ALBERT

Description: The alternative splicing of the tau gene, MAPT , generates six protein isoforms in the adult human central nervous system (CNS). Tau splicing is developmentally regulated and dysregulated in disease. Mutations in MAPT that alter tau splicing cause frontotemporal dementia (FTD) with tau pathology, providing evidence for a causal link between altered tau splicing and disease. The use of induced pluripotent stem cell (iPSC)-derived neurons has revolutionized the way we model neurological disease in vitro . However, as most tau mutations are located within or around the alternatively spliced exon 10, it is important that iPSC–neurons splice tau appropriately in order to be used as disease models. To address this issue, we analyzed the expression and splicing of tau in iPSC-derived cortical neurons from control patients and FTD patients with the 10 + 16 intronic mutation in MAPT . We show that control neurons only express the fetal tau isoform (0N3R), even at extended time points of 100 days in vitro . Neurons from FTD patients with the 10 + 16 mutation in MAPT express both 0N3R and 0N4R tau isoforms, demonstrating that this mutation overrides the developmental regulation of exon 10 inclusion in our in vitro model. Further, at extended time points of 365 days in vitro , we observe a switch in tau splicing to include six tau isoforms as seen in the adult human CNS. Our results demonstrate the importance of neuronal maturity for use in in vitro modeling and provide a system that will be important for understanding the functional consequences of altered tau splicing.

Description: Paget's disease of bone (PDB) is a common disorder with a strong genetic component characterized by increased but disorganized bone remodelling. Previous genome-wide association studies identified a locus on chromosome 14q32 tagged by rs10498635 which was significantly associated with susceptibility to PDB in several European populations. Here we conducted fine-mapping and targeted sequencing of the candidate locus to identify possible functional variants. Imputation in 741 PDB patients and 2699 controls confirmed that the association was confined to a 60 kb region in the RIN3 gene and conditional analysis adjusting for rs10498635 identified no new independent signals. Sequencing of the RIN3 gene identified a common missense variant (p.R279C) that was strongly associated with the disease (OR = 0.64; P = 1.4 x 10 –9 ), and was in strong linkage disequilibrium with rs10498635. A further 13 rare missense variants were identified, seven of which were novel and detected only in PDB cases. When combined, these rare variants were over-represented in cases compared with controls (OR = 3.72; P = 8.9 x 10 –10 ). Most rare variants were located in a region that encodes a proline-rich, intrinsically disordered domain of the protein and many were predicted to be pathogenic. RIN3 was expressed in bone tissue and its expression level was ~10-fold higher in osteoclasts compared with osteoblasts. We conclude that susceptibility to PDB at the 14q32 locus is mediated by a combination of common and rare coding variants in RIN3 and suggest that RIN3 may contribute to PDB susceptibility by affecting osteoclast function.

Description: Interleukin-17 (IL-17) has been shown to participate in the development of Lyme arthritis in experimental mice. For example, neutralization of IL-17 with antibodies inhibits induction of arthritis in Borrelia -primed and -infected C57BL/6 wild-type mice. We hypothesized that mice lacking IL-17 would fail to develop Borrelia -induced arthritis. IL-17-deficient and wild-type C57BL/6 mice were primed with heat-inactivated Borrelia and then infected with viable spirochetes 3 weeks later. No swelling or major histopathological changes of the hind paws were detected in IL-17-deficient or wild-type mice that were primed with Borrelia or infected with viable spirochetes. By contrast, IL-17-deficient and wild-type mice that were primed and subsequently infected with heterologous Borrelia developed severe swelling and histopathological changes of the hind paws. In addition, Borrelia -primed and -infected IL-17-deficient mice exhibited elevated gamma-interferon (IFN-) levels in sera and increased frequencies of IFN--expressing lymphocytes in popliteal lymph nodes compared to Borrelia -primed and -infected wild-type mice. These results demonstrate that IL-17 is not required for development of severe pathology in response to infection with Borrelia burgdorferi , but may contribute to disease through an interaction with IFN-.

Description: We report on the discovery of an eclipsing dwarf nova (DN) inside the peculiar, bilobed nebula Te 11. Modelling of high-speed photometry of the eclipse finds the accreting white dwarf to have a mass 1.18 M and temperature 13 kK. The donor spectral type of M2.5 results in a distance of 330 pc, colocated with Barnard's loop at the edge of the Orion-Eridanus superbubble. The perplexing morphology and observed bow shock of the slowly expanding nebula may be explained by strong interactions with the dense interstellar medium in this region. We match the DN to the historic nova of 483 CE in Orion and postulate that the nebula is the remnant of this eruption. This connection supports the millennia time-scale of the post-nova transition from high to low mass-transfer rates. Te 11 constitutes an important benchmark system for CV and nova studies as the only eclipsing binary out of just three DNe with nova shells.

Description: Time series photometry of 20 cataclysmic variables (CVs) detected by the Catalina Real-Time Transient Survey is presented. 14 of these systems have not been observed previously and only two have been examined in-depth. From the observations we determined 12 new orbital periods and independently found a further two. Eight of the CVs are eclipsing systems, five of which have eclipse depths of more than 0.9 mag. Included in the sample are six SU UMa systems (three of which show superhumps in our photometry), a polar (SSS 1944–42) and one system (CSS 1417–18) that displays an abnormally fast decline from outburst.

Description: Full-waveform inversion (FWI) is an advanced seismic imaging technique that has recently become computationally feasible in three dimensions, and that is being widely adopted and applied by the oil and gas industry. Here we explore the potential for 3-D FWI, when combined with appropriate marine seismic acquisition, to recover high-resolution high-fidelity P -wave velocity models for subsedimentary targets within the crystalline crust and uppermost mantle. We demonstrate that FWI is able to recover detailed 3-D structural information within a radially faulted dome using a field data set acquired with a standard 3-D petroleum-industry marine acquisition system. Acquiring low-frequency seismic data is important for successful FWI; we show that current acquisition techniques can routinely acquire field data from airguns at frequencies as low as 2 Hz, and that 1 Hz acquisition is likely to be achievable using ocean-bottom hydrophones in deep water. Using existing geological and geophysical models, we construct P -wave velocity models over three potential subsedimentary targets: the Soufrière Hills Volcano on Montserrat and its associated crustal magmatic system, the crust and uppermost mantle across the continent–ocean transition beneath the Campos Basin offshore Brazil, and the oceanic crust and uppermost mantle beneath the East Pacific Rise mid-ocean ridge. We use these models to generate realistic multi-azimuth 3-D synthetic seismic data, and attempt to invert these data to recover the original models. We explore resolution and accuracy, sensitivity to noise and acquisition geometry, ability to invert elastic data using acoustic inversion codes, and the trade-off between low frequencies and starting velocity model accuracy. We show that FWI applied to multi-azimuth, refracted, wide-angle, low-frequency data can resolve features in the deep crust and uppermost mantle on scales that are significantly better than can be achieved by any other geophysical technique, and that these results can be obtained using relatively small numbers (60–90) of ocean-bottom receivers combined with large numbers of airgun shots. We demonstrate that multi-azimuth 3-D FWI is robust in the presence of noise, that acoustic FWI can invert elastic data successfully, and that the typical errors to be expected in starting models derived using traveltimes will not be problematic for FWI given appropriately designed acquisition. FWI is a rapidly maturing technology; its transfer from the petroleum sector to tackle a much broader range of targets now appears to be entirely achievable.

Description: A relatively small number of signaling pathways govern the early patterning processes of metazoan development. The architectural changes over time to these signaling pathways offer unique insights into their evolution. In the case of Hedgehog (Hh) signaling, two very divergent mechanisms of pathway transduction have evolved. In vertebrates, signaling relies on trafficking of Hh pathway components to nonmotile specialized primary cilia. In contrast, protostomes do not use cilia of any kind for Hh signal transduction. How these divergent lineages adapted such dramatically different ways of activating the signaling pathway is an unanswered question. Here, we present evidence that in the sea urchin, a basal deuterostome, motile cilia are required for embryonic Hh signal transduction, and the Hh receptor Smoothened (Smo) localizes to cilia during active Hh signaling. This is the first evidence that Hh signaling requires motile cilia and the first case of an organism requiring cilia outside of the vertebrate lineage.

Description: Congenital sodium diarrhea (CSD) refers to an intractable diarrhea of intrauterine onset with high fecal sodium loss. CSD is clinically and genetically heterogeneous. Syndromic CSD is caused by SPINT2 mutations. While we recently described four cases of the non-syndromic form of CSD that were caused by dominant activating mutations in intestinal receptor guanylate cyclase C (GC-C), the genetic cause for the majority of CSD is still unknown. Therefore, we aimed to determine the genetic cause for non-GC-C non-syndromic CSD in 18 patients from 16 unrelated families applying whole-exome sequencing and/or chromosomal microarray analyses and/or direct Sanger sequencing. SLC9A3 missense, splicing and truncation mutations, including an instance of uniparental disomy, and whole-gene deletion were identified in nine patients from eight families with CSD. Two of these nine patients developed inflammatory bowel disease (IBD) at 4 and 16 years of age. SLC9A3 encodes Na + /H + antiporter 3 (NHE3), which is the major intestinal brush-border Na + /H + exchanger. All mutations were in the NHE3 N-terminal transport domain, and all missense mutations were in the putative membrane-spanning domains. Identified SLC9A3 missense mutations were functionally characterized in plasma membrane NHE null fibroblasts. SLC9A3 missense mutations compromised NHE3 activity by reducing basal surface expression and/or loss of basal transport function of NHE3 molecules, whereas acute regulation was normal. This study identifies recessive mutations in NHE3, a downstream target of GC-C, as a cause of CSD and implies primary basal NHE3 malfunction as a predisposition for IBD in a subset of patients.

Description: 3-D full-waveform inversion (FWI) is an advanced seismic imaging technique that has been widely adopted by the oil and gas industry to obtain high-fidelity models of P -wave velocity that lead to improvements in migrated images of the reservoir. Most industrial applications of 3-D FWI model the acoustic wavefield, often account for the kinematic effect of anisotropy, and focus on matching the low-frequency component of the early arriving refractions that are most sensitive to P -wave velocity structure. Here, we have adopted the same approach in an application of 3-D acoustic, anisotropic FWI to an ocean-bottom-seismometer (OBS) field data set acquired across the Endeavour oceanic spreading centre in the northeastern Pacific. Starting models for P -wave velocity and anisotropy were obtained from traveltime tomography; during FWI, velocity is updated whereas anisotropy is kept fixed. We demonstrate that, for the Endeavour field data set, 3-D FWI is able to recover fine-scale velocity structure with a resolution that is 2–4 times better than conventional traveltime tomography. Quality assurance procedures have been employed to monitor each step of the workflow; these are time consuming but critical to the development of a successful inversion strategy. Finally, a suite of checkerboard tests has been performed which shows that the full potential resolution of FWI can be obtained if we acquire a 3-D survey with a slightly denser shot and receiver spacing than is usual for an academic experiment. We anticipate that this exciting development will encourage future seismic investigations of earth science targets that would benefit from the superior resolution offered by 3-D FWI.

Description: MicroRNAs (miRNAs) are short non-coding RNAs that silence mRNAs. They are generated following transcription and cleavage by the DROSHA/DGCR8 and DICER/TRBP/PACT complexes. Although it is known that components of the miRNA biogenesis machinery can be phosphorylated, it remains poorly understood how these events become engaged during physiological cellular activation. We demonstrate that S6 kinases can phosphorylate the extended C-terminal domain of TRBP and interact with TRBP in situ in primary cells. TRBP serines 283/286 are essential for S6K-mediated TRBP phosphorylation, optimal expression of TRBP, and the S6K-TRBP interaction in human primary cells. We demonstrate the functional relevance of this interaction in primary human dermal lymphatic endothelial cells (HDLECs). Angiopoietin-1 (ANG1) can augment miRNA biogenesis in HDLECs through enhancing TRBP phosphorylation and expression in an S6K2-dependent manner. We propose that the S6K2/TRBP node controls miRNA biogenesis in HDLECs and provides a molecular link between the mTOR pathway and the miRNA biogenesis machinery.