Myostatin, a transforming growth factor ␤ (TGF-␤) family member, is a potent negative regulator of skeletal muscle growth. In this study we characterized the myostatin signal transduction pathway and examined its effect on bone morphogenetic protein (BMP)-induced adipogenesis. While both BMP7 and BMP2 activated transcription from the BMP-responsive I-BRE-Lux reporter and induced adipogenic differentiation, myostatin inhibited BMP7-but not BMP2-mediated responses. To dissect the molecular mechanism of this antagonism, we characterized the myostatin signal transduction pathway. We showed that myostatin binds the type II Ser/ Thr kinase receptor. ActRIIB, and then partners with a type I receptor, either activin receptor-like kinase 4 (ALK4 or ActRIB) or ALK5 (T␤RI), to induce phosphorylation of Smad2/Smad3 and activate a TGF-␤-like signaling pathway. We demonstrated that myostatin prevents BMP7 but not BMP2 binding to its receptors and that BMP7-induced heteromeric receptor complex formation is blocked by competition for the common type II receptor, ActRIIB. Thus, our results reveal a strikingly specific antagonism of BMP7-mediated processes by myostatin and suggest that myostatin is an important regulator of adipogenesis.Mesenchymal stem cell differentiation is generally thought to be initiated by the inductive action of specific growth factors, and abundant evidence demonstrates that transforming growth factor ␤ (TGF-␤) superfamily members can profoundly regulate these processes (12,17,18,34,58). For instance, TGF-␤ can inhibit adipogenesis and myogenesis while bone morphogenetic proteins (BMPs) can promote chondrogenesis, osteogenesis, and adipogenesis. Myostatin (previously known as growth and differentiation factor 8 [GDF8]) is a key critical regulator of skeletal muscle development (26). Myostatin-null mice display widespread increases in muscle mass (36) and decreased body fat accumulation (28,38), and inhibition of myostatin with blocking antibodies increases muscle mass (8). Myostatin function appears to be well conserved, since mutations in the myostatin gene have been identified in the doublemuscled Belgium Blue and Piedmontese cattle breeds (37). Consistent with this, myostatin mRNA is first expressed in somites, in the myotome layer that gives rise to skeletal muscle (36), and is highly expressed in skeletal muscle at later developmental stages and in adults and has been detected in both fetal and adult heart and in adipose tissue (36, 50). Of note, systemic administration of myostatin to adult mice results in a cachexia-like syndrome that is associated with a profound loss of both muscle and fat (64). Since decreased fat accumulation is observed both in knock-out mice that lack myostatin and in wild-type adult mice in which myostatin has been systemically administered (28, 38), it appears that myostatin may play distinct physiological roles during early development and during adult homeostatic processes.Like all TGF-␤ superfamily members, myostatin is synthesized in a precursor form that is proteolyti...

We identified a protein, Aer, as a signal transducer that senses intracellular energy levels rather than the external environment and that transduces signals for aerotaxis (taxis to oxygen) and other energy-dependent behavioral responses in Escherichia coli. Domains in Aer are similar to the signaling domain in chemotaxis receptors and the putative oxygen-sensing domain of some transcriptional activators. A putative FAD-binding site in the N-terminal domain of Aer shares a consensus sequence with the NifL, Bat, and Wc-1 signal-transducing proteins that regulate gene expression in response to redox changes, oxygen, and blue light, respectively. A double mutant deficient in aer and tsr, which codes for the serine chemoreceptor, was negative for aerotaxis, redox taxis, and glycerol taxis, each of which requires the proton motive force and͞or electron transport system for signaling. We propose that Aer and Tsr sense the proton motive force or cellular redox state and thereby integrate diverse signals that guide E. coli to environments where maximal energy is available for growth.

In three case-control studies and a household transmission cohort, Danuta Skowronski and colleagues find an association between prior seasonal flu vaccination and increased risk of 2009 pandemic H1N1 flu.

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor (TGF)␤ superfamily of ligands that regulate many crucial aspects of embryonic development and organogenesis. Unlike other TGF␤ ligands, co-receptors for BMP ligands have not been described. Here we show that DRAGON, a glycosylphosphatidylinositol-anchored member of the repulsive guidance molecule family, which is expressed early in the developing nervous system, enhances BMP but not TGF␤ signaling. DRAGON binds directly to BMP2 and BMP4 but not to BMP7 or other TGF␤ ligands. The enhancing action of DRAGON on BMP signaling is also reduced by administration of Noggin, a soluble BMP antagonist, indicating that the action of DRAGON is ligand-dependent. DRAGON associates directly with BMP type I (ALK2, ALK3, and ALK6) and type II (ActRII and ActRIIB) receptors, and its signaling is reduced by dominant negative Smad1 and ALK3 or -6 receptors. In the Xenopus embryo, DRAGON both reduces the threshold of the ability of Smad1 to induce mesodermal and endodermal markers and alters neuronal and neural crest patterning. The direct interaction of DRAGON with BMP ligands and receptors indicates that it is a BMP co-receptor that potentiates BMP signaling. Transforming growth factor beta (TGF␤)1 superfamily ligands that include the TGF␤, bone morphogenetic protein (BMP), growth and differentiation factor, and nodal-related families play a pleiotropic role in vertebrate development by influencing cell specification, differentiation, proliferation, patterning, and migration (1, 2). These functions require the tight control of ligand production, ensuring a highly ordered spatiotemporal distribution and specific activation, via receptor complexes, of particular intracellular signaling pathways. The TGF␤/activin/nodal ligand subfamily contributes to the specification of endoderm and mesoderm in pregastrula embryos and at gastrula stages, to dorsal mesoderm formation and anterior-posterior patterning (3, 4). Later, TGF␤ ligands influence the body axis and patterning of the nervous system (5). BMPs, a second major ligand subfamily, contribute to the ventralization of germ layers in the early embryo and suppress the default neural cell fate of the ectoderm (6). BMPs also participate later in development in the formation and patterning of the neural crest, heart, blood, kidney, limb, muscle, and skeletal system (7).Signal transduction in the BMP subfamily is initiated by ligand binding to a receptor complex composed of two type I and two type II receptors. Three different BMP type I receptors (activin receptor-like kinase ALK2, ALK3, and ALK6) and three BMP type II receptors (BMP type II receptor (BMPRII), activin type IIA receptor (ActRIIA), activin type IIB receptor (ActRIIB)), each with intracellular serine/threonine kinase domains, have been identified (8). Ligand binding induces phosphorylation of the type I receptor by the type II receptor, which leads to phosphorylation of cytoplasmic receptor-activated Smads. The BMP subfamily signals through one set...

PAS domains sense oxygen, redox potential and light, and are implicated in behaviour, circadian rhythmicity, development and metabolic regulation. Although PAS domains are widespread in archaea, bacteria and eukaryota, the mechanism of signal transduction has been elucidated only for the bacterial photo sensor PYP and oxygen sensor FixL. We investigated the signalling mechanism in the PAS domain of Aer, the redox potential sensor and aerotaxis transducer in Escherichia coli. Forty‐two residues in Aer were substituted using cysteine‐replacement mutagenesis. Eight mutations resulted in a null phenotype for aerotaxis, the behavioural response to oxygen. Four of them also led to the loss of the non‐covalently bound FAD cofactor. Three mutant Aer proteins, N34C, F66C and N85C, transmitted a constant signal‐on bias. One mutation, Y111C, inverted signalling by the transducer so that positive stimuli produced negative signals and vice versa. Residues critical for signalling were mapped onto a three‐dimensional model of the Aer PAS domain, and an FAD‐binding site and ‘active site’ for signal transduction are proposed.

The rate of clinical failure following treatment of N. gonorrhoeae infections with cefixime was relatively high at a Toronto clinic and was associated with elevated MICs.

Cervical human papillomavirus (HPV) infection may increase HIV risk. Since other genital infections enhance HIV susceptibility by inducing inflammation, we assessed the impact of HPV infection and clearance on genital immunology and the cervico-vaginal microbiome. Genital samples were collected from 65 women for HPV testing, immune studies and microbiota assessment; repeat HPV testing was performed after 6 months. All participants were HIV-uninfected and free of bacterial STIs. Cytobrush-derived T cell and dendritic cell subsets were assessed by multiparameter flow cytometry. Undiluted cervico-vaginal secretions were used to determine cytokine levels by multiplex ELISA, and to assess bacterial community composition and structure by 16S rRNA gene sequence analysis. Neither HPV infection nor clearance were associated with broad differences in cervical T cell subsets or cytokines, although HPV clearance was associated with increased Langerhans cells and HPV infection with elevated IP-10 and MIG. Individuals with HPV more frequently had a high diversity cervico-vaginal microbiome (community state type IV) and were less likely to have an L. gasseri predominant microbiome. In summary, HPV infection and/or subsequent clearance was not associated with inflammation or altered cervical T cell subsets, but associations with increased Langerhans cells and the composition of the vaginal microbiome warrant further exploration.

The findings suggest a mucosal vicious circle in which HSV2 infection increases HIV target cells in the genital mucosa, subsequent HIV infection impairs HSV2 mucosal immune control, and local HSV2 reactivation enhances both HSV2 and HIV transmission.