Stringency of antisense regulation varies based on volatility of mRNA target region

Bacteria can regulate gene expression by transcribing antisense RNA to interfere with protein translation. Antisense has been shown to control a wide variety of prokaryotic proteins, including membrane proteins, protein toxins, and proteins involved in transport and metabolism. This type of regulation can be used in the production of biologics to optimize the health of the culture and maximize production of the desired product. We examined naturally occurring antisense to enhance design principles for product optimization. We found that the level of secondary structure fluctuation of the antisense binding site varied depending on the function of the target. We hypothesized that stringency of regulation by naturally evolved antisense was driven by the impact of the target molecule on cellular survival. Specifically, high stringency was important for toxin-antitoxin systems where survival depended on high levels of control. Toxin-antitoxin systems rely on effective antisense to prevent the translation of self-damaging proteins. Antisense-based systems regulating transport and metabolism potentially benefited from less stringent antisense control. Basal levels of antisense-regulated proteins involved in metabolic processes could allow for quick adaptation to changing nutrient conditions. More than fifty naturally occurring sense/antisense pairs were analyzed to demonstrate that antisense binding sites correlate to the level of stringency needed in regulating the target protein. Please click Additional Files below to see the full abstract

Chk1 kinase negatively regulates mitotic function of Cdc25A phosphatase through 14-3-3 binding

The order and fidelity of cell cycle events in mammals is intimately linked to the integrity of the Chk1 kinase-Cdc25A phosphatase pathway. Chk1 phosphorylation targets Cdc25A for destruction and, as shown here, inhibits interactions between Cdc25A and its mitotic substrate cyclin B1-Cdk1. Phosphorylation of Cdc25A on serine 178 and threonine 507 facilitates 14-3-3 binding, and Chk1 phosphorylates both residues in vitro. Mutation of T507 to alanine (T507A) enhanced the biological activity of Cdc25A. Cdc25A(T507A) was more efficient in binding to cyclin B1, activating cyclin B1-Cdk1, and promoting premature entry into mitosis. We propose that the Chk1/Cdc25A/14-3-3 pathway functions to prevent cells from entering into mitosis prior to replicating their genomes to ensure the fidelity of the cell division process

Core Gas Sloshing in Abell 1644

We present an analysis of a 72 ks Chandra observation of the double cluster Abell 1644 (z = 0.047). The X-ray temperatures indicate that the masses are M 500 = (2.6 ± 0.4) × 1014 h –1 M ☉ for the northern sub-cluster and M 500 = (3.1 ± 0.4) × 1014 h –1 M ☉ for the southern, main cluster. We identify a sharp edge in the radial X-ray surface brightness of the main cluster, which we find to be a cold front, with a jump in temperature of a factor of ~3. This edge possesses a spiral morphology characteristic of core gas sloshing around the cluster potential minimum. We present observational evidence, supported by hydrodynamic simulations, that the northern sub-cluster is the object that initiated the core gas sloshing in the main cluster at least 700 Myr ago. We discuss reheating of the main cluster\u27s core gas via two mechanisms brought about by the sloshing gas: first, the release of gravitational potential energy gained by the core\u27s displacement from the potential minimum, and second, a dredging inward of the outer, higher entropy cluster gas along finger-shaped streams. We find that the available gravitational potential energy is small compared to the energy released by the cooling gas in the core

Deep Chandra Observations of Abell 2199: the Interplay between Merger-Induced Gas Motions and Nuclear Outbursts in a Cool Core Cluster

We present new Chandra observations of Abell 2199 that show evidence of gas sloshing due to a minor merger, as well as impacts of the radio source, 3C 338, hosted by the central galaxy, NGC 6166, on the intracluster gas. The new data are consistent with previous evidence of a Mach 1.46 shock 100" from the cluster center, although there is still no convincing evidence for the expected temperature jump. Other interpretations of this feature are possible, but none is fully satisfactory. Large scale asymmetries, including enhanced X-ray emission 200" southwest of the cluster center and a plume of low entropy, enriched gas reaching 50" to the north of the center, are signatures of gas sloshing induced by core passage of a merging subcluster about 400 Myr ago. An association between the unusual radio ridge and low entropy gas are consistent with this feature being the remnant of a former radio jet that was swept away from the AGN by gas sloshing. A large discrepancy between the energy required to produce the 100" shock and the enthalpy of the outer radio lobes of 3C 338 suggests that the lobes were formed by a more recent, less powerful radio outburst. Lack of evidence for shocks in the central 10" indicates that the power of the jet now is some two orders of magnitude smaller than when the 100" shock was formed.Comment: 17 pages, 20 figures, accepted for publication in Ap

Denying renal transplantation to an adolescent medical cannabis user: An ethical case study

Medical cannabis is now legal in over half of the United States. As more patients adopt this unconventional therapy, it is inevitable that potential transplant recipients will disclose their cannabis use during transplant evaluation. Transplant teams are tasked with the decision to utilize a pressure resource, often with little guidance from international and national professional organizations. Many healthcare providers remain uniformed or misinformed about the risks of cannabis use and organ transplantation. In order to illustrate the multifaceted and complex evaluation of transplant patients using medical cannabis, this article presents the case of a 20‐year‐old woman recommended for renal transplant who was originally denied active listing due to her medical cannabis use. A review of the literature explores the perceived and actual risks of cannabis use in the immunocompromised patient. Furthermore, a discussion of the ethics of medical cannabis use and organ transplantation is included with recommendations for multidisciplinary transplant teams.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150568/1/petr13467.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150568/2/petr13467_am.pd

Targeting the Mechanisms of Resistance to Chemotherapy and Radiotherapy with the Cancer Stem Cell Hypothesis

Despite advances in treatment, cancer remains the 2nd most common cause of death in the United States. Poor cure rates may result from the ability of cancer to recur and spread after initial therapies have seemingly eliminated detectable signs of disease. A growing body of evidence supports a role for cancer stem cells (CSCs) in tumor regrowth and spread after initial treatment. Thus, targeting CSCs in combination with traditional induction therapies may improve treatment outcomes and survival rates. Unfortunately, CSCs tend to be resistant to chemo- and radiation therapy, and a better understanding of the mechanisms underlying CSC resistance to treatment is necessary. This paper provides an update on evidence that supports a fundamental role for CSCs in cancer progression, summarizes potential mechanisms of CSC resistance to treatment, and discusses classes of drugs currently in preclinical or clinical testing that show promise at targeting CSCs

An SREBP-Responsive microRNA Operon Contributes to a Regulatory Loop for Intracellular Lipid Homeostasis

SummarySterol regulatory element-binding proteins (SREBPs) have evolved as a focal point for linking lipid synthesis with other pathways that regulate cell growth and survival. Here, we have uncovered a polycistrionic microRNA (miRNA) locus that is activated directly by SREBP-2. Two of the encoded miRNAs, miR-182 and miR-96, negatively regulate the expression of Fbxw7 and Insig-2, respectively, and both are known to negatively affect nuclear SREBP accumulation. Direct manipulation of this miRNA pathway alters nuclear SREBP levels and endogenous lipid synthesis. Thus, we have uncovered a mechanism for the regulation of intracellular lipid metabolism mediated by the concerted action of a pair of miRNAs that are expressed from the same SREBP-2-regulated miRNA locus, and each targets a different protein of the multistep pathway that regulates SREBP function. These studies reveal an miRNA “operon” analogous to the classic model for genetic control in bacterial regulatory systems