bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenylketonuria (
PKU
)
Authors: Gonzalez‐Lopez Eugene , McFalls Ashley J , Vrana Kent E 
Published: November 2016

Abstract

Phenylketonuria (PKU) is one of the first characterised metabolic diseases. PKU is an autosomal recessive metabolic disorder resulting in increased phenylalanine concentrations. Without intervention, such as pharmaceutical or dietary restriction of phenylalanine, most children with PKU develop a profound and irreversible intellectual disability. In fact, this treatable condition is one of the leading causes of mental retardation. PKU can occur via two main mechanisms: classical and nonclassical. Classical PKU results from impaired activity of the liver enzyme phenylalanine hydroxylase, which converts phenylalanine to tyrosine. In nonclassical PKU, there is an absence or deficiency of dihydropteridine reductase which impairs the regeneration of tetrahydrobiopterin, a necessary cofactor in the conversion of phenylalanine to tyrosine. The advent of neonatal screening for PKU has enabled the start of a low‐phenylalanine diet early in life and thus, the prevention of intellectual retardation associated with the disease. The mainstay of treatment is a phenylalanine‐restricted diet, but its application varies both internationally and nationally.

Key Concepts

Phenylketonuria (PKU) is a rare metabolic disorder, characterised by an impaired ability to metabolise the amino acid phenylalanine and resultant high circulating levels of phenylalanine.

Classical PKU (the most common form) is caused by mutations in the gene for phenylalanine hydroxylase (PAH).

Nonclassical PKU can be caused by defects in the synthesis or function of the cofactor for PAH (BH
4
).

If not treated shortly after birth, PKU can be destructive to the nervous system, causing intellectual disability.

The identification of PKU during routine newborn screening and management with a diet low in phenylalanine became standard practice in the early 1960s.

PKU is a disorder that has an unequal geographic and ethnic distribution.

Individuals on well‐controlled phenylalanine‐free diet may still develop cognitive symptoms.

Several new therapies have recently emerged that provide alternatives to the strict low‐phenylalanine diet. A description of these treatments (medical foods, BH
4
administration, large neutral amino acid supplementation and enzymatic therapy) is covered herein.
Death and Dying
Authors: Rhodes Rosamond , Hitt James M , Nair‐Collins Michael 
Published: November 2016

Abstract
New understandings of biology as well as new treatments and imaging capacities raise difficult questions about death and dying. In its biological sense, ‘death’ is a vague term that in different contexts marks the loss of metabolic exchange in the entire organism, a part of the organism, an organ, a nest of cells or a cell. ‘Death’ is also a distinctly social term with significant moral implications. The key terms involved in the ethical controversies involving death and dying are standards for declaring death, the minimally conscious state, the concepts of killing, letting die and the doctrine of double effect.
Preimplantation Diagnosis
Authors: Kuliev Anver , Rechitsky Svetlana 
Published: November 2016

Abstract

Preimplantation diagnosis is testing for a causative gene before pregnancy, allowing the preselection of unaffected embryos before implantation into the uterus. It has currently become an alternative to prenatal diagnosis, providing an option for at‐risk couples to have unaffected children of their own without facing the risk of a pregnancy termination after prenatal diagnosis. Preimplantation diagnosis is also extended to late‐onset common disorders with genetic predisposition, such as cancer and heart disease, for which no preclinical diagnosis and effective preventive management exists. The other nontraditional application of preimplantation diagnosis is preimplantation HLA (human leukocyte antigen) typing to improve the access to the HLA‐identical stem cell transplantation, and this will contribute to the development of the cellular therapy for genetic and acquired disorders. However, the major current application of preimplantation genetic testing is detection and avoidance of aneuploid embryos, based on the currently used next‐generation technologies for 24‐chromosome aneuploidy testing, as the practical means in assisted reproduction technology (ART) to improve the
in vitro
fertilisation (IVF) effectiveness and general standards of ART.

Key Concepts

PGD is no longer a research tool, but the established procedure in the genetic practices and ART.

PGD not only avoids the birth of affected offspring but, most importantly, also ensures an unaffected pregnancy from the onset.

Indications for PGD have currently been extended from the traditional ones, which are similar to prenatal diagnosis, to those that are not acceptable for prenatal diagnosis, such as late‐onset common disorders or identification of HLA match for stem cell transplantation.

The majority of PGD is still performed for aneuploidy testing, as a tool to improve the efficiency of IVF.

One of the most recent changes in PGD procedure in the last few years is shifting from blastomere biopsy to blastocyst sampling and vitrification, followed by the frozen transfer of tested embryos.

The other important development in PGD is a shift of genetic testing from FISH testing for a few chromosomes most commonly involved in trisomies to the next‐generation technologies for 24‐chromosome aneuploidy testing.

The number of different genetic conditions tested by PGD at the present time is over 400 and can be done not only for inherited conditions but also for those determined by
de novo
mutations.

PGD for single‐gene disorders became extremely accurate and reliable, with as high as 99.5% accuracy in our PGD experience, which is the world's largest PGD series.

The shift of PGD for aneuploidies from FISH to NGS‐based testing has further improved the pregnancy and implantation rates, leading also to a considerable reduction of spontaneous abortions.

PGD is already moving towards the universal approaches, combining the testing for single‐gene and chromosomal disorders in a single test.
Public Understanding of Genetics: The Deficit Model
Authors: Marks Nicola J 
Published: November 2016

Abstract

Genetics is relevant to many aspects of our lives. According to the deficit model of public understanding, any misgivings that people have about genetics and its applications are caused by a lack of understanding. Consequently, education in genetics is expected to lead to improved literacy in, and therefore support for, this area. However, studies show that education does not automatically lead to increased public support and that increased knowledge of controversial research may lead to decreased support for it.
Understanding
is thus a complex and dynamic process which depends on people's prior knowledge and on their social and cultural locations. Members of the public should not be seen as
deficient
in understanding. Rather, they have sophisticated understandings which should be acknowledged. Public support for genetics cannot be improved simply through more or better education; alternatives such as public
engagement
in science or institutional changes promoting
trustworthiness
may be more useful.

Key Concepts

According to the deficit model, lack of public understanding of genetics leads to an inability to fully participate in social life and potentially lack of support for new technologies. This can be remedied by education.

According to critical approaches to public understanding, understanding is a complex process that involves social and cultural factors.

Public understanding of genetics is more sophisticated than the deficit model assumes.

The idea of lay expertise suggests that people who are not certified scientists may nonetheless have useful and relevant, often experience‐based, knowledge that helps them make sense of science and genetics.

Public engagement, where people with different kinds of knowledge and opinions are consulted instead of merely educated, may help improve science–society relations.

The deficit model is a sticky concept: it remains popular in some areas of science, policy and science communication despite its shortcomings.
Aberrant Patterns of
DNA
Methylation in Cancer
Authors: Hudler Petra 
Published: November 2016

Abstract

Deoxyribonucleic acid (DNA) methylation is an epigenetic mechanism involved in the regulation of gene expression and preservation of genome stability in normal cells. Alterations of DNA methylation code have been associated with the development and progression of many diseases, including cancer. Novel technologies allow genome‐wide interrogation of methylation patterns. Data on different types of cancer are accumulating; however, elucidation of the consequences of all observed demethylation or methylation events and understanding their associations with other genomic aberrations present great challenges for the future research. Nevertheless, several findings regarding gene silencing by hypermethylation of CpG islands in promoters of genes have been successfully transferred in clinical setting aiding in diagnosis or prognosis of different types of cancer. In addition, therapeutic application of small molecule inhibitors of DNA methyltransferases (DNMTs) to reverse epigenetic silencing has been proven to be beneficial for treatment of various cancers.

Key Concepts

Alterations of epigenetic mechanisms, including DNA methylation, are implicated in the pathogenesis of many diseases, including cancer.

DNA methylation of CpG dinucleotides distributed in the genome can either repress or enable transcription of genes, depending on the location of CpGs and the level of methylation.

DNA methylation can be influenced by different internal and external factors, which contribute to the establishment of heterogeneous DNA methylation patterns in cancers.

Observed heterogeneity of methylation profiles between tumours and within tumours represents an obstacle in obtaining relevant biological information that could be translated into the knowledge of molecular mechanisms leading to cancer.

Advancements in genome‐wide methodologies and bioinformatic tools used for deciphering the consequences of altered DNA methylation patterns will enable deeper understanding of molecular mechanisms leading to the development of cancer.
Genetics and Demographic History of the
B
antu
Authors: Rocha Jorge , Fehn Anne‐Maria 
Published: November 2016

Abstract

Peoples speaking languages of the Bantu family are widespread in sub‐Saharan Africa, from the equatorial rainforest to the Cape of Good Hope. Their present‐day distribution is the result of a remarkable expansion, which started about 4000–5000 years ago in the borderland between Cameroon and Nigeria. The genetic distances among Bantu‐speaking populations are significantly lower than those between the Bantu and other ethnolinguistic groups from Africa, suggesting an actual movement of people, rather than cultural diffusion. However, this genetic homogeneity places a challenge to the reconstruction of their actual routes of dispersal, with existing hypotheses being mainly based on data from linguistics and archaeology. While the indigenous populations they encountered did not provide a major contribution to the Bantu gene pool at large, admixture studies reveal different patterns of social interaction, which range from Bantu dominance in the rainforest to a more levelled exchange in southern Africa.

Key Concepts

Most speakers of modern‐day Bantu languages share a distinctive genetic component.

The spread of the Bantu languages corresponds to a migratory movement, rather than to cultural diffusion.

The Bantu migrations correlate with the appearance of technological innovations and new subsistence strategies in western Central Africa.

The range of sampled populations and the resolution of the genetic analyses need to be increased to further explore the genetic relationships among different Bantu groups and infer the dispersal models that best explain them.

The best documented cases of admixture between Bantu and non‐Bantu populations are provided by studies that were undertaken in the Central African rainforest and the southern African Kalahari basin.
Plant Conservation and Botanic Gardens
Authors: Fay Michael F , Christenhusz Maarten JM 
Published: November 2016

AbstractWith a history dating back to the sixteenth century, modern botanic gardens have had an important role in plant conservation, most notably since the second half of the twentieth century. The formation of Botanic Gardens Conservation International in the 1980s and the development of the Global Strategy for Plant Conservation have led to many botanic gardens across the world now having conservation as a major focus. The combination of historical collections and expertise in areas including plant taxonomy, population genetics, propagation and seed banking mean that botanic gardens are ideally placed to play a major role inex situandin situplant conservation. Maintaining living collections of the rarest species in botanic gardens has been a way of saving these from extinction, albeit often in isolation from the other organisms (plants, animals and fungi) with which they would interact in nature.Key ConceptsApproximately 20% of the world's plants are threatened with extinction.Botanic gardens play a major role inex situandin situplant conservation.Botanic Gardens Conservation International is an umbrella group of more than 500 gardens in approximately 100 countries.The Global Strategy for Plant Conservation has resulted in many gardens becoming more involved in conservation as a major part of their activities.The rarest plants find a secure home in botanic gardens and seed banks.Botanic gardens need to practise vigilance to avoid the introduction of invasive species.
Embryonic Mammary Gland Development
Authors: Tickle Cheryll , Jung Han‐Sung 
Published: November 2016

AbstractMammary glands are derived from the ectoderm and are a defining feature of mammals. The number of glands that develop along the ‘mammary lines’ on either side of the ventral trunk depends on the mammalian species. The mesoderm specifies the position in which glands develop. Positional information is encoded by transcription factors and transmitted to overlying ectoderm by signalling molecules. Determination of the mammary epithelium arises from induction of transcription factors and signalling molecules. Signals from the mammary epithelium induce the underlying mesoderm to form the mammary mesenchyme required for further development. The gland initiates as a discrete placode which sinks into the mesoderm to form a bud; the bud then lengthens to form an elongated sprout, which undergoes branching morphogenesis in a pattern dictated by the mesoderm. The gland lining is generated by formation of the lumen, and bipotent mammary stem cells give rise to luminal epithelial and myoepithelial cells.Key ConceptsMammary glands develop along ‘mammary lines’ that run from axilla (anterior) to groin (posterior) along both right and left sides of the ventral aspect of the mammalian trunk.Ectoderm cells of the mammary line migrate and aggregate to form individual discrete mammary placodes.The precise location of the mammary line and the placodes in the ectoderm is controlled by signals from underlying mesodermal tissues.Signals that control the formation of the mammary line and placodes include members of the WNT, FGF, NEUREGULIN and BMP signalling pathways. The Hedgehog signalling pathway is also involved.The TBX3 transcription factor is essential for the formation of the mammary placodes in mouse embryos, and mutations in theTBX3gene have been found in patients with Ulnar‐mammary syndrome.The epithelial cells of the mammary bud produce parathyroid hormone‐related protein, which induces nearby mesoderm to form the mammary mesenchyme.Interactions between the mammary epithelial cells and the mammary mesenchyme are essential for further development and the subsequent elongation of the mammary bud to form a mammary sprout, which then undergoes branching morphogenesis in a pattern dictated by the deeper mesenchyme.Formation of the lumen of the embryonic gland involves fusion of microlumina created by local development of nonadhesive surfaces on the mammary epithelial cells and generates the epithelial lining which consists of an inner layer of luminal cells and an outer layer of myoepithelial cells.The cells of the mammary placode are determined to give rise to mammary epithelial cells; in the mammary bud, mammary stem cells can be detected that can give rise to both luminal and myoepithelial cells.Parallels, such as invasiveness, exist between the development of embryonic mammary glands and breast tumours and many of same molecules are involved.
Molecular Genetics of
M
yhre Syndrome
Authors: Michot Caroline , Le Goff Carine , Cormier‐Daire Valérie 
Published: November 2016

Abstract

Myhre syndrome (MIM 139210) is a rare autosomal‐dominant disorder characterised by short stature, brachydactyly, facial dysmorphism (short palpebral fissures, prognathism and short philtrum), developmental delay with mental retardation or/and behavioural troubles, progressive deafness of mixed conductive and sensory type and a trio of thickened skin, generalised muscle hypertrophy and restricted joint mobility. Life‐threatening complications (obesity, arterial hypertension and bronchopulmonary insufficiency) are observed in the course of the disease leading to an early death. In 2011,
SMAD4
(SMAD family member 4) has been identified as the disease‐causing gene. All mutations identified so far are
de novo
heterozygous missense mutations, mainly involving Ile500. While SMAD4 inactivation is reported in juvenile polyposis syndrome with increased colorectal cancer risk, no increased tumoural risk has been observed in Myhre syndrome. SMAD4 is a key mediator of TGF‐β (transforming growth factor beta)/BMP (bone morphogenetic protein) signalling and the understanding of the consequences of
SMAD4
mutations during development will decipher new regulatory network related to TGF‐β/BMP signalling.

Key Concepts

Myhre syndrome is a rare genetic condition of autosomal‐dominant inheritance due to
SMAD4
mutations affecting Arg496 or Ile500 residues.

Myhre syndrome is characterised by short stature, brachydactyly, facial dysmorphism, developmental delay, progressive deafness and a trio of thickened skin, generalised muscle hypertrophy and restricted joint mobility.

Myhre syndrome is associated to a risk of early death due to possibly life‐threatening health conditions (obesity, arterial hypertension, bronchopulmonary insufficiency, laryngotracheal stenosis and pericarditis).

Similar to mothers against decapentaplegic family member 4 (
SMAD4
) encodes the common partner SMAD of the eight‐member family of SMAD proteins.

SMAD4 aggregates into heterotrimer with the receptor‐regulated SMADs (R‐SMADs) once they are activated by phosphorylation by transmembrane serine–threonine receptor kinases in response to stimulation of TGF‐β, activin or BMP receptor pathways.

The
SMAD4
mutations identified in Myhre syndrome are expected to disturb the monoubiquitination of SMAD4 which occurs at Lys519 and also to disturb the function of the SMAD heterotrimer which regulates the expression of target genes.

Germline heterozygous mutations in
SMAD4
are known to cause juvenile polyposis syndrome (JPS) and JPS‐hereditary hemorrhagic telangiectasia.

The
SMAD4
mutations observed in JPS and JPS‐HHT include nonsense, missense, splice‐site changes and deletions, consistent with a loss‐of‐function mechanism.

Increased tumoural risk has not been observed so far in Myhre syndrome.

The development of tissue‐specific mouse models of Smad4 deficiency further highlighted the important role of Smad4 in a wide range of embryonic developmental processes.
Genetics of Aortic Aneurysmal Disease
Authors: Toghill Bradley J , Saratzis Athanasios , Liyanage Lakmini S , Sidloff David , Bown Matthew J 
Published: November 2016

Abstract

Aortic aneurysmal disease may affect the thoracic and abdominal segments, but the pathophysiology and genetic causal background differ significantly. Abdominal aortic aneurysms (AAAs) are multifactorial and polygenic, whereas thoracic aortic aneurysms and dissections (TAAD) are typically familial and/or associated with certain syndromes. Various genomic loci have been linked to both diseases. Syndromic and nonsyndromic TAADs are the result of large‐effect gene mutations in genes controlling extracellular matrix (ECM) structure, transforming growth factor‐beta signalling and vascular cell contraction. AAA predisposition is determined by many small‐effect genomic loci involved in inflammation, lipid metabolism, ECM remodelling and vascular cell apoptosis. Nongenetic risk factors are also very important in AAA pathophysiology. Surgical management/repair is currently the only available treatment to prevent aneurysmal rupture. Functional genetic and epigenetic studies may result in the successful management of patients at risk, or ideally a medical treatment to prevent or cure aneurysmal disease.

Key Concepts

Aortic aneurysmal disease represents a condition that develops at two main regions in the aorta: thoracic aortic aneurysm and abdominal aortic aneurysm (TAA and AAA).

TAA is a risk factor of, and often coexists with, thoracic aortic dissection, which is also a medical emergency and can result in death, usually referred to together as thoracic aortic aneurysm and dissection (TAAD).

There is currently no effective pharmacotherapeutic strategy for either disease, and the only treatment option available is surgical repair to prevent rupture. Emergency repair, once rupture has occurred, is associated with adverse outcomes compared to elective surgery.

The pathophysiology between AAA and TAAD is different due to differences in composition between the two aortic regions, which is reflected in different genetic causal backgrounds.

AAA is more common than TAAD and has a multifactorial and polygenic basis of disease, whereas familial and syndromic TAAD is predominantly genetic.

High‐profile genome‐wide association studies using large sample sizes have discovered several small‐effect genomic risk loci involved in AAA development.

Genetic studies of syndromic and nonsyndromic TAAD, usually in the form of family linkage studies with generally low sample numbers, have yielded several high‐effect gene mutations involved in disease development.

The ongoing study of the functional genetic and epigenetic basis of TAAD and AAA could potentially result in better identification, intervention and clinical outcomes for patients.