Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome

We took advantage of overlapping interstitial deletions at chromosome 8p11-p12 in two individuals with contiguous gene syndromes and defined an interval of roughly 540 kb associated with a dominant form of Kallmann syndrome, KAL2. We establish here that loss-of-function mutations in FGFR1 underlie KAL2 whereas a gain-of-function mutation in FGFR1 has been shown to cause a form of craniosynostosis. Moreover, we suggest that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling and propose that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males.     

Orbital and millennial-scale features of atmospheric CH4 over the past 800,000 years

Atmospheric methane is an important greenhouse gas and a sensitive indicator of climate change and millennial-scale temperature variability. Its concentrations over the past 650,000 years have varied between approximately 350 and approximately 800 parts per 10(9) by volume (p.p.b.v.) during glacial and interglacial periods, respectively. In comparison, present-day methane levels of approximately 1,770 p.p.b.v. have been reported. Insights into the external forcing factors and internal feedbacks controlling atmospheric methane are essential for predicting the methane budget in a warmer world. Here we present a detailed atmospheric methane record from the EPICA Dome C ice core that extends the history of this greenhouse gas to 800,000 yr before present. The average time resolution of the new data is approximately 380 yr and permits the identification of orbital and millennial-scale features. Spectral analyses indicate that the long-term variability in atmospheric methane levels is dominated by approximately 100,000 yr glacial-interglacial cycles up to approximately 400,000 yr ago with an increasing contribution of the precessional component during the four more recent climatic cycles. We suggest that changes in the strength of tropical methane sources and sinks (wetlands, atmospheric oxidation), possibly influenced by changes in monsoon systems and the position of the intertropical convergence zone, controlled the atmospheric methane budget, with an additional source input during major terminations as the retreat of the northern ice sheet allowed higher methane emissions from extending periglacial wetlands. Millennial-scale changes in methane levels identified in our record as being associated with Antarctic isotope maxima events are indicative of ubiquitous millennial-scale temperature variability during the past eight glacial cycles.     

Bv8 regulates myeloid-cell-dependent tumour angiogenesis

Bone-marrow-derived cells facilitate tumour angiogenesis, but the molecular mechanisms of this facilitation are incompletely understood. We have previously shown that the related EG-VEGF and Bv8 proteins, also known as prokineticin 1 (Prok1) and prokineticin 2 (Prok2), promote both tissue-specific angiogenesis and haematopoietic cell mobilization. Unlike EG-VEGF, Bv8 is expressed in the bone marrow. Here we show that implantation of tumour cells in mice resulted in upregulation of Bv8 in CD11b+Gr1+ myeloid cells. We identified granulocyte colony-stimulating factor as a major positive regulator of Bv8 expression. Anti-Bv8 antibodies reduced CD11b+Gr1+ cell mobilization elicited by granulocyte colony-stimulating factor. Adenoviral delivery of Bv8 into tumours was shown to promote angiogenesis. Anti-Bv8 antibodies inhibited growth of several tumours in mice and suppressed angiogenesis. Anti-Bv8 treatment also reduced CD11b+Gr1+ cells, both in peripheral blood and in tumours. The effects of anti-Bv8 antibodies were additive to those of anti-Vegf antibodies or cytotoxic chemotherapy. Thus, Bv8 modulates mobilization of CD11b+Gr1+ cells from the bone marrow during tumour development and also promotes angiogenesis locally.     

An Optimal Algorithm To Recognize Robinsonian Dissimilarities

A dissimilarity D on a finite set S is said to be Robinsonian if S can be totally ordered in such a way that, for every i < j < k, D (i, j) ≤ D (i, k) and D (j, k) ≤ D (i, k). Intuitively, D is Robinsonian if S can be represented by points on a line. Recognizing Robinsonian dissimilarities has many applications in seriation and classification. In this paper, we present an optimal O (n ²) algorithm to recognize Robinsonian dissimilarities, where n is the cardinal of S. Our result improves the already known algorithms.     

Structural snapshots along the reaction pathway of ferredoxin-thioredoxin reductase

Oxygen-evolving photosynthetic organisms regulate carbon metabolism through a light-dependent redox signalling pathway. Electrons are shuttled from photosystem I by means of ferredoxin (Fdx) to ferredoxin-thioredoxin reductase (FTR), which catalyses the two-electron-reduction of chloroplast thioredoxins (Trxs). These modify target enzyme activities by reduction, regulating carbon flow. FTR is unique in its use of a [4Fe-4S] cluster and a proximal disulphide bridge in the conversion of a light signal into a thiol signal. We determined the structures of FTR in both its one- and its two-electron-reduced intermediate states and of four complexes in the pathway, including the ternary Fdx-FTR-Trx complex. Here we show that, in the first complex (Fdx-FTR) of the pathway, the Fdx [2Fe-2S] cluster is positioned suitably for electron transfer to the FTR [4Fe-4S] centre. After the transfer of one electron, an intermediate is formed in which one sulphur atom of the FTR active site is free to attack a disulphide bridge in Trx and the other sulphur atom forms a fifth ligand for an iron atom in the FTR [4Fe-4S] centre--a unique structure in biology. Fdx then delivers a second electron that cleaves the FTR-Trx heterodisulphide bond, which occurs in the Fdx-FTR-Trx complex. In this structure, the redox centres of the three proteins are aligned to maximize the efficiency of electron transfer from the Fdx [2Fe-2S] cluster to the active-site disulphide of Trxs. These results provide a structural framework for understanding the mechanism of disulphide reduction by an iron-sulphur enzyme and describe previously unknown interaction networks for both Fdx and Trx (refs 4-6).