Tristetraprolin Regulates Interleukin-6 Expression Through p38 MAPK-Dependent Affinity Changes with mRNA 3' Untranslated Region

Tristetraprolin (TTP) is a well-characterized, zinc finger-containing, RNA-binding protein. TTP targets tumor necrosis factor alpha for degradation via the 3- untranslated region (3-UTR). Although AU-rich elements (AREs) in the 3-UTR of interleukin-6 (IL-6) mRNA dictate mRNA degradation, the role of TTP in the post-transcriptional regulation of IL-6 gene expression is unclear. Here we used TTP-deficient mice to test the hypothesis that IL-6 expression is influenced by TTP. Genetic and siRNA-mediated knockdown of TTP resulted in increased IL-6 production and overexpression of TTP had the reverse effect. IL-6 and tumor necrosis factor alpha production were elevated after injection of IL-1- in TTP-deficient mice. Further, embryonic fibroblasts from these mice (mouse embryonic fibroblasts) exhibited greater IL-6 mRNA expression and longer half-life than wild-type mouse embryonic fibroblasts. Overexpression of TTP reduced IL-6 3-UTR luciferase reporter activity in an ARE-dependent manner. Proximal and distal regions of the 3-UTR acted synergistically to produce the full repression of TTP. Mutation-based luciferase assays show that ARE2, ARE3, and ARE4 are required for TTP-mediated repression. The constitutively activated p38-MK2 pathway abrogated TTP-mediated repression of IL-6 3-UTR reporter activity. RNA immunoprecipitation assay indicated that the deficiency of p38alpha resulted in the increased affinity of TTP to IL-6 mRNA. Taken together, we propose that TTP downregulates IL-6 gene expression at the post-transcriptional level by targeting ARE elements in the 3-UTR region.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/90500/1/jir-2E2010-2E0154.pd

Flow instabilities of magnetic flux tubes II. Longitudinal flow

Flow-induced instabilities are relevant for the storage and dynamics of magnetic fields in stellar convection zones and possibly also in other astrophysical contexts. We continue the study started in the first paper of this series by considering the stability properties of longitudinal flows along magnetic flux tubes. A linear stability analysis was carried out to determine criteria for the onset of instability in the framework of the approximation of thin magnetic flux tubes. In the non-dissipative case, we find Kelvin-Helmholtz instability for flow velocities exceeding a critical speed that depends on the Alfv{\'e}n speed and on the ratio of the internal and external densities. Inclusion of a friction term proportional to the relative transverse velocity leads to a friction-driven instability connected with backward (or negative energy) waves. We discuss the physical nature of this instability. In the case of a stratified external medium, the Kelvin-Helmholtz instability and the friction-driven instability can set in for flow speeds significantly lower than the Alfv{\'e}n speed. Dissipative effects can excite flow-driven instability below the thresholds for the Kelvin-Helmholtz and the undulatory (Parker-type) instabilities. This may be important for magnetic flux storage in stellar convection zones and for the stability of astrophysical jets.Comment: accepted by Astronomy & Astrophysic

Recreational marathon running does not cause exercise-induced left ventricular hypertrabeculation.

BACKGROUND: Marathon running in novices represents a natural experiment of short-term cardiovascular remodeling in response to running training. We examine whether this stimulus can produce exercise-induced left ventricular (LV) trabeculation. METHODS: Sixty-eight novice marathon runners aged 29.5 ± 3.2 years had indices of LV trabeculation measured by echocardiography and cardiac magnetic resonance imaging 6 months before and 2 weeks after the 2016 London Marathon race, in a prospective longitudinal study. RESULTS: After 17 weeks unsupervised marathon training, indices of LV trabeculation were essentially unchanged. Despite satisfactory inter-observer agreement in most methods of trabeculation measurement, criteria defining abnormally hypertrabeculated cases were discordant with each other. LV hypertrabeculation was a frequent finding in young, healthy individuals with no subject demonstrating clear evidence of a cardiomyopathy. CONCLUSION: Training for a first marathon does not induce LV trabeculation. It remains unclear whether prolonged, high-dose exercise can create de novo trabeculation or expose concealed trabeculation. Applying cut off values from published LV noncompaction cardiomyopathy criteria to young, healthy individuals risks over-diagnosis

Protein translocation channel of mitochondrial inner membrane and matrix-exposed import motor communicate via two-domain coupling protein

The majority of mitochondrial proteins are targeted to mitochondria by N-terminal presequences and use the TIM23 complex for their translocation across the mitochondrial inner membrane. During import, translocation through the channel in the inner membrane is coupled to the ATP-dependent action of an Hsp70-based import motor at the matrix face. How these two processes are coordinated remained unclear. We show here that the two domain structure of Tim44 plays a central role in this process. The N-terminal domain of Tim44 interacts with the components of the import motor, whereas its C-terminal domain interacts with the translocation channel and is in contact with translocating proteins. Our data suggest that the translocation channel and the import motor of the TIM23 complex communicate through rearrangements of the two domains of Tim44 that are stimulated by translocating proteins

GAMA/DEVILS: Cosmic star formation and AGN activity over 12.5 billion years

We use the Galaxy and Mass Assembly (GAMA) and the Deep Extragalactic Visible Legacy Survey (DEVILS) observational data sets to calculate the cosmic star formation rate (SFR) and active galactic nuclei (AGN) bolometric luminosity history (CSFH/CAGNH) over the last 12.5 billion years. SFRs and AGN bolometric luminosities were derived using the spectral energy distribution fitting code ProSpect, which includes an AGN prescription to self consistently model the contribution from both AGN and stellar emission to the observed rest-frame ultra-violet to far-infrared photometry. We find that both the CSFH and CAGNH evolve similarly, rising in the early Universe up to a peak at look-back time $\approx 10$~Gyr ($z \approx 2$), before declining toward the present day. The key result of this work is that we find the ratio of CAGNH to CSFH has been flat ($\approx 10^{42.5}\mathrm{erg \, s^{-1}M_{\odot}^{-1}yr}$) for $11$~Gyr up to the present day, indicating that star formation and AGN activity have been coeval over this time period. We find that the stellar masses of the galaxies that contribute most to the CSFH and CAGNH are similar, implying a common cause, which is likely gas inflow. The depletion of the gas supply suppresses cosmic star formation and AGN activity equivalently to ensure that they have experienced similar declines over the last 10 Gyr. These results are an important milestone for reconciling the role of star formation and AGN activity in the life cycle of galaxies.Comment: 16 pages, 10 figures. Figures 9 and 10 are the main results. Accepted for publication in Monthly Notices of the Royal Astronomical Societ

Biomarkers in advanced larynx cancer

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/102058/1/lary24245.pd

Metastatic breast carcinoma in the mandible presenting as a periodontal abscess: a case report

<p>Abstract</p> <p>Introduction</p> <p>Tumors can metastasize to the oral cavity and affect the jaws, soft tissue and salivary glands. Oral cavity metastases are considered rare and represent approximately 1% of all oral malignancies. Because of their rarity and atypical clinical and radiographic appearance, metastatic lesions are considered a diagnostic challenge. The purpose of this report is to present a rare case of a metastatic breast carcinoma mimicking a periodontal abscess in the mandible.</p> <p>Case presentation</p> <p>A 55-year-old Caucasian woman was referred to our clinic for evaluation of bisphosphonate-induced jaw osteonecrosis. She had undergone modified radical mastectomy with axillary lymph node dissection for invasive ductal carcinoma of the left breast. Her clinical examination showed diffuse swelling and a periodontal pocket of 6 mm exhibiting suppuration in the posterior right mandible. Moreover, paresthesia of the lower right lip and chin was noted. There were no significant radiographic findings other than alveolar bone loss due to her periodontal disease. Although the lesion resembled a periodontal abscess, metastatic carcinoma of the breast was suspected on the basis of the patient's medical history. The area was biopsied, and histological analysis confirmed the final diagnosis of metastatic breast carcinoma.</p> <p>Conclusion</p> <p>The general dentist or dental specialist should maintain a high level of suspicion while evaluating patients with a history of cancer. Paresthesias of the lower lip and the chin should be considered ominous signs of metastatic disease. This case highlights the importance of the value of a detailed medical history and thorough clinical examination for the early detection of metastatic tumors in the oral cavity.</p

Novel germline variants identified in the inner mitochondrial membrane transporter TIMM44 and their role in predisposition to oncocytic thyroid carcinomas

Familial Non-Medullary Thyroid Carcinoma (fNMTC) represents 3–7% of all thyroid tumours and is associated with some of the highest familial risks among all cancers, with an inheritance pattern compatible with an autosomal dominant model with reduced penetrance. We previously mapped a predisposing locus, TCO (Thyroid tumour with Cell Oxyphilia) on chromosome 19p13.2, for a particular form of thyroid tumour characterised by cells with an abnormal proliferation of mitochondria (oxyphilic or oncocytic cells). In the present work, we report the systematic screening of 14 candidate genes mapping to the region of linkage in affected TCO members, that led us to identify two novel variants respectively in exon 9 and exon 13 of TIMM44, a mitochondrial inner membrane translocase for the import in the mitochondria of nuclear-encoded proteins. These variants were co-segregating with the TCO phenotype, were not present in a large group of controls and were predicted to negatively affect the protein (exon 9 change) or the transcript (exon 13 change). Functional analysis was performed in vitro for both changes and although no dramatic loss of function effects were identified for the mutant alleles, subtler effects might still be present that could alter Timm44 function and thus promote oncocytic tumour development. Thus we suggest that TIMM44 should be considered for further studies in independent samples of affected individuals with TCO

Role of Magmas in protein transport and human mitochondria biogenesis

Magmas, a conserved mammalian protein essential for eukaryotic development, is overexpressed in prostate carcinomas and cells exposed to granulocyte-macrophage colony-stimulating factor (GM-CSF). Reduced Magmas expression resulted in decreased proliferative rates in cultured cells. However, the cellular function of Magmas is still elusive. In this report, we have showed that human Magmas is an ortholog of Saccharomyces cerevisiae Pam16 having similar functions and is critical for protein translocation across mitochondrial inner membrane. Human Magmas shows a complete growth complementation of Δpam16 yeast cells at all temperatures. On the basis of our analysis, we report that Magmas localizes into mitochondria and is peripherally associated with inner mitochondrial membrane in yeast and humans. Magmas forms a stable subcomplex with J-protein Pam18 or DnaJC19 through its C-terminal region and is tethered to TIM23 complex of yeast and humans. Importantly, amino acid alterations in Magmas leads to reduced stability of the subcomplex with Pam18 that results in temperature sensitivity and in vivo protein translocation defects in yeast cells. These observations highlight the central role of Magmas in protein import and mitochondria biogenesis. In humans, absence of a functional DnaJC19 leads to dilated cardiac myophathic syndrome (DCM), a genetic disorder with characteristic features of cardiac myophathy and neurodegeneration. We propose that the mutations resulting in decreased stability of functional Magmas:DnaJC19 subcomplex at human TIM23 channel leads to impaired protein import and cellular respiration in DCM patients. Together, we propose a model showing how Magmas:DnaJC19 subcomplex is associated with TIM23 complex and thus regulates mitochondrial import process