Answering a century old riddle: brachydactyly type Al

In 1903, Farabee analyzed the heredity of the human digital malformation, brachydactyly, the first recorded disorder of the autosomal dominant Mendelian trait. In 1951, Bell classified this type of brachydactyly as type A1 (BDA1). Over 100 cases from different ethnic groups have so far been reported. However, the real breakthrough in identifying the cause of BDA1 has only taken place in the last few years with the progress of the mapping and identification of one of the genes responsible for this disorder, thus providing an answer for a century old riddle. In this article, we attempt to review the current state of knowledge on the genetic features of BDA1 with its century-old history and signalling pathway of IHH, and also discuss genotype-phenotype correlation not only of BDA1, but also of all types of brachydactyly.     

p53 in stem cells

p53 is well known as a "guardian of the genome" for differentiated cells,in which it induces cell cycle arrest and cell death after DNA damage and thus contributes to the maintenance of genomic stability.In addition to this tumor suppressor function for differentiated cells,p53 also plays an important role in stem cells.In this cell type,p53 not only ensures genomic integrity after genotoxic insults but also controls their proliferation and differentiation.Additionally,p53 provides an effective barrier for the generation of pluripotent stem celllike cells from terminally differentiated cells.In this review,we summarize our current knowledge about p53 activities in embryonic,adult and induced pluripotent stem cells.     

Inscuteable maintains type I neuroblast lineage identity via Numb/Notch signaling in the Drosophila larval brain

In the Drosophila larval brain, type I and type Ⅱ neuroblasts(NBs) undergo a series of asymmetric divisions which give rise to distinct progeny lineages. The intermediate neural progenitors(INPs) exist only in type Ⅱ NB lineages. In this study, we reveal a novel function of Inscuteable(Insc) that acts to maintain type I NB lineage identity. In insc type I NB clones of mosaic analyses with a repressible cell marker(MARCM), the formation of extra Deadpan(Dpn)tNB-like and GMC-like cells is observed. The lack of Insc leads to the defective localization and segregation of Numb during asymmetric cell division. By the end of cytokinesis, this results in insufficient Numb in ganglion mother cells(GMCs). The formation of extra Deadpan(Dpn)tcells in insc clones is prevented by the attenuation of Notch activity. This suggests that Insc functions through the Numb/Notch signaling pathway. We also show that in the absence of Insc in type I NB lineages, the cellular identity of GMCs is altered where they adopt an INP-like cell fate as indicated by the initiation of Dpn expression accompanied by a transient presence of Earmuff(Erm).These INP-like cells have the capacity to divide multiple times. We conclude that Insc is necessary for the maintenance of type I NB lineage identity. Genetic manipulations to eliminate most type I NBs with overproliferating type Ⅱ NBs in the larval brain lead to altered circadian rhythms and defective phototaxis in adult flies. This indicates that the homeogenesis of NB lineages is important for the adult's brain function.     

Antiviral activity of Basidiomycete mycelia against influenza type A(serotype H1N1) and herpes simplex virus type 2 in cell culture

In this study, we investigated the in vitro antiviral activity of the mycelia of higher mushrooms against influenza virus type A(serotype H1N1) and herpes simplex virus type 2(HSV-2), strain BH. All 10 investigated mushroom species inhibited the reproduction of influenza virus strain A/FM/1/47(H1N1) in MDCK cells reducing the infectious titer by 2.0–6.0 lg ID50. Four species, Pleurotus ostreatus, Fomes fomentarius, Auriporia aurea, and Trametes versicolor, were also determined to be effective against HSV-2 strain BH in RK-13 cells, with similar levels of inhibition as for influenza. For some of the investigated mushroom species—Pleurotus eryngii, Lyophyllum shimeji, and Flammulina velutipes—this is the first report of an anti-influenza effect. This study also reports the first data on the medicinal properties of A. aurea, including anti-influenza and antiherpetic activities. T. versicolor 353 mycelium was found to have a high therapeutic index(324.67), and may be a promising material for the pharmaceutical industry as an anti-influenza and antiherpetic agent with low toxicity. Mycelia with antiviral activity were obtained in our investigation by bioconversion of agricultural wastes(amaranth flour after CO2 extraction), which would reduce the cost of the final product and solve some ecological problems.     

Antiviral activity of Basidiomycete mycelia against influenza type A (serotype H1N1) and herpes simplex virus type 2 in cell culture

In this study, we investigated the in vitro antiviral activity of the mycelia of higher mushrooms against influenza virus type A(serotype H1N1) and herpes simplex virus type 2(HSV-2), strain BH. All 10 investigated mushroom species inhibited the reproduction of influenza virus strain A/FM/1/47(H1N1) in MDCK cells reducing the infectious titer by 2.0–6.0 lg ID50. Four species, Pleurotus ostreatus, Fomes fomentarius, Auriporia aurea, and Trametes versicolor, were also determined to be effective against HSV-2 strain BH in RK-13 cells, with similar levels of inhibition as for influenza. For some of the investigated mushroom species—Pleurotus eryngii, Lyophyllum shimeji, and Flammulina velutipes—this is the first report of an anti-influenza effect. This study also reports the first data on the medicinal properties of A. aurea, including anti-influenza and antiherpetic activities. T. versicolor 353 mycelium was found to have a high therapeutic index(324.67), and may be a promising material for the pharmaceutical industry as an anti-influenza and antiherpetic agent with low toxicity. Mycelia with antiviral activity were obtained in our investigation by bioconversion of agricultural wastes(amaranth flour after CO2 extraction), which would reduce the cost of the final product and solve some ecological problems.     

Evaluation of Genetic and Epigenetic Modification in Rapeseed （Brassica napus） Induced by Salt Stress

Salinity is an important limiting environmental factor for rapeseed production worldwide. In this study, we assessed the extent and pattern of DNA damages caused by salt stress in rapeseed plants. Amplified fragment length polymorphism （AFLP） analysis revealed dose-related increases in sequence alterations in plantlets exposed to 10-1000 mmol/L sodium chloride. In addition, individual plantlets exposed to the same salt concentration showed different AFLP and selected region amplified polymorphism banding patterns. These observations suggested that DNA mutation in response to salt stress was random in the genome and the effect was dose-dependant. DNA methylation changes in response to salt stress were also evaluated by methylation sensitive amplified polymorphism （MSAP）. Three types of MSAP bands were recovered. Type Ⅰ bands were observed with both isoschizomers Hpa Ⅱ and Msp Ⅰ, while type Ⅱ and type Ⅲ bands were observed only with Hpa Ⅱ and Msp Ⅰ, respectively. Extensive changes in types of MSAP bands after NaCI treatments were observed, including appearance and disappearance of type Ⅰ, Ⅱ and Ⅲ bands, as well as exchanges between either type Ⅰand type Ⅱ or type Ⅰ and type Ⅲ bands. An increase of 0.2-17.6% cytosine methylated CCGG sites were detected in plantlets exposed to 10- 200 mmol/L salt compared to the control, and these changes included both de novo methylation and demethylation events. Nine methylation related fragments were also recovered and sequenced, and one sharing a high sequence homology with the ethylene responsive element binding factor was identified. These results demonstrated clear DNA genetic and epigenetic alterations in planUets as a response to salt stress, and these changes may suggest a mechanism for plants adaptation under salt stress.     

A Neuro-Muscular Elasto-Dynamic Model of the Human Arm Part 1: Model Development

In this paper we develop an elasto-dynamic model of the human arm for use in neuro-muscular control and dynamic interactionstudies.The motivation for this work is to present a case for developing and using non-quasistatic models of humanmusculo-skeletal biomechanics.The model is based on hybrid parameter multiple body system(HPMBS)variational projectionprinciples.In this paper,we present an overview of the HPMBS variational principle applied to the full elasto-dynamic model ofthe arm.The generality of the model allows one to incorporate muscle effects as either loads transmitted through the tendon atpoints of origin and insertion or as an effective torque at a joint.Though the technique is suitable for detailed bone and jointmodeling,we present in this initial effort only simple geometry with the bones discretized as Rayleigh beams with elongation,while allowing for large deflections.Simulations demonstrate the viability of the mcthod for use in the companion paper and infuture studies.     

Effect of Salinity on the Composition, Number and Size of Epidermal Cells along the Mature Blade of Wheat Leaves

Salinity inhibits leaf growth in association with changes in cell size. The objective of this study was to determine the spatial distributions of the composition, number and dimensions of epidermal cells in the mature blades of leaf four of wheat seedlings under saline conditions. Plants were grown in loamy soil either with or without 120 mmol/L NaCl in a growth chamber, and harvested after leaf four was fully developed. The results of the spatial distribution analyses of width along the blade showed that salinity not only reduced the width of the leaf blade, but that it also altered the distribution pattern of blade width along the leaf axis. The reduction in the final size of the leaf blade was associated with a reduction in the total number of epidermal cells and in their widths and lengths. This study also revealed the spatial effects of salinity on the blade and epidermal cell dimensions along the leaf axis. In particular, salinity inhibited the total cell number for interstomatal, sister and elongated cells, implying that cell division in wheat leaves is inhibited by salinity. However, the lengths of interstomatal cells were not affected by salinity （unlike those for the sister and elongated cells）, suggesting the relative contributions of cell length and numbers to the reduction in the final length of the blade under salinity is dependent on cell type.     

Regenerative medicine research in China: from basic research to clinical practice

<正>I am very happy to write editorial for this Special Issue of Stem Cells and Regenerative Medicine in China in Science China Life Sciences.As we all know,stem cells and regenerative medicine research is the frontiers not only in China,but also in the world.In recent decades,rapid research progressing,strong governmental support and recruitment of highly trained scientists from abroad together with domestic outstanding researchers and clinicians have made it possible     

A GDF5 Point Mutation Strikes Twice - Causing BDA1 and SYNS2

Growth and Differentiation Factor 5 (GDF5) is a secreted growth factor that belongs to the Bone Morphogenetic Protein (BMP) family and plays a pivotal role during limb development. GDF5 is a susceptibility gene for osteoarthritis (OA) and mutations in GDF5 are associated with a wide variety of skeletal malformations ranging from complex syndromes such as acromesomelic chondrodysplasias to isolated forms of brachydactylies or multiple synostoses syndrome 2 (SYNS2). Here, we report on a family with an autosomal dominant inherited combination of SYNS2 and additional brachydactyly type A1 (BDA1) caused by a single point mutation in GDF5 (p.W414R). Functional studies, including chondrogenesis assays with primary mesenchymal cells, luciferase reporter gene assays and Surface Plasmon Resonance analysis, of the GDF5^W414R variant in comparison to other GDF5 mutations associated with isolated BDA1 (p.R399C) or SYNS2 (p.E491K) revealed a dual pathomechanism characterized by a gain- and loss-of-function at the same time. On the one hand insensitivity to the main GDF5 antagonist NOGGIN (NOG) leads to a GDF5 gain of function and subsequent SYNS2 phenotype. Whereas on the other hand, a reduced signaling activity, specifically via the BMP receptor type IA (BMPR1A), is likely responsible for the BDA1 phenotype. These results demonstrate that one mutation in the overlapping interface of antagonist and receptor binding site in GDF5 can lead to a GDF5 variant with pathophysiological relevance for both, BDA1 and SYNS2 development. Consequently, our study assembles another part of the molecular puzzle of how loss and gain of function mutations in GDF5 affect bone development in hands and feet resulting in specific types of brachydactyly and SYNS2. These novel insights into the biology of GDF5 might also provide further clues on the pathophysiology of OA.     

Heritability of brachydactyly type A3 in children, adolescents, and young adults from an endogamous population in eastern Nepal

Brachymesophalangia-V (BMP-V), a short and broad middle phalanx of the fifth digit, is the most common of all skeletal anomalies of the hand. When this feature appears alone, it is clinically known as brachydactyly type A3 (BDA3). A high prevalence of BDA3 has been observed among the children of the Jirel ethnic group in eastern Nepal. As part of the Jiri Growth Study, a hand-wrist radiograph is taken annually of each child to assess skeletal development. For this study the most recent radiographs of 1,357 Jirel children, adolescents, and young adults (676 boys, 681 girls), age 3-20 years, were examined for the presence or absence of BDA3, to report the prevalence and estimate the heritability of BDA3 in the Jirel population. The overall prevalence of BDA3 in this sample was 10.5% (12.9% of the males and 8.9% of the females were classified as BDA3 affected). The additive genetic heritability of BDA3 was statistically significant in this sample (h2 +/- SE = 0.87 +/- 0.16, p < 0.0001). This study is the first to estimate the prevalence and heritability of BDA3 in a large South Asian family-based sample.     

Identification of one novel mutation in the C-propeptide of COL2A1 in a Chinese family with spondyloperipheral dysplasia

Spondyloperipheral dysplasia (SPD; OMIM 271700) is an autosomal dominant connective tissue disorder characterized by vertebral body abnormalities (platyspondyly, end-plate indentations), hip dysplasia and brachydactyly type E. Here, we identified a novel truncating mutation (p.Lys1444AsnfsX27) in the C-propeptide of type II collagen in an affected Chinese individual with SPD. Our findings will provide clues to the phenotype–genotype relations and may assist not only in the clinical diagnosis of SPD but also in the interpretation of genetic information used for prenatal diagnosis and genetic counseling.     

Nevoid basal cell carcinoma syndrome (Gorlin syndrome)

Brachydactyly ("short digits") is a general term that refers to disproportionately short fingers and toes, and forms part of the group of limb malformations characterized by bone dysostosis. The various types of isolated brachydactyly are rare, except for types A3 and D. Brachydactyly can occur either as an isolated malformation or as a part of a complex malformation syndrome. To date, many different forms of brachydactyly have been identified. Some forms also result in short stature. In isolated brachydactyly, subtle changes elsewhere may be present. Brachydactyly may also be accompanied by other hand malformations, such as syndactyly, polydactyly, reduction defects, or symphalangism. For the majority of isolated brachydactylies and some syndromic forms of brachydactyly, the causative gene defect has been identified. In isolated brachydactyly, the inheritance is mostly autosomal dominant with variable expressivity and penetrtance. Diagnosis is clinical, anthropometric and radiological. Prenatal diagnosis is usually not indicated for isolated forms of brachydactyly, but may be appropriate in syndromic forms. Molecular studies of chorionic villus samples at 11 weeks of gestation and by amniocentesis after the 14^th week of gestation can provide antenatal diagnosis if the causative mutation in the family is known. The nature of genetic counseling depends both on the pattern of inheritance of the type of brachydactyly present in the family and on the presence or absence of accompanying symptoms. There is no specific management or treatment that is applicable to all forms of brachydactyly. Plastic surgery is only indicated if the brachydactyly affects hand function or for cosmetic reasons, but is typically not needed. Physical therapy and ergotherapy may ameliorate hand function. Prognosis for the brachydactylies is strongly dependent on the nature of the brachydactyly, and may vary from excellent to severely influencing hand function. If brachydactyly forms part of a syndromic entity, prognosis often depends on the nature of the associated anomalies.     

A new mutation in the gene ROR2 causes brachydactyly type B1

Brachydactyly type B, an autosomal dominant disorder that is characterized by hypoplasia of the distal phalanges and nails, can be divided into brachydactyly type B1 (BDB1) and brachydactyly type B2 (BDB2). BDB1 is caused by mutations in the receptor tyrosine kinase gene ROR2, which maps to chromosome 9q22, whereas BDB2 is caused by point mutations in the bone morphogenetic protein antagonist NOGGIN. Here, we report a three-generation Chinese family with dominant inheritance of the BDB1 limb phenotype. Sequence analysis identified a novel heterozygous base deletion (c.1396–1398delAA) in the gene ROR2 in all affected family members. This new deletion is expected to produce a truncated Ror2 protein with a new polypeptide of 57 amino acids at the C-terminal.     

Intrafamilial clinical variability in type C brachydactyly

Intrafamilial clinical variability in type C brachydactyly: In this report we describe a 4-generation family in which three members present variable clinical and radiological manifestations of brachydactyly type C. The observation of 'skipped generations' in the present family and in a few other families reported previously, may indicate that brachydactyly type C is not a true autosomal dominant condition due to mutations in a single gene.     

Congenital forms of brachydactyly and dermatoglyphics

Relative length and ridge count in dermatoglyphs of patients with various forms of brachydactyly were compared to those of the corresponding controls. In most cases of brachydactyly, fingers shortening was associated with the decreased ridge count, and only in two patients with brachydactyly D this relationship wasn't detected. It appears that brachydactyly may be due either to the abnormal positional information or disturbed function of certain growth factors responsible for the expression of inborn growth potential.     

Indian hedgehog mutations causing brachydactyly type A1 impair Hedgehog signal transduction at multiple levels

Brachydactyly type A1 (BDA1), the first recorded Mendelian autosomal dominant disorder in humans, is characterized by a shortening or absence of the middle phalanges. Heterozygous missense mutations in the Indian Hedgehog (IHH) gene have been identified as a cause of BDA1; however, the biochemical consequences of these mutations are unclear. In this paper, we analyzed three BDA1 mutations (E95K, D100E, and E131K) in the N-terminal fragment of Indian Hedgehog (IhhN). Structural analysis showed that the E95K mutation changes a negatively charged area to a positively charged area in a calcium-binding groove, and that the D100E mutation changes the local tertiary structure. Furthermore, we showed that the E95K and D100E mutations led to a temperature-sensitive and calcium-dependent instability of IhhN, which might contribute to an enhanced intracellular degradation of the mutant proteins via the lysosome. Notably, all three mutations affected Hh binding to the receptor Patched1 (PTC1), reducing its capacity to induce cellular differentiation. We propose that these are common features of the mutations that cause BDA1, affecting the Hh tertiary structure, intracellular fate, binding to the receptor/partners, and binding to extracellular components. The combination of these features alters signaling capacity and range, but the impact is likely to be variable and mutation-dependent. The potential variation in the signaling range is characterized by an enhanced interaction with heparan sulfate for IHH with the E95K mutation, but not the E131K mutation. Taken together, our results suggest that these IHH mutations affect Hh signaling at multiple levels, causing abnormal bone development and abnormal digit formation.     

A novel mutation in the IHH gene causes brachydactyly type A1: a 95-year-old mystery resolved

Brachydactyly type A1 (BDA1) was the first disorder described in terms of autosomal dominant Mendelian inheritance. Early in the 1900s Farabee and Drinkwater described a number of families with BDA1. Examination of two of Drinkwater's families has revealed that, although they are not known to be related, both share a common mutation within the Indian hedgehog gene ( IHH). This novel mutation is a guanine to adenine transition at nucleotide 298, resulting in an Asn100Asp amino acid substitution. Both families demonstrate significant intrafamilial phenotypic heterogeneity among the affected individuals. Examination of single nucleotide polymorphisms (SNP) has shown that the affected individuals in both families share SNPs within IHH consistent with that of a common founder. The identification of the same mutation in these families has answered a question that is nearly a century old about the genetic cause of their disease and supports the hypothesis that IHH plays a pivotal role in normal human skeletogenesis.