bluuebunny/crossref_metadata_2025_split huggingface dataset:
Copper Homeostasis: Regulation in Plants
Authors: Pilon Marinus , Tapken Wiebke 
Published: December 2013

AbstractCopper (Cu) is essential for plant life because of its key role in photosynthetic electron transport, respiration, and perception of the plant hormone ethylene. The most abundant Cu protein in plants is plastocyanin, an electron carrier in the chloroplast thylakoid lumen that is essential for photoautotrophic growth of plants. Copper is also a cofactor of superoxide dismutase and a number of extracellular cell wall enzymes for which the biological function is not yet fully elucidated. Cellular uptake is accomplished by theCopTCu(I) family of transporters.CopT1andCopT2are especially important at the root surface, whereasCopT6is important for Cu uptake in green cells.CopT5serves to release Cu from vacuolar stores. Members of the largeZIPfamily of divalent metal transporters might add capacity for uptake of Cu(II). Members of the yellow stripe‐like (YSL) family are proposed to function in the transport of Cu(II) complexed to the chelator nicotianamine, which might be important for mobilization of Cu from vegetative tissues to developing seeds.ATP‐dependent P‐typeATPasesof theHMAfamily transport Cu(I) out of the cytosol. Of these P‐typeATPases,HMA5serves to allow Cu exit from the cell, which is required for tolerance to excess and for long‐distance root‐to‐shoot transport in the vasculature. OtherHMAtransporters deliver the Cu cofactor to the ethylene receptors in the endomembrane system (HMA7) or to the chloroplasts (HMA6). A fourth Cu‐transporting P‐TypeATPase(HMA8) delivers Cu to plastocyanin in the thylakoid lumen. Cu‐specific metallochaperones have been identified in plants similarly to other eukaryotes. Under impending Cu deficiency, plants use three mechanisms to adjust their physiology. The cell‐surface‐localizedCopTtransporters are up‐regulated in response to low Cu availability in the cytosol via the conserved Cu‐responsive transcription factorSPL7in order to up‐regulate assimilation. In addition, plants enter a Cu economy mode by theSPL7‐mediated up‐regulation of a set of smallRNAmolecules called thecoppermicroRNAsbecause they target the messengerRNAsthat encode for certain apparently dispensable Cu proteins. This mechanism should ensure that enough Cu is left for essential functions such as photosynthesis. Finally, theHMA8transporter in the thylakoid membrane undergoes turnover, but low Cu availability stabilizes the transporter to ensure efficient delivery of Cu to plastocyanin. Together, these homeostatic mechanisms fine‐tune cellular and whole plant Cu distribution and allow plants to thrive on a broad range of Cu concentrations.
Iron Homeostasis: Hepcidin Regulation
Authors: Camaschella Clara , Silvestri Laura 
Published: December 2013

AbstractThe liver hormone hepcidin is the key regulator of systemic iron homeostasis in mammals. Hepcidin controls the release of iron into plasma by binding and degrading the sole cellular iron exporter ferroportin on the surface of enterocytes, macrophages, and hepatocytes. The transcription of hepcidin is enhanced in conditions of increased body iron through the bone morphogenic protein–sons of mothers against decapentaplegic (BMP6–SMAD) signaling pathway that uses hemojuvelin (HJV) as a coreceptor. Mutational inactivation of HJV, BMP6, and other components of the pathway leads to iron overload in both humans and mice, similar to what occurs in hepcidin inactivation. Because hepcidin is an antimicrobial peptide, its transcription is also increased in inflammation, especially in response to IL‐6, through JAK2‐STAT3 activation. Inhibition of the BMP–SMAD signaling reduces the hepcidin response to inflammatory cytokines, indicating a crosstalk between the two regulatory pathways. In conditions of increased iron requirement, such as iron deficiency, hypoxia, or stimulated erythropoiesis, hepcidin expression is inhibited by multiple, yet incompletely understood, mechanisms. The main hepcidin inhibitor is TMPRSS6 encoding a serine protease, which negatively affects the BMP–SMAD signaling. Mutational inactivation of this protease leads to inappropriately high hepcidin synthesis, defective intestinal iron absorption, and iron‐deficient iron‐refractory anemia in both mice and humans. Other molecules may contribute to hepcidin inhibition, including a soluble form of HJV, hypoxia, or mediators released by maturing erythroid cells, but their molecular mechanisms are uncertain.Although the picture of all potential hepcidin regulators is still incompletely defined, the identification of hepcidin and of its regulatory pathways has revolutionized our understating of iron metabolism and clarified the pathophysiology of iron‐related disorders. In addition, the discovery of the role of the hepcidin–ferroportin axis in the control of systemic iron homeostasis has stimulated a great interest in developing targeted drugs to control several human disorders characterized by iron deregulation. Novel promising therapeutic strategies are under development and some newly synthesized components have already been shown to be effective in animal models.
Iron Starvation Response inSaccharomyces cerevisiae
Authors: Philpott Caroline C. , Smith Pamela M. 
Published: December 2013

AbstractIron deficiency is the most common human nutritional disorder in the world, affecting more than 2 billion individuals; yet, the mechanisms behind many of the manifestations of iron deficiency remain obscure. Iron uptake and utilization has been studied in detail in the budding yeastSaccharomyces cerevisiae. Single‐celled organisms are similar to humans in their susceptibility to iron deficiency. Yeast respond to iron deficiency by the uptake of iron from the extracellular environment, the mobilization of iron from sites of intracellular storage, and the conservation of iron through metabolic adaptations.
Nickel Homeostasis: Mechanism and function ofNikR
Authors: Jones Michael D. , Sydor Andrew M. , Zamble Deborah B. 
Published: December 2013

AbstractNickel plays an important role in many organisms as a cofactor of enzyme active sites. However, nickel ions can be toxic and therefore require a robust regulation system. Found in a wide variety of bacteria and archaea,NikRis a transcription factor that regulates intracellular nickel homeostasis. The activities ofNikRhomologs from several microorganisms have been examined in detail both in vitro and in vivo. Ni2+loading promotesDNAbinding byNikR, an activity supplemented by additional, homolog‐specific cation requirements. Furthermore, there is evidence that the mechanism of nickel‐activatedDNAbinding includes stabilization of secondary structural elements of the protein that promote the formation of nonspecificDNAcontacts. Although a key function ofNikRis to regulate nickel uptake, the extent of its influence and its connection with other cellular pathways varies between organisms. Common features and contrasting activities withinNikRhomologs are presented and major outstanding questions are described.
Zinc Transport: Regulation
Authors: Kambe Taiho 
Published: December 2013

AbstractZinc homeostasis in cells is tightly controlled within narrow boundaries through the highly integrated processes of zinc uptake, sequestration, and efflux across the cell membrane, which enable a variety of zinc‐dependent proteins and enzymes to play physiologically important roles in numerous and varied biological responses. Thus, zinc transport proteins are essential to these processes. In general, two solute carrier (SLC) transporters, ZnT and ZIP, primarily regulate zinc transport in metazoans, but other membrane proteins (such as permeable channels) are also involved in zinc transport. Zinc exists as a divalent cation under physiological conditions, and thus it is transported across the cell membrane in this state, unlike iron and copper, which are reduced or oxidized before or after transport. This feature of zinc suggests that the expression levels of active zinc transporters at the cellular sites where they normally operate are important for defining net zinc transport, and thus the regulated expression of zinc transporters is critical for systemic and cellular zinc homeostasis. Regulation of zinc transport by ZnT and ZIP transporters is achieved by the coordination of a number of processes such as posttranslational modifications, modulation of transporter expression, and trafficking and degradation, in a zinc‐dependent or a zinc‐independent manner. In both transporters, the conserved amino acid residues in the putative intramembranous zinc‐binding sites, which are essential for zinc transport activity, appear to be involved in zinc selectivity.
Toxicity: Resistance Pathways for Metalloids and Toxic Metals
Authors: Liu Zijuan , Rensing Christopher , Rosen Barry P. 
Published: December 2013

AbstractOne of the initial challenges of the earliest cells would have been the ability to detoxify heavy metal ions and metalloids. This article focuses on microbial pathways for transport and biotransformation of the metalloid arsenic and the heavy metals cadmium and zinc. The emphasis is on recent findings on transporters and enzymes responsible for their uptake, efflux, redox cycling, and methylation.
Copper TransportingATPases in Mammalian Cells
Authors: Yang Nan , Lutsenko Svetlana 
Published: December 2013

AbstractCopper‐transportingATPases (Cu‐ATPases) are essential for growth and development of mammalian organisms. These ubiquitous and evolutionarily conserved transporters participate in the biosynthesis of copper‐dependent enzymes and maintain copper levels within the range necessary to meet metabolic demands and avoid toxicity.Cu‐ATPasesare the key components of sophisticated cellular machinery that evolved to provide precise inter‐ and intracellular distribution of metals, and the function of these transporters is tightly regulated. Copper along with a growing number of cytosolic proteins controls the activity, stability, and localization ofCu‐ATPases; this regulation ensures balance between the delivery of copper to metalloenzymes in various cell compartments and copper export. Inactivating mutations in human Cu‐ATPases ATP7AandATP7Bare associated with debilitating and often lethal disorders (Menkes disease and Wilson's disease, respectively). Biochemical and biophysical studies ofATP7AandATP7Brevealed multiple metal‐binding sites, complex multi‐domain architecture, and a significant role of interdomain interactions in the function and regulation of these transporters. This article summarizes the current data on the structure and mechanism of human Cu‐ATPases ATP7AandATP7B, as well as the biochemical basis of their regulation.
Copper in Immune Cells
Authors: Djoko Karrera Y. , Achard Maud E.S. , McEwan Alastair G. 
Published: December 2013

AbstractCopper is an essential trace nutrient but when used in slight excess it is highly cytotoxic. This toxicity has been exploited for centuries in medicine and agriculture, and today, the use of copper as an antimicrobial agent is still widespread. Intriguingly, this transition metal ion has recently emerged in a physiological role in the host innate immune response. Macrophages have been observed to use copper ions to promote killing of invading pathogens. These findings coincide with the wealth of reports that identify genes conferring copper resistance as key virulence factors in several medically significant pathogens, includingMycobacterium tuberculosis, Salmonellasp.,Streptococcus pneumoniae, Neisseria gonorrhoeae, Pseudomonas aeruginosa, andListeria monocytogenes. Here we summarize the present understanding of the role of copper ions at the host–pathogen interface.
Body frame variation and adiposity in development, a mixed‐longitudinal study of “cape coloured” children
Authors: Teghan Lucas , Henneberg Maciej 
Published: December 2013

ObjectivesThe obesity epidemic is impacting both developed and undeveloped countries worldwide. It has only been recently that wide scale public campaigning has focused on prevention rather than intervention. Individual variations in food metabolism and energy expenditure may be responsible for much of the adiposity present amongst individuals. This article studies individual variation in relationship between lean trunk size and adiposity.MethodsA mixed longitudinal growth study was conducted between 1986 and 1995 among urban and rural “Cape Coloured” schoolchildren from the Western Cape Province of South Africa. The sample consists of 127 females and 130 males between the ages of 6 and 20 years measured 6–9 times each. Correlations between age‐standardized triceps, subscapular and abdominal skinfold thicknesses and quotient indices obtained by expressing trunk length, lower limb, and upper limb lengths and bi‐acromial and bi‐iliocristal diameters as percentages of body height were explored for each year of growth.ResultsSignificant correlation coefficients (P < 0.05) between 0.087 and 0.511 were found in both males and females, between bi‐acromial and bi‐iliocristal indices and three skinfold thicknesses, but not between trunk and limb lengths and skinfolds.ConclusionsSkeletal frame width and amount of adiposity are correlated. The correlation persists longitudinally throughout childhood and adolescence in individuals living in very poor, as well as, in good environmental conditions. Am. J. Hum. Biol. 26:151–155, 2014. © 2013 Wiley Periodicals, Inc.
Haploinsufficiency of BMP4 gene may be the underlying cause of Frías syndrome
Authors: Martínez‐Fernández María Luisa , Bermejo‐Sánchez Eva , Fernández Belén , MacDonald Alexandra , Fernández‐Toral Joaquín , Martínez‐Frías María Luisa 
Published: December 2013

ABSTRACTIn 2005, we reported on a family as having Frías syndrome (OMIM: 609640), with four affected members displaying a pattern of congenital defects nearly identical to those observed in a mother and son described by Frias [Frías et al. (1975). Birth Defects Orig Artic Ser 11:30–33]. These defects included growth deficiency, facial anomalies, and hand and foot alterations. We had the opportunity to study this family again due to the birth of another affected girl, who presented with similar facial characteristics to those of her elder half‐sister and the rest of affected relatives, which consisted of mild exophthalmia, bilateral palpebral ptosis, downslanting palpebral fissures, and hypertelorism. We performed array‐CGH, which identified an identical interstitial deletion of chromosome 14q22.1–q22.3 in the mother and two daughters. The deletion is 4.06 Mb in length and includes the BMP4 gene, a member of the bone morphogenetic protein (BMP) family of secreted proteins. A review of the literature showed that deletions or mutations of this gene underlie congenital defects affecting brain, eye, teeth, and digit development. Although the clinical manifestations of the current family correlate with the defects observed in patients having either 14q22–q23 deletions or mutations of BMP4, they show a milder phenotype. In order to understand the clinical variability, we evaluated the already known functional characteristics of the BMP gene members. This gene family plays an important role during early embryogenesis, and the complex synergistic functions and redundancies of the BMPs led us to conclude that haploinsufficiency of BMP4 is likely to be responsible for the clinical expression of Frías syndrome. © 2013 Wiley Periodicals, Inc.
Gómez‐López‐hernández syndrome versus rhombencephalosynapsis spectrum: A rare co‐occurrence with bipartite parietal bone
Authors: Abdel‐Salam Ghada M.H. , Abdel‐Hadi Sawsan , Thomas Manal M. , Eid Ola M. , Ali Manal M. , Afifi Hanan H. 
Published: December 2013

AbstractRhombencephalosynapsis (RES) is a rare hindbrain malformation that could occur in isolation or as a part of a syndrome for example, Gómez‐López‐Hernández syndrome (GLH) or VACTERL‐H. We identified male patient with severe RES. Ventriculomegaly, agenesis of septum pellucidum, very thin corpus callosum with interhemispheric cyst were additional neuroimaging findings. He had brachyturricephaly, midface retrusion, low‐set posteriorly rotated ears and bilateral parietal well circumscribed areas of alopecia. No corneal anesthesia was observed; thus, demonstrating many of the diagnostic criteria of GLH. Interestingly, he additionally had bilateral bipartite parietal bone (BPB) that is an extremely rare anomaly of the parietal sutures. This is the first co‐occurrence of this rare anomaly with GLH. We believe the presence of this unique finding could represent an important clue for understanding the pathogenesis of this malformation. © 2013 Wiley Periodicals, Inc.
Partial trisomy 1q41‐qter and partial trisomy 9pter‐9q21.32 in a newborn infant: An array CGH analysis and review
Authors: Akalin Ibrahim , Bozdag Senol , Spielmann Malte , Basaran Sarenur Yilmaz , Nanda Indrajit , Klopocki Eva 
Published: December 2013

AbstractWe report on a girl who presented with distinctive abducted hip and hyperextended knee. Cytogenetic analysis detected an extra derivative chromosome resulting from a balanced translocation in the mother and 3:1 segregation. Using array comparative genomic hybridization (CGH) in combination with conventional high resolution GTG banding, we designate the karyotype as 47, XX, +der(9)t(1;9)(q41;q21.32)mat, indicating tertiary trisomy of chromosome segments 1q41‐qter and 9pter‐9q21.32. A review and genotype–phenotype correlation suggested that the patient represented most of the manifestations of duplication of chromosome arms 1q and 9p. To our knowledge, a similar case has so far not been reported. © 2013 Wiley Periodicals, Inc.
Changing interpretation of chromosomal microarray over time in a community cohort with intellectual disability
Authors: Palmer Emma , Speirs Helen , Taylor Peter J , Mullan Glenda , Turner Gill , Einfeld Stewart , Tonge Bruce , Mowat David 
Published: December 2013

AbstractChromosomal microarray (CMA) is the first‐line diagnostic test for individuals with intellectual disability, autism, or multiple congenital anomalies, with a 10–20% diagnostic yield. An ongoing challenge for the clinician and laboratory scientist is the interpretation of variants of uncertain significance (VOUS)—usually rare, unreported genetic variants. Laboratories differ in their threshold for reporting VOUS, and clinical practice varies in how this information is conveyed to the family and what follow‐up is arranged. Workflows, websites, and databases are constantly being updated to aid the interpretation of VOUS. There is a growing literature reporting new microdeletion and duplication syndromes, susceptibility, and modifier copy number variants (CNVs). Diagnostic methods are also evolving with new array platforms and genome builds. In 2010, high‐resolution arrays (Affymetrix 2.7 M Oligo and SNP, 50 kB resolution) were performed on a community cohort of 67 individuals with intellectual disability of unknown aetiology. Three hundred and one CNVs were detected and analyzed using contemporary resources and a simple scoring system. Thirteen (19%) of the arrays were assessed as potentially pathogenic, 4 (6%) as benign and 50 (75%) of uncertain clinical significance. The CNV data were re‐analyzed in 2012 using the contemporary interpretative resources. There was a statistically significant difference in the assessment of individual CNVs (P < 0.0001). An additional eight patients were reassessed as having a potentially pathogenic array (n = 21, 31%) and several additional susceptibility or modifier CNVs were identified. This study highlights the complexity involved in the interpretation of CMA and uniquely demonstrates how, even on the same array platform, it can be subject to change over time. © 2013 Wiley Periodicals, Inc.
Somatic and germ‐line mosaicism of deletion 15q11.2–q13 in a mother of dyzigotic twins with Angelman syndrome
Authors: Sánchez Javier , Fernández Raquel , Madruga Marcos , Bernabeu‐Wittel José , Antiñolo Guillermo , Borrego Salud 
Published: December 2013

AbstractAngelman syndrome (AS, OMIM105830) is a neurogenetic disorder caused by different genetic mechanisms. Determining the genetic mechanism is essential to establish the recurrence risk and the accuracy of genetic/reproductive counseling. The majority of AS patients present with a deletion of the 15q11.2–q13 region on the maternally derived chromosome. The other genetic mechanisms are: paternal disomy of chromosome 15, imprinting center defects, and mutations in the ubiquitin–protein ligase E3A gene (UBE3A). Different recurrence risks are associated with each specific genetic mechanism involved. We report on the study of dizygotic twins with classic phenotypic AS due to deletion of the same maternally derived chromosome 15. The mother presented with hypopigmented macular lesions on the inner side of both arms. Fibroblast culture studies of the maternal hypopigmented skin areas from both arms showed mosaicism for a normal cell line and for a second cell line with a 15q11.2–q13 deletion. This family represents the first demonstrated case of maternal somatic and germ line mosaicism for 15q11.2–q13 deletion as the cause of AS. © 2013 Wiley Periodicals, Inc.
Compound heterozygous deletions in pseudoautosomal region 1 in an infant with mild manifestations of langer mesomelic dysplasia
Authors: Tsuchiya Takayoshi , Shibata Minoru , Numabe Hironao , Jinno Tomoko , Nakabayashi Kazuhiko , Nishimura Gen , Nagai Toshiro , Ogata Tsutomu , Fukami Maki 
Published: December 2013

AbstractHaploinsufficiency of SHOX on the short arm pseudoautosomal region (PAR1) leads to Leri–Weill dyschondrosteosis (LWD), and nullizygosity of SHOX results in Langer mesomelic dysplasia (LMD). Molecular defects of LWD/LMD include various microdeletions in PAR1 that involve exons and/or the putative upstream or downstream enhancer regions of SHOX, as well as several intragenic mutations. Here, we report on a Japanese male infant with mild manifestations of LMD and hitherto unreported microdeletions in PAR1. Clinical analysis revealed mesomelic short stature with various radiological findings indicative of LMD. Molecular analyses identified compound heterozygous deletions, that is, a maternally inherited ∼46 kb deletion involving the upstream region and exons 1–5 of SHOX, and a paternally inherited ∼500 kb deletion started from a position ∼300 kb downstream from SHOX. In silico analysis revealed that the downstream deletion did not affect the known putative enhancer regions of SHOX, although it encompassed several non‐coding elements which were well conserved among various species with SHOX orthologs. These results provide the possibility of the presence of a novel enhancer for SHOX in the genomic region ∼300 to ∼800 kb downstream of the start codon. © 2013 Wiley Periodicals, Inc.