bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chromosomes 21 and 22: Gene Density
Authors: Saccone Salvatore , Bernardi Giorgio 
Published: January 2018

Abstract

Isochores are long DNA (deoxyribonucleic acid) segments that are fairly homogeneous in base composition. The GC (guanine+cytosine)‐richest and GC‐poorest isochores of the genomes from warm‐blooded vertebrates are characterised by the highest and the lowest gene concentrations, respectively. They correspond to specific types of chromosomal bands, namely the GC‐richest isochores are in the subset of R‐positive bands generally located at the telomeric chromosomal end and the GC‐poorest are in the darker G‐positive bands. The distribution of the isochores along the chromosomes determines the formation of the light/dark G/R bands, with the compositional difference at the local level having a great relevance. Chromosomes 21 and 22 can be used to show some properties of both the GC‐richest and GC‐poorest isochores of the human genome, being composed by chromosomal bands covering the entire range of GC composition, from the GC‐poorest L1
+
bands to the GC‐richest H3
+
bands.

Key Concepts

The human genome is composed of two compartments endowed with very different genomic properties.

The GC‐richest genomic compartment is prevalently composed of isochores from the H2 and H3 families.

The GC‐poorest genomic compartment is prevalently composed of isochores from the L1 family.

The GC‐richest and the GC‐poorest genomic compartments are located, in the mitotic chromosomes, distantly from one another.

The GC‐richest and the GC‐poorest genomic compartments correspond to the gene‐richest and the gene‐poorest region, respectively.

The GC‐richest and the GC‐poorest genomic compartments are located in the inner part and at the periphery of the cell nuclei.

Human chromosomes 21 and 22 summarise all the properties endowed with the GC‐richest and the GC‐poorest regions.
Ion Channels and Human Disorders
Authors: Raja Rayan Dipa L , Hanna Michael G 
Published: January 2018

Abstract

The human channelopathies are a rapidly expanding group of primarily genetic conditions. They are characterised by dysfunction of membrane‐bound glycoproteins (ion channels). Several neurological and general medical disorders have been shown to be owing to underlying ion‐channel dysfunction and genetic analysis is now often a routine clinical practice. These disorders exhibit extensive phenotypic and genetic heterogeneity with many distinct diseases caused by dysfunction of the same channel by differing mechanisms. With the advent of the next‐generation sequencing, we are discovering even greater genetic heterogeneity and our understanding of the mechanisms behind these diseases continues to extend as more functional analysis is performed and new techniques are developed. In the future, this will lead to the identification of better targeted treatments for these diseases.

Key Concepts

Channelopathies are commonly owing to mutations in functionally important regions of either pore‐forming or auxiliary channel subunits resulting in episodic disorders.

Mutations often cause disease by altering channel gating, voltage dependence or channel assembly and now there is also evidence for effects in posttranslational modification.

Channelopathies are now understood to present either with intermittent symptoms which may completely recover, have a secondary progression or may be a severe primary progressive disease. The location and type of the mutation often influence this.

Genetic heterogeneity is very common amongst the channelopathies and is likely to increase with the use of modern genetic analysis.

Channelopathies, such as myotonia congenita, have extensive phenotypic variability even within a single pedigree, making it difficult to predict and give accurate genetic counselling.
Genetic Linkage Mapping
Authors: Imai‐Okazaki Atsuko , Ott Jurg 
Published: January 2018

Abstract

Random occurrences of crossovers along a chromosome permit definition of a genetic distance. Such distances are used to create genetic maps and localise disease genes on these maps. Human genetic maps consist of dense sets of DNA polymorphisms, notably single‐nucleotide polymorphisms (SNPs) and, resulting from DNA sequencing, single‐nucleotide variants (SNVs). The main application of linkage mapping is to localise hypothesised disease genes on the human marker maps, which in turn represents the first step towards understanding of disease aetiology. While linkage analysis represents the mainstay for genetic mapping, newer approaches have been developed, for example, methods allowing the use of a single affected individual in conjunction with a number of control individuals, a situation not tractable by standard linkage and genetic association analyses.

Key Concepts

Genetic distances are based on the random occurrence of crossovers along a chromosome, and a crossover will lead to a recombination in half of the gametes.

Genetic loci in close proximity will rarely experience a recombination between them, so the recombination fraction will be small.

For short distances, the recombination fraction represents genetic distance in units of Morgans.

DNA sequencing has established the order of variants on a chromosome, so genetic linkage mapping essentially aims to measure distances in each interval (between two adjacent variants) on a chromosome.

Disease gene mapping hypothesises the presence of a disease locus, for which genetic distances to one after another genetic variant are estimated. A significantly small such distance (recombination fraction significantly smaller than 50%) establishes genetic linkage between the disease locus and a given variant.
Renal Carcinoma and
von H
ippel–
L
indau Disease
Authors: Connor Thomas M , Maxwell Patrick H 
Published: January 2018

Abstract

von Hippel–Lindau (VHL) disease is a rare autosomal dominant condition with a high risk of renal carcinoma. The underlying tumour suppressor gene is also mutated in most sporadic clear cell renal carcinomas. The
VHL
gene product functions as an E3 ubiquitin ligase that mediates the degradation of the hypoxia‐inducible factor (HIF). Loss of
VHL
leads to constitutive activation of HIF target genes that normally mediate responses to hypoxia, including those that regulate diverse processes such as angiogenesis and cellular metabolism. Novel therapies for renal cancer target angiogenesis mediated by the vascular endothelial growth factor (VEGF). Renal cancers also exhibit common driver mutations subsequent to
VHL
loss, which influence pathways involved in chromatin remodelling and mammalian target of rapamycin (mTOR) signalling. A number of other kidney cancer genes have been found from studying other familial cancer syndromes. These genes are involved in metabolism and responses to cellular stress and nutrient deprivation.

Key Concepts

von Hippel–Lindau (VHL) disease is a dominantly inherited familial cancer syndrome caused by mutations in the
VHL
tumour suppressor gene.

VHL disease exhibits a striking genotype–phenotype correlation.

The great majority of sporadic clear cell renal cancers also show loss of VHL function.

The VHL gene product functions as an E3 ubiquitin ligase that mediates the degradation of hypoxia‐inducible factor (HIF) alpha.

Loss of VHL leads to constitutive activation of HIF target genes that play key roles in angiogenesis and metabolism.

Novel therapies for renal cancer target specific effects of VHL loss, including inhibitors of angiogenesis.

Renal cancers exhibit common driver mutations affecting chromatin remodelling and nutrient signalling.

A number of other kidney cancer genes have been found to be involved in cellular pathways involved in cellular stress and nutrient deprivation.
Molecular Genetics ofEmery–Dreifuss Muscular Dystrophy
Authors: Meinke Peter 
Published: January 2018

AbstractEmery–Dreifuss muscular dystrophy (EDMD) is a rare neuromuscular disorder typically characterised by early contractures, slowly progressive muscular wasting and life‐threatening heart conduction disturbances, which can develop into a cardiomyopathy. There is a wide intrafamilial and interfamilial clinical variability. Genetically, X‐linked recessive, autosomal dominant and autosomal recessive forms can be distinguished. Female carriers of the X‐linked forms may manifest with cardiac symptoms. By molecular genetic methods, EDMD can be associated with mutations in several genes encoding nuclear envelope proteins. These proteins are lamin A, emerin, FHL1, nesprins and SUN proteins. Still only approximately half of unrelated patients diagnosed with EDMD have a mutation in known genes pointing to further genetic heterogeneity in EDMD. The molecular pathogenesis is not fully resolved, but there are effects on signalling, mechanical stability and gene expression.Key ConceptsEmery–Dreifuss muscular dystrophy (EDMD) is a neuromuscular disorder recognised clinically by three features: early contractures, a characteristic pattern of muscle wasting and cardiac conduction defects.EDMD was originally described as an X‐linked disorder, later found to be caused by mutations in theEMDgene encoding a nuclear membrane protein, emerin.Molecular genetic analysis allows precise subtyping of EDMD into X‐linked forms (EMDandFHL1associated), autosomal dominant forms (LMNA,SYNE1/SYNE2associated) and autosomal recessive forms (LMNAandSUN1associated).Wide clinical variability of EDMD and clinical overlap with other clinical entities frequently require consideration of patients not completely fulfilling the EDMD diagnostic criteria for molecular genetic differentiation inEMD,LMNA,SYNE1/SYNE2,SUN1andFHL1.Digenic pathogenesis has been observed includingLMNA/EMD,LMNA/DES,SYNE1/SYNE2,LMNA/SUN1,LMNA/SUN2andEMD/SUN1.In all cases, EDMD mutations affect proteins located at the nuclear envelope where they interact with each other.Many patients do not have mutations in genes identified so far, so further genes are expected to be involved in the pathogenesis of EDMD.
Non‐B DNAStructure and Mutations Causing Human Genetic Disease
Authors: Bacolla Albino , Cooper David N , Vasquez Karen M , Tainer John A 
Published: January 2018

AbstractBesides the canonical right‐handed double helix, biologically important noncanonical deoxyribonucleic acid (DNA) secondary structures have been characterised, including quadruplexes, triplexes, slipped/hairpins, Z‐DNA and cruciforms, collectively termed non‐B DNA. Formation of non‐B DNA is mediated by repetitive sequence motifs, such as G‐rich sequences, purine/pyrimidine tracts, direct (tandem) repeats, alternating purine–pyrimidines and inverted repeats, respectively. Such repeats are abundant in the human genome and non‐B DNA occurs at specific genomic locations, supporting a role in gene regulation, RNA translation and protein function. Repetitive motifs are also found at sites of chromosomal alterations associated with both human genetic disease and cancer. Characterised by an inherent capacity to expand spontaneously, such sequences not only cause >30 neurological diseases but may also contribute to disease susceptibility. The formation of non‐B DNA structures is believed to promote genomic alterations by impeding efficient and error‐free DNA replication, transcription and repair.Key ConceptsThe structure of DNA is polymorphic as well as its sequence; besides canonical right‐handed double helix (B‐DNA), repetitive sequences can also adopt alternative (non‐B DNA) conformations such as quadruplexes, triplexes, slipped/hairpins, Z‐DNA and cruciforms.Repetitive DNA sequences are found at particular locations within many human genes, suggesting that they can affect transcription and encode homopolymeric amino acid runs that are important for protein–protein and protein–DNA/RNA interactions.G4 and Z‐DNA structures have been detected in cells through specific antibodies, mostly in correspondence of actively transcribed genes and, in the case of G4, at telomeres.Copy number variation (CNV) is a form of genetic alteration that, by involving thousands of loci in the genome, contributes to human individuality.Repetitive sequences capable of forming non‐B DNA are found at sites of chromosomal breaks, CNVs and other rearrangements such as translocations, deletions and gene conversion events, which can contribute to human genetic disease and cancer.The recurrent translocation t(22;11) events associated with Emanuel syndrome are mediated by cruciform structures that occur at inverted repeats.Tandem repeats (microsatellites) may expand within gene sequences, contributing to more than 30 neurological diseases; present in a variable number in genes in the population, they may contribute to human disease susceptibility.An increasing number of enzymes are being reported that resolve non‐B DNA and RNA structures, and whose mutations lead to genomic instability and human disease; however, in some cases, the recognition of non‐B DNA structures is the cause of genetic instability.lncRNAs repress gene expression by forming triplex structures with their target duplex DNA.Non‐B DNA structures stimulate mutations via mechanisms that alter DNA synthesis, transcription and repair.
Activity‐Based Protein Profiling
Authors: van Rooden Eva J , Bakker Alexander T , Overkleeft Herman S , van der Stelt Mario 
Published: January 2018

Abstract

Activity‐based protein profiling is a method to study a subset of the enzymatically active proteome. This method uses chemical probes that covalently react with active enzymes. These labelled proteins can subsequently be analysed by means of a detection tag on the probe. A diverse set of probes has been developed for many enzyme classes, such as serine hydrolases, proteases, glycosidases and kinases. Different analytical techniques are currently available to visualise, identify and quantify probe‐labelled proteins with high efficiency. Activity‐based protein profiling has well‐developed applications in discovering new drug targets and in profiling inhibitors for potency and selectivity. Activity‐based protein profiling will, therefore, continue to aid research both in fundamental biology and drug discovery.

Key Concepts

Activity‐based protein profiling (ABPP) is a method to study an enzymatically active subset of the proteome and complements abundance‐based proteomics.

An activity‐based probe is a compound that covalently labels only the active form of an enzyme.

Activity‐based probes have been developed for several classes of enzymes, such as serine hydrolases, proteases, lipases and kinases.

Every ABPP experiment consists of two parts: an activity‐dependent labelling part, followed by an analytical part to visualise and characterise this labelling event.

Different analytical platforms have been developed for ABPP, including SDS‐PAGE, LC‐MS, CE‐LIF, FluoPol, EnPlex and microarray platforms.

ABPP is mainly used for target discovery by comparing different proteomes (comparative ABPP) and for characterising inhibitor selectivity and potency (competitive ABPP).

ABPP is a powerful method for drug discovery.

It is surprising that ABPP is not more widely used outside of specialised labs developing new probes.
Immunity against Hepatitis
B
Virus and
HBV
Vaccines
Authors: Doi Hiroyoshi , Morikawa Kenichi , Kanto Tatsuya 
Published: January 2018

Abstract

Hepatitis B virus (HBV) remains a global health problem, with 257 million carriers in 2015. Birth‐dose administration of hepatitis B vaccine (HB vaccine) has significantly reduced the numbers of HBV carriers in high‐endemic countries. The clinical course of infection is dependent on viral and host factors. It is known from patients with acute hepatitis that vigorous innate and adaptive immunity is needed to clear HBV. However, HBV employs covalently closed circular DNA – a mini chromosome in the nucleus – as a replicative template that helps the virus to hide under the radar of the host immunosurveillance system, and once HBV escapes from immune clearance, pervasive impairment of various immune cells is observed in chronically infected patients. In such circumstances, complete HBV eradication is rarely attainable despite lifelong treatment with nucleos(t)ide analogues. Functional cure, the state of HB surface antigen loss, is a surrogate clinical target for patients at risk of progression to cirrhosis and hepatocellular carcinoma. Appropriate induction of both innate and adaptive immunity is vital to achieve a functional cure. Understanding the immune reaction against HBV and its impact on the clinical course of acute and chronic hepatitis, along with recent advances in HB vaccination, is key to combating this infection.

Key Concepts

HBV infection is a worldwide health problem that causes potentially life‐threatening liver diseases, such as liver cirrhosis and hepatocellular carcinoma.

HBV cccDNA exists as a mini chromosome in the nucleus of infected hepatocytes and works as a replicative template for the production of progeny virus or HBV‐related proteins.

The outcomes of primary HBV infection are influenced by the age of the host at the time of exposure.

Adult patients with acute HBV infection eradicate HBV by robust activation of innate and adaptive immune reactions.

Chronic HBV infection impairs the function of various immune cells, leading to the difficulty of HBV elimination.

Implementation of HB vaccine in endemic countries has contributed significantly to the reduction of HBsAg‐positive carriers in the world.
Zika Virus
Authors: Harper David R , Litaker John , Logan James 
Published: January 2018

AbstractZika virus is closely related to the viruses causing yellow fever, West Nile or Dengue fever and, similar to them, is an arbovirus, actively transmitted by mosquito vectors. Sexual transmission between humans also occurs.Zika virus was not associated with serious human disease until after its arrival in the Americas. Since 2015 it has been associated with a range of pathologies. The most significant is congenital Zika syndrome, marked by foetal microcephaly.The number of Zika infections has fallen since 2016. Confirmed infections in the Americas total over 200 000 cases, with more than 50% of these in Brazil. Deaths are rare, and congenital effects have been the major concern, particularly in Brazil, where more than 80% of such cases have occurred. The reasons for this high rate are unclear, although poverty is often cited as a likely contributor.Eighty‐four countries or territories worldwide have had evidence of mosquito‐borne Zika virus transmission. Relatively small numbers of infections have been reported in the United States, with transmission restricted to the far south of Texas and Florida.There is no vaccine or antiviral drug effective against Zika. The best preventive measures as of 2017 involve controlling or avoiding the vector mosquitoes.Key ConceptsZika virus is a Flavivirus with an RNA genome, related to other viruses such as yellow fever, West Nile and Dengue fever.The virus was identified in Africa in 1947 and exists as two broad lineages, African and Asian.The virus is an arbovirus (arthropod‐borne virus), spread by bites from vector mosquitoes of the genusAedes, although direct person to person transmission also occurs.Historically, most people infected with Zika did not develop symptoms, and even when they did these were relatively mild.Until 2007, Zika virus infection was restricted to an equatorial belt in Africa and Asia, but in 2015, the Asian form of Zika was identified in Brazil, the first time it was seen in the Americas. By the end of 2016, more than 100 000 confirmed cases had occurred in Brazil.Later in 2015, Zika infection was associated with severe forms of microcephaly in newborns, predominantly in the northeast of Brazil.Zika infection has also been associated with the autoimmune‐mediated Guillain–Barré syndrome.In 2017, numbers of infections in the Americas have dropped sharply, but the virus continues to spread, with mosquito‐borne infections seen in 84 countries and territories around the world.There is no vaccine or therapeutic drug for Zika virus, although clinical trials are proceeding. The best strategy at present is to control mosquitoes and avoid mosquito bites.Future control approaches need to be informed by effective public health surveillance to support both analysis and response.
Evolutionary History of Vipers
Authors: Alencar Laura RV , Martins Marcio , Greene Harry W 
Published: January 2018

Abstract

Vipers are venomous snakes characterised by having two enlarged highly mobile fangs. They comprise more than 300 species belonging to the Viperidae, which in turn includes viperines (or ‘true vipers’), azemiopines and crotalines (or ‘pitvipers’). They first radiated in the Old World more than 50 million years ago and later rapidly diversified in the New World. Several interesting traits emerged during their evolutionary history, including thermosensitive loreal pits and parental care in crotalines and specialised sound production in rattlesnakes. Vipers are currently found in almost every available habitat on earth and occupy diverse ecological niches. Ancestrally, they evolved the ability to eat unusually heavy, bulky prey and exhibit an impressive range of diet specialisations. Although vipers represent an interesting and successful radiation, many species are threatened with extinction and several aspects of their evolutionary history still need investigation.

Key Concepts

Vipers represent one of three extant groups of snakes in which a front‐fanged venomous system evolved.

Vipers belong to the family Viperidae comprising the subfamilies Viperinae, Azemiopinae and Crotalinae.

Oldest viper fossils are from the lower Miocene, but molecular phylogenies suggest an older origin for Viperidae, dating back to the early Eocene.

Vipers originated in the Old World with pitvipers later invading the New World and rapidly spreading throughout North, Central and South America.

Besides an advanced venom delivery system, other key features emerged during the evolution of vipers such as loreal pits characterising all pitvipers and the rattle of rattlesnakes.

The several unique features characterising vipers allowed them to diversify into a wide range of ecological niches.

Vipers evolved into different diets, comprising both generalists and those specialised in specific prey types, such as lizards, mammals, birds or frogs.

Arboreal habits, nocturnal and diurnal activities and different reproductive modes also evolved in several lineages of vipers.