Genetik der monogenen isolierten Alopezien

The monogenic inherited isolated alopecias comprise a group of clinically and genetically heterogeneous forms of hairlessness or hair loss. Clinical classification of the isolated alopecias is based on the onset of the disorder, the regions affected, and the structure of the hair shaft. Men and women are equally affected, and the mode of inheritance is autosomal dominant or autosomal recessive. Since the identification of the keratin gene KRT86 as a cause of the so-called monilethrix in 1997, mutations in nine other genes have been identified for various isolated alopecias. These include other keratin genes for monilethrix (KRT81 and KRT83), the hairless gene for atrichia congenita/papular atrichia, the corneodesmosin gene for the autosomal dominant form of hypotrichosis simplex, and the genes desmoglein 4, lipase H, and the G-protein-coupled receptor P2RY5 (LPAR6) for the autosomal recessive forms of hypotrichosis. Molecular genetic and pathophysiological studies of these rare disorders of hair development have contributed significantly to our understanding of the basic mechanisms of hair loss as well as the physiological mechanisms of hair growth.     

CD14 C-159T and early infection with Pseudomonas aeruginosa in children with cystic fibrosis

Early acquisition of Pseudomonas aeruginosa is associated with a poorer prognosis in patients with cystic fibrosis. We investigated whether polymorphisms in CD14, the lipopolysaccharide receptor, increase the risk of early infection. Forty-five children with cystic fibrosis were investigated with annual bronchoalveolar lavage (BAL) and plasma sCD14 levels. Plasma sCD14 levels were significantly lower in children from whom P.aeruginosa was subsequently isolated (492.75 μg/ml vs. 1339.43 μg/ml, p = 0.018). Those with the CD14 -159CC genotype had a significantly increased risk of early infection with P.aeruginosa suggesting that CD14 C-159T plays a role in determining the risk of early infection with P.aeruginosa.     

The dimeric dihydroorotate dehydrogenase A from Lactococcus lactis dissociates reversibly into inactive monomers

The flavoenzyme dihydroorotate dehydrogenase A from Lactococcus lactis is a homodimeric protein of 311 residues/subunit, and the two active sites are positioned at a distance from the dimer interface. To promote formation of the monomeric form of the enzyme, we changed the residues involved in formation of two salt bridges formed between the residues Glu206 of the one polypeptide and Lys296 of the other polypeptide. The mutant enzymes formed inactive precipitates when cells were grown at 37 degrees C, but remained soluble and active when cells were grown at 25 degrees C. The salt bridges were not needed for activity, because the mutant enzymes in which one of the residues was converted to an alanine (E206A or K296A) retained almost full activity. The mutant enzymes in which the charge of one of the residues of the salt bridge was inverted (i.e., E206K or K296E) were severely impaired. The double mutant E206K-K296E, which has the possibility of forming salt bridges in the opposite orientation of the wild type, was fully active in concentrated solutions, but dissociated into inactive monomers upon dilution. The K(D) for the dimer to monomer dissociation reaction was 12 microM, and dimer formation was favored by the product, orotate, or by high ionic strength, indicating that the hydrophobic interactions are important for the subunit contacts. Wild-type dihydroorotate dehydrogenase A was similarly found to dissociate into inactive monomers, but with a K(D) for dissociation equal to 0.12 microM. These results imply that the dimeric state is necessary for activity of the enzyme.     

Lactococcus lactis dihydroorotate dehydrogenase A mutants reveal important facets of the enzymatic function

Dihydroorotate dehydrogenases (DHODs) are flavoenzymes catalyzing the oxidation of (S)-dihydroorotate to orotate in the biosynthesis of UMP, the precursor of all other pyrimidine nucleotides. On the basis of sequence, DHODs can be divided into two classes, class 1, further divided in subclasses 1A and 1B, and class 2. This division corresponds to differences in cellular location and the nature of the electron acceptor. Herein we report a study of Lactococcus lactis DHODA, a representative of the class 1A enzymes. Based on the DHODA structure we selected seven residues that are highly conserved between both main classes of DHODs as well as three residues representing surface charges close to the active site for site-directed mutagenesis. The availability of both kinetic and structural data on the mutant enzymes allowed us to define the roles individual structural segments play in catalysis. We have also structurally proven the presence of an open active site loop in DHODA and obtained information about the interactions that control movements of loops around the active site. Furthermore, in one mutant structure we observed differences between the two monomers of the dimer, confirming an apparent asymmetry between the two substrate binding sites that was indicated by the kinetic results.     

Spectral effects of LEDs on chlorophyll fluorescence and pigmentation in Phalaenopsis ‘Vivien’ and ‘Purple Star’

We examined the effect of light emitting diode (LED) lighting in greenhouse facilities on growth, chlorophyll fluorescence and pigmentation in Phalaenopsis ‘Vivien’ and ‘Purple Star’ under purpose‐built LED arrays yielding c. 200 µmol m^?2 s^?1 at plant height for 14 h per day and 24/18°C day/night temperature, respectively, from January to April 2013. The light treatments were (1) 40% blue in 60% red (40% B/R), (2) 0% blue in 100% red (0% B/R) and (3) white LEDs with 32% blue in white (32% B/W, control), with background daylight under shade screens. The plants were harvested twice for leaf growth and pigmentation. There was no clear pattern in the spectral effect on growth since the order of leaf size differed between harvests in March and April. F_v/F_m was in the range of 0.52–0.72, but overall slightly higher in the control, which indicated a permanent downregulation of PSII in the colored treatments. The fluorescence quenching showed no acclimation to color in ‘Purple Star’, while ‘Vivien’ had lower ETR and higher NPQ in the 40% B/R, resembling low light acclimation. The pigmentation showed corresponding spectral response with increasing concentration of lutein while increasing the fraction of blue light, which increased the light absorption in the green/yellow part of the spectrum. The permanent downregulation of PSII moved a substantial part of the thermal dissipation from the light regulated NPQ to non‐regulated energy losses estimated by Φ_NPQ and Φ_NO and the difference found in the balance between Φ_PSII and Φ_NPQ in ‘Vivien’ disappeared when Φ_NO was included in the thermal dissipation.     

Entwicklung der Zähne

Dental development takes place in stages over a long period of time. From the 6ths embryonal week, when the dental lamina develops, tooth number and shape are formed, followed by the production of dental hard tissues. Genetic dental developmental defects are not rare. Mostly these defects affect the tooth number, predominantly resulting in a decrease tooth number (hypodontia) which can occur isolated or as a finding in genetic syndromes such as Rieger syndrome, Witkop syndrome or several ectodermal dysplasias. Genetic defects of dental hard tissues are less frequent, different types of isolated enamel defects (amelogenesis imperfecta) are known. Dentinogenesis imperfecta or other dentinal defects are either caused by different mutations of the DSPP gene or a part of osteogenesis imperfecta.     

Das Marfan-Syndrom und verwandte monogene Krankheiten der Aorta

Marfan syndrome (MFS) is an autosomal dominant, pleiotropic disease of the connective tissue with a prevalence of about 1 in 5000 persons. MFS is characterized by manifestations in the cardiovascular system, eye, skeleton, lung, skin, and dura mater that show a high degree of intra- and interfamilial variability. Many manifestations develop during or shortly before puberty; severe complications rarely occur before adulthood. Many patients with MFS display a so-called marfanoid habitus with tall stature, dolichostenomelia (long, narrow extremities), dolichocephaly (disproportionately long and narrow head), as well as other skeletal abnormalities such as scoliosis and pes planus. Scoliosis occurs in approximately 60% of those affected, pectus deformities in up to two thirds. Ectopia lentis is seen in many patients with MFS and is almost always bilateral. MFS is characterized by a high risk for complications such as severe scoliosis or pectus deformities, spontaneous pneumothorax, retinal detachment, or glaucoma secondary to lens luxation. The most severe complications occur in the cardiovascular system, including in particular acute dissection of the ascending aorta, which generally follows a long period of progressive aortic dilatation. Before the introduction of modern treatment modalities, the average life expectancy of persons with MFS was estimated to be 32 years. Today, with medical care in multidisciplinary centers, an average life expectancy of over 60 years can be achieved. This article offers a review of established and novel concepts for the diagnosis and treatment of MFS and other hereditary diseases of the aorta.     

The UDP-GalNAcA biosynthesis genes gna-gne2 are required to maintain cell envelope integrity and in vivo fitness in multi-drug resistant Acinetobacter baumannii

Acinetobacter baumannii infects a wide range of anatomic sites including the respiratory tract and bloodstream. Despite its clinical importance, little is known about the molecular basis of A. baumannii pathogenesis. We previously identified the UDP-N-acetyl-d -galactosaminuronic acid (UDP-GalNAcA) biosynthesis genes, gna-gne2, as being critical for survival in vivo. Herein, we demonstrate that Gna-Gne2 are part of a complex network connecting in vivo fitness, cell envelope homeostasis and resistance to antibiotics. The ∆gna-gne2 mutant exhibits a severe fitness defect during bloodstream infection. Capsule production is abolished in the mutant strain, which is concomitant with its inability to survive in human serum. In addition, the ∆gna-gne2 mutant was more susceptible to vancomycin and unable to grow on MacConkey plates, indicating an alteration in cell envelope integrity. Analysis of lipid A by mass spectrometry showed that the hexa- and hepta-acylated species were affected in the gna-gne2 mutant. Finally, the ∆gna-gne2 mutant was more susceptible to several classes of antibiotics. Together, this study demonstrates the importance of UDP-GalNAcA in the pathobiology of A. baumannii. By interrupting its biosynthesis, we showed that this molecule plays a critical role in capsule biosynthesis and maintaining the cell envelope homeostasis.     

Klinik und Genetik des familiären Darmkrebses

Familial clustering of colorectal cancer (CRC) and early disease onset are indicators of an inherited tumour syndrome. Monogenic dispositions account for 3–5% of all CRC cases and are subdivided into hereditary non-polyposis colorectal cancer (HNPCC/Lynch syndrome) and various gastrointestinal polyposis syndromes. Many of these syndromes are characterised by a broad spectrum of extracolonic tumours. Early detection and accurate classification are essential in providing effective surveillance and treatment. Initial diagnosis is based on endoscopic and histological findings as well as on the presence of extracolonic manifestations and family history. Molecular genetic examination is important for the differential diagnosis, evaluation of recurrence risk, and predictive testing of asymptomatic at risk individuals; it is performed according to largely standardised algorithms. Diagnostic difficulties are common among the hamartomatous polyposes due to their broad phenotypic overlap and frequent uncertainties in histological evaluation, as well as among patients with few adenomas. Risk-adapted surveillance guidelines have been established for HNPCC and for the more frequently observed polyposis syndromes. Beyond established tumour syndromes, familial clustering of CRC (which is often of late onset) or the occurrence of few adenomas is likely to be based upon a multifactorial (complex) etiology. Although identification of the underlying genetic risk factors and biological pathways is still in the early stages, rapid progress is being made due to methodical developments such as genome-wide association studies and CNV analysis.     

Botanische Gärten in der Zeit des Kolonialismus. Auf der Jagd nach dem “Grünen Gold”

Plant Transfer and Botanical Gardens in Colonial Times A constant of economic history is the need of natural resources – in the past often of vegetable origin and available only from the countries of natural distribution. These countries often tried to protect their interests against the traders or users by declaring monopoles. Between these both poles botanic gardens acted very successfully and by far not according to modern ethic standards. Results of their activities were the transcontinental movements of plants and the initiation of new agricultural based industries. These should be exemplified by the British botanical gardens and species as tea shrub, rubber tree, and cinchona tree.