bluuebunny/crossref_metadata_2025_split huggingface dataset:
Parkinson Disease
Authors: Hatano Taku , Hattori Nobutaka 
Published: April 2013

Abstract

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

Abstract

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

Abstract

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

AbstractThyroid 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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

Abstract

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

AbstractSarcoidosis 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

Abstract

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.