Survival of Male Patients with Incontinentia Pigmenti Carrying a Lethal Mutation Can Be Explained by Somatic Mosaicism or Klinefelter Syndrome

Incontinentia pigmenti (IP), or "Bloch-Sulzberger syndrome," is an X-linked dominant disorder characterized by abnormalities of skin, teeth, hair, and eyes; skewed X-inactivation; and recurrent miscarriages of male fetuses. IP results from mutations in the gene for NF-kappaB essential modulator (NEMO), with deletion of exons 4-10 of NEMO accounting for >80% of new mutations. Male fetuses inheriting this mutation and other "null" mutations of NEMO usually die in utero. Less deleterious mutations can result in survival of males subjects, but with ectodermal dysplasia and immunodeficiency. Male patients with skin, dental, and ocular abnormalities typical of those seen in female patients with IP (without immunodeficiency) are rare. We investigated four male patients with clinical hallmarks of IP. All four were found to carry the deletion normally associated with male lethality in utero. Survival in one patient is explained by a 47,XXY karyotype and skewed X inactivation. Three other patients possess a normal 46,XY karyotype. We demonstrate that these patients have both wild-type and deleted copies of the NEMO gene and are therefore mosaic for the common mutation. Therefore, the repeat-mediated rearrangement leading to the common deletion does not require meiotic division. Hypomorphic alleles, a 47,XXY karyotype, and somatic mosaicism therefore represent three mechanisms for survival of males carrying a NEMO mutation.     

A predictive method for the evaluation of peptide binding in pocket 1 of HLA-DRB1 via global minimization of energy interactions

Human leukocyte antigens (HLA) or histocompatibility molecules are glycoproteins that play a pivotal role in the development of an effective immune response. An important function of the HLA molecules is the ability to bind and present antigen peptides to T lymphocytes. Presently there is no comprehensive way of predicting and energetically evaluating peptide binding on HLA molecules. To quantitatively determine the binding specificity of a class II HLA molecule interacting with peptides, a novel decomposition approach based on deterministic global optimization is proposed that takes advantage of the topography of HLA binding grove, and examined the interactions of the bound peptide with the five different pockets. In particular, the main focus of this paper is the study of pocket 1 of HLA DR1 (DRB1*0101 allele). The determination of the minimum energy conformation is based on the ECEPP/3 potential energy model that describes the energetics of the atomic interactions. The minimization of the total potential energy is formulated on the set of peptide dihedral angles, Euler angles, and translation variables to describe the relative position. The deterministic global optimization algorithm, αBB, which has been shown to be ϵ-convergent to the global minimum potential energy through the solution of a series of nonlinear convex optimization problems, is utilized. The PACK conformational energy model that utilizes the ECEPP/3 model but also allows the consideration of protein chain interactions is interfaced with αBB. MSEED, a program used to calculate the solvation contribution via the area accessible to the solvent, is also interfaced with αBB. Results are presented for the entire array of naturally occurring amino acids binding to pocket 1 of the HLA DR1 molecule and very good agreement with experimental binding assays is obtained. Proteins 29:87–102, 1997. © 1997 Wiley-Liss, Inc.     

The European carbon balance. Part 3: forests

We present a new synthesis, based on a suite of complementary approaches, of the primary production and carbon sink in forests of the 25 member states of the European Union (EU‐25) during 1990–2005. Upscaled terrestrial observations and model‐based approaches agree within 25% on the mean net primary production (NPP) of forests, i.e. 520±75 g C m^?2 yr^?1 over a forest area of 1.32 × 10⁶ km² to 1.55 × 10⁶ km² (EU‐25). New estimates of the mean long‐term carbon forest sink (net biome production, NBP) of EU‐25 forests amounts 75±20 g C m^?2 yr^?1. The ratio of NBP to NPP is 0.15±0.05. Estimates of the fate of the carbon inputs via NPP in wood harvests, forest fires, losses to lakes and rivers and heterotrophic respiration remain uncertain, which explains the considerable uncertainty of NBP. Inventory‐based assessments and assumptions suggest that 29±15% of the NBP (i.e., 22 g C m^?2 yr^?1) is sequestered in the forest soil, but large uncertainty remains concerning the drivers and future of the soil organic carbon. The remaining 71±15% of the NBP (i.e., 53 g C m^?2 yr^?1) is realized as woody biomass increments. In the EU‐25, the relatively large forest NBP is thought to be the result of a sustained difference between NPP, which increased during the past decades, and carbon losses primarily by harvest and heterotrophic respiration, which increased less over the same period.     

A dual negative regulation model of Toll-like receptor 4 signaling for endotoxin preconditioning in human endotoxemia

We discuss a model illustrating how the outcome of repeated endotoxin administration experiments can emerge as a natural consequence of the tightly regulated signaling pathways and also highlight the importance of a dual negative feedback regulation including PI3K/Akt and IRAK-M (IRAK3). We identify the relative time scales of the onset and the magnitude of the stimulus as key determinants of outcome in repeated administration experiments. The results of our simulations involve potentiated response, tolerance, and protective tolerance. Moreover, the knockout of negative regulators shows that IRAK-M is a necessary and sufficient factor for generation of endotoxin tolerance (ET). The effects of the knockout of IRAK-M gene or administration of PI3K inhibitor do yield predictions that have been verified experimentally. Finally, the pretreatment with PI3K inhibitor reveals the interaction between these two negative regulations.     

Nucleotide sequence of the genes for tryptophan synthase in Pseudomonas aeruginosa

We have determined the DNA sequence of the two adjacent genes for the alpha and beta chains of tryptophan synthase in Pseudomonas aeruginosa, along with 34 5'-flanking and 799 3'-flanking base pairs. The gene order is trpBA as predicted from earlier genetic studies, and the two cistrons overlap by 4 bp; a ribosome binding site for the second gene is evident in the coding sequence of the first gene. We have also determined the location of three large deletions eliminating portions of each gene. A detailed comparison of the deduced P. aeruginosa amino acid sequence with those published for E. coli, Bacillus subtilis, and Saccharomyces cerevisiae shows much similarity throughout the beta and most of the alpha subunit. Most of the residues implicated by chemical modification or mutation as being critical for enzymatic activity are conserved, along with many others, suggesting that three-dimensional structure has remained largely constant during evolution. We also report the construction of a recombinant plasmid that overproduces a slightly modified alpha subunit from P. aeruginosa that can form a functionally effective multimer with normal E. coli beta 2 subunit in vivo.      

Pathway analysis of liver metabolism under stressed condition

Pathway analysis is a useful tool which reveals important metabolic network properties. However, the big challenge is to propose an objective function for estimating active pathways, which represent the actual state of network. In order to provide weight values for all possible pathways within the metabolic network, this study presents different approaches, considering the structural and physiological properties of the metabolic network, aiming at a unique decomposition of the flux vector into pathways. These methods were used to analyze the hepatic metabolism considering available data sets obtained from the perfused livers of fasted rats receiving burn injury. Utilizing unique decomposition techniques and different fluxes revealed that higher weights were always attributed to short pathways. Specific pathways, including pyruvate, glutamate and oxaloacetate pools, and urea production from arginine, were found to be important or essential in all methods and experimental conditions. Moreover the pathways, including serine production from glycine and conversion between acetoacetate and B—OH-butyrate, were assigned higher weights. Pathway analysis was also used to identify the main sources for the production of certain products in the hepatic metabolic network to gain a better understanding of the effects of burn injury on liver metabolism.