Evolution of the Greater Caucasus Basement and Formation of the Main Caucasus Thrust, Georgia

Along the northern margin of the Arabia‐Eurasia collision zone in the western Greater Caucasus, the Main Caucasus Thrust (MCT) juxtaposes Paleozoic crystalline basement to the north against Mesozoic metasedimentary and volcaniclastic rocks to the south. The MCT is commonly assumed to be the trace of an active plate‐boundary scale structure that accommodates Arabia‐Eurasia convergence, but field data supporting this interpretation are equivocal. Here we investigate the deformation history of the rocks juxtaposed across the MCT in Georgia using field observations, microstructural analysis, U‐Pb and 40Ar/39Ar geochronology, and 40Ar/39Ar and (U‐Th)/He thermochronology. Zircon U‐Pb analyses show that Greater Caucasus crystalline rocks formed in the Early Paleozoic on the margin of Gondwana. Low‐pressure/temperature amphibolite‐facies metamorphism of these metasedimentary rocks and associated plutonism likely took place during Carboniferous accretion onto the Laurussian margin, as indicated by igneous and metamorphic zircon U‐Pb ages of ~330–310 Ma. 40Ar/39Ar ages of ~190–135 Ma from muscovite in a greenschist‐facies shear zone indicate that the MCT likely developed during Mesozoic inversion and/or rifting of the Caucasus Basin. A Mesozoic 40Ar/39Ar biotite age with release spectra indicating partial resetting and Cenozoic (<40 Ma) apatite and zircon (U‐Th)/He ages imply at least ~5–8 km of Greater Caucasus basement exhumation since ~10 Ma in response to Arabia‐Eurasia collision. Cenozoic reactivation of the MCT may have accommodated a fraction of this exhumation. However, Cenozoic zircon (U‐Th)/He ages in both the hanging wall and footwall of the MCT require partitioning a substantial component of this deformation onto structures to the south.Plain Language SummaryCollisions between continents cause deformation of the Earth’s crust and the uplift of large mountain ranges like the Himalayas. Large faults often form to accommodate this deformation and may help bring rocks once buried at great depths up to the surface of the Earth. The Greater Caucasus Mountains form the northernmost part of a zone of deformation due to the ongoing collision between the Arabian and Eurasian continents. The Main Caucasus Thrust (MCT) is a fault juxtaposing old igneous and metamorphic (crystalline) rocks against younger rocks that has often been assumed to be a major means of accommodating Arabia‐Eurasia collision. This study examines the history of rocks along the MCT with a combination of field work, study of microscopic deformation in rocks, and dating of rock formation and cooling. The crystalline rocks were added to the margins of present‐day Eurasia about 330–310 million years ago, and the MCT first formed about 190–135 million years ago. The MCT is likely at most one of many structures accommodating present‐day Arabia‐Eurasia collision.Key PointsAmphibolite‐facies metamorphism and plutonism in the Greater Caucasus basement took place ~330–310 MaThe Main Caucasus Thrust formed as a greenschist‐facies shear zone during Caucasus Basin inversion and/or rifting (~190–135 Ma)The Main Caucasus Thrust may have helped facilitate a portion of at least 5–8 km of basement exhumation during Arabia‐Eurasia collisionPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154626/1/tect21292-sup-0002-2019TC005828-ts01.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154626/2/tect21292-sup-0006-2019TC005828-ts05.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154626/3/tect21292_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154626/4/tect21292-sup-0003-2019TC005828-ts02.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154626/5/tect21292-sup-0005-2019TC005828-ts04.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154626/6/tect21292.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154626/7/tect21292-sup-0004-2019TC005828-ts03.pd

Magnetic dating of the Holocene monogenetic Tkarsheti volcano in the Kazbeki region (Great Caucasus)

The radiocarbon technique is widely used to date Late Pleistocene and Holocene lava flows. The significant difference with palaeomagnetic methods is that the 14C dating is performed on the organic matter carbonized by the rock formation or the paleosols found within or below the lava flow. On the contrary, the archaeomagnetic dating allows to date the moment when the lava is cooling down below the Curie temperatures. In the present study, we use the paleomagnetic dating to constrain the age of the Tkarsheti monogenetic volcano located within the Kazbeki Volcanic Province (Great Caucasus). A series of rock-magnetic experiments including the measurement of hysteresis curves, isothermal remanence, back-field and continuous thermomagnetic curves were applied. These experiments indicated that Pseudo-Single-Domain Ti-poor titanomagnetite is responsible for remanence. A characteristic remanent magnetization was obtained for all twenty analyzed samples yielding a stable single magnetization component observed upon both thermal and alternating field treatments. Comparison of the mean directions obtained (Inc = 48.6º, Dec = 6.4º, A95 = 4.0° and K = 67) with the SCHA.DIF.14k model yielded two main time intervals (4740–4650 or 4427– 4188 BC) as the best age estimate of the Lesser Tkarsheti lava flow. These results suggest an earlier age (between approximately 200 and 700 years) for this monogenetic lava flow than expected from the estimated age provided by a former 14C dating obtained in 1973 on woody remains. This first attempt to use the archaeomagnetic technique in the Caucasus indicates that the SCHA.DIF.14k geomagnetic model may be successfully used for dating purposes in the region.Projects BU0066U16 and BU235P18 (Junta de Castilla y Leon, Spain) and the European Regional Development Fund (ERDF). AG is grateful for financial support of CONACyT 252149 and UNAM-PAPIIT project 101717. MC-R and AC acknowledge the financial support given by the Junta de Castilla y León (project BU235P18) and the European Regional Development Fund (ERD)

miR-23b/SP1/c-myc forms a feed-forward loop supporting multiple myeloma cell growth

Deregulated microRNA (miR)/transcription factor (TF)-based networks represent a hallmark of cancer. We report here a novel c-Myc/miR-23b/Sp1 feed-forward loop with a critical role in multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM) cell growth and survival. We have found miR-23b to be downregulated in MM and WM cells especially in the presence of components of the tumor bone marrow milieu. Promoter methylation is one mechanism of miR-23b suppression in myeloma. In gain-of-function studies using miR-23b mimics-transfected or in miR-23b-stably expressing MM and WM cell lines, we observed a significant decrease in cell proliferation and survival, along with induction of caspase-3/7 activity over time, thus supporting a tumor suppressor role for miR-23b. At the molecular level, miR-23b targeted Sp1 3'UTR and significantly reduced Sp1-driven nuclear factor-kappa B activity. Finally, c-Myc, an important oncogenic transcription factor known to stimulate MM cell proliferation, transcriptionally repressed miR-23b. Thus MYC-dependent miR-23b repression in myeloma cells may promote activation of oncogenic Sp1-mediated signaling, representing the first feed-forward loop with critical growth and survival role in myeloma

Constitutive Overexpression of Muscarinic Receptors Leads to Vagal Hyperreactivity

BACKGROUND: Alterations in muscarinic receptor expression and acetylcholinesterase (AchE) activity have been observed in tissues from Sudden Infant Death Syndrome (SIDS). Vagal overactivity has been proposed as a possible cause of SIDS as well as of vasovagal syncopes. The aim of the present study was to seek whether muscarinic receptor overexpression may be the underlying mechanism of vagal hyperreactivity. Rabbits with marked vagal pauses following injection of phenylephrine were selected and crossed to obtain a vagal hyperreactive strain. The density of cardiac muscarinic receptors and acetylcholinesterase (AchE) gene expression were assessed. Blood markers of the observed cardiac abnormalities were also sought. METHODOLOGY/PRINCIPAL FINDINGS: Cardiac muscarinic M(2) and M(3) receptors were overexpressed in hyperreactive rabbits compared to control animals (2.3-fold and 2.5-fold, respectively) and the severity of the phenylephrine-induced bradycardia was correlated with their densities. A similar overexpression of M(2) receptors was observed in peripheral mononuclear white blood cells, suggesting that cardiac M(2) receptor expression can be inferred with high confidence from measurements in blood cells. Sequencing of the coding fragment of the M(2) receptor gene revealed a single nucleotide mutation in 83% of hyperreactive animals, possibly contributing for the transcript overexpression. Significant increases in AchE expression and activity were also assessed (AchE mRNA amplification ratio of 3.6 versus normal rabbits). This phenomenon might represent a compensatory consequence of muscarinic receptors overexpression. Alterations in M(2) receptor and AchE expression occurred between the 5th and the 7th week of age, a critical period also characterized by a higher mortality rate of hyperreactive rabbits (52% in H rabbits versus 13% in normal rabbits) and preceeded the appearance of functional disorders. CONCLUSIONS/SIGNIFICANCE: The results suggest that cardiac muscarinic receptor overexpression plays a critical role in the development of vagal hyperreactivity, whereas AchE hyperactivity appears as a compensatory consequence of it. Since similar vagal disorders were observed recently by us in SIDS, muscarinic receptor overexpression could become a marker of risk of vasovagal syncopes and SIDS

Differentiation of breast cancer stem cells by knockdown of CD44: promising differentiation therapy

<p>Abstract</p> <p>Background</p> <p>Breast cancer stem cells (BCSCs) are the source of breast tumors. Compared with other cancer cells, cancer stem cells show high resistance to both chemotherapy and radiotherapy. Targeting of BCSCs is thus a potentially promising and effective strategy for breast cancer treatment. Differentiation therapy represents one type of cancer stem-cell-targeting therapy, aimed at attacking the stemness of cancer stem cells, thus reducing their chemo- and radioresistance. In a previous study, we showed that down-regulation of CD44 sensitized BCSCs to the anti-tumor agent doxorubicin. This study aimed to determine if CD44 knockdown caused BCSCs to differentiate into breast cancer non-stem cells (non-BCSCs).</p> <p>Methods</p> <p>We isolated a breast cancer cell population (CD44⁺CD24^-cells) from primary cultures of malignant breast tumors. These cells were sorted into four sub-populations based on their expression of CD44 and CD24 surface markers. CD44 knockdown in the BCSC population was achieved using small hairpin RNA lentivirus particles. The differentiated status of CD44 knock-down BCSCs was evaluated on the basis of changes in CD44⁺CD24^-phenotype, tumorigenesis in NOD/SCID mice, and gene expression in relation to renewal status, metastasis, and cell cycle in comparison with BCSCs and non-BCSCs.</p> <p>Results</p> <p>Knockdown of CD44 caused BCSCs to differentiate into non-BCSCs with lower tumorigenic potential, and altered the cell cycle and expression profiles of some stem cell-related genes, making them more similar to those seen in non-BCSCs.</p> <p>Conclusions</p> <p>Knockdown of CD44 is an effective strategy for attacking the stemness of BCSCs, resulting in a loss of stemness and an increase in susceptibility to chemotherapy or radiation. The results of this study highlight a potential new strategy for breast cancer treatment through the targeting of BCSCs.</p