Molecular background of three lethal fetal syndromes

This study identified the molecular defects underlying three lethal fetal syndromes. Lethal Congenital Contracture Syndrome 1 (LCCS1, MIM 253310) and Lethal Arthrogryposis with Anterior Horn Cell Disease (LAAHD, MIM 611890) are fetal motor neuron diseases. They affect the nerve cells that control voluntary muscle movement, and eventually result in severe atrophy of spinal cord motor neurons and fetal immobility. Both LCCS1 and LAAHD are caused by mutations in the GLE1 gene, which encodes for a multifunctional protein involved in posttranscriptional mRNA processing. LCCS2 and LCCS3, two syndromes that are clinically similar to LCCS1, are caused by defective proteins involved in the synthesis of inositol hexakisphosphate (IP6), an essential cofactor of GLE1. This suggests a common mechanism behind these fetal motor neuron diseases, and along with accumulating evidence from genetic studies of more late-onset motor neuron diseases such as Spinal muscular atrophy (SMA) and Amyotrophic lateral sclerosis (ALS), implicates mRNA processing as a common mechanism in motor neuron disease pathogenesis. We also studied gle1-/- zebrafish in order to investigate whether they would be a good model for studying the pathogenesis of LCCS1 and LAAHD. Mutant zebrafish exhibit cell death in their central nervous system at two days post fertilization, and the distribution of mRNA within the cells of mutant zebrafish differs from controls, encouraging further studies. The third lethal fetal syndrome is described in this study for the first time. Cocoon syndrome (MIM 613630) was discovered in a Finnish family with two affected individuals. Its hallmarks are the encasement of the limbs under the skin, and severe craniofacial abnormalities, including the lack of skull bones. We showed that Cocoon syndrome is caused by a mutation in the gene encoding the conserved helix-loop-helix ubiquitous kinase CHUK, also known as IκB kinase α (IKKα). The mutation results in the complete lack of CHUK protein expression. CHUK is a subunit of the IκB kinase enzyme that inhibits NF-κB transcription factors, but in addition, it has an essential, independent role in controlling keratinocyte differentiation, as well as informing morphogenetic events such as limb and skeletal patterning. CHUK also acts as a tumor suppressor, and is frequently inactivated in cancer. This study has brought significant new information about the molecular background of these three lethal fetal syndromes, as well as provided knowledge about the prerequisites of normal human development.

Interruptions of (CG)n sequences by GG, TG and CA need not prevent B to Z transition in solution

Oligonucleotides containing alternating purines-pyrimidines with AT base pairs have been shown to exist in the Z-form preferably in solid state. We report that oligodeoxyribonucleotides with GG, TG and CA interruptions in their alternating CG sequences can undergo B to Z transition in solution in the absence of any chemical modification or topological constraint. The sequences, d(CGCGCGGCGCGC) and d(CGTGCGCACG) have been synthesised and shown to adopt Z- conformation in presence of millimolar concentrations of Ni2+ under low water activity conditions. Significance of GG, TG and CA interruptions in the B to Z transition is discussed.

Thermodynamic measurements of b.c.c. Cr-Mn solid solutions at 1373 K

Thermodynamics of Cr-Mn alloys have been studied by Eremenko et al (l) using a fused salt e.m.f.technique. Their results indicate positive deviations from ideality at 1023 K. Kaufman (2) has independently estimated negative enthaipy and excess entropy for the b.c.c. Cr-Mn alloys, such that at high temperatures, the entropy term predominates over the enthalpy term giving positive deviations from ideality. Recently the thermodynamic properties of the alloys have been measured by 3acob (3) using a Knudsen cell technique in the temperature range of 1200 to 1500 K. The results indicate mild negative deviations from ideality over the entire composition range. Because of the differences in the reported results and Mn being a volatile component in the alloys which leads to surface depletion under a dynamic set up, an isopiestic technique is used to measure the properties of the alloys.

Measurement of the ttbar production cross section with an in situ calibration of b-jet identification efficiency

A measurement of the top-quark pair-production cross section in ppbar collisions at sqrt{s}=1.96 TeV using data corresponding to an integrated luminosity of 1.12/fb collected with the Collider Detector at Fermilab is presented. Decays of top-quark pairs into the final states e nu + jets and mu nu + jets are selected, and the cross section and the b-jet identification efficiency are determined using a new measurement technique which requires that the measured cross sections with exactly one and multiple identified b-quarks from the top-quark decays agree. Assuming a top-quark mass of 175 GeV/c^2, a cross section of 8.5+/-0.6(stat.)+/-0.7(syst.) pb is measured.

Total syntheses of the fungal metabolites (+/-)-acremines A, B and I

A concise and diversity-oriented approach, incorporating elements of regio- and stereocontrol, to the recently isolated bioactive polyoxygenated cyclohexanoid natural products acremines A. B and I. from commercially accessible building blocks, is outlined. (c) 2010 Elsevier Ltd. All rights reserved.

Synthetic studies toward the PPAP natural products, prolifenones A and B and hyperforin: an Effenberger cyclization approach

A synthetic approach toward the geranylated PPAP natural products, prolifenones A and B. employing Effenberger cyclization as the key step, is delineated. The efficacy of this approach is further expanded through access to an advanced precursor of hyperforin. (C) 2010 Elsevier Ltd. All rights reserved.

Peptide models for b-turns.A circular dichroism study

The circular dichroism spectra of four 0-turn model peptides, Z-Aib-Pro-Aib-Pro- OMe (l), Piv-Pro-Aib-NHMe (2), Piv-Pro-D-Ala-NHMe (3) and Piv-Pro-Val-NHMe (4) have been examined under a wide range of solvent conditions, using methanol, hexafluoroisopropanol and cyclohexane. Type I and Type I1 0-turns have been observed for peptides 1 and 2 respectively, in the solid state, while the Pro-D-Ala sequence adopts a Type I1 Sturn in a related peptide crystal structure. A class C spectrum is observed for 1 in various solvents, suggesting a variant of a Type I(II1) structure. The Type I1 f3-turn is characterized by a CD spectrum having two positive CD bands at - 230 nm and - 202 nm, a feature observed in Piv-Pro- D-Ala-NHMe in cyclohexane and methanol and for Piv-Pro-Aib-NHMe in methanol. Peptide 2 exhibits solvent dependent CD spectra, which may be rationalized by considering Type 11, I11 and V reverse turn structures. Piv-Pro- Val-NHMe adopts nonaturn structures in polar solvents, but exhibits a class B spectrum in cyclohexane suggesting a population of Type I &turns.

Differences in the climatic adaptation of silver birch (Betula pendula) and downy birch (B. pubescens) in Finland based on male flowering phenology.

Male flowering was studied at the canopy level in 10 silver birch (Betula pendula Roth) stands from 8 localities and in 14 downy birch (B. pubescens Ehrh.) stands from 10 localities in Finland from 1963 to 1973. Distributions of cumulative pollen catches were compared to the normal Gaussian distribution. The basis for the timing of flowering was the 50 per cent point of the anthesis-fitted normal distribution. To eliminate effects of background pollen, only the central, normally distributed part of the cumulative distribution was used. Development up to the median point of the distribution was measured and tested in calendar days, in degree days (> 5 °C) and in period units. The count of each parameter began on and included March 19. Male flowering in silver birch occurred from late April to late June depending on latitude, and flowering in downy birch took place from early May to early July. The heat sums needed for male flowering varied in downy birch stands latitudinally but there was practically no latitudinal variation in heat sums needed for silver birch flowering. The amount of male flowering in stands of both birch species were found to have a large annual variation but without any clear periodicity. The between years pollen catch variation in stands of either birch species did not show any significant latitudinal correlation in contrast to Norway spruce stands. The period unit heat sum gave the most accurate forecast of the timing of flowering for 60 per cent of the silver birch stands and for 78.6 per cent of the for downy birch stands. Calendar days, however, gave the best forecast for silver birch in 25 per cent of the cases, while degree days gave the best forecast for downy birch in 21.4 per cent of the cases. Silver birch seems to have a local inclination for a more fixed flowering date compared to downy birch, which could mean a considerable photoperiodic influence on flowering time of silver birch. Silver birch and downy birch had different geographical correlations. Frequent hybridization of birch species occurs more often in northern Finland in than in more southern latitudes. The different timing in flowering caused increasing scatter in flowering times in the north, especially in the case of downy birch. The chance of simultaneous flowering of silver birch and downy birch so increased northwards due to a more variable climate and also higher altitudinal variations. Compared with conifers, the reproduction cycles of both birch species were found to be well protected from damage by frost.

High-Temperature (1023 K to 1273 K 750 degrees C to 1000 degrees C]) Plastic Deformation Behavior of B-Modified Ti-6Al-4V Alloys: Temperature and Strain Rate Effects

A minor addition of B to the Ti-6Al-4V alloy, by similar to 0.1 wt pct, reduces its as-cast prior beta grain size by an order of magnitude, whereas higher B content leads to the presence of in situ formed TiB needles in significant amounts. An experimental investigation into the role played by these microstructural modifications on the high-temperature deformation behavior of Ti-6Al-4V-xB alloys, with x varying between 0 wt pct and 0.55 wt pct, was conducted. Uniaxial compression tests were performed in the temperature range of 1023 K to 1273 K (750 degrees C to 1000 degrees C) and in the strain rate range of 10(-3) to 10(+1) s(-1). True stress-true strain responses of all alloys exhibit flow softening at lower strain rates and oscillations at higher strain rates. The flow softening is aided by the occurrence of dynamic recrystallization through lath globularization in high temperature (1173 K to 1273 K 900 degrees C to 1000 degrees C]) and a lower strain rate (10(-2) to 10(-3) s(-1)) regime. The grain size refinement with the B addition to Ti64, despite being marked, had no significant effect on this. Oscillations in the flow curve at a higher strain rate (10(0) to 10(+1) s(-1)), however, are associated with microstructural instabilities such as bending of laths, breaking of lath boundaries, generation of cavities, and breakage of TiB needles. The presence of TiB needles affected the instability regime. Microstructural evidence suggests that the matrix cavitation is aided by the easy fracture of TiB needles.

b-Turn conformations in crystal structures of model peptides containing a,a-di-n-propylglycine (Dpg) and a,a-di-n-butyl-glycine (Dbg).

The crystal state conformations of three peptides containing the a,a-dialkylated residues, a,adi n-propylglycine (Dpg) and a,@-di-n-butylglycine (Dbg), have been established by x-ray diffraction. Boc-Ala-Dpg-Ala-OMe ( I ) and Boc-Ala-Dbg-Ala-OMe (III) adopt distorted type II @-turn conformations with Ala ( I ) and Dpg/Dbg (2) as the corner residues. In both peptides the conformational angles at the Dxg residue (I: 4 = 66.23 J/ = 19.3'; III: 4 = 66S0, J. = 21 .la)deviate appreciablyfrom ideal values for the i + 2 residue in a type II @-turn. In both peptides the observed(N. 0) distances between the Boc CO andAla(3) NHgroups are far too long (I:3.44 k; III: 3.63 k) for an intramolecular 4 + 1 hydrogen bond. Boc-Ala-Dpg-Ala-NHMe (II)crystallizes with two independent molecules in the asymmetric unit. Both molecules IIA and IIB adopt consecutive @-turn (type III-III in IIA and type III-I in IIB) or incipient 3,,,-helical structures, stabilized by two intramolecular 4 --t I hydrogen bonds. In all four molecules the bond angle N-C"-C' ( T ) at the Dxg residues are 2 1109 The observation of conformational angles in the helical region of 4,J/ space at these residues is consistent with theoretical predictions

Inelastic dynamic response of R.C. beam column joints by using B.E.M.

A BEM formulation to obtain the inelastic response of R.C. Beam-Column joints subjected to sinusoidal loading along the boundary is presented. The equations of motion are written along with kinematical and constitutive equations. The dynamic reciprocal theorem is presented and the temporal dependence is removed by assuming steady state response.

Fatigue in Ti-6Al-4V-B alloys

The addition of small amounts of B to Ti-6Al-4V alloy reduces the as-cast grain size by an order of magnitude and introduces TiB phase into the microstructure. The effects of these microstructural modifications on both the high cycle fatigue and cyclic stress-strain response were investigated. Experimental results show that B addition markedly enhances the fatigue strength of the alloy; however, the influence of prior-beta grain size was found to be only marginal. The presence of TiB particles in the matrix appears to be beneficial with the addition of 0.55 wt.% B to Ti-6Al-4V enhancing the fatigue strength by more than 50%. Strain-controlled fatigue experiments reveal softening in the cyclic stress-strain response, which increases with the B content in the alloy. Transmission electron microscopy of the fatigued specimens indicates that generation of dislocations during cyclic loading and creation of twins due to strain incompatibility between the matrix and the TiB phase are possible reasons for the observed softening. (c) 2010 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Structural features of B-DNA dodecamer crystal structures: Influence of crystal packing versus base sequence

We have analyzed the set of inter and intra base pair parameters for each dinucleotide step in single crystal structures of dodecamers, solved at high and medium resolution and all crystallized in P2(1)2(1)2(1) space group. The objective was to identify whether all the structures which have either the Drew-Dickerson (DD) sequence d[CGCGAATTCGCG] with some base modification or related sequence (non-DD), would display the same sequence dependent structural variability about its palindromic sequence, despite the molecule being bent at one end because of similar crystal lattice packing effect. Most of the local doublet parameters for base pairs steps G2-C3 and G10-C11 positions, symmetrically situated about the lateral twofold, were significantly correlated between themselves. In non-DD sequences, significant correlations between these positional parameters were absent. The different range of local step parameter values at each sequence position contributed to the gross feature of smooth helix axis bending in all structures. The base pair parameters in some of the positions, for medium resolution DD sequence, were quite unlike the high-resolution set and encompassed a higher range of values. Twist and slide are the two main parameters that show wider conformational range for the middle region of non-DD sequence structures in comparison to DD sequence structures. On the contrary, the minor and major groove features bear good resemblance between DD and non-DD sequence crystal structure datasets. The sugar-phosphate backbone torsion angles are similar in all structures, in sharp contrast to base pair parameter variation for high and low resolution DD and non-DD sequence structures, consisting of unusual (epsilon =g(-), xi =t) B-II conformation at the 10(th) position of the dodecamer sequence. Thus examining DD and non-DD sequence structures packed in the same crystal lattice arrangement, we infer that inter and intra base pair parameters are as symmetrically equivalent in its value as the symmetry related step for the palindromic DD sequence about lateral two-fold axis. This feature would lead us to agree with the conclusion that DNA conformation is not substantially affected by end-to-end or lateral inter-molecular interaction due to crystal lattice packing effect. Non-DD sequence structures acquire step parameter values which reflect the altered sequence at each of the dodecamer sequence position in the orthorhombic lattice while showing similar gross features of DD sequence structures