bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene Conversion in Evolution and Disease
Authors: Chen Jian‐Min , Cooper David N , Chuzhanova Nadia , Férec Claude , Patrinos George P 
Published: September 2009

Abstract

Gene conversion involves the unidirectional transfer of genetic material from a ‘donor’ sequence to a highly homologous ‘acceptor’. Gene conversion is initiated by double‐strand breaks and can arise from mutually exclusive pathways. Over evolutionary time, gene conversion has homogenized the paralogous sequences within each species whereas diversifying the orthologous sequences between closely related species; interallelic gene conversion has generated a high level of allelic diversity at certain loci. Not only has gene conversion played a key role in fashioning extant human genes but it has also been implicated as the molecular cause of an increasing number of human genetic diseases.

Key concepts

Gene conversion involves the unidirectional transfer of genetic material from a ‘donor’ sequence to a highly homologous ‘acceptor’ and occurs in both meiosis and mitosis.

Gene conversion is initiated by DNA double‐strand breaks and appears to arise from different mutually exclusive pathways.

The rate of gene conversion is mainly determined by sequence homology and by the distance between the interacting sequences, but it may also be affected by specific sequence motifs or/and sequences capable of forming non‐B DNA structures.

Interallelic gene conversion events occur between alleles on homologous chromosomes whereas nonallelic or interlocus events can occur between paralogues on the same chromatid, sister chromatids or homologous chromosomes.

Interlocus gene conversion events have driven the concerted evolution of many human gene families whereas interallelic events have generated a high level of allelic diversity at certain loci.

Gene conversion has also been implicated as the cause of a variety of different human inherited diseases.

In stark contrast to the frequent detection of pathogenic interlocus gene conversion events, the occurrence of interallelic gene conversion events causing human inherited disease is quite rare.

Only a few well‐documented examples of gene conversion events in cancer have been reported in the literature.

Gene conversion can account for the occurrence of some recurrent mutations on different chromosomal backgrounds in different ethnic groups.

Gene conversion may provide a possible future means to bring about ‘natural gene therapy’ by offering an important alternative to the introduction of an entire functional gene.
Genetic Counselling Profession in Europe
Authors: Skirton Heather 
Published: September 2009

AbstractGenetic healthcare is developed as a speciality in Europe over the past five decades and initially services were provided by medical specialists. However, due to changes in awareness of the psychosocial impact of genetic conditions and the increase in options available to families, clinical genetic services are now frequently provided by multidisciplinary teams. In many European countries, nonmedical genetic counsellors are working as part of the clinical team, providing both information and support for individuals and families at risk of or affected by a genetic condition. Many genetic counsellors have a background in nursing or other allied health profession or have completed a Master level degree in genetic counselling. The European Network of Genetic Nurses and Counsellors is active in establishing genetic counselling as a profession in Europe through setting standards of competence and prescribing appropriate educational pathways for practitioners.Key conceptsAwareness of human heredity was advanced in the nineteenth century through the work of Mendel and Galton.Specialist clinical genetic services were established in Europe in the mid‐twentieth century.Genetic counselling may be undertaken by practitioners from a range of health professions.Genetic counsellors are practitioners have a background in one of the health professions or have undertaken a Master degree in genetic counselling.Genetic counsellors provide information, discuss options, support adjustment and facilitate the client to make decisions.Genetic counsellors are specially trained to offer the client psychological support.There are disparities in the ways in which genetic counsellors work in different European countries.The European Network of Genetic Counsellors is working to setting standards of competence and prescribing appropriate educational pathways for practitioners.A set of core competences for genetic counsellors is available as a basis for setting educational standards.
Haemoglobin Disorders: Gene Therapy
Authors: Persons Derek A , Nienhuis Arthur W 
Published: September 2009

Abstract
The ability to transfer a globin gene into stem cells and achieve regulated expression during erythropoiesis following transplantation of genetically modified autologous cells could provide curative therapy for haemoglobin disorders such as sickle cell anaemia or β‐thalassaemia. Success has been achieved in several severe immunodeficiencies in which there is a selective advantage for gene corrected cells. The development of effective globin lentiviral vectors has resulted in resolution of the manifestations of sickle cell anaemia and β‐thalassaemia in mouse models of these diseases. However, a higher stem cell transduction efficiency must be achieved in humans than has been achieved in large animal models to date before success in treatment of haemoglobinopathies could be expected. Various strategies are being evaluated in animal models to increase the proportion of genetically modified, haematopoietic cells following infusion of transduced stem cells.
Nitrification
Authors: Arp Daniel J 
Published: September 2009

Abstract

Nitrification is the process whereby reduced forms of inorganic and organic nitrogen, particularly ammonium, are oxidized to nitrate. The process is mediated by microorganisms and contributes to the movement of nitrogen through the biogeochemical nitrogen cycle. Ammonia‐oxidizing bacteria first oxidize ammonia to nitrite, followed by the oxidation of nitrite to nitrate by the nitrite‐oxidizing bacteria. In both cases, these bacteria are able to derive energy for growth from the oxidation of these inorganic compounds and can use carbon dioxide as their sole carbon source.
Crenarchaeota
were recently shown to also be capable of deriving energy from the oxidation of ammonia to nitrite. Ammonia monooxygenase initiates the metabolism of ammonia and produces hydroxylamine. This intermediate is converted to nitrite by
hydroxylamine oxidoreductase
, a trimer of an octaheme subunit. Nitrite oxidation to nitrate is catalysed by
nitrite oxidoreductase
, a molybdenum‐containing enzyme.

Key Concepts

Nitrification is the process whereby reduced forms of inorganic and organic nitrogen, primarily ammonia, are oxidized to nitrate.

Nitrification is mediated by microorganisms including
Bacteria
and
Crenarchaeota
and occurs in two steps. In the first step, ammonia is oxidized to nitrite and in the second step nitrite is oxidized to nitrate.

Ammonia‐oxidizing bacteria and
Crenarchaeota
can derive energy for growth from the oxidation of ammonia to nitrite.

Nitrite‐oxidizing bacteria derive energy for growth from the oxidation of nitrite to nitrate.

Many ammonia‐ and nitrite‐oxidizing bacteria are autotrophs and assimilate carbon dioxide via the Calvin cycle.

Key enzymes involved in nitrification are ammonia monooxygenase, which catalyses the oxidation of ammonia to hydroxylamine, hydroxylamine oxidoreductase, which catalyses the oxidation of hydroxylamine to nitrite and nitrite oxidoreductase, which catalyses the oxidation of nitrite to nitrate.

Microorganisms involved in nitrification are broadly distributed in nature and found virtually everywhere that ammonia and oxygen are present.

The genomes of several representative ammonia‐ and nitrite‐oxidizing bacteria reveal the presence of genes consistent with the autotrophic lifestyle and only limited genes to support growth on organic compounds, again consistent with their lifestyle.
Channelrhodopsin: Potential Applications in Vision Restoration
Authors: Pan Zhuo‐Hua , Dizhoor Alexander M 
Published: September 2009

Abstract

Channelrhodopsins, the directly light‐gated ion channels from green algae, provide a powerful tool for basic research in neuroscience as well as potential applications for treating neurological diseases and disorders. One of the promising clinical applications is to cure blindness caused by the death of rod and cone photoreceptors.

Key concepts:

Light, through multiple conformational changes caused by reversible isomerization of retinal chromophore group, transiently creates ion conductance in microbial retinal binding proteins, channelrhodopsins.

Photocycle of channelrhodopsins remains preserved when they are heterologously expressed in animal and human cells.

Channelrhodoposins are directly light‐gated cation channels with million second activation and deactivation kinetics.

A sufficient number of functional channelrhodopsins can be formed in animal neurons, with endogenous chromophore groups as supplied by regular diet. Thus, only introducing a single gene of channelrhodopsins is required to turn various types of animal neurons into artificial photoreceptor cells.

Converting surviving inner retinal neurons into directly photosensitive cells is a new strategy to treating blindness after the death of rod and cone photoreceptors.

Using delivery by adeno‐associated viral vectors, long‐term expression of channelrhodopsin‐2 can be achieved in rodent inner retinal neurons

in vivo

.

Expression of channelrhodopsin‐2 in surviving inner retinal neurons of a mouse model with retinal degeneration can restore the ability of the retina to encode light signals and transmit the light signals to the visual cortex.
Thermosensation
Authors: Mak Stephanie , Zhang Xuming , McNaughton Peter 
Published: September 2009

Abstract

Detection of temperature, both of the surroundings and of the body itself, is critical for maintaining normal physiological functioning. To date, a number of thermo‐sensitive ion channels have been reported to be involved in thermosensation, six of which belong to the transient receptor potential (TRP) superfamily of nonselective cation channels. Each of these operates over a distinct temperature range and many respond to natural compounds that elicit sensations of heat or cold. The best studied is TRP vanilloid 1 (TRPV1), which is both a receptor for capsaicin, the active principle of chilli peppers, and a painful heat receptor which responds to temperatures over 42°C. Our understanding of cold transduction has also rapidly increased in recent years with the intriguing discovery of the cold receptors TRP melastatin 8 (TRPM8) and TRP ankyrin 1 (TRPA1).

Key concepts

Our current understanding of thermosensation comes mainly from the identification of six temperature‐sensitive ion channels (thermo‐TRP channels) belonging to the transient receptor potential (TRP) superfamily of nonselective calcium channels.

Each thermo‐TRP operates over a distinct temperature range. Four of them (TRPV1–4) are activated by heat, and two of them (TRPM8 and TRPA1) are activated by cold.

Thermo‐TRPs also respond to natural compounds that elicit corresponding psychophysical sensations of heat or cold.

The response of these channels is regulated after tissue damage and is subjected to modulation by inflammatory mediators released at the site of injury. The altered sensitivity of these channels accounts for the phenomenon of thermal hyperalgesia.

Inflammatory mediators sensitize TRPV1 via the activation of protein kinases such as protein kinase C (PKC), protein kinase A (PKA) and Src. The modulation of TRPV1 by PKC and PKA depends on the correct positioning of the kinases by a scaffolding protein, AKAP79/150.

There are other possible mechanisms involved in thermosensation, for example, modulation of potassium channels such as TREK‐2.
Paraneoplastic Neurologic Syndromes
Authors: Maat Peter , Sillevis Smitt Peter AE 
Published: September 2009

Abstract
Paraneoplastic neurologic syndromes (PNS) are remote effects of cancer. Immunological factors appear important in the pathogenesis of PNS since the detection of antineuronal autoantibodies. Detection of paraneoplastic antibodies is very helpful in diagnosing an unexplained neurological syndrome as paraneoplastic and in directing the search towards the underlying neoplasm. There are seven well‐characterized paraneoplastic antibodies reactive with the onconeural Hu, Yo, Ri, Ma2, CV2, amphiphysin and recoverin antigens. Recently, anti‐VGKC and anti‐NMDA receptor antibodies were identified in patients with limbic encephalitis (LE). Thirty per cent of patients with anti‐VGKC and LE have an underlying tumour, while most patients with anti‐NMDAR and LE are young women with an ovarian teratoma. Both VGKC‐ and NMDAR‐related LE respond well to immunotherapy. In contrast, the effect of immunotherapy in patients with PNS associated with antibodies against the intracellular onconeural antigens is disappointing. These patients benefit most from early detection and treatment of the underlying tumour.
Molecular Genetics of Hereditary Spastic Paraplegias
Authors: Novelli Giuseppe , Contino Gianmarco 
Published: September 2009

Abstract

Hereditary spastic paraplegias (HSPs) are a group of single‐gene disorders in which the axons of the corticospinal tract either fail to develop normally or undergo progressive degeneration. The main clinical feature of all HSPs is a bilateral, symmetrical, slowly progressive spastic paraparesis predominantly of the lower extremities, which occurs in relative isolation in pure or uncomplicated HSPs (PHSPs) or in combination with other features in complicated HSPs (CHSPs). So far, about 40 different chromosomal HSP loci have been identified by genetic linkage analysis and an increasing number of gene mutations are being identified, representing one of the most significant examples of genetic heterogeneity. Autosomal and X‐linked patterns of inheritance, both dominant and recessive, have been described. Defects in intracellular trafficking and transport in myelination and abnormalities of mitochondrial proteins have been involved in HSP pathogenesis.

Key Concepts:

Hereditary spastic paraplegias (HSP) are a group of single‐gene disorders characterized by bilateral, symmetrical, slowly progressive spastic paraparesis predominantly of the lower extremities (pure or uncomplicated HSPs).

The phenotype can be complicated by additional features (complicated HSPs).

HSPs affect 1/10 000 individuals.

Pathogenesis depends on abnormalities in intracellular trafficking, trasnsport and endocytosis, neural cell recognition and signalling, myelination and mitochondrial proteins.

About 40 different chromosomal loci and 20 genes have been identified indicating the extraordinarly strong genetic heterogeneity.

Patterns of inheritance include autosomal and X‐linked, both recessive and dominant.

Mutations in
Spastin
(SPG4) account for approximately 40% of autosomal dominant HSPs, and more then any other HSP defect. Autosomal recessive HSP account for approximately 15–20% of all types of HSPs.

Genotype–phenotype correlation and penetrance can be extremely variable even among the same family and/or gene defect.

Genetic counselling is particularly challenging because of genetic heterogeneity and should take in consideration pattern of inheritance, geographical epidemiology and clinical evaluation with a multidisciplinary approach.

To date, treatment of HSPs is primarily directed symptomatically towards reducing muscle spasticity.
Biallelic Germline Mutations of Mismatch‐Repair Genes and Paediatric Malignancies
Authors: Wimmer Katharina , Etzler Julia 
Published: September 2009

Abstract

Constitutional impairment of the human
deoxyribonucleic acid
(DNA) mismatch repair (MMR) system due to biallelic germline mutations in one of the MMR genes

MLH1

,

MSH2

,

MSH6

or

PMS2

causes a condition that may best be described as constitutional MMR‐deficiency (CMMR‐D) syndrome. Clinically, the syndrome is characterized by a strong predisposition to various paediatric malignancies, primarily haematological malignancies, brain tumours and early onset colorectal cancer as well as signs reminiscent of neurofibromatosis type 1 (NF1). This phenotypic overlap of CMMR‐D syndrome and NF1 may hamper or delay proper diagnosis of the underlying genetic condition, thus bearing a challenge for clinicians and geneticists alike. The article briefly reports the clinical findings in the so far described CMMR‐D syndrome patients and points out possible phenotype–genotype correlations with respect to tumour spectrum and age of malignancy onset.

Key concepts

The DNA MMR system is responsible for the correction of single base pair mismatches and small misalignments that continuously arise during DNA replication.

Defective MMR will lead to the accumulation of uncorrected mismatches in the genome and may ultimately result in cancer development.

In humans, biallelic germline mutations in one of the MMR genes
MLH1
,
MSH2
,
MSH6
and
PMS2
cause a strong predisposition to paediatric malignancies.

The condition may best be termed CMMR‐D syndrome.

Children affected by CMMR‐D syndrome primarily develop haematological malignancies, brain tumours and early onset colorectal cancers as well as
café‐au‐lait
spots (CLS) and other signs reminiscent of neurofibromatosis type 1.

The phenotypic overlap of CMMR‐D syndrome and neurofibromatosis type 1 (NF1), one of the most common autosomal dominant genetic disorders, might hamper or delay proper diagnosis of the condition.

There are indications that CMMR‐D syndrome patients carrying biallelic
MLH1/MSH2
and
MSH6/PMS2
mutations, respectively, might differ in tumour types and age of malignancy onset.

Microsatellite instability testing and/or immunohistochemical expression analysis for the MMR genes as well as reliable mutation analysis of
MLH1
,
MSH2
,
MSH6
and
PMS2
is important not only for proper diagnosis of CMMR‐D syndrome patients but also has implications for their relatives, as heterozygous germline mutations in these MMR genes are known to cause hereditary nonpolyposis colorectal cancer (HNPCC).
HIV
Vaccine Approaches
Authors: McKnight Á , Pennington Daniel J 
Published: September 2009

Abstract

The goal of vaccination is to establish long‐term immunological readiness that allows rapid protection against infectious disease. All current successful vaccines achieve this by inducing neutralizing antibodies, which are effective against acute, cytopathic infections that could otherwise prove fatal. By contrast, potential vaccines against highly variable pathogens that establish persistent infections, such as HIV, have been unsuccessful, as responses in addition to neutralizing antibodies, directed to specific anatomical locations, are probably necessary. Human studies on
human immunovirus
(HIV)‐exposed/infected long‐term nonprogressors to acquired immunodeficiency syndrome (AIDS) are beginning to reveal the correlates of immune protection that new vaccines should attempt to reproduce. Coupled with exciting new vaccine design and delivery strategies, these novel HIV vaccine approaches offer real hope that the HIV/AIDS pandemic can finally be overcome.
Death Receptors
Authors: Krammer Peter H , Lavrik Inna N 
Published: September 2009

Abstract

Apoptosis or programmed cell death is a common property of all multicellular organisms. It can be triggered by a number of factors including ultraviolet (UV) or γ‐irradiation, chemotherapeutic drugs or growth factor withdrawal. A death signal can either be induced by death receptors (extrinsic pathway) or via the mitochondria (intrinsic pathway). The death receptor (DR) family is the subfamily of the tumour necrosis factor receptor (TNFR) superfamily. Stimulation of the death receptors results in the transduction of either apoptotic or survival signals. Here we present a general overview of death receptor signalling and describe the main mechanisms leading to activation of death receptor signalling pathways.

Key concepts:

Stimulation of the death receptors (DR) leads to apoptosis.

All DR are distinguished by the presence of the death domain.

Crosslinking of DR with death ligands results in formation of the death‐inducing signalling complex (DISC).

Caspases play the central role in the transduction of death receptor apoptotic signal.

As a result of DISC formation procaspase‐8 is activated with the formation of the active caspase‐8 heterotetramer, which then triggers apoptotic signal.

c‐FLIP proteins block caspase‐8 activation at the DISC and thereby death receptor‐induced apoptosis.

There are two types of apoptotic signalling: Type I and Type II cells.

Stimulation of DR also might lead to the induction of nonapoptotic pathways.
The Apoptosome: The Executioner of Mitochondria‐mediated Apoptosis
Authors: Ferraro Elisabetta , Cecconi Francesco 
Published: September 2009

Abstract

The apoptosome is a molecular complex of two major components – the adapter protein
apoptotic protease
activating factor 1 (
Apaf1
) and the protease caspase‐9. These are assembled during apoptosis upon
Apaf1
interaction with cytochrome
c
, which is released from the intermembrane space of mitochondria under precise cell death stimuli. Apoptosome assembly triggers effector caspase activation, which – in turn – drives cell demise. Several proteins bind and regulate apoptosome. This complex is found in vertebrates, even though similar functions are played by ortholog proteins through slightly different mechanisms also in lower eukaryotes. Given the involvement of apoptosome dysfunctions in human diseases, this complex is also a relevant molecular target in biomedicine.

Key concepts

It was a stunning discovery to find out that cytochrome
c
, essential for adenosine triphosphate (ATP) production and cell life, was involved in a cell death pathway.

Apoptosis regulation is essential for avoiding unwanted cell death and allowing the correct development and homoeostasis of the whole organism. Therefore there are several regulators of apoptosome activity.

Caspases and Apaf1 have a key phylogenetically conserved role in apoptosis.

Apoptosis is evolutionary well‐conserved in terms of its basic mechanisms; however, the role of mitochondria in apoptosis of organisms other than vertebrates needs to be clearly defined.