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Successful pregnancies rely on adaptations within the mother.sup.1, including marked changes within the immune system.sup.2. It has long been known that the thymus, the central lymphoid organ, changes markedly during pregnancy.sup.3. However, the molecular basis and importance of this process remain largely obscure. Here we show that the osteoclast differentiation receptor RANK.sup.4,5 couples female sex hormones to the rewiring of the thymus during pregnancy. Genetic deletion of Rank (also known as Tnfrsf11a) in thymic epithelial cells results in impaired thymic involution and blunted expansion of natural regulatory T (T.sub.reg) cells in pregnant female mice. Sex hormones, in particular progesterone, drive the development of thymic T.sub.reg cells through RANK in a manner that depends on AIRE.sup.+ medullary thymic epithelial cells. The depletion of Rank in the mouse thymic epithelium results in reduced accumulation of natural T.sub.reg cells in the placenta, and an increase in the number of miscarriages. Thymic deletion of Rank also results in impaired accumulation of T.sub.reg cells in visceral adipose tissue, and is associated with enlarged adipocyte size, tissue inflammation, enhanced maternal glucose intolerance, fetal macrosomia, and a long-lasting transgenerational alteration in glucose homeostasis, which are all key hallmarks of gestational diabetes. Transplantation of T.sub.reg cells rescued fetal loss, maternal glucose intolerance and fetal macrosomia. In human pregnancies, we found that gestational diabetes also correlates with a reduced number of T.sub.reg cells in the placenta. Our findings show that RANK promotes the hormone-mediated development of thymic T.sub.reg cells during pregnancy, and expand the functional role of maternal T.sub.reg cells to the development of gestational diabetes and the transgenerational metabolic rewiring of glucose homeostasis. RANK promotes the hormone-mediated development of thymic regulatory T cells during pregnancy; loss of RANK is associated with impaired maturation of maternal regulatory T cells, leading to fetal loss and the development of gestational diabetes., Author(s): Magdalena Paolino [sup.1] [sup.2] [sup.3] , Rubina Koglgruber [sup.1] , Shane J. F. Cronin [sup.1] , Iris Uribesalgo [sup.1] , Esther Rauscher [sup.1] , Jürgen Harreiter [sup.4] , Michael [...]

We examine the connected history of dacite-dominant volcanic rocks of the Tschicoma Formation, erupted between 5.5 and 2 Ma from the Jemez Mountains volcanic field, western USA. Zircon samples from two separate eruptions have continuous SHRIMP U-Pb age spectra spanning 0.84-1.08 Myr duration (3.12-3.96 Ma and 3.50-4.58 Ma, respectively), following an episode of zircon crystallization 0.28-0.50 Myr earlier (at 4.46 Ma and 4.86 Ma, respectively). Zircon chemical variations, as well as ubiquitous resorption textures that commonly show large core-rim age differences (up to 720-740 kyr), suggest that they grew in separate melt lenses. Zircons were likely stored at near-solidus or even sub-solidus conditions after crystallization, but may have been reactivated in response to at least four major magma recharge events every 300-400 kyr and smaller events in between. A cycle of zircon dissolution (from heating), recrystallization (during cooling), and storage repeated in different locations in the Tschicoma mush system throughout its lifespan; each recharge-induced heating stage may last for several hundred to more than a thousand years based on calculations of zircon dissolution. We envisage the melt lenses to be distributed in a crystal mush zone, coalescing into a single magma batch as magma recharge occurs shortly before eruption. Once active, increasing magma supply rates may trigger large-scale partial melting of the pre-existing mush and caldera-forming eruptions., Author(s): Jie Wu [sup.1], Michael C. Rowe [sup.1], Shane J. Cronin [sup.1], John A. Wolff [sup.2], Bin Fu [sup.3] Author Affiliations: (1) grid.9654.e, 0000 0004 0372 3343, School of Environment, [...]

Genetic regulators and environmental stimuli modulate T cell activation in autoimmunity and cancer. The enzyme co-factor tetrahydrobiopterin (BH4) is involved in the production of monoamine neurotransmitters, the generation of nitric oxide, and pain.sup.1,2. Here we uncover a link between these processes, identifying a fundamental role for BH4 in T cell biology. We find that genetic inactivation of GTP cyclohydrolase 1 (GCH1, the rate-limiting enzyme in the synthesis of BH4) and inhibition of sepiapterin reductase (the terminal enzyme in the synthetic pathway for BH4) severely impair the proliferation of mature mouse and human T cells. BH4 production in activated T cells is linked to alterations in iron metabolism and mitochondrial bioenergetics. In vivo blockade of BH4 synthesis abrogates T-cell-mediated autoimmunity and allergic inflammation, and enhancing BH4 levels through GCH1 overexpression augments responses by CD4- and CD8-expressing T cells, increasing their antitumour activity in vivo. Administration of BH4 to mice markedly reduces tumour growth and expands the population of intratumoral effector T cells. Kynurenine--a tryptophan metabolite that blocks antitumour immunity--inhibits T cell proliferation in a manner that can be rescued by BH4. Finally, we report the development of a potent SPR antagonist for possible clinical use. Our data uncover GCH1, SPR and their downstream metabolite BH4 as critical regulators of T cell biology that can be readily manipulated to either block autoimmunity or enhance anticancer immunity. Tetrahydrobiopterin (BH4) is an enzyme co-factor that is involved in the nervous system; it is shown here to also function in T cell activation and proliferation, with roles in autoimmunity, allergic inflammation and cancer., Author(s): Shane J. F. Cronin [sup.1] [sup.2] [sup.3] , Corey Seehus [sup.2] [sup.3] , Adelheid Weidinger [sup.4] , Sebastien Talbot [sup.2] [sup.3] [sup.5] , Sonja Reissig [sup.6] , Markus Seifert [...]

Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy (1). New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies (2). Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity invivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology (3). This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases., Genetic ablation of Cbl-b or functional inactivation of its E3 ligase activity in mice results in [CD8.sup.+] T-cell-mediated rejection of primary tumours in several different models (4-6). In a control [...]

CLP1 was the first mammalian RNA kinase to be identified. However, determining its in vivo function has been elusive. Here we generated kinase-dead Clpl ([Clp1.sup.K/K]) mice that show a progressive loss of spinal motor neurons associated with axonal degeneration in the peripheral nerves and denervation of neuromuscular junctions, resulting in impaired motor function, muscle weakness, paralysis and fatal respiratory failure. Transgenic rescue experiments show that CLP1 functions in motor neurons. Mechanistically, loss of CLP1 activity results in accumulation of a novel set of small RNA fragments, derived from aberrant processing of tyrosine pre-transfer RNA. These tRNA fragments sensitize cells to oxidative-stress-induced p53 (also known as TRP53) activation and p53-dependent cell death. Genetic inactivation of p53 rescues [Clp1.sup.K/K] mice from the motor neuron loss, muscle denervation and respiratory failure. Our experiments uncover a mechanistic link between tRNA processing, formation of a new RNA species and progressive loss of lower motor neurons regulated by p53., RNA molecules undergo co- and post-transcriptional processing, leading to mature, functional RNAs. In mammals and archaea CLP1 proteins are kinases that phosphorylate the 5' hydroxyl ends of RNA (1-3). Human [...]

Byline: Marco Brenna (1), Shane J. Cronin (1), Ian E. M. Smith (2), Young Kwan Sohn (3), Karoly Nemeth (1) Keywords: Monogenetic volcanism; Basalt geochemistry; Jeju Island; Plumbing system; Alkali basalt Abstract: High-resolution, stratigraphically ordered samples of the Udo tuff cone and lava shield offshore of Jeju Island, South Korea, show complex geochemical variation in the basaltic magmas that fed the eruption sequence. The eruption began explosively, producing phreatomagmatic deposits with relatively evolved alkali magma. The magma became more primitive over the course of the eruption, but the last magma to be explosively erupted had shifted back to a relatively evolved composition. A separate sub-alkali magma batch was subsequently effusively erupted to form a lava shield. Absence of weathering and only minor reworking between the tuff and overlying lava implies that there was no significant time break between the eruptions of the two magma batches. Modelling of the alkali magma suggests that it was generated from a parent melt in garnet peridotite at c. 3 to 3.5 GPa and underwent mainly clinopyroxene + olivine +- spinel fractionation at c. 1.5 to 2 GPa. The sub-alkali magma was, by contrast, generated from a chemically different peridotite with residual garnet at c. 2.5 GPa and evolved through olivine fractionation at a shallower level compared to its alkali contemporary. The continuous chemostratigraphic trend in the tuff cone, from relatively evolved to primitive and back to evolved, is interpreted to have resulted from a magma batch having risen through a single dyke and erupted the batch's head, core and margins, respectively. The alkali magma acted as a path-opener for the sub-alkali magma. The occurrence of the two distinct batches suggests that different magmatic systems in the Jeju Island Volcanic Field have interacted throughout its history. The polymagmatic nature of this monogenetic eruption has important implications for hazard forecasting and for our understanding of basaltic field volcanism. Author Affiliation: (1) Volcanic Risk Solutions, Massey University, Palmerston North, New Zealand (2) School of Geography, Geology and Environmental Science, The University of Auckland, Auckland, New Zealand (3) Department of Earth & Environmental Sciences, Gyeongsang National University, Jinju, South Korea Article History: Registration Date: 17/03/2010 Received Date: 17/11/2009 Accepted Date: 17/03/2010 Online Date: 03/04/2010 Article note: Communicated by G. Moore. Electronic supplementary material The online version of this article (doi: 10.1007/s00410-010-0515-1) contains supplementary material, which is available to authorized users.

At 11:18 h (New Zealand time, GMT +12) on 18 March 2007 an impoundment of 0.01 x [10.sup.6] [m.sup.3] of tephra collapsed, releasing 1.3 x [10.sup.6] [m.sup.3] of water from Crater Lake at 2536 m elevation on Mount Ruapehu. The lahar traveled 200 km along the Whangaehu River. Aerial LiDAR surveys of the upper 62 km of flow path were made before and after the lahar. We present here the first large-scale quantification of the geomorphic impact of the dam-break flood along with the rates and controls on its sediment entrainment and deposition. The flood mobilized a net value of 2.5-3.1 x [10.sup.6] [m.sup.3] of boulders, gravel, and sand over the first 5 km of travel to form a lahar of at least 4.4 x [10.sup.6] [m.sup.3] passing instruments at 6.9 km. LiDAR volume-transfer calculations match dynamic measurements made. After a logarithmic increase in cumulative net sediment entrainment, the lahar appeared to reach its maximum sediment-carrying capacity at 22 km. Patterns of alternating sediment erosion and deposition occurred that dominantly reflect a combination of channel morphology and confinement on the local sediment-carrying capacity of the flow. doi: 10.1130/G30129.1

The near-invisibility of ice-slurry flows in the geological record belies their significant hazard at snow-capped volcanoes. These four-phase flows exhibit extreme rates of volumetric bulking and unusually high mobility. Mechanisms of their motion are clarified through two examples generated on 25 September 2007 at Mount Ruapehu, New Zealand. Brief explosions through Crater Lake ejected 5700 [m.sup.3] of acidic water that entrained 60 times this volume of snow as it traveled over a snow-covered glacier. The resulting ice-slurry traveled up to 7.7 km (height/length [H/L] ratio of 0.16). A cogenerated second flow took a more tortuous initial path before riding over the already frozen deposits of the first unit and beyond (H/L 0.13). For the first time, downstream evolution of the kinematic properties of propagating ice-slurry fronts could be characterized as well as the longitudinal variation of the physical properties of their resulting deposits. The chemistry and composition of the deposits show that during flow, vertical percolation of water through the porous ice-particle-water-air mixture generated a basal zone of high internal pore pressure. This effect was particularly strong when a thick, high-density flow front formed, which raced ahead of the tail to control runout and consequent hazard.

Mineral assemblages in volcanic rocks record both pre-eruptive conditions and changes experienced by magma as it rises. Titanomagnetite in andesitic magmas is especially sensitive to changes in temperature and oxygen fugacity immediately prior to and during eruptions. Two end-member eruption states can be distinguished by examining titanomagnetite textures in erupted rocks. Slow-ascent eruptions--characterized by near-stagnant magma bodies and slow effusion of lava domes--show solid-state exsolution of titano-hematite/ilmenite lamellae within titanomagnetite hosts. By contrast, fast-ascent eruptions--characterized by rapid chilling of magma in sub-Plinian eruptions--contain titanomagnetites without such exsolution features. This mineralogical distinction is particularly useful in examining very fine-grained distal tephra layers where other characteristic properties of the two eruptions types are not present. Such tephra records in lake deposits typically provide the most precise long-term eruption records from andesitic volcanoes. Using an example from Mount Taranaki, New Zealand, we show that by classifying eruption styles within such sequences, the underlying magmatic system processes at a volcano can be elucidated and separated from other environmental factors such as vent/crater configuration. Keywords: titanomagnetite, exsolution, andesite volcanism, Mount Taranaki

The first lahars of the 1995 Ruapehu eruptive sequence were generated by explosively ejected Crater Lake water, sediment, and juvenile material, which incorporated snow and ice to form 'snow slurry' lahars. On September 18, small amounts of Crater Lake water were ejected, which mobilized large amounts of snow. This was because unstable seasonal snow pack was present in the lahar flow path. Five days later, a larger volume of water was ejected but proportionally less snow was mobilized. Beyond the volcanic cone, the initially homogenized snow slurries segregated into watery flows with a floating snow-slurry cap. Frozen deposits were emplaced as far as 45 km from the source and 1840 m lower in altitude. More than 50% of the sediment within the flow was derived from the initial eruption; the remainder was entrained before it reached 9.5 km. Beyond 9.5 km from the source, the flows progressively lost their gravel and sand.

An Amendment to this paper has been published and can be accessed via a link at the top of the paper., Author(s): Shane J. F. Cronin [sup.1] [sup.2] [sup.3] , Corey Seehus [sup.2] [sup.3] , Adelheid Weidinger [sup.4] , Sebastien Talbot [sup.2] [sup.3] [sup.5] , Sonja Reissig [sup.6] , Markus Seifert [...]

Three lahars were sampled in the Whangaehu River on the eastern flank of Ruapehu volcano, New Zealand, at 23.5 and 42 km from the source as they were flowing on September 27 and 29 and October 6, 1995. The lahars were generated by water explosively ejected from the highly mineralized Crater Lake. We used the chemical contrast between the lahars and resident stream water in their paths to describe a four-phase model of a noncohesive lahar wave in a river channel: (1) ambient stream water pushed ahead of the lahar in a process of miscible displacement due to hydrodynamic dispersion; (2) a zone of mixing between the stream water and the lahar that increases in length with distance from source; (3) a remnant of the original lahar, least diluted by stream water, that decreases in length and dilutes downstream; (4) the tail of the lahar surge. Peak discharge occurs at the end of phase 1 as water is pushed ahead of the lahar. Peak sediment concentration occurs at the end of phase 2, where debris entrainment by the flow is at its greatest (i.e., in front of the lahar proper). Deposits record only phases 2 and 3 of the lahar wave, phase 1 flow left only a tide line of organic debris, and phase 4 deposits were rapidly eroded by later streamflow. Downstream dilution by stream water eventually caused transformation of phases 2 and 3 of the lahars from debris flow to hyper-concentrated streamflow and then to normal streamflow as the flows became progressively finer grained and more turbulent.