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mAbs directed against immunologic molecules have emerged as a new class of drugs for treating patients with various immunologic conditions. However, mAb-based treatments may confer a predisposition to various infections. The authors argue that infections in individuals treated with mAbs directed against molecules of the immune system may display some similarities to those in patients with primary immunodeficiency of the corresponding mAb target. A comprehensive dissection of the tremendously diverse human primary immunodeficiencies and the careful description of their clinical features in different populations living in diverse environments thus represents an original, neglected, but promising approach to assessing the potential risk of infection associated with therapeutic mAbs, or with any therapeutic compound inhibiting a specific immunologic molecule. (J Allergy Clin Immunol 2010; 126:910-7.)

Regulatory networks in cells may comprise a variety of types of molecular interactions. The most basic are pairwise interactions, in which one species controls the behaviour of another (e.g. a transcription factor activates or represses a gene). Higher-order interactions, while more subtle, may be important for determining the function of networks. Here, the authors systematically expand a simple master equation model for a gene to derive an approach for robustly assessing the cooperativity (effective copy number) with which a transcription factor acts. The essential idea is that moments of a joint distribution of protein copy numbers determine the Hill coefficient of a cis-regulatory input function without non-linear fitting. The authors show that this method prescribes a definition of cooperativity that is meaningful even in highly complex situations in which the regulation does not conform to a simple Hill function. To illustrate the utility of the method, the authors measure the cooperativity of the transcription factor CI in simulations of phage-lambda and show how the cooperativity accurately reflects the behaviour of the system. The authors numerically assess the effects of deviations from ideality, as well as possible sources of error. The relationship to other definitions of cooperativity and issues for experimentally realising the procedure are discussed.

Mutations in the X-linked MECP2 gene, which encodes the transcriptional regulator methyl-CpG-binding protein 2 (MeCP2), cause Rett syndrome and several neurodevelopmental disorders including cognitive disorders, autism, juvenile-onset schizophrenia and encephalopathy with early lethality. Rett syndrome is characterized by apparently normal early development followed by regression, motor abnormalities, seizures and features of autism, especially stereotyped behaviours. The mechanisms mediating these features are poorly understood. Here we show that mice lacking Mecp2 from GABA (c-aminobutyric acid)-releasing neurons recapitulate numerous Rett syndrome and autistic features, including repetitive behaviours. Loss of MeCP2 from a subset of forebrain GABAergic neurons also recapitulates many features of Rett syndrome. MeCP2-deficient GABAergic neurons show reduced inhibitory quantal size, consistent with a presynaptic reduction in glutamic acid decarboxylase 1 (Gad1) and glutamic acid decarboxylase 2 (Gad2) levels, and GABA immunoreactivity. These data demonstrate that MeCP2 is critical for normal function of GABA-releasing neurons and that subtle dysfunction of GABAergic neurons contributes to numerous neuropsychiatric phenotypes.

Cellular Fc gamma receptors are essential for IgG-dependent effector functions in vivo. There is convincing evidence that selective activating Fc gamma receptors are responsible for the activity of individual IgG subclasses. Thus, IgG1 activity is absent in Fc gamma RIII-deficient mice, and several studies suggest that the activity of the most potent IgG subclasses, IgG2a and IgG2b, might be dependent on either individual or a combination of activating Fc gamma Rs. To study the role of individual activating Fc gamma Rs for IgG subclass activity, we generated an Fc gamma RIV-deficient mouse and showed that a variety of IgG2a- and IgG2b- dependent effector functions are impaired in the absence of this activating Fc gamma receptor in models of autoimmunity and antibody-dependent cellular cytotoxicity.

A detailed bioinformatics analysis of six glycopeptide biosynthetic gene clusters isolated from soil environmental DNA (eDNA) megalibraries indicates that a subset of these gene clusters contains collections of tailoring enzymes that are predicted to result in the production of new glycopeptide congeners. In particular, sulfotransferases appear in eDNA-derived gene clusters at a much higher frequency than would be predicted from the characterization of glycopeptides from cultured Actinomycetes. Enzymes found on tailoring-enzyme-rich eDNA clones associated with these six gene clusters were used to produce a series of new sulfated glycopeptide derivatives in both in vitro and in vivo derivatization studies. The derivatization of known natural products with eDNA-derived tailoring enzymes is likely to be a broadly applicable strategy for generating libraries of new natural product variants.

Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder. Early in the pathophysiology of AD, synaptic function is disrupted by soluble A beta oligomers, possibly through A beta-mediated internalization of NMDA receptors. Striatal-enriched phosphatase (STEP) is a tyrosine phosphatase that regulates the internalization of NMDA receptors. Recent work shows that STEP is elevated in the prefrontal cortex of human AD patients and in animal models of AD. Here, we use genetic manipulations to reduce STEP activity in a triple transgenic AD mouse model and show that a decrease in STEP levels reverses cognitive and cellular deficits observed in these mice. Our results suggest that STEP inhibitors may prove therapeutic for this devastating disorder.

In contrast to the current state of knowledge in the field of eukaryotic chromosome segregation, relatively little is known about the mechanisms coordinating the appropriate segregation of bacterial chromosomes. In Escherichia coli, the MukB/E/F complex and topoisomerase IV (Topo IV) are both crucial players in this process. Topo IV removes DNA entanglements following the replication of the chromosome, whereas MukB, a member of the structural maintenance of chromosomes protein family, serves as a bacterial condensin. We demonstrate here a direct physical interaction between the dimerization domain of MukB and the C-terminal domain of the ParC subunit of Topo IV. In addition, we find that MukB alters the activity of Topo IV in vitro. Finally, we isolate a MukB mutant, D692A, that is deficient in its interaction with ParC and show that this mutant fails to rescue the temperature-sensitive growth phenotype of a mukB(-) strain. These results show that MukB and Topo IV are linked physically and functionally and indicate that the activities of these proteins are not limited to chromosome segregation but likely also play a key role in the control of higher-order bacterial chromosome structure.