The nuclear pore complex has entered the atomic age

Nuclear pore complexes (NPCs) perforate the nuclear envelope and represent the exclusive passageway into and out of the nucleus of the eukaryotic cell. Apart from their essential transport function, components of the NPC have important, direct roles in nuclear organization and in gene regulation. Because of its central role in cell biology, it is of considerable interest to determine the NPC structure at atomic resolution. The complexity of these large, 40–60 MDa protein assemblies has for decades limited such structural studies. More recently, exploiting the intrinsic modularity of the NPC, structural biologists are making progress toward understanding this nanomachine in molecular detail. Structures of building blocks of the stable, architectural scaffold of the NPC have been solved, and distinct models for their assembly proposed. Here we review the status of the field and lay out the challenges and the next steps toward a full understanding of the NPC at atomic resolution.Pew Charitable Trusts (Scholars Program)National Institutes of Health (U.S.) (Grant GM077537

Statistical Properties of Radio Emission from the Palomar Seyfert Galaxies

We have carried out an analysis of the radio and optical properties of a statistical sample of 45 Seyfert galaxies from the Palomar spectroscopic survey of nearby galaxies. We find that the space density of bright galaxies (-22 mag <= M_{B_T} <= -18 mag) showing Seyfert activity is (1.25 +/- 0.38) X 10^{-3} Mpc^{-3}, considerably higher than found in other Seyfert samples. Host galaxy types, radio spectra, and radio source sizes are uncorrelated with Seyfert type, as predicted by the unified schemes for active galaxies. Approximately half of the detected galaxies have flat or inverted radio spectra, more than expected based on previous samples. Surprisingly, Seyfert 1 galaxies are found to have somewhat stronger radio sources than Seyfert 2 galaxies at 6 and 20 cm, particularly among the galaxies with the weakest nuclear activity. We suggest that this difference can be accommodated in the unified schemes if a minimum level of Seyfert activity is required for a radio source to emerge from the vicinity of the active nucleus. Below this level, Seyfert radio sources might be suppressed by free-free absorption associated with the nuclear torus or a compact narrow-line region, thus accounting for both the weakness of the radio emission and the preponderance of flat spectra. Alternatively, the flat spectra and weak radio sources might indicate that the weak active nuclei are fed by advection-dominated accretion disks.Comment: 18 pages using emulateapj5, 13 embedded figures, accepted by Ap

Back Pay in Employment Discrimination Cases

This Special Project examines the back pay decisions and analyzes the problems that have confronted the courts dealing with this remedy for employment discrimination in the context of Title VII and section 1981. Because of the enormity of the issues that have arisen in Stage I of the proceedings, however, and the extensive coverage given those problems by the courts and commentators, the Special Project will deal only with the recovery stage, or Stage II, of the litigation. Consequently, the reader should assume that liability for employment discrimination has already been established in each of the cases discussed below. Before reaching the various procedural and substantive issues surrounding back pay awards, however, the Project, in part II, presents an over-view of the statutory authority for back pay including the legislative history of Title VII and section 1981. Part II also discusses the development of the appropriate standard for the exercise of judicial discretion in awarding back pay. Part III examines the parties liable for the payment of back pay. In part IV the Project explores presumptive eligibility for back pay and in part V considers possible grounds on which a defendant may seek to rebut the presumption. Parts VI and VII discuss the proof-of-claim procedure that must be followed by discriminatees claiming back pay and the procedure for determining individual awards. Part VIII then identifies and analyzes the various problems facing courts in allocating the burdens of proof that plaintiffs and defendants must meet before the court can determine individual awards. Following the discussion of the order and allocation of the burdens of proof, part IX outlines the various methods used by the courts to compute individual back pay awards and also discusses other issues such as the elements includable and deductible, the mitigation requirement,and the limitation periods for back pay. In part X the Special Project examines the problems that may arise when the parties agree to a settlement of back pay claims

A Quantum Langevin Formulation of Risk-Sensitive Optimal Control

In this paper we formulate a risk-sensitive optimal control problem for continuously monitored open quantum systems modelled by quantum Langevin equations. The optimal controller is expressed in terms of a modified conditional state, which we call a risk-sensitive state, that represents measurement knowledge tempered by the control purpose. One of the two components of the optimal controller is dynamic, a filter that computes the risk-sensitive state. The second component is an optimal control feedback function that is found by solving the dynamic programming equation. The optimal controller can be implemented using classical electronics. The ideas are illustrated using an example of feedback control of a two-level atom

Interactions among mitochondrial proteins altered in glioblastoma

Mitochondrial dysfunction is putatively central to glioblastoma (GBM) pathophysiology but there has been no systematic analysis in GBM of the proteins which are integral to mitochondrial function. Alterations in proteins in mitochondrial enriched fractions from patients with GBM were defined with label-free liquid chromatography mass spectrometry. 256 mitochondrially-associated proteins were identified in mitochondrial enriched fractions and 117 of these mitochondrial proteins were markedly (fold-change &#8805;2) and significantly altered in GBM (p &#8804; 0.05). Proteins associated with oxidative damage (including catalase, superoxide dismutase 2, peroxiredoxin 1 and peroxiredoxin 4) were increased in GBM. Protein–protein interaction analysis highlighted a reduction in multiple proteins coupled to energy metabolism (in particular respiratory chain proteins, including 23 complex-I proteins). Qualitative ultrastructural analysis in GBM with electron microscopy showed a notably higher prevalence of mitochondria with cristolysis in GBM. This study highlights the complex mitochondrial proteomic adjustments which occur in GBM pathophysiology

Household-level predictors of the presence of servants in Northern Orkney, Scotland, 1851–1901

Servants were an important part of the northwestern European household economy in the preindustrial past. This study examines household-level characteristics that are predictive of the presence of rural servants using data from Orkney, Scotland. The number of servants present in a household is related to household composition, landholding size, and the marital status of the household head. In addition, the sex of the particular servant hired reveals that the labor of male and female servants is not fungible. The sex of the servant hired is related to the ratio of male and female household members of working age, the occupation of the head, household composition, and the size of the household\u27s landholding

RAB-Like 2 Has an Essential Role in Male Fertility, Sperm Intra-Flagellar Transport, and Tail Assembly

A significant percentage of young men are infertile and, for the majority, the underlying cause remains unknown. Male infertility is, however, frequently associated with defective sperm motility, wherein the sperm tail is a modified flagella/cilia. Conversely, a greater understanding of essential mechanisms involved in tail formation may offer contraceptive opportunities, or more broadly, therapeutic strategies for global cilia defects. Here we have identified Rab-like 2 (RABL2) as an essential requirement for sperm tail assembly and function. RABL2 is a member of a poorly characterized clade of the RAS GTPase superfamily. RABL2 is highly enriched within developing male germ cells, where it localizes to the mid-piece of the sperm tail. Lesser amounts of Rabl2 mRNA were observed in other tissues containing motile cilia. Using a co-immunoprecipitation approach and RABL2 affinity columns followed by immunochemistry, we demonstrated that within developing haploid germ cells RABL2 interacts with intra-flagella transport (IFT) proteins and delivers a specific set of effector (cargo) proteins, including key members of the glycolytic pathway, to the sperm tail. RABL2 binding to effector proteins is regulated by GTP. Perturbed RABL2 function, as exemplified by the Mot mouse line that contains a mutation in a critical protein-protein interaction domain, results in male sterility characterized by reduced sperm output, and sperm with aberrant motility and short tails. Our data demonstrate a novel function for the RABL protein family, an essential role for RABL2 in male fertility and a previously uncharacterised mechanism for protein delivery to the flagellum.This work was supported by grants from the NHMRC to MKO (#606445) and CJO, the Australian Research Council (MKO, RJA, and CJO), the New South Wales Cancer Council (CJO), Cancer Institute New South Wales (CJO), Banque Nationale de Paris-Paribas Australia and New Zealand (CJO), RT Hall Trust (CJO), and the National Breast Cancer Foundation (CJO). JCYL is the recipient of a NHMRC PhD scholarship. MKO and CJO are the recipients of NHMRC Senior Research Fellowships (#545805 and #481310). CCG is the recipient an NHMRC Australia Fellowship. JCW is the recipient of an Australian Research Council Federation Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Anti-cancer effects and mechanism of actions of aspirin analogues in the treatment of glioma cancer

INTRODUCTION: In the past 25 years only modest advancements in glioma treatment have been made, with patient prognosis and median survival time following diagnosis only increasing from 3 to 7 months. A substantial body of clinical and preclinical evidence has suggested a role for aspirin in the treatment of cancer with multiple mechanisms of action proposed including COX 2 inhibition, down regulation of EGFR expression, and NF-κB signaling affecting Bcl-2 expression. However, with serious side effects such as stroke and gastrointestinal bleeding, aspirin analogues with improved potency and side effect profiles are being developed. METHOD: Effects on cell viability following 24 hr incubation of four aspirin derivatives (PN508, 517, 526 and 529) were compared to cisplatin, aspirin and di-aspirin in four glioma cell lines (U87 MG, SVG P12, GOS – 3, and 1321N1), using the PrestoBlue assay, establishing IC50 and examining the time course of drug effects. RESULTS: All compounds were found to decrease cell viability in a concentration and time dependant manner. Significantly, the analogue PN517 (IC50 2mM) showed approximately a twofold increase in potency when compared to aspirin (3.7mM) and cisplatin (4.3mM) in U87 cells, with similar increased potency in SVG P12 cells. Other analogues demonstrated similar potency to aspirin and cisplatin. CONCLUSION: These results support the further development and characterization of novel NSAID derivatives for the treatment of glioma

First narrow-band search for continuous gravitational waves from known pulsars in advanced detector data

Spinning neutron stars asymmetric with respect to their rotation axis are potential sources of continuous gravitational waves for ground-based interferometric detectors. In the case of known pulsars a fully coherent search, based on matched filtering, which uses the position and rotational parameters obtained from electromagnetic observations, can be carried out. Matched filtering maximizes the signalto- noise (SNR) ratio, but a large sensitivity loss is expected in case of even a very small mismatch between the assumed and the true signal parameters. For this reason, narrow-band analysis methods have been developed, allowing a fully coherent search for gravitational waves from known pulsars over a fraction of a hertz and several spin-down values. In this paper we describe a narrow-band search of 11 pulsars using data from Advanced LIGO’s first observing run. Although we have found several initial outliers, further studies show no significant evidence for the presence of a gravitational wave signal. Finally, we have placed upper limits on the signal strain amplitude lower than the spin-down limit for 5 of the 11 targets over the bands searched; in the case of J1813-1749 the spin-down limit has been beaten for the first time. For an additional 3 targets, the median upper limit across the search bands is below the spin-down limit. This is the most sensitive narrow-band search for continuous gravitational waves carried out so far

Enhancer Remodeling during Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacologic Targeting of the P-TEFb Complex

Targeting the dysregulated BRaf-MEK-ERK pathway in cancer has increasingly emerged in clinical trial design. Despite clinical responses in specific cancers using inhibitors targeting BRaf and MEK, resistance develops often involving non-genomic adaptive bypass mechanisms. Inhibition of MEK1/2 by trametinib in triple negative breast cancer (TNBC) patients induced dramatic transcriptional responses, including upregulation of receptor tyrosine kinases (RTKs) comparing tumor samples before and after one week of treatment. In preclinical models MEK inhibition induced genome-wide enhancer formation involving the seeding of BRD4, MED1, H3K27 acetylation and p300 that drives transcriptional adaptation. Inhibition of P-TEFb associated proteins BRD4 and CBP/p300 arrested enhancer seeding and RTK upregulation. BRD4 bromodomain inhibitors overcame trametinib resistance, producing sustained growth inhibition in cells, xenografts and syngeneic mouse TNBC models. Pharmacological targeting of P-TEFb members in conjunction with MEK inhibition by trametinib is an effective strategy to durably inhibit epigenomic remodeling required for adaptive resistance