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Shprintzen-Goldberg syndrome (SGS) is a rare, systemic connective tissue disorder characterized by craniofacial, skeletal, and cardiovascular manifestations that show a significant overlap with the features observed in the Marfan (MFS) and Loeys-Dietz syndrome (LDS). A distinguishing observation in SGS patients is the presence of intellectual disability, although not all patients in this series present this finding. Recently, SGS was shown to be due to mutations in the SKI gene, encoding the oncoprotein SKI, a repressor of TGFβ activity. Here, we report eight recurrent and three novel SKI mutations in eleven SGS patients. All were heterozygous missense mutations located in the R-SMAD binding domain, except for one novel in-frame deletion affecting the DHD domain. Adding our new findings to the existing data clearly reveals a mutational hotspot, with 73% (24 out of 33) of the hitherto described unrelated patients having mutations in a stretch of five SKI residues (from p.(Ser31) to p.(Pro35)). This implicates that the initial molecular testing could be focused on mutation analysis of the first half of exon 1 of SKI. As the majority of the known mutations are located in the R-SMAD binding domain of SKI, our study further emphasizes the importance of TGFβ signaling in the pathogenesis of SGS. © 2015 Macmillan Publishers Limited All rights reserved.

A computational aeroacoustic (CAA) solver was developed on Graphics Processing Units (GPUs) to solve linearized Euler equations (LEE) for sound propagation. The spatial derivatives are approximated by a 4 order optimized prefactored compact scheme and the increment in time uses a low dissipative and low dispersive Runge-Kutta method. In the current study, the implementation of the prefactored compact scheme, which is normally the “hotspot” of CAA solver, is in a bidiagonal matrix form. Four methods are employed to investigate the solution of a bidiagonal matrix on GPUs. The first method is a coarse-grained parallel approach and assigns one GPU thread to solve a recursive system. The second method employs a parallel cyclic reduction (PCR) approach and assigns one GPU thread to solve a row in the matrix. The third method is a matrix multiplication method. Both the second and the third methods are fine-grained parallel. The last method is a hybrid approach which combines the first method with either the second or the third method. The PCR approach is more suited to two-dimensional (2D) problems whereas the matrix multiplication method achieves a higher speedup for three-dimensional (3D) problems. For a 2D Gaussian pulse scattering problem, the code runs 77 times faster on a Tesla M2050 GPU than on a single Intel Xeon core (2.4GHz). For a spinning mode propagation in a 3D engine bypass duct case, the code runs 40 times faster on two GPUs than on two CPU processes.

Molecular dynamics computer simulations have been performed on Mouse (Mo) and Syrian Hamster (SHa) prion proteins. These proteins differ, primarily, in that the SHa form incorporates additional residues at the C-terminus and also includes a segment of the unstructured N-terminal region that is required for infectivity, The 1-ns simulations have been analyzed by using a combination of dynamical cross-correlation maps, residue-residue contact plots, digital filtering, and residue-based root-mean-square deviations. The results show that the extra residues present in the SHa form at the C- and N-termini produce changes in the stability of key regions of the protein. The loop region between strand S2 and helix B that contains part of the proposed discontinuous binding site for the chaperone, protein X, is found to be more stable in SHa than in the Mo protein; these results are consistent with the NMR data of James et al, (James et al, Proc Natl Acad Sci USA 1997;94:10086-10091), In addition, a degree of flexibility within the region between and including strand S1 and helix A is also shown in SHa, which is not present in the Mo form; the cross-correlation maps suggest that this is a consequence of the additional unstructured N-terminal region. Furthermore, the extra residues in the N-terminal region of SHa are found to form a beta-bridge with the beta-sheet, within which critical point mutations associated with prion diseases lie. The implications of these results for the conformational interconversion pathway of the prion protein are discussed.

The structure and energetics of zinc chlorides (ZnCln2-n, n = 0−4) in aqueous solution are studied by ab initio molecular orbital methods. The first solvation shell is included explicitly, the remainder of the solvent being modeled by the polarizable continuum method. The species Zn(H2O)62+, ZnCl2(H2O)2, ZnCl3(H2O)-, and ZnCl42- are predicted to occur in an aqueous environment. The predictions are consistent with the limited structural and energetic data available. A comparison with the predictions of the continuum model alone shows the necessity of including the first solvation shell explicitly to model solvation energies, although the continuum model is successful in predicting structural changes of ZnCl+ and ZnCl2 upon hydration.

It is suggested that Breit and Tuve's 1925 application of pulses to ionospheric sounding, which led to the most widely used form of radar, also gave rise to a scientific instrument whose utility, flexibility, and general suitability for intended applications place it on a par with such familiar and standard devices as the telescope or spectrograph. By way of background, there is included a discussion of the circumstances attendant upon the first measurement of ionospheric layer height, which took place in 1912.

Experimental and theoretical estimates or the tautomeric equilibria in aqueous 3-hydroxypyrazole are discussed. The use or pK a data is shown to be critically dependent upon the inclusion or corrections reflecting the substitution pattern or the compounds employed. Ab initio calculations, including a high level or electron correlation, or the gas-phase species are combined with both molecular dynamics simulations and continuum methods, to model solvation effects

Experimental and theoretical estimates or the tautomeric equilibria in aqueous 3-hydroxypyrazole are discussed. The use or pK a data is shown to be critically dependent upon the inclusion or corrections reflecting the substitution pattern or the compounds employed. Ab initio calculations, including a high level or electron correlation, or the gas-phase species are combined with both molecular dynamics simulations and continuum methods, to model solvation effects

A method for the rapid detection of Coxiella burnetii and differentiation between strains that cause endocarditis and those that cause acute Q fever is based on the observation that the different strains contain unique plasmid sequences. This method employs the polymerase chain reaction (PCR) and requires knowledge of specific DNA sequences in the region (target) of DNA to be amplified. To detect and differentiate between C. burnetii isolates, two sets of primers are required. The first set was derived from a fragment of plasmid QpH1 which has been detected in all C. burnetii isolates. A second PCR reaction was conducted using primers specific for DNA sequences that are shared only by QpRS plasmid-containing strains of C. burnetii. The first reaction detects the presence of C. burnetii. The second PCR is necessary to determine whether the isolate contains DNA sequences associated with strains causing chronic disease. These procedures detect as few as one to ten organisms.

Evidence is mounting in support of the idea that different isolates of Coxiella burnetii, the etiologic agent of Q fever, are responsible for the distinct disease syndromes observed clinically. Recent studies have shown distinct antibiotic susceptibilities of different isolates of C. burnetii implicated in distinct clinical Q fever syndromes. With this in mind, we performed antibiotic susceptibility testing of the "S" isolate, a chronic-type isolate retrieved from a human patient with chronic disease. Antibiotics with differing efficacies upon the Nine Mile and Priscilla isolates were tested for their abilities to control acute and persistent "S" isolate infection of L-929 cells in vitro. The efficacies of doxycycline, rifampin, and three fluoroquinolone drugs--ciprofloxacin, ofloxacin, and norfloxacin--were tested. Compared to the chronic Q fever-implicated Priscilla isolate, which has been shown to exhibit a significant resistance to these antibiotics, the "S" isolate was much more susceptible. In persistently infected cells (greater than 300 d), the "S" isolate proved to be significantly more resistant to doxycycline, slightly more resistant to ciprofloxacin, slightly more susceptible to rifampin, and equally sensitive to ofloxacin and norfloxacin compared to the acute Q fever-implicated Nine Mile isolate. As with both the Nine Mile and Priscilla isolates, the "S" isolate was more susceptible to doxycycline, rifampin, and ofloxacin in recently infected cells (22 d) compared to cells having been persistently infected. With respect to the resistant nature of the chronic Q fever-implicated Priscilla isolate, as well as the lack of success in treating the "S" isolate in vivo, these results were unexpected. Such data supports an evolving hypothesis that the distinct C. burnetii isolates which may be responsible for the clearly different Q fever syndromes exhibit a spectrum of antibiotic susceptibility ranging from very susceptible (acute-implicate), Nine Mile isolate), to moderately susceptible (chronic-implicated "S" isolate), to moderately resistant (chronic-implicated Priscilla isolate).