UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1α accumulation

<p>Abstract</p> <p>Background</p> <p>The proteins from the UBA-UBX family interact with ubiquitylated proteins via their UBA domain and with p97 via their UBX domain, thereby acting as substrate-binding adaptors for the p97 ATPase. In particular, human UBXN7 (also known as UBXD7) mediates p97 interaction with the transcription factor HIF1α that is actively ubiquitylated in normoxic cells by a CUL2-based E3 ligase, CRL2. Mass spectrometry analysis of UBA-UBX protein immunoprecipitates showed that they interact with a multitude of E3 ubiquitin-ligases. Conspicuously, UBXN7 was most proficient in interacting with cullin-RING ligase subunits. We therefore set out to determine whether UBXN7 interaction with cullins was direct or mediated by its ubiquitylated targets bound to the UBA domain.</p> <p>Results</p> <p>We show that UBXN7 interaction with cullins is independent of ubiquitin- and substrate-binding. Instead, it relies on the UIM motif in UBXN7 that directly engages the NEDD8 modification on cullins. To understand the functional consequences of UBXN7 interaction with neddylated cullins, we focused on HIF1α, a CUL2 substrate that uses UBXD7/p97 as a ubiquitin-receptor on its way to proteasome-mediated degradation. We find that UBXN7 over-expression converts CUL2 to its neddylated form and causes the accumulation of non-ubiquitylated HIF1α. Both of these effects are strictly UIM-dependent and occur only when UBXN7 contains an intact UIM motif. We also show that HIF1α carrying long ubiquitin-chains can recruit alternative ubiquitin-receptors, lacking p97's ATP-dependent segregase activity.</p> <p>Conclusions</p> <p>Our study shows that independently of its function as a ubiquitin-binding adaptor for p97, UBXN7 directly interacts with neddylated cullins and causes the accumulation of the CUL2 substrate HIF1α. We propose that by sequestering CUL2 in its neddylated form, UBXN7 negatively regulates the ubiquitin-ligase activity of CRL2 and this might prevent recruitment of ubiquitin-receptors other than p97 to nuclear HIF1α.</p

Treatment of Breast Cancer in Countries with Limited Resources

Early and accurate diagnosis of breast cancer is important for optimizing treatment. Local treatment of early stage breast cancer involves either mastectomy or breast-conserving surgery followed by whole-breast irradiation. The pathologic and biologic properties of a woman's breast cancer may be used to estimate her probability for recurrence of and death from breast cancer, as well as the magnitude of benefit she is likely to receive from adjuvant endocrine therapy or cytotoxic chemotherapy. Ovarian ablation or suppression with or without tamoxifen is an effective endocrine therapy in the adjuvant treatment of breast cancer in premenopausal women with estrogen receptor (ER)-positive or ER-unknown breast cancer. In postmenopausal women with ER- and/or progesterone receptor (PR)-positive or PR-unknown breast cancer, the use of tamoxifen or anastrozole is effective adjuvant endocrine therapy. The benefit of tamoxifen is additive to that of chemotherapy. Cytotoxic chemotherapy also improves recurrence rates and survival, with the magnitude of benefit decreasing with increasing age. Substantial support systems are required to optimally and safely use breast-conserving approaches to local therapy or cytotoxic chemotherapy as systemic therapy. Locally advanced breast cancer (LABC) accounts for at least half of all breast cancers in countries with limited resources and has a poor prognosis. Initial treatment of LABC with anthracycline-based chemotherapy is standard and effective. Addition of a sequential, neoadjuvant taxane thereafter increases the rate of pathologic complete responses. Neoadjuvant endocrine therapy may benefit postmenopausal women with hormone receptor-positive LABC. After an initial response to neoadjuvant chemotherapy, the use of local-regional surgery is appropriate. Most women will require a radical or modified radical mastectomy. In those women in whom mastectomy is not possible after neoadjuvant chemotherapy, the use of whole-breast and regional lymph node irradiation alone is appropriate. In those women who cannot receive neoadjuvant chemotherapy because of resource constraints, mastectomy with node dissection, when feasible, may still be considered in an attempt to achieve local-regional control. After local-regional therapy, most women should receive additional systemic chemotherapy. Women with LABC that has a positive or unknown hormone receptor status benefit from endocrine therapy with tamoxifen. The treatment of LABC requires multiple disciplines and is resource intensive. Efforts to reduce the number of breast cancers diagnosed at an advanced stage thus have the potential to improve rates of survival while decreasing the use of limited resources

Letalitatea prin tuberculoză în imsp Spitalul Clinic Municipal de Ftiziopneumologie mun. Chişinău

Catedra Pneumoftiziologie USMF „Nicolae Testemiţanu”, Institutul de Ftiziopneumologie „Chiril Draganiuc”, IMSP SCMF, ChişinăuThe aim of the survey was to study the frequence, structure and the reasons of the deaths through tuberculosis in the PMSI MCHP Chisinau during three periods of time. The mortality through tuberculosis in the IInd and IIIrd period has increased fi ve times in comparison of the fi rst period. The lethality in the hospital has increased from 6,8% in the Ist period, till 38,2% in the second period and 55,0% in the IIIrd period. It is stated an enormous increase of the deaths through tuberculosis from 51,2%, 81,7% till 88, 5% and a decrease through other diseases (48,8%, 18,3%, 11,5%). The rate of the new reasons of dead people is 1/3 among those analysed, but the period of the hospitalization until death is the most increased one during the fi rst 10 days till one month with a tendency of increase in the II-nd and III-rd period. Scopul acestui studiu a fost studierea frecvenţei, structurii şi cauzelor deceselor prin tuberculoză în IMSP SCMF Chişinău în trei perioade de timp. Mortalitatea prin tuberculoza în perioada II şi III a crescut de 5 ori relativ cu I perioadă. Letalitatea în staţionar a crescut de la 6,8% în I perioadă, la 38,2% în a II şi 55,0% în a III perioadă. Se atestă o majorare evidentă a deceselor din contul tuberculozei de la 51,2%, 81,7% la 88,5% respectiv şi o descreş- tere prin alte boli (48,8%, 18,3%, 11,5%). Rata cazurilor noi la decedaţi constituie 1/3 din persoanele analizate, iar durata spitalizării pînă la deces este cea mai înaltă în primele 10 zile şi pînă la o lună, avînd o tendinţă de creştere în perioadele II şi III comparativ cu prima

Comprehensive behavioral and biochemical outcomes of novel murine models of GM1-gangliosidosis and Morquio syndrome type B

Deficiencies in the lysosomal hydrolase β-galactosidase (β-gal) lead to two distinct diseases: the skeletal disease Morquio syndrome type B, and the neurodegenerative disease GM1-gangliosidosis. Utilizing CRISPR-Cas9 genome editing, the mouse β-gal encoding gene, Glb1, was targeted to generate both models of β-gal deficiency in a single experiment. For Morquio syndrome type B, the common human missense mutation W273L (position 274 in mice) was introduced into the Glb1 gene (Glb

The QCD phase diagram at nonzero quark density

We determine the phase diagram of QCD on the \mu-T plane for small to moderate chemical potentials. Two transition lines are defined with two quantities, the chiral condensate and the strange quark number susceptibility. The calculations are carried out on N_t =6,8 and 10 lattices generated with a Symanzik improved gauge and stout-link improved 2+1 flavor staggered fermion action using physical quark masses. After carrying out the continuum extrapolation we find that both quantities result in a similar curvature of the transition line. Furthermore, our results indicate that in leading order the width of the transition region remains essentially the same as the chemical potential is increased.Comment: 12 pages, 6 figure

Gauge-invariant screening masses and static quark free energies in Nf=2+1 QCD at nonzero baryon density

We discuss the extension of gauge-invariant electric and magnetic screening masses in the quark-gluon plasma to the case of a finite baryon density, defining them in terms of a matrix of Polyakov loop correlators. We present lattice results for Nf=2+1 QCD with physical quark masses, obtained using the imaginary chemical potential approach, which indicate that the screening masses increase as a function of μB. A separate analysis is carried out for the theoretically interesting case μB/T=3iπ, where charge conjugation is not explicitly broken and the usual definition of the screening masses can be used for temperatures below the Roberge-Weiss transition. Finally, we investigate the dependence of the static quark free energy on the baryon chemical potential, showing that it is a decreasing function of μB, which displays a peculiar behavior as the pseudocritical transition temperature at μB=0 is approached

Lattice QCD Simulations in External Background Fields

We discuss recent results and future prospects regarding the investigation, by lattice simulations, of the non-perturbative properties of QCD and of its phase diagram in presence of magnetic or chromomagnetic background fields. After a brief introduction to the formulation of lattice QCD in presence of external fields, we focus on studies regarding the effects of external fields on chiral symmetry breaking, on its restoration at finite temperature and on deconfinement. We conclude with a few comments regarding the effects of electromagnetic background fields on gluodynamics.Comment: 31 pages, 10 figures, minor changes and references added. To appear in Lect. Notes Phys. "Strongly interacting matter in magnetic fields" (Springer), edited by D. Kharzeev, K. Landsteiner, A. Schmitt, H.-U. Ye