Mutations in NMNAT1 cause Leber congenital amaurosis with early-onset severe macular and optic atrophy

In addition to its activity in nicotinamide adenine dinucleotide (NAD(+)) synthesis, the nuclear nicotinamide mononucleotide adenyltransferase NMNAT1 acts as a chaperone that protects against neuronal activity-induced degeneration. Here we report that compound heterozygous and homozygous NMNAT1 mutations cause severe neonatal neurodegeneration of the central retina and early-onset optic atrophy in 22 unrelated individuals. Their clinical presentation is consistent with Leber congenital amaurosis and suggests that the mutations affect neuroprotection of photoreceptor cells.     

Thromboxane synthase mutations in an increased bone density disorder (Ghosal syndrome)

Studying consanguineous families with Ghosal hematodiaphyseal dysplasia syndrome (GHDD), a disorder of increased bone density, we identified mutations in TBXAS1, which encodes thromboxane synthase (TXAS). TXAS, an enzyme of the arachidonic acid cascade, produces thromboxane A(2) (TXA(2)). Platelets from subjects with GHDD showed a specific deficit in arachidonic acid-produced aggregation. We also found that TXAS and TXA(2) modulated expression of TNFSF11 and TNFRSF11B (encoding RANKL and osteoprotegerin (OPG), respectively) in primary cultured osteoblasts.     

Fulfillment and Fitting Fulfillment

Susan Wolf argues that meaning arises when subjective attraction meets objective attractiveness. Whereas we can agree with her claim that the conception of meaning invokes an objective standard, we think it is questionable whether a radically subjective fulfillment is a real possibility. Several reasons are provided why this cannot be the case.     

Vascular normalization in Rgs5-deficient tumours promotes immune destruction

The vasculature of solid tumours is morphologically aberrant and characterized by dilated and fragile vessels, intensive vessel sprouting and loss of hierarchical architecture. Constant vessel remodelling leads to spontaneous haemorrhages and increased interstitial fluid pressure in the tumour environment. Tumour-related angiogenesis supports tumour growth and is also a major obstacle for successful immune therapy as it prevents migration of immune effector cells into established tumour parenchyma. The molecular mechanisms for these angiogenic alterations are largely unknown. Here we identify regulator of G-protein signalling 5 (Rgs5) as a master gene responsible for the abnormal tumour vascular morphology in mice. Loss of Rgs5 results in pericyte maturation, vascular normalization and consequent marked reductions in tumour hypoxia and vessel leakiness. These vascular and intratumoral changes enhance influx of immune effector cells into tumour parenchyma and markedly prolong survival of tumour-bearing mice. This is the first demonstration, to our knowledge, of reduced tumour angiogenesis and improved immune therapeutic outcome on loss of a vascular gene function and establishes a previously unrecognized role of G-protein signalling in tumour angiogenesis.     

Reduction and selective oxo group silylation of the uranyl dication

Uranium occurs in the environment predominantly as the uranyl dication [UO2]2+. Its solubility renders this species a problematic contaminant which is, moreover, chemically extraordinarily robust owing to strongly covalent U-O bonds. This feature manifests itself in the uranyl dication showing little propensity to partake in the many oxo group functionalizations and redox reactions typically seen with [CrO2]2+, [MoO2]2+ and other transition metal analogues. As a result, only a few examples of [UO2]2+ with functionalized oxo groups are known. Similarly, it is only very recently that the isolation and characterization of the singly reduced, pentavalent uranyl cation [UO2]+ has been reported. Here we show that placing the uranyl dication within a rigid and well-defined molecular framework while keeping the environment anaerobic allows simultaneous single-electron reduction and selective covalent bond formation at one of the two uranyl oxo groups. The product of this reaction is a pentavalent and monofunctionalized [O = U...OR]+ cation that can be isolated in the presence of transition metal cations. This finding demonstrates that under appropriate reaction conditions, the uranyl oxo group will readily undergo radical reactions commonly associated only with transition metal oxo groups. We expect that this work might also prove useful in probing the chemistry of the related but highly radioactive plutonyl and neptunyl analogues found in nuclear waste.     

Language evolution: semantic combinations in primate calls

Syntax sets human language apart from other natural communication systems, although its evolutionary origins are obscure. Here we show that free-ranging putty-nosed monkeys combine two vocalizations into different call sequences that are linked to specific external events, such as the presence of a predator and the imminent movement of the group. Our findings indicate that non-human primates can combine calls into higher-order sequences that have a particular meaning.     

Synthesis of 6-deoxy-6-fluoro-L-ascorbic acid

Summary 6-Deoxy-6-fluoro-L-ascorbic acid has been synthesized in 5 steps starting from 2,3-4,6-di-O-isopropylidene-2-keto-L-gulonic acid.Dedicated to Professor Albert Szent-Györgyi, National Foundation for Cancer Research, Marine Biological Laboratory, Woods Hole, Massachusetts, on the occasion of his 85th birthday.     

Platelet secretory products inhibit lipoprotein metabolism in macrophages

Macrophages possess a receptor that binds low-density lipoproteins (LDL) containing lysine residues modified by acetylation (Ac LDL), acetoacetylation (AcAc LDL) or malondialdehyde treatment. This receptor (referred to as the Ac LDL receptor or scavenger receptor) internalizes the bound lipoprotein. As a consequence, massive amounts of cholesteryl esters accumulate so that macrophages in culture resemble foam cells found in atherosclerotic lesions. In an effort to identify an unmodified mammalian macromolecule that binds to the Ac LDL receptor, we investigated whether platelet secretory products affect the receptor-mediated endocytosis of chemically modified lipoproteins. Platelets are a potential source of such activity because they exist in close association with foam cells in developing atherosclerotic lesions. Our study demonstrates that human blood platelets secrete a product that inhibits the binding and uptake of AcAc LDL by mouse peritoneal macrophages and the subsequent accumulation of cholesteryl esters. This is the first indication that an endogenous macromolecule interacts with Ac LDL receptor on macrophages.     

Strong xenogeneic HLA response in transgenic mice after introducing an alpha 3 domain into HLA B27.

The pronounced response by mouse T cells to the major histocompatibility complex (MHC) class I antigens of the same species is characterized by a relatively large fraction of responding cells. Responses to MHC class I allelles of other species are, however, generally much weaker. T lymphocytes are positively selected on thymic MHC antigens, resulting in a T-cell repertoire with strong alloreactivity. This has been explained in terms of a mouse T-cell repertoire that is not efficiently selected for recognition of HLA molecules owing to the absence of HLA in mice. Here we show that mice transgenic for HLA mount a T-cell response against allogeneic HLA that is no better than in normal mice. We decided instead to test whether the mouse accessory molecule Lyt-2 on cytotoxic T lymphocytes could interact efficiently with the alpha 3 domain of HLA. To do this, we replaced the alpha 3 domain of HLA-B27 by a murine alpha 3 domain in a gene construct used to produce transgenic mice, and then used the spleen cells from these mice to stimulate normal mouse T cells. Under these conditions cytotoxic T lymphocytes were generated with the same frequency against xenogeneic HLA-B27 determinants as against allogeneic mouse class I antigens. These findings indicate that the normally weak xeno-MHC response is due to the inefficient interaction of the murine Lyt-2 accessory molecule with HLA class I, and not to limitations of the mouse T-cell repertoire.