphate (ATP)
hydrolysis to move along microtubules. During cell division, motor proteins are required for spindle formation, chromosome alignment and segregation. Thus, mitotic motor proteins are required for the cell to avoid aneuploidy, a hallmark of cancer.

Key Concepts:

Molecular motors, including dynein/dynactin and several families of kinesin, are required for mitosis.

Kinesins contribute to establishing spindle bipolarity, positioning chromosomes between spindle poles and focusing spindle poles.

Dynein contributes to the metaphase checkpoint, spindle positioning, regulating spindle length and pole focusing.

To establish and maintain a mitotic spindle, motor proteins achieve a balance of forces on microtubules.
The Role of the RanGTPase in Mitotic Spindle Assembly
Authors: Renshaw Matthew J , Wilde Andrew
Published: April 2013

Mitosis is the process whereby a cell separates its paired chromosomes into two new identical daughter cells. To achieve this and maintain the correct amount of
deoxyribo nuclic acid
(DNA) in the cells, the cell forms a framework called the mitotic spindle onto which the chromosomes attach and then get pulled into the new daughter cells. The mitotic spindle is made up of microtubules and associated proteins. The GTPase Ran, which is important for nuclear import and export, plays important roles in regulating the formation of the mitotic spindle. Ran can bind and hydrolyse guanosine triphosphate (GTP), which enables it to regulate several cellular processes. Generation of Ran‐GTP at the chromosomes creates an intracellular gradient that provides directionality to nuclear cytoplasmic transport during interphase and creates an environment around the chromosomes to facilitate spindle assembly.

Key Concepts:

Ran is a small GTPase.

During interphase, spindle assembly factors bind to Importin‐β and are transported into the nucleus.

Ran‐GTP is generated at chromosomes and releases spindle assembly factors from inhibitory binding to Importin‐β.

Gradients of Ran‐GTP and released cargo proteins are generated in mitotic cells that are important for regulating many activities.
Muscle Satellite Cell Structure, Proliferation and Fusion
Authors: Partridge Terence A
Published: April 2013

Skeletal muscle comprises some 30–40% of body mass, consisting mainly of contractile muscle fibres. For most vertebrates, survival is compromised by any serious loss of mobility arising from failure of efficient muscle function. This places a high priority on rapid and efficient repair and on a finely tuned adjustment in size and strength both during postnatal growth and on change in imposed workload. The muscle fibres themselves are syncytia containing large numbers of myonuclei, which are postmitotic and do not proliferate during growth or repair. Thus the functions of cellular replacement in this tissue fall largely, if not entirely on a small population of ‘satellite cells’, so‐called because of their position between the plasmalemma of the muscle fibre and the overlying basement membrane. The precise role of these cells and their relationships to other cell types are topics of current research and debate.

Key Concepts:

The differentiated skeletal muscle cell is an ‘end cell’ that cannot proliferate to replace itself.

The muscle satellite cell is the predominant identified source of myogenic cells for growth repair and regeneration of postnatal skeletal muscle.

The anatomically defined muscle satellite cell appears to be heterogeneous.

Non‐satellite cell sources of myogenic cells have been identified in skeletal muscle.

There is evidence of conversion of non‐satellite cells to a myogenic fate and of satellite cells to non‐myogenic fates but the importance of these processes
in vivo
has not been ascertained.