Two-step membrane binding by the bacterial SRP receptor enable efficient and accurate Co-translational protein targeting

The signal recognition particle (SRP) delivers ~30% of the proteome to the eukaryotic endoplasmic reticulum, or the bacterial plasma membrane. The precise mechanism by which the bacterial SRP receptor, FtsY, interacts with and is regulated at the target membrane remain unclear. Here, quantitative analysis of FtsY-lipid interactions at single-molecule resolution revealed a two-step mechanism in which FtsY initially contacts membrane via a Dynamic mode, followed by an SRP-induced conformational transition to a Stable mode that activates FtsY for downstream steps. Importantly, mutational analyses revealed extensive auto-inhibitory mechanisms that prevent free FtsY from engaging membrane in the Stable mode; an engineered FtsY pre-organized into the Stable mode led to indiscriminate targeting in vitro and disrupted FtsY function in vivo. Our results show that the two-step lipid-binding mechanism uncouples the membrane association of FtsY from its conformational activation, thus optimizing the balance between the efficiency and fidelity of co-translational protein targeting

Dirac Leptogenesis with a Non-anomalous U(1)′U(1)^{\prime} Family Symmetry

We propose a model for Dirac leptogenesis based on a non-anomalous $U(1)^{\prime}$ gauged family symmetry. The anomaly cancellation conditions are satisfied with no new chiral fermions other than the three right-handed neutrinos, giving rise to stringent constraints among the charges. Realistic masses and mixing angles are obtained for all fermions. The model predicts neutrinos of the Dirac type with naturally suppressed masses. Dirac leptogenesis is achieved through the decay of the flavon fields. The cascade decays of the vector-like heavy fermions in the Froggatt-Nielsen mechanism play a crucial role in the separation of the primodial lepton numbers. We find that a large region of parameter space of the model gives rise to a sufficient cosmological baryon number asymmetry through Dirac leptogenesis.Comment: 8 pages, 8 figures, version to appear in JHE

Targeting Tumor-Associated Fibroblasts for Therapeutic Delivery in Desmoplastic Tumors

The off-target distribution of anticancer nanoparticles to fibroblasts creates a barrier to the effective treatment of desmoplastic tumors. However, we hypothesized that this nanoparticle detriment might be exploited to target the expression of secreted cytotoxic proteins from tumor-associated fibroblasts (TAF) as an anticancer strategy. In addressing this hypothesis, plasmids encoding the secretable TNF-related factor sTRAIL were loaded into lipid-coated protamine DNA complexes and administered by infusion in a murine xenograft model of human desmoplastic bladder carcinoma. Three doses were sufficient to generate approximately 70% of TAFs as sTRAIL-producing cells. sTRAIL triggered apoptosis in tumor cell nests adjacent to TAFs. Furthermore, it reverted residual fibroblasts to a quiescent state due to insufficient activation, further compromising tumor growth and remodeling the microenvironment to favor second-wave nanotherapy. We confirmed the efficacy of this strategy in an orthotopic xenograft model of human pancreatic cancer, where the desmoplastic stroma is well known to be a major barrier to the delivery of therapeutic nanoparticles. Collectively, our results offer a proof of concept for the use of nanoparticles to modify TAFs as an effective strategy to treat desmoplastic cancers. Cancer Res; 77(3); 719-31. ©2016 AACR

The flavonoid nobiletin inhibits tumor growth and angiogenesis of ovarian cancers via the Akt pathway

Despite its importance, the death rate of ovarian cancer has remained unchanged over the past five decades, demanding an improvement in prevention and treatment of this malignancy. With no known carcinogens, targeted prevention is currently unavailable, and efforts in early detection of this malignancy by screening biomarkers have failed. The inhibition of angiogenesis, also known as angioprevention, is a promising strategy to limit the growth of solid tumors, including ovarian cancers. Nobiletin, a polymethoxy flavonoid compound isolated from the tiansheng plant, has been shown to inhibit the growth of multiple types of human cancers. However, there are no reports involving the effect on nobiletin on human ovarian cancer. The present report shows that nobiletin potently decreases the viability of ovarian cancer cells in vitro. However, nobiletin does not affect the viability of normal ovarian epithelial cells at \u3c40 µM. The antitumor activity of nobiletin was also observed in athymic mouse models and in chicken chorioallantoic membrane (CAM) models. The anti-neoplastic activity of nobiletin was due to its ability to inhibit angiogenesis. We also studied the molecular mechanisms by which nobiletin suppresses angiogenesis. We observed that nobiletin inhibits secretion of the key angiogenesis mediators, Akt, HIF-1α, NF-κB and vascular epithelial growth factor (VEGF) by ovarian cancer cells. Transient transfection experiments showed that nobiletin inhibits production of HIF-1α by downregulation of Akt. Such decreased levels of HIF-1α were responsible for nobiletin-induced suppression of VEGF. Our data suggest that nobiletin may be a promising anti-angiogenic agent relevant for therapy of ovarian cancers

Large-Scale Atomistic Simulations of Environmental Effects on the Formation and Properties of Molecular Junctions

Using an updated simulation tool, we examine molecular junctions comprised of benzene-1,4-dithiolate bonded between gold nanotips, focusing on the importance of environmental factors and inter-electrode distance on the formation and structure of bridged molecules. We investigate the complex relationship between monolayer density and tip separation, finding that the formation of multi-molecule junctions is favored at low monolayer density, while single-molecule junctions are favored at high density. We demonstrate that tip geometry and monolayer interactions, two factors that are often neglected in simulation, affect the bonding geometry and tilt angle of bridged molecules. We further show that the structures of bridged molecules at 298 and 77 K are similar.Comment: To appear in ACS Nano, 30 pages, 5 figure

A microsatellite marker for yellow rust resistance in wheat

Bulk segregant analysis (BSA) was used to identify molecular markers associated with yellow rust disease resistance in wheat (Triticum aestivum L.). DNAs isolated from the selected yellow rust tolerant and susceptible F-2 individuals derived from a cross between yellow rust resistant and susceptible wheat genotypes were used to established a "tolerant" and a "susceptible" DNA pool. The BSA was then performed on these DNA pools using 230 markers that were previously mapped onto the individual wheat chromosomes. One of the SSR markers (Xgwm382) located on chromosome group 2 (A, B, D genomes) was present in the resistant parent and the resistant bulk but not in the susceptible parent and the susceptible bulk, suggesting that this marker is linked to a yellow rust resistance gene. The presence of Xgwm382 was also tested in 108 additional wheat genotypes differing in yellow rust resistance. This analysis showed that 81% of the wheat genotypes known to be yellow rust resistant had the Xgwm382 marker, further suggesting that the presence of this marker correlates with yellow rust resistance in diverse wheat germplasm. Therefore, Xgwm382 could be useful for marker assisted selection of yellow rust resistances genotypes in wheat breeding programs

PARP-1 regulates DNA repair factor availability.

PARP-1 holds major functions on chromatin, DNA damage repair and transcriptional regulation, both of which are relevant in the context of cancer. Here, unbiased transcriptional profiling revealed the downstream transcriptional profile of PARP-1 enzymatic activity. Further investigation of the PARP-1-regulated transcriptome and secondary strategies for assessing PARP-1 activity in patient tissues revealed that PARP-1 activity was unexpectedly enriched as a function of disease progression and was associated with poor outcome independent of DNA double-strand breaks, suggesting that enhanced PARP-1 activity may promote aggressive phenotypes. Mechanistic investigation revealed that active PARP-1 served to enhance E2F1 transcription factor activity, and specifically promoted E2F1-mediated induction of DNA repair factors involved in homologous recombination (HR). Conversely, PARP-1 inhibition reduced HR factor availability and thus acted to induce or enhance BRCA-ness . These observations bring new understanding of PARP-1 function in cancer and have significant ramifications on predicting PARP-1 inhibitor function in the clinical setting