Progesterone Signaling Inhibits Cervical Carcinogenesis in Mice

Human papillomavirus is the main cause of cervical cancer, yet other nonviral cofactors are also required for the disease. The uterine cervix is a hormone-responsive tissue, and female hormones have been implicated in cervical carcinogenesis. A transgenic mouse model expressing human papillomavirus oncogenes E6 and/or E7has proven useful to study a mechanism of hormone actions in the context of this common malignancy. Estrogen and estrogen receptor ? are required for the development of cervical cancer in this mouse model. Estrogen receptor ? is known to up-regulate expression of the progesterone receptor, which, on activation by its ligands, either promotes or inhibits carcinogenesis, depending on the tissue context. Here, we report that progesterone receptor inhibits cervical and vaginal epithelial cell proliferation in a ligand-dependent manner. We also report that synthetic progestin medroxyprogesterone acetate promotes regression of cancers and precancerous lesions in the female lower reproductive tracts (ie, cervix and vagina) in the human papillomavirus transgenic mouse model. Our results provide the first experimental evidence that supports the hypothesis that progesterone signaling is inhibitory for cervical carcinogenesis in vivo

Crystal structure of xenotropic murine leukaemia virus-related virus (XMRV) ribonuclease H

RNase H (retroviral ribonuclease H) cleaves the phosphate backbone of the RNA template within an RNA/DNA hybrid to complete the synthesis of double-stranded viral DNA. In the present study we have determined the complete structure of the RNase H domain from XMRV (xenotropic murine leukaemia virus-related virus) RT (reverse transcriptase). The basic protrusion motif of the XMRV RNase H domain is folded as a short helix and an adjacent highly bent loop. Structural superposition and subsequent mutagenesis experiments suggest that the basic protrusion motif plays a role in direct binding to the major groove in RNA/DNA hybrid, as well as in establishing the co-ordination among modules in RT necessary for proper function.Molecular and Cellular Biolog

Wall-Eyed Monocular Internuclear Ophthalmoplegia (WEMINO) with Contraversive Ocular Tilt Reaction

Wall-eyed monocular internuclear ophthalmoplegia (WEMINO) with contraversive ocular tilt reaction has not been previously reported. A 71-year-old woman suddenly developed blurred vision. Examination revealed left internuclear ophthalmoplegia, left exotropia, right hypotropia, and rightward head tilt. Magnetic resonance imaging showed a tiny infarction at the area of the left medial longitudinal fasciculus in the upper pons. WEMINO with contraversive ocular tilt reaction may be caused by a paramedian pontine tegmental infarction that selectively involves the medial longitudinal fasciculus

P-wave Quarkonium Decays to Meson Pairs

The processes of P-wave Quarkonium exclusive decays to two mesons are investigated, in which the final state vector mesons with various polarizations are considered separately. In the calculation, the initial heavy quarkonia are treated in the framework of non-relativistic quantum chromodynamics, whereas for light mesons, the light cone distribution amplitudes up to twist-3 are employed. It turns out that the higher twist contribution is significant and provides a possible explanation for the observation of the hadron helicity selection rule violated processes $\chi_{c1}\rightarrow \phi\phi,\omega\omega$ by the BESIII collaboration in recently. We also evaluate the $\chi_{b1}\to J/\psi J/\psi$ process and find that its branching ratio is big enough to be measured at the B-factories.Comment: more results and discussions adde

Large-scale preparation of active caspase-3 in E. coli by designing its thrombin-activatable precursors

<p>Abstract</p> <p>Background</p> <p>Caspase-3, a principal apoptotic effector that cleaves the majority of cellular substrates, is an important medicinal target for the treatment of cancers and neurodegenerative diseases. Large amounts of the protein are required for drug discovery research. However, previous efforts to express the full-length caspase-3 gene in <it>E. coli </it>have been unsuccessful.</p> <p>Results</p> <p>Overproducers of thrombin-activatable full-length caspase-3 precursors were prepared by engineering the auto-activation sites of caspase-3 precursor into a sequence susceptible to thrombin hydrolysis. The engineered precursors were highly expressed as soluble proteins in <it>E. coli </it>and easily purified by affinity chromatography, to levels of 10–15 mg from 1 L of <it>E. coli </it>culture, and readily activated by thrombin digestion. Kinetic evaluation disclosed that thrombin digestion enhanced catalytic activity (<it>k</it>_cat/<it>K</it>_<it>M</it>) of the precursor proteins by two orders of magnitude.</p> <p>Conclusion</p> <p>A novel method for a large-scale preparation of active caspase-3 was developed by a strategic engineering to lack auto-activation during expression with amino acid sequences susceptible to thrombin, facilitating high-level expression in <it>E. coli</it>. The precursor protein was easily purified and activated through specific cleavage at the engineered sites by thrombin, generating active caspase-3 in high yields.</p

mTORC1 Controls Phase Separation and the Biophysical Properties of the Cytoplasm by Tuning Crowding

International audienceMacromolecular crowding has a profound impact on reaction rates and the physical properties of the cell interior, but the mechanisms that regulate crowding are poorly understood. We developed genetically encoded multimeric nanoparticles (GEMs) to dissect these mechanisms. GEMs are homomultimeric scaffolds fused to a fluorescent protein that self-assemble into bright, stable particles of defined size and shape. By combining tracking of GEMs with genetic and pharmacological approaches, we discovered that the mTORC1 pathway can modulate the effective diffusion coefficient of particles ≥20 nm in diameter more than 2-fold by tuning ribosome concentration, without any discernable effect on the motion of molecules ≤5 nm. This change in ribosome concentration affected phase separation both in vitro and in vivo. Together, these results establish a role for mTORC1 in controlling both the mesoscale biophysical properties of the cytoplasm and biomolecular condensation