Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity

Vertebral and metaphyseal dysplasia, spasticity with cerebral calcifications, and strong predisposition to autoimmune diseases are the hallmarks of the genetic disorder spondyloenchondrodysplasia. We mapped a locus in five consanguineous families to chromosome 19p13 and identified mutations in ACP5, which encodes tartrate-resistant phosphatase (TRAP), in 14 affected individuals and showed that these mutations abolish enzyme function in the serum and cells of affected individuals. Phosphorylated osteopontin, a protein involved in bone reabsorption and in immune regulation, accumulates in serum, urine and cells cultured from TRAP-deficient individuals. Case-derived dendritic cells exhibit an altered cytokine profile and are more potent than matched control cells in stimulating allogeneic T cell proliferation in mixed lymphocyte reactions. These findings shed new light on the role of osteopontin and its regulation by TRAP in the pathogenesis of common autoimmune disorders.     

Challenges and successes in developing new therapies for hepatitis C

Hepatitis C virus (HCV) will continue to be a serious global health threat for many years to come because of the chronic nature of the infection, its high prevalence and the significant morbidity of the resulting disease. Recently, a small number of molecules have produced encouraging results in proof-of-concept clinical trials. At the same time, preclinical evidence is accumulating that development of resistance will eventually limit the efficacy of new drugs. Thus, combinations of multiple agents will be required to treat chronic HCV infection.     

Bridging epigenomics and complex disease: the basics

The DNA sequence largely defines gene expression and phenotype. However, it is becoming increasingly clear that an additional chromatin-based regulatory network imparts both stability and plasticity to genome output, modifying phenotype independently of the genetic blueprint. Indeed, alterations in this “epigenetic” control layer underlie, at least in part, the reason for monozygotic twins being discordant for disease. Functionally, this regulatory layer comprises post-translational modifications of DNA and histones, as well as small and large noncoding RNAs. Together these regulate gene expression by changing chromatin organization and DNA accessibility. Successive technological advances over the past decade have enabled researchers to map the chromatin state with increasing accuracy and comprehensiveness, catapulting genetic research into a genome-wide era. Here, aiming particularly at the genomics/epigenomics newcomer, we review the epigenetic basis that has helped drive the technological shift and how this progress is shaping our understanding of complex disease.     

Ultra-broadband semiconductor laser

The fundamental mechanism behind laser action leads in general only to narrowband, single-wavelength emission. Several approaches for achieving spectrally broadband laser action have been put forward, such as enhancing the optical feedback in the wings of the gain spectrum, multi-peaked gain spectra, and the most favoured technique at present, ultrashort pulse excitation. Each of these approaches has drawbacks, such as a complex external laser cavity configuration, a non-flat optical gain envelope function, or an inability to operate in continuous mode, respectively. Here we present a monolithic, mid-infrared 'supercontinuum' semiconductor laser that has none of these drawbacks. We adopt a quantum cascade configuration, where a number of dissimilar intersubband optical transitions are made to cooperate in order to provide broadband optical gain from 5 to 8 microm wavelength. Laser action with a Fabry-Pérot spectrum covering all wavelengths from 6 to 8 microm simultaneously is demonstrated with this approach. Lasers that emit light over such an extremely wide wavelength range are of interest for applications as varied as terabit optical data communications or ultra-precision metrology and spectroscopy.