Mouse tafazzin is required for male germ cell meiosis and spermatogenesis

Barth syndrome is an X-linked mitochondrial disease, symptoms of which include neutropenia and cardiac myopathy. These symptoms are the most significant clinical consequences of a disease, which is increasingly recognised to have a variable presentation. Mutation in the Taz gene in Xq28 is thought to be responsible for the condition, by altering mitochondrial lipid content and mitochondrial function. Male chimeras carrying a targeted mutation of Taz on their X-chromosome were infertile. Testes from the Taz knockout chimeras were smaller than their control counterparts and this was associated with a disruption of the progression of spermatocytes through meiosis to spermiogenesis. Taz knockout ES cells also showed a defect when differentiated to germ cells in vitro. Mutant spermatocytes failed to progress past the pachytene stage of meiosis and had higher levels of DNA double strand damage and increased levels of endogenous retrotransposon activity. Altogether these data revealed a novel role for Taz in helping to maintain genome integrity in meiosis and facilitating germ cell differentiation. We have unravelled a novel function for the Taz protein, which should contribute to an understanding of how a disruption of the Taz gene results in the complex symptoms underlying Barth Syndrome

MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway.

The Hippo pathway plays a central role in tissue homoeostasis, and its dysregulation contributes to tumorigenesis. Core components of the Hippo pathway include a kinase cascade of MST1/2 and LATS1/2 and the transcription co-activators YAP/TAZ. In response to stimulation, LATS1/2 phosphorylate and inhibit YAP/TAZ, the main effectors of the Hippo pathway. Accumulating evidence suggests that MST1/2 are not required for the regulation of YAP/TAZ. Here we show that deletion of LATS1/2 but not MST1/2 abolishes YAP/TAZ phosphorylation. We have identified MAP4K family members--Drosophila Happyhour homologues MAP4K1/2/3 and Misshapen homologues MAP4K4/6/7-as direct LATS1/2-activating kinases. Combined deletion of MAP4Ks and MST1/2, but neither alone, suppresses phosphorylation of LATS1/2 and YAP/TAZ in response to a wide range of signals. Our results demonstrate that MAP4Ks act in parallel to and are partially redundant with MST1/2 in the regulation of LATS1/2 and YAP/TAZ, and establish MAP4Ks as components of the expanded Hippo pathway

Defining functional classes of Barth syndrome mutation in humans

The X-linked disease Barth syndrome (BTHS) is caused by mutations in TAZ; TAZ is the main determinant of the final acyl chain composition of the mitochondrial-specific phospholipid, cardiolipin. To date, a detailed characterization of endogenous TAZ has only been performed in yeast. Further, why a given BTHS-associated missense mutation impairs TAZ function has only been determined in a yeast model of this human disease. Presently, the detailed characterization of yeast tafazzin harboring individual BTHS mutations at evolutionarily conserved residues has identified seven distinct loss-of-function mechanisms caused by patient-associated missense alleles. However, whether the biochemical consequences associated with individual mutations also occur in the context of human TAZ in a validated mammalian model has not been demonstrated. Here, utilizing newly established monoclonal antibodies capable of detecting endogenous TAZ, we demonstrate that mammalian TAZ, like its yeast counterpart, is localized to the mitochondrion where it adopts an extremely protease-resistant fold, associates non-integrally with intermembrane space-facing membranes and assembles in a range of complexes. Even though multiple isoforms are expressed at the mRNA level, only a single polypeptide that co-migrates with the human isoform lacking exon 5 is expressed in human skin fibroblasts, HEK293 cells, and murine heart and liver mitochondria. Finally, using a new genome-edited mammalian BTHS cell culture model, we demonstrate that the loss-of-function mechanisms for two BTHS alleles that represent two of the seven functional classes of BTHS mutation as originally defined in yeast, are the same when modeled in human TAZ

Delineating Intra-Urban Spatial Connectivity Patterns by Travel-Activities: A Case Study of Beijing, China

Travel activities have been widely applied to quantify spatial interactions between places, regions and nations. In this paper, we model the spatial connectivities between 652 Traffic Analysis Zones (TAZs) in Beijing by a taxi OD dataset. First, we unveil the gravitational structure of intra-urban spatial connectivities of Beijing. On overall, the inter-TAZ interactions are well governed by the Gravity Model $G_{ij} = {\lambda}p_{i}p_{j}/d_{ij}$, where $p_{i}$, $p_{j}$ are degrees of TAZ $i$, $j$ and $d_{ij}$ the distance between them, with a goodness-of-fit around 0.8. Second, the network based analysis well reveals the polycentric form of Beijing. Last, we detect the semantics of inter-TAZ connectivities based on their spatiotemporal patterns. We further find that inter-TAZ connections deviating from the Gravity Model can be well explained by link semantics.Comment: 6 pages, 4 figure

Novel Amorphous Iron-Dysprosium-Terbium-Oxide Thin Films: Synthesis, Properties, and Application

Amorphous oxides which are transparent and conducting find use in display devices and as top electrodes in energy applications, while those which are conducting and magnetic have the potential to be used in spintronics. With the fast approaching limit of Moore’s law, new materials are needed where the spin and polarization of the electrons are coupled. Despite progress in transparent conductors, materials selection is limited by the need to have wide optical bandgap and conduction via s-orbital. In contrast, search for new spintronics materials has picked up only in the last decade. Here we report the synthesis, characterization, and application of a new oxide made from Fe, Tb, and Dy - elements that do not conduct via the s-orbital. Thin films (\u3c100 nm) of this oxide were synthesized by pulsed laser deposition (PLD) as a function of varying oxygen pressure, and by electron-beam evaporation as a function of the cation composition, and then annealed under different conditions. Films deposited at 5x10-8 Torr exhibited high optical transparency (\u3e90%) and conductivity (~104 S/m). Films deposited at O2 pressures below 1x10-5 Torr were conductive (~104 S/m), magnetic (up to 480 emu/cc), and optically transparent, while the ones above 1x10-5 Torr were optically transparent but insulating and non-magnetic. Changes in the cation stoichiometry showed the films’ transition from being metallic to semiconducting with decreasing Fe content relative to the Lanthanides. However, when a very iron-rich film was annealed through several heating and cooling cycles in low vacuum, the film evolved into a semiconductor that was stable in ambient conditions and showed very high conductivity (2.8x105 S/m) and room temperature magnetism (380 emu/cc). The PLD deposited films were utilized as the ferromagnetic layer for magneto-electric coupling with bismuth ferrite as well as a top electrode for bismuth ferrite capacitors. A giant magneto-resistance (GMR) device made from the Fe-Tb-Dy-oxide and bismuth ferrite showed evidence of magneto-electric coupling at room temperature. The discovery of this oxide not only introduces new materials physics that could be explored and exploited to engineer new multifunctional materials, but the oxide itself proves to be very promising for spintronics device applications

Thermal fatigue and oxidation data on TAZ-8A, MAR-M 200, and Udimet 700 superalloys

The fluidized bed technique was used to determine the relative thermal fatigue and oxidation resistance of three superalloys: TAZ-8A, Mar-M 200, and Udimet 700. The alloys TAZ-8A and MAR-M 200 were also tested in the directionally-solidified form. For the 13 combinations of composition, solidification method, surface protection, and specimen geometry, the cycles to cracking varied from 1250 to 15,000. The alloy/coating having the best resistance to thermal fatigue cracking was coated directionally-solidified NASA TAZ-8A. This combination also had excellent oxidation resistance

Role of YAP and TAZ in pancreatic ductal adenocarcinoma and in stellate cells associated with cancer and chronic pancreatitis.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a fibrotic and inflammatory microenvironment that is formed primarily by activated, myofibroblast-like, stellate cells. Although the stellate cells are thought to contribute to tumorigenesis, metastasis and drug resistance of PDAC, the signaling events involved in activation of the stellate cells are not well defined. Functioning as transcription co-factors, Yes-associated protein (YAP) and its homolog transcriptional co-activator with PDZ-binding motif (TAZ) modulate the expression of genes involved in various aspects of cellular functions, such as proliferation and mobility. Using human tissues we show that YAP and TAZ expression is restricted to the centroacinar and ductal cells of normal pancreas, but is elevated in cancer cells. In particular, YAP and TAZ are expressed at high levels in the activated stellate cells of both chronic pancreatitis and PDAC patients as well as in the islets of Langerhans in chronic pancreatitis tissues. Of note, YAP is up regulated in both acinar and ductal cells following induction of acute and chronic pancreatitis in mice. These findings indicate that YAP and TAZ may play a critical role in modulating pancreatic tissue regeneration, neoplastic transformation, and stellate cell functions in both PDAC and pancreatitis

Genetic variants of flavin-containing monooxygenases: consequences for drug metabolism

The metabolism of the anti-tubercular drug, thiacetazone (TAZ) by human FMOs in vitro and the disposition of TAZ in vivo in mice were studied. Reverse phase chromatography confirmed TAZ to be a substrate for human FMO1, FMO2.1 and FMO3 with the formation of TAZ-sulphinic acid and TAZ-carbodiimide via a TAZ- sulphenic acid intermediate. The products are the same as those formed by the Mycobacterium tuberculosis enzyme EtaA, the enzyme responsible for TAZ activation. Kinetic studies found FMO2.1 to be significantly more efficient at TAZ oxygenation than EtaA, FMO1 and FMO3. Asians and Europeans do not express functional FMO2 in their lungs as a result of a premature stop codon. However about 28% of African individuals lack this mutation. The products of FMO2 are expected to be toxic to mammalian cells; therefore individuals expressing FMO2 in their lungs may be at higher risk of FMO-dependent TAZ bioactivation. Protein variants of FMO3 were analysed for their ability to catalyse TAZ oxygenation. Kinetic studies showed that the L360P variant displayed a significantly higher catalytic activity towards TAZ than the wild type protein. The K158/G308 protein was inactive towards TAZ, whereas K158 or G308 variants oxygenated TAZ. These findings may reflect the underlying mechanism of TAZ-dependent liver toxicity reported in patients taking TAZ as part of treatment for TB. Mouse liver and lung microsome experiments indicated that both FMOs and cytochromes P450 (CYPs) metabolise TAZ in vitro. FMO contribution was higher in the lung than the liver. Kinetic studies using microsomes from Fmo1 knockout mice show FMO1 to be the predominant contributor to TAZ oxygenation in vitro. Metabolism of TAZ in liver and lungs of mice in vivo was not observed, however TAZ, TAZ-sulphenic acid, TAZ-sulphinic acid and TAZ-carbodiimide were identified in kidney

Driving to Opportunity: Understanding the Links among Transportation Access, Residential Outcomes, and Economic Opportunity for Housing Voucher Recipients

In the 1990s and early 2000s, the Department of Housing and Urban Development sponsored two major experiments to test whether housing choice vouchers propelled low-income households into greater economic security, the Moving to Opportunity for Fair Housing program (MTO) and the Welfare to Work Voucher program (WTW). Using data from these programs, this study examines differences in residential location and employment outcomes between voucher recipients with access to automobiles and those without. Overall, the findings underscore the positive role of automobiles in outcomes for housing voucher participants