bluuebunny/crossref_metadata_2025_split huggingface dataset:
Molecular Genetics of Metabolic Syndrome
Authors: Chang Yi‐Cheng , Yu Yu‐Hsiang , Chuang Lee‐Ming 
Published: April 2013

Abstract

The clustering of metabolic traits (known as metabolic syndrome), including central obesity, abnormal glucose regulation, dyslipidemia and elevated blood pressure, was associated with increased risk of cardiovascular disease and type 2 diabetes. The close clustering and strong heritability of these metabolic traits suggest a common underlying genetic basis. Genetically modified mice models and identification of causative gene for human monogenic obesity/insulin resistance syndrome provided important insights into the pathogenesis of the metabolic syndrome. Recent genome‐wide association studies (GWAS) also identified several genes reproducibly associated with the metabolic syndrome or multiple metabolic traits, including genes involved in lipid metabolism (
CETP, APOA1/C3/A4/A5
cluster,
LPL
,
LIPC
and
ABCB11
), glucose sensing (
GCKR
), insulin signalling (
IRS1
), beta‐cell function (TCF7L2) and appetite control (
FTO
). However, these variants explain only a small fraction of the observed heritability. Further pursuit for structural variants, rare sequence variants and epigenetic modification related to the metabolic syndrome may help to elucidate the unexplained heritability.

Key Concepts:

The estimated heritability of the metabolic syndrome and related metabolic traits (including obesity, dyslipidemia, abnormal glucose regulation and elevated blood pressure) is relatively high.

Genetically modified knockout mice models and human monogenic obese/insulin resistant syndrome provide important molecular insights into the pathogenesis of the metabolic syndrome.

Family linkage mapping for the metabolic syndrome is of limited success because of inconsistency among studies.

Large‐scale genome‐wide association mapping identified many genetic loci associated with the metabolic syndrome and related traits. Important loci are located in genes involved in lipid metabolism (
CETP, APOA1/C3/A4/A5
cluster,
LPL
,
LIPC
and
ABCB11
), glucose sensing (
GCKR
), insulin signalling (
IRS1
), beta‐cell function (TCF7L2) and appetite control (
FTO
).

The genetic variants identified by genome‐wide association mapping explain only a minor fraction of the estimated heritability. Other potential contributors to the unexplained heritability are structural variants, rare sequence variants and epigenetic modification.
Molecular Genetics of Fanconi Anaemia
Authors: Green Allison M , Kupfer Gary M 
Published: April 2013

Abstract

Cells derived from Fanconi anaemia (FA) patients display hypersensitivity to
deoxyribonucleic acid
(DNA) cross‐linking agents such as MMC and DEB. Treatment with these agents induces an abnormally prolonged cell cycle arrest in S phase and an accumulation of cells with 4N DNA. Based on this response, the FA pathway has been hypothesised to function in sensing DNA damage induced by these agents and in initiating its repair. This hypothesis has been supported by work elucidating the interactions of FA proteins with proteins known to be involved in DNA‐damage sensing, signalling and repair. Additionally, a significant body of work has pointed to a role of the FA pathway in the cellular response to oxidative stress. Although the exact mechanisms and functions of the FA pathway are yet to be discovered, the interaction of the members of the FA pathway with proteins associated with DNA repair, cellular signalling and oxidative stress management leads to the hypothesis that the FA pathway proteins serve many varied functions throughout the cell.

Key Concepts:

The FA pathway overlaps significantly with other DNA repair pathways such as homologous recombination, translesion synthesis and mismatch repair.

FA pathway proteins are involved in the intricate cellular signalling that occurs following DNA damage.

FA pathway proteins are involved in regulating oxidative stress.

FA mutant cells display hypersensitivity to DNA damage, particularly DNA crosslink's.

FA patients are particularly prone to malignancy, especially myeloid leukemia and squamous cell carcinomas of the head and neck and genitourinary track.
Molecular Genetics of Incontinentia Pigmenti
Authors: Ursini Matilde Valeria , Conte Matilde Immacolata , Pescatore Alessandra , Miano Maria Giuseppina , Fusco Francesca 
Published: April 2013

Abstract

Incontinentia Pigmenti (IP) is a rare X‐linked dominant neuroectodermal disorder caused by mutations in the nuclear factor kappaB essential modulator (
NEMO
)/Inhibitor of Kappa light polypeptide gene enhancer in B‐cells Kinase Gamma (
IKBKG
) gene. The
NEMO locus
maps in a region with a unique genomic organisation: in the centromeric direction,
NEMO
partially overlaps the
glucose‐6‐phosphate dehydrogenase
gene; in the telomeric direction,
NEMO
is part of a 35.7 kb segmental duplication containing its nonfunctional truncated copy
pseudoNEMO
. Moreover, a high frequency of micro‐/macro‐homologies, tandem repeats and repeat/repetitive sequences characterise the local architecture of the
locus
increasing its vulnerability to the production of

de novo

genomic rearrangements through different mechanisms. Indeed, instances of nonallelic homologous recombination (NAHR) causing both benign and pathological alleles, nonhomologous end joining (NHEJ) and
Alu
–
Alu
‐mediated recombination events producing either recurrent or nonrecurrent deletions have been reported. These events, occurring during both meiosis and mitosis, reveal that the region is prone to generate complex human genomic rearrangements.

Key Concepts:

Genomic rearrangements in the
NEMO
gene can be generated during meiosis or mitosis.

Low copy repeats or segmental duplication regions can act as substrates for aberrant recombination and for gene conversion events.

The complex architecture of the
locus
enhances its vulnerability to the production of
de novo
genomic rearrangements through different mechanisms.

The mutational mechanisms that can give rise to genomic rearrangements in the IP
locus
are: NAHR, NHEJ,
Alu–Alu
mediated recombination and gene conversion.

NAHR, mediated through sequences that exhibit a considerable homology called
MER67B
, is one of the major mechanisms for the generation of
de novo
rearrangements in the IP
locus
.
Application of Chromosome Conformation Capture (3C) to the Study of Human Genetic Disease
Authors: Horan Martin P , Ballard J William O 
Published: April 2013

Abstract

Chromosome conformation capture (3C) is a powerful technique that allows for the generation of 3‐dimensional transcriptome organisational maps. 3C facilitates the identification and quantitative measurement of distant chromosomal regulatory elements with proximal gene promoter regions. This is achieved by fixing protein onto
deoxyribonucleic acid
(DNA) followed by restriction enzyme digestion or sonication to shear the DNA prior to re‐ligation of the fixed DNA region. PCR amplification of a chromosomal region of interest can then be performed and quantified. Next generation sequencing platforms on prepared 3C chromatin can provide information on whole genome regulatory networks. The technology and its modified derivatives provide high levels of resolution and throughput for determining nuclear organisation and allows for the identification of novel noncoding DNA regions that are associated with controlling gene expression. 3C is providing important insights into underlying mechanisms that may be responsible for various human diseases including cancer, muscular dystrophies, neurological and metabolic disorders.

Key Concepts:

Chromosome conformation capture (3C) is a key strategy used to determine distant chromosomal regulatory regions involved with controlling gene expression.

Single nucleotide polymorphic (SNP) DNA variations in noncoding region DNA can now be interrogated to determine a functional role in altering gene expression.

The 3‐dimensional chromosome looping architecture can be dissected to determine multiple chromosomal regions involved with regulating gene expression through transcription factory interaction.

Mutations in distant chromosomal regulatory regions may lead to uncontrolled repression of oncogenes allowing for increases in tumour growth and development.

Identifying noncoding chromosomal regions associated with nuclear adaptive mechanisms in response to DNA mutation may allow us to determine critical regions involved with maintaining cellular homoeostasis.

High‐throughput sequencing strategies are allowing for unparalleled identification of DNA variation in the human genome.
GLI
Proteins in Human Genetic Disease
Authors: Olena Zhulyn , Chi‐chung Hui 
Published: April 2013

Abstract

GLI1, GLI2 and GLI3 transcription factors are the key effectors of mammalian Hedgehog signalling. Mutations in these transcription factors are implicated in severe congenital malformations and malignancies in humans and in mice. Analysis of mouse models has revealed that the patterning and development of multiple organ systems is dependent on a tightly regulated balance of Gli activator and repressor activity. Consequently, mutations in the Hh pathway machinery that affect Gli function or processing result in phenotypes with a striking resemblance to GLI‐associated disorders. The primary cilium was identified as a critical component of Hh signalling due to the phenotypic overlap between Hh‐pathway mutants and mice with defects in ciliogenesis. Many mutations in genes regulating cilia structure and function have been identified in human ciliopathies. This new class of diseases shares significant phenotypic overlap with GLI‐related syndromes. Phenotypic analysis of mice with compromised cilia function has revealed new aspects of Gli regulation demonstrating the utility of mouse models in the characterisation of novel disease phenotypes.

Key Concepts:

Balance of GLI activator and repressor is required for normal development.

Shift of the balance towards low or high GLI3R levels results in severe congenital malformations.

Shift of the balance towards high GLI activator results in cancer.

Mutations affecting different domains of bifunctional transcription factor Gli3 give rise to distinct phenotypes.

Mutations affecting Hh pathway machinery affect Gli processing and activity and result in Gli‐related phenotypes.

The primary cilium is critical for Hh signal transduction.

Mutations in regulators of primary cilia structure and function result in ciliopathies, which share many overlapping phenotypes with GLI‐associated syndromes.
Molecular Genetics of Cystinuria
Authors: Eggermann Thomas 
Published: April 2013

Abstract

Among the kidney stone diseases, cystinuria (OMIM
220100
) is unique as it is exclusively caused by genomic alterations. Cystinuria is associated with mutations in the
SLC3A1
and the
SLC7A9
genes encoding the subunits rBAT and b
0,+
AT of the renal b
0,+
transporter. Mutations in
SLC3A1
are usually inherited autosomal recessively, but
SLC7A9
mutations result in a broad clinical variability. The detection rate for mutations is influenced by the ethnic origin of the patient and by the functional significance of the variant. As a result, mutations cannot be detected in 100% of alleles, but it reaches approximately 85%. In case of
SLC3A1
, large rearrangements in 2p21 cause cystinuria and severe hypotonia (hypotonia–cystinuria syndrome – HCS). Meanwhile, a large number of mutations in both genes have been reported, several of these variants were functionally analysed. Thereby, the aetiology of the disease as well as the physiological mechanisms of the renal trafficking of cystine could be deciphered.

Key Concepts:

Cystinuria is characterised by the defect transport of cystine, resulting in cystine stone formation.

With
SLC3A1
and
SLC7A9,
two disease causing genes have been identified.

SLC3A1
and
SLC7A9
encode the two subunits of the amino acid transporter b
0,+
.

Mutations in
SLC3A1
are predominantly associated with an autosomal recessive inheritance, whereas
SLC7A9
mutations show an autosomal dominant inheritance with an incomplete penetrance.

Homozygosity for large genomic deletions affecting both the
SLC3A1
and the
PREPL
gene in 2p21 cause the hypotonia–cystinuria syndrome.
Li
NC
Complex and Human Genetic Muscular Disease
Authors: Wehnert Manfred S , Meinke Peter 
Published: April 2013

Abstract

The linker of nucleoskeleton and cytoskeleton (LiNC) complex is a proposed mechanical link tethering the nucleo‐ and cytoskeleton via the nuclear envelope (NE). The LiNC components emerin, lamin A/C, SUN1, SUN2, nesprin 1 and nesprin 2 interact with each other at the NE and also with other binding partners including actin filaments and B‐type lamins. Besides the mechanostructural functions, cell‐ or tissue‐specific LiNC complexes are also involved in signalling pathways and gene regulation. Emerin was the first LiNC component associated with a human disease, namely Emery–Dreifuss muscular dystrophy (EDMD). Later on, other components of a hypothetically muscle‐specific LiNC complex, such as lamins A/C and small muscle‐specific isoforms of nesprin 1 and nesprin 2, were found to be associated with EDMD, reflecting a genetic heterogeneity that has not been resolved so far. Only approximately 47% of the EDMD patients can be linked to genes of LiNC and non‐LiNC components, probably interacting with muscle‐specific LiNC(s) involved in the pathology of muscular disorders.

Key Concepts:

Linker of nucleoskeleton and cytoskeleton (LiNC) complexes are tethering the nucleo‐ and cytoskeleton via the nuclear envelope.

The inhibition of LiNC components results in changes of the biomechanical behaviour of contractile cells.

Mutations in genes encoding muscle‐specific LiNC components lead to a variety of inherited human muscular disorders, in particular Emery–Dreifuss muscular dystrophy.

The wide phenotypic variability of LiNC‐associated muscular diseases can be explained by digenic inheritance.

The association of LiNC and LiNC‐related components with human disease helps to resolve genetic heterogeneity and clinical variability and provides tools to understand their functions within the cell as well.
Plakin Proteins, Hemidesmosomes and Human Disease
Authors: Chidgey Martyn 
Published: April 2013

AbstractThe plakin proteins are a family of cytolinker proteins that connect elements of the cell cytoskeleton to each other and to junctional complexes at the cell membrane. There are seven mammalian plakin proteins and they are characterised by the presence of a plakin domain and/or a plakin repeat domain. The plakins play a vital role in maintaining the integrity of tissues, such as the skin and heart, which are subjected to mechanical stress. Two plakin proteins, plectin and bullous pemphigoid antigen 1 (BPAG1), are essential components of hemidesmosomes, cell–extracellular matrix junctions of epithelial cells, and inherited mutations in either can result in the skin blistering disease epidermolysis bullosa simplex. Mutations in the desmosomal plakin protein desmoplakin can cause the heart muscle disorder arrhythmogenic right ventricular dysplasia, a common cause of sudden cardiac arrest and death in young adults. Plakin proteins are targeted by pathogenic autoantibodies in the skin blistering diseases bullous pemphigoid and paraneoplastic pemphigus.Key Concepts:The plakin proteins are a family of cytolinker proteins that connect elements of the cell cytoskeleton to each other and to junctional complexes at the cell membrane.Seven plakin proteins are found in mammals; plectin, BPAG1, desmoplakin, envoplakin, periplakin, microtubule–actin crosslinking factor 1 and epiplakin.Plectin and BPAG1 are important constituents of hemidesmosomes, cell–extracellular matrix junctions.Mutations in plakin proteins can result in skin blistering disease, muscular dystrophy, autonomic neuropathy and cardiomyopathy.Plakin proteins have been implicated in the autoimmune skin blistering diseases bullous pemphigoid and paraneoplastic pemphigus.
Evolution of Uric Acid Metabolism in Humans
Authors: Alvarez‐Lario Bonifacio , Macarrón‐Vicente Jesús 
Published: April 2013

Abstract

Several evolutionary changes have led to uric acid levels being much higher in humans than in other mammals. Uric acid is the end product of purine metabolism in hominoids, including humans, due to the genetic loss of uricase activity during the Miocene epoch, and this is the main cause of the increased uric acid in hominoids. Additional factors that have contributed to increased levels of uric acid are the high renal tubular reabsorption of uric acid and the previous loss of the ability to synthesise vitamin C in hominoids. Several hypotheses have been proposed on the evolutionary advantage of increased serum uric acid levels in hominoids, although the biological reasons for this increase remain unclear. The large current increase in uric acid levels in humans in developed countries is mainly influenced by dietary factors and lifestyle changes.

Key Concepts:

Uric acid (UA) is the end product of purine metabolism in humans due to the loss of uricase activity by various mutations of its gene during the Miocene epoch.

Loss of uricase activity led to humans having higher UA levels than other mammals.

The high renal tubular reabsorption of UA and the previous loss of the ability to synthesise vitamin C may have also contributed to increased levels of UA in humans.

The biological reason for the loss of uricase activity and increased levels of UA in humans and certain primates is unknown.

UA is one of the most important antioxidants in human biological fluids.

UA probably has neuroprotective activity.

The current large increase in UA levels in humans in developed countries is mainly influenced by eating habits and lifestyle changes.

Hyperuricaemia can cause gout and uric lithiasis, and is associated with hypertension, metabolic syndrome, renal disease and cardiovascular disease.
Tandem Repeat Instability and Genome Evolution
Authors: Matthew Ward R , Mittelman David 
Published: April 2013

AbstractEvolvability is the potential for a biological system to produce variation that can be acted upon by natural selection. Processes that promote selectable variation can facilitate adaptation to dynamic environments. Microsatellite repeats – sequences composed of repeated sets of up to nine nucleotides – provide one source of adaptive variation. Repeats mutate by the addition or loss of their unit nucleotide sequence, up to 100 000 times more frequently than point mutations. In a number of species, including humans, repeat mutations can cause disease (including neurological and skeletal disorders) as well as exert subtle and quantitative consequences on gene function, morphology, behaviour and life history traits. Understanding the underlying properties of repeat mutation – including causes and mechanisms – is critical for understanding trait variation, adaptation and a growing list of human disorders.Key Concepts:Recent discoveries in molecular genetics are challenging current dogma that claims independence between selection and mutation.Tandem repeats in the genome are highly mutable, sometimes at frequencies of up to 100 000 times more than point mutations.Nearly all aspects of DNA processing, and even transcription and stress, contribute to repeat mutation, making repeats important markers for genomic instability.Microsatellite repeats encode their own mutability, thereby enabling local manipulation of mutation rates.Changes in the lengths of tandem repeats can subtly and quantitatively modulate gene function, traits and disease.Many genomic regions, including tandem repeats, mutate during cellular stress, suggesting that the genome is far more dynamic and susceptible to environmental processes than previously recognised.
A Negative Conductivity Material Makes a dc Invisibility Cloak Hide an Object at a Distance
Authors: Yang Fan , Mei Zhong Lei , Yang Xin Yu , Jin Tian Yu , Cui Tie Jun 
Published: April 2013

AbstractThe theoretical design and the first experimental verification of an exterior dc invisibility cloak that can hide an object from dc detection at a distance are presented. Based on the transformation optics theory, the exterior dc cloak requires negative conductivity material to create folded geometry, which will cancel the real geometry of detected object in distance and make it invisible. Negative conductivities are designed and realized using active devices, together with resistor networks, to generate the equivalent conductivity materials required by the exterior dc cloak. An experimental sample of the dc cloak is fabricated on the printed circuit board and the measured result has excellent agreement with numerical and circuit simulations, showing very good cloaking performance at a distance.
Chemical strategies to understand the language of ubiquitin signaling
Authors: Weller Caroline E. , Pilkerton Meagan E. , Chatterjee Champak 
Published: April 2013

ABSTRACTUbiquitin (Ub) is a small 76 amino acid long protein that is highly conserved in all eukaryotes studied to date. In humans, more than 600 ligases are involved in the reversible modification of specific lysine side‐chain amines in substrate proteins by conjugation with the C‐terminal carboxylate of Ub. Initially monoubiquitylated proteins can undergo repetitive ubiquitylation starting from one of seven lysine residues or the α‐amine in the first Ub to generate a variety of polyUb chains with different topologies and functions. The most well known role for protein ubiquitylation is in targeting substrates for proteolytic destruction by 26S proteasomes. However, a growing body of evidence indicates that both mono‐ and polyubiquitylation play proteasome‐independent roles in modulating the structure, function, and localization of protein substrates. Understanding the complexity of Ub‐mediated functions in our cells is a major challenge for modern biology. In addition to well‐established in vivo genetic methods, biochemical and biophysical investigations of ubiquitylated proteins in vitro can shed light on the direct mechanistic roles for Ub in different contexts. Such studies have traditionally been limited by the ability to obtain sufficient quantities of homogenously ubiquitylated proteins with precisely defined linkages. This review focuses on recent advances in both synthetic and recombinant protein‐based methods that have yielded access to homogenously site‐specifically ubiquitylated proteins. Mechanistic studies of the roles for protein ubiquitylation and of the enzymes involved in protein deubiquitylation that are enabled by these chemical tools are highlighted. © 2013 Wiley Periodicals, Inc. Biopolymers 101: 144–155, 2014.
ChemInform Abstract: (Sb7Te8)5+ — A Double Cube Shaped Polycationic Cluster.
Authors: Eich Andreas , Schlueter Stefan , Schnakenburg Gregor , Beck Johannes 
Published: April 2013

AbstractOrange, highly air sensitive crystals of (Sb7Te8)[Ga2Cl7]2 [GaCl4]3 (I), (Sb7Te8)[Ga2Cl7]3 [GaCl4]2 (II), Na(Sb7Te8)[GaCl4]6 (III) and Na(Sb7Te8)[AlCl4]6 (IV) are prepared by reaction of Sb and Te in molten GaCl3 or AlCl3 in the presence of MCl (M: Li, Na, In, Cu) and SbCl3 as the oxidant (I: 100°C, 15 d, II: 100°C, 60 d, III: 100°C, 69 d, IV: 125°C, 15 d).
ChemInform Abstract: Asymmetric Synthesis of 4‐Formyl‐1‐(ω‐haloalkyl)‐β‐lactams and Their Transformation to Functionalized Piperazines and 1,4‐Diazepanes.
Authors: Dekeukeleire Stijn , D'hooghe Matthias , Vanwalleghem Matthieu , Van Brabandt Willem , De Kimpe Norbert 
Published: April 2013

AbstractThe chiral piperazine (III) and 1,4‐diazepane annulated β‐lactams (VII) are transformed into the novel compounds (V) and (VIII) via ring opening.
ChemInform Abstract: Michael Addition of N‐Heteroaromatics to Vinylphosphonates and Synthesis of Phosphoryl Pyrrolizones by Cyclization of Michael Adducts.
Authors: Tasgin Dilek Isik , Unaleroglu Canan 
Published: April 2013

AbstractThe conversion of Knoevenagel products to N‐hetaryl‐substituted vinylphosphonates is developed.