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We describe the current state of the Burke-Gaffney Observatory (BGO) at Saint Mary's University - a unique fully roboticized remote-access observatory that allows students to carry out imaging, photometry, and spectroscopy projects remotely from anywhere in the world via a web browser or social media. Stellar spectroscopy is available with the ALPY 600 low resolution grism spectrograph equipped with a CCD detector. We describe our custom CCD spectroscopy reduction procedure written in the Python programming language and demonstrate the quality of fits of synthetic spectra computed with the ChromaStarServer (CSS) code to BGO spectra. The facility along with the accompanying Python BGO spectroscopy reduction package and the CSS spectrum synthesis code provide an accessible means for students anywhere to carry our projects at the undergraduate honours level. BGO web pages for potential observers are at the site: observatory.smu.ca/bgo-useme. All codes are available from the OpenStars www site: openstars.smu.ca/, Comment: 23 pages double-spaced, 12 figures. arXiv admin note: text overlap with arXiv:2307.01279 . HR3580 now correctly identified and modelled as a giant, not a dwarf

We analyzed Asteroid Terrestrial-impact Last Alert System (ATLAS), Zwicky Transient Facility (ZTF) and All-Sky Automated Survey for Supernovae (ASAS-SN) data of MASTER OT J055845.55+391533.4 and found that this object repeats superoutburst with a dip in the middle of the outburst followed by long and sometimes oscillating rebrightening, just like a WZ Sge-type dwarf nova or an AM CVn-type object. The mean supercycle was 298(8) d, too short for a WZ Sge star, but with only a few normal outbursts. We also observed the 2023 February-March superoutburst and established the superhump period of 0.05509(2) d. This period appears to exclude the possibility of an AM CVn star. Although the 2023 observations could not detect superhumps after the dip, the 2014, 2016 and 2021 data seem to suggest that low-amplitude superhumps were present during the rebrightening phase. We note that a dip during a superoutburst is a feature common to the unusual SU UMa-type dwarf nova MASTER OT J172758.09+380021.5 during some of its superoutbursts. These objects may comprise a new class of rebrightening phenomenon in SU UMa-type dwarf novae., Comment: 15 pages, 8 figures, VSOLJ Variable Star Bulletin No. 113

The RON receptor tyrosine kinase is an exceptionally interesting target in oncology and immunology. It is not only overexpressed in a wide variety of tumors but also has been shown to be expressed on myeloid cells associated with tumor infiltration, where it serves to dampen tumour immune responses and reduce the efficacy of anti-CTLA4 therapy. Potent and selective inhibitory antibodies to RON might therefore both inhibit tumor cell growth and stimulate immune rejection of tumors. We derived cloned and sequenced a new panel of exceptionally avid anti-RON antibodies with picomolar binding affinities that inhibit MSP-induced RON signaling and show remarkable potency in antibody dependent cellular cytotoxicity. Antibody specificity was validated by cloning the antibody genes and creating recombinant antibodies and by the use of RON knock out cell lines. When radiolabeled with 89-Zirconium, the new antibodies 3F8 and 10G1 allow effective immuno-positron emission tomography (immunoPET) imaging of RON-expressing tumors and recognize universally exposed RON epitopes at the cell surface. The 10G1 was further developed into a novel bispecific T cell engager with a 15 pM EC50 in cytotoxic T cell killing assays.

Lenin transposed Marx’s analysis of capitalism from the advanced capitalist economies to the dependent colonial countries. He combined political economy, geopolitics, political organisation and a sociology of social structure to form an innovative revolutionary praxis. The expansion of Western capitalism shifted the social and political contradictions to countries moving from feudalism to capitalism. Lenin was correct in his appraisal of the social forces in support of a bourgeois revolution. But he provided an over-optimistic prediction for the disintegration of monopoly capitalism and only a partial analysis of the working classes in the advanced capitalist countries. His political approach requires a redefinition of countervailing forces and class alliances and a shift of focus from the semi-periphery to the ‘strongest links’ in the capitalist chain. A ‘return to Lenin’ is not to adopt his policies but a prompt to reinvent a socialist sociological vision derived from the expectations of the Enlightenment and Marx’s analysis of capitalism.

This repository contains the research materials used in the manuscript "The Effects of Peaks, Nadirs, and Turning Points Depend on Basic Psychological Needs."

The tenovins are a frequently studied class of compounds capable of inhibiting sirtuin activity, which is thought to result in increased acetylation and protection of the tumor suppressor p53 from degradation. However, as we and other laboratories have shown previously, certain tenovins are also capable of inhibiting autophagic flux, demonstrating the ability of these compounds to engage with more than one target. In this study, we present two additional mechanisms by which tenovins are able to activate p53 and kill tumor cells in culture. These mechanisms are the inhibition of a key enzyme of the de novo pyrimidine synthesis pathway, dihydroorotate dehydrogenase (DHODH), and the blockage of uridine transport into cells. These findings hold a 3-fold significance: first, we demonstrate that tenovins, and perhaps other compounds that activate p53, may activate p53 by more than one mechanism; second, that work previously conducted with certain tenovins as SirT1 inhibitors should additionally be viewed through the lens of DHODH inhibition as this is a major contributor to the mechanism of action of the most widely used tenovins; and finally, that small changes in the structure of a small molecule can lead to a dramatic change in the target profile of the molecule even when the phenotypic readout remains static.

The paper summarises the extent and incidence of the Covid-19 pandemic and evaluates government policies in different countries. The consequences of lock-down policy are discussed. The most negatively affected groups of the population are the low-skilled workers and self-employed. Psychological welfare has seriously declined and provision of health services have deteriorated. Population density, age structure and state management strongly influence the spread and containment of the disease. State coordinated economies and social-democratic countries have managed the effects of the disease better than market coordinated economies, though there are important exceptions. A failure of some governments to provide sufficient reserve capacity of healthcare facilities indicates government policy failure. The paper suggests that a more focused policy of social isolation of people susceptible to coronavirus with less stringent lockdown measures would have significantly reduced social costs and increased public health benefits.

Background: In humans, multiple researchers have not only determined that there is a relationship between urinary incontinence (UI) and lower back pain (LBP), but that by treating the LBP, clinicians are able to improve or resolve the UI. Up until now, no equivalent canine research has investigated whether treatment of LBP can improve the clinicalsigns of acquired, non-neurologic UI in dogs.Aim: To determine if a relationship exists between LBP and urethral sphincter mechanism incompetence (USMI) in dogs.Methods: Review of medical records of all patients that presented to Points East West Veterinary Services with a history of naturally occurring acquired UI from May 2013 to December 2019. Thirty-nine patients treated for LBP using combined acupuncture and manual therapy, and 33/39 patients that also received concurrent photobiomodulation (PBM) therapy, qualified for this study.Results: Treated patients showed a statistically significant reduction in both the frequency (p < 0.01) and volume (p < 0.01) of UI episodes. Treatment responses ranged from no improvement, to complete resolution of the USMI clinicalsigns.Conclusion: The reduction of USMI clinical signs following LBP treatment suggests a relationship between these two conditions. Combined acupuncture, manual therapy, with or without PBM was shown to be an effective treatment for USMI. By corollary, USMI incontinence should be considered a potential pain symptom.

Peptide-based molecules hold great potential as targeted inhibitors of intracellular protein–protein interactions (PPIs)., Peptide-based molecules hold great potential as targeted inhibitors of intracellular protein–protein interactions (PPIs). Indeed, the vast diversity of chemical space conferred through their primary, secondary and tertiary structures allows these molecules to be applied to targets that are typically deemed intractable via small molecules. However, the development of peptide therapeutics has been hindered by their limited conformational stability, proteolytic sensitivity and cell permeability. Several contemporary peptide design strategies are aimed at addressing these issues. Strategic macrocyclization through optimally placed chemical braces such as olefinic hydrocarbon crosslinks, commonly referred to as staples, may improve peptide properties by (i) restricting conformational freedom to improve target affinities, (ii) improving proteolytic resistance, and (iii) enhancing cell permeability. As a second strategy, molecules constructed entirely from d-amino acids are hyper-resistant to proteolytic cleavage, but generally lack conformational stability and membrane permeability. Since neither approach is a complete solution, we have combined these strategies to identify the first examples of all-d α-helical stapled and stitched peptides. As a template, we used a recently reported all d-linear peptide that is a potent inhibitor of the p53–Mdm2 interaction, but is devoid of cellular activity. To design both stapled and stitched all-d-peptide analogues, we used computational modelling to predict optimal staple placement. The resultant novel macrocyclic all d-peptide was determined to exhibit increased α-helicity, improved target binding, complete proteolytic stability and, most notably, cellular activity.

Inactivating p53 mutations are the most abundant genetic alterations found in cancer. Here we show that CRISPR/Cas9-induced double-stranded DNA breaks enrich for cells deficient in p53 and in genes of a core CRISPR-p53 tumor suppressor interactome. Such enrichment could predispose to cancer development and thus pose a challenge for clinical CRISPR use. Transient p53 inhibition could suppress the enrichment of cells with these mutations. The level of DNA damage response induced by an sgRNA influenced the enrichment of p53-deficient cells and could be a relevant parameter in sgRNA design to limit cellular enrichment. Furthermore, a dataset of >800 human cancer cell lines identified additional factors influencing the enrichment of p53-mutated cells, including strong baseline CDKN1A expression as a predictor for an active CRISPR-p53 axis. Taken together, these data provide details about p53 biology in the context of CRISPR-induced DNA damage and identify strategies to enable safer CRISPR use. SIGNIFICANCE: CRISPR-mediated DNA damage enriches for cells with escape mutations in a core CRISPR-p53 interactome, which can be suppressed by transient inhibition of p53. Published version The authors acknowledge support from the National Genomics Infrastructure in Stockholm funded by Science for Life Laboratory, the Knut and Alice Wallenberg Foundation, and the Swedish Research Council, and SNIC/Uppsala Multidisciplinary Center for AdvancedComputational Science for assistance with massively parallel sequencing and access to the UPPMAX computational infrastructure. This research was partly funded by grants from the Swedish Research Council (to F. Wermeling and D.P. Lane) , the Swedish Cancer Society, Karolinska Institutet and Magnus Bergvalls stiftelse (to F. Wermeling) , the China Scholarship Council (to L. Jiang and Y. Shen) , and the Nanyang Technological University-Karolinska Institutet Joint PhD Program (to V.S. Iyer).

p53 is involved in DNA damage response and is an exciting target for radiosensitization in cancer. Targeted radionuclide therapy against somatostatin receptors with 177Lu-DOTATATE is currently being explored as a treatment for neuroblastoma. The aim of this study was to investigate the novel p53-stabilizing peptide VIP116 in neuroblastoma, both as monotherapy and together with 177Lu-DOTATATE. Five neuroblastoma cell lines, including two patient-derived xenograft (PDX) lines, were characterized in monolayer cultures. Four out of five were positive for 177Lu-DOTATATE uptake. IC50 values after VIP116 treatments correlated with p53 status, ranging between 2.8–238.2 μM. IMR-32 and PDX lines LU-NB-1 and LU-NB-2 were then cultured as multicellular tumor spheroids and treated with 177Lu-DOTATATE and/or VIP116. Spheroid growth was inhibited in all spheroid models for all treatment modalities. The most pronounced effects were observed for combination treatments, mediating synergistic effects in the IMR-32 model. VIP116 and combination treatment increased p53 levels with subsequent induction of p21, Bax and cleaved caspase 3. Combination treatment resulted in a 14-fold and 1.6-fold induction of MDM2 in LU-NB-2 and IMR-32 spheroids, respectively. This, together with differential MYCN signaling, may explain the varying degree of synergy. In conclusion, VIP116 inhibited neuroblastoma cell growth, potentiated 177Lu-DOTATATE treatment and could, therefore, be a feasible treatment option for neuroblastoma. Title in Web of Science: p53-Mediated Radiosensitization of Lu-177-DOTATATE in Neuroblastoma Tumor Spheroids

We have revealed a non-canonical recognition feature that can modulate the binding kinetics of hydrocarbon stapled-peptides interactions with the eIF4E protein., Stapled-peptides have emerged as an exciting class of molecules which can modulate protein–protein interactions. We have used a structure-guided approach to rationally develop a set of hydrocarbon stapled-peptides with high binding affinities and residence times against the oncogenic eukaryotic translation initiation factor 4E (eIF4E) protein. Crystal structures of these peptides in complex with eIF4E show that they form specific interactions with a region on the protein-binding interface of eIF4E which is distinct from the other well-established canonical interactions. This recognition element is a major molecular determinant underlying the improved binding kinetics of these peptides with eIF4E. The interactions were further exploited by designing features in the peptides to attenuate disorder and increase helicity which collectively resulted in the generation of a distinct class of hydrocarbon stapled-peptides targeting eIF4E. This study details new insights into the molecular basis of stapled-peptide: eIF4E interactions and their exploitation to enhance promising lead molecules for the development of stapled-peptide compounds for oncology.

Authors’ original file for figure 1

Additional file 1:Expanded and annotated diagram of Figure 2A(early steps in the RAM reaction), and extension of the model for product prediction. Figure S1.1 expands on Figure 3, showing generation of RAM products by primer extension on a template generated by rolling circle amplification. Figure S1.2 illustrates the recursive, or nested, model of RAM products. Tables S1.1, S1.2, and S1.3 extend the table of products concept to generate a prediction of exponential dsDNA product accumulation shown in Figure S1.3. Table S1.4 shows an example of RAM stoichiometry calculation, followed by data and arguments to show that RAM reactions as performed could exhaust the reagent pool. (PDF 245 KB)

This issue provides a broad overview of Russian politics and society in the run-up to the 2021 parliamentary elections, which are scheduled for September. In eleven shorter contributions, international experts on Russia discuss domestic and foreign affairs as well as the economy. The focus of most of them is on attempts of the Russian leadership to deal with growing discontent among the population. This includes the regime’s quest for legitimacy as well as repression and strategies to manipulate the actual election process. Individual contributions also discuss the implications for foreign policy and economic development. The contributions are published in alphabetical order of authors., Diese Ausgabe bietet einen Überblick über die russische Politik und Gesellschaft im Vorfeld der diesjährigen Parlamentswahlen, die für September angesetzt sind. In elf kürzeren Beiträgen diskutieren internationale Russland-Experten die Innen- und Außenpolitik sowie die Wirtschaft. Der Schwerpunkt der meisten Beiträge liegt auf den Versuchen der russischen Führung, mit der wachsenden Unzufriedenheit in der Bevölkerung umzugehen. Dies umfasst neben Strategien zur Legitimation des politischen Regimes sowie Repressionen auch Möglichkeiten der Manipulation des eigentlichen Wahlprozesses. In einzelnen Beiträgen werden auch die Auswirkungen auf die Außenpolitik und die wirtschaftliche Entwicklung erörtert. Die Beiträge werden in alphabetischer Reihenfolge der Autoren veröffentlicht., Russian Analytical Digest (RAD), 266, ISSN:1863-0421

Additional file 3:Residuals of fitted real-time model. (PDF 133 KB)

Authors’ original file for figure 4

Additional file 2:Experimental test of the assumption that RAM products are inert in the RAM reaction. (PDF 112 KB)

Raffles Bulletin of Zoology, Supplement 36, 386-425

Additional file of A mechanism for ramified rolling circle amplification

Lane, David J.W., Vimono, Indra B. (2020): Two new species of sea star (Asteroidea, Echinodermata) from mesopelagic depths in the Sunda Strait, Indonesia. Raffles Bulletin of Zoology 68: 662-669, DOI: 10.26107/RBZ-2020-0081

Membrane proteins engage in a variety of contacts with theirsurrounding lipids, but distinguishing between specifically boundlipids, and non-specific annular interactionsis a challenging problem. Applying native mass spectrometry to three membrane protein complexes with different lipid binding properties, we explore the ability of detergents to compete with lipids bound in different environments. We show that lipids in annular positions on the Presenilin Homologue protease are subject to constant exchange with detergent. Bycontrast,detergent-resistantlipids bound at the dimer interface in the Leucine transportershowdecreased koffrates in molecular dynamics simulations.Turning tothe lipid flippase MurJ, we findthat addition of the natural substrate lipid-II results in the formation of a 1:1 protein-lipid complex, where the lipid cannot be displaced by detergentfromthe highly protected active site.In summary, we distinguish annular from non-annular lipids based on their exchange rates in solution. [Abstract copyright: © 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.]

Rational: cMet is abnormally regulated in gastrointestinal cancer, and is associated with increased invasiveness of the disease and poor overall survival. There are indications that targeted therapy against cMet, alone or in combination with additional cancer therapies, can help improve treatment outcome. Thus, in the present study we investigated the therapeutic efficacy of a novel cMet-targeting antibody therapy in gastrointestinal cancer models, and assessed potential augmenting effects in combination with tyrosine kinase inhibitor (TKI) targeted therapy or radiotherapy. Methods: Three different cMet-targeting antibodies were first characterized with respect to antigen binding and effects on cell viability in vitro. The best performing candidate seeMet 12 was then further assessed for effects on colorectal cancer cell growth, proliferation and migration. Combinations with the TKI-inhibitor sorafenib or external beam radiotherapy were then evaluated for potential additive or synergistic effects in vitro using monolayer- and multicellular tumor spheroid assays. Finally, the combination of seeMet 12 and radiotherapy was evaluated in vivo in a proof-of-concept colorectal cancer xenograft study. Results: Dose-dependent therapeutic effects were demonstrated for all three cMet-targeting antibodies. Monotherapy using seeMet 12 resulted in impaired cellular migration/proliferation and reduced tumor spheroid growth. Moreover, seeMet 12 was able to potentiate therapeutic effects in vitro for both sorafenib and radiotherapy treatments. Finally, the in vivo therapy study demonstrated promising results, where a combination of seeMet 12 and fractionated radiotherapy increased median survival by 79% compared to radiotherapy alone, and tripled maximum survival. Conclusion: The novel anti-cMet antibody seeMet 12 demonstrated therapeutic effects in cMet positive gastrointestinal cancer cells in vitro. Moreover, the addition of seeMet 12 augmented the effects of sorafenib and radiotherapy. An in vivo proof-of-concept study of seeMet 12 and radiotherapy further validated the results. Thus, cMet-targeted therapy should be further explored as a promising approach to increase therapeutic effects, circumvent treatment resistance, and reduce side effects.

Human dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, is a target for the treatment of rheumatoid arthritis and multiple sclerosis and is re-emerging as an attractive target for cancer therapy. Here we describe the optimization of recently identified tetrahydroindazoles (HZ) as DHODH inhibitors. Several of the HZ analogues synthesized in this study are highly potent inhibitors of DHODH in an enzymatic assay, while also inhibiting cancer cell growth and viability and activating p53-dependent transcription factor activity in a reporter cell assay. Furthermore, we demonstrate the specificity of the compounds toward the de novo pyrimidine synthesis pathway through supplementation with an excess of uridine. We also show that induction of the DNA damage marker gamma-H2AX after DHODH inhibition is preventable by cotreatment with the pancaspase inhibitor Z-VAD-FMK. Additional solubility and in vitro m etabolic stability profiling revealed compound 51 as a favorable candidate for preclinical efficacy studies.

Tissue factor pathway inhibitor (TFPI), the main inhibitor of initiation of coagulation, exerts an important anticoagulant role through the factor Xa (FXa)-dependent inhibition of tissue factor/factor VIIa. Protein S is a TFPI cofactor, enhancing the efficiency of FXa inhibition. TFPI can also inhibit prothrombinase assembly by directly interacting with coagulation factor V (FV), which has been activated by FXa. Because full-length TFPI associates with FV in plasma, we hypothesized that FV may influence TFPI inhibitory function. Using pure component FXa inhibition assays, we found that although FV alone did not influence TFPI-mediated FXa inhibition, it further enhanced TFPI in the presence of protein S, resulting in an ∼8-fold reduction in Ki compared with TFPI alone. A FV variant (R709Q/R1018Q/R1545Q, FVΔIIa) that cannot be cleaved/activated by thrombin or FXa also enhanced TFPI-mediated inhibition of FXa ∼12-fold in the presence of protein S. In contrast, neither activated FV nor recombinant B-domain-deleted FV could enhance TFPI-mediated inhibition of FXa in the presence of protein S, suggesting a functional contribution of the B domain. Using TFPI and protein S variants, we show further that the enhancement of TFPI-mediated FXa inhibition by protein S and FV depends on a direct protein S/TFPI interaction and that the TFPI C-terminal tail is not essential for this enhancement. In FXa-catalyzed prothrombin activation assays, both FV and FVΔIIa (but not activated FV) enhanced TFPI function in the presence of protein S. These results demonstrate a new anticoagulant (cofactor) function of FV that targets the early phase of coagulation before prothrombinase assembly.

One way to recognise an object is to study how the echo has been shaped during the interaction with the target. Wideband sonar allows the study of the energy distribution for a large range of frequencies. The frequency distribution contains information about an object, including its inner structure. This information is a key for automatic recognition. The scattering by a target can be quantitatively described by its Form Function. The Form Function can be calculated based on the data of the initial pulse, reflected pulse and parameters of a medium where the pulse is propagating. In this work spherical objects are classified based on their filler material - water or air. We limit the study to spherical 2 layered targets immersed in water. The Form Function is used as a descriptor and fed into a Neural Network classifier, Multilayer Perceptron (MLP). The performance of the classifier is compared with Support Vector Machine (SVM) and the Form Function descriptor is examined in contrast to the Time and Frequency Representation of the echo.

Peptide-based inhibitors hold great potential for targeted modulation of intracellular protein-protein interactions (PPIs) by leveraging vast chemical space relative to primary structure via sequence diversity as well as conformationally through varying secondary and tertiary structures. However, the development of peptide therapeutics has been hindered because of their limited conformational stability, proteolytic sensitivity and cell permeability. Several contemporary peptide design strategies address these issues to varying degrees. Strategic macrocyclization through optimally placed chemical braces such as olefinic hydrocarbon crosslinks, commonly referred to as staples, may address these issues by i) restricting conformational freedom to improve target affinities, ii) improving proteolytic resistance, and iii) enhancing cell permeability. Conversely, molecules constructed entirely from D-amino acids are hyper-resistant to proteolytic cleavage, but generally lack conformational stability and membrane permeability. Since neither approach is a complete solution, we have combined these strategies to identify the first examples of all-D α-helical stapled and stitched peptides. As a template, we used a recently reported all D-linear peptide that is a potent inhibitor of the p53-Mdm2 interaction, but is devoid of cellular activity. To design both stapled and stitched all-D-peptide analogues, we used computational modelling to predict optimal staple placement. The resultant novel macrocyclic all D-peptide was determined to exhibit increased α-helicity, improved target binding, complete proteolytic stability and, most notably, cellular activity.

The intermediate polar FO Aquarii experienced its first-reported low-accretion states in 2016, 2017, and 2018. We establish that these low states occurred shortly after the system's white dwarf (WD) began spinning down, after having spent a quarter-century spinning up. FO Aquarii is the only intermediate polar whose period derivative has undergone a sign change, and it has now done so twice. By combining our spin-pulse timings with previous data, we determine that the WD's spin period has varied quasi-sinusoidally since the system's discovery, and an extrapolation predicts that the white dwarf was spinning down during newly discovered low states in photographic plates from 1964, 1965, and 1974. Thus, FO Aquarii's low states appear to occur exclusively during epochs of spindown. Additionally, our time-series photometry of the 2016-18 low states reveals that the mode of accretion is extremely sensitive to the accretion rate; when the system is fainter than V~14.0, the accretion onto the WD is largely stream-fed, but when it is brighter, it is almost exclusively disk-fed. The system's grazing eclipse remained detectable throughout all observations, confirming the uninterrupted presence of a disk-like structure, regardless of the accretion state. Our observations are consistent with theoretical predictions that during the low states, the accretion disk dissipates into a ring of diamagnetic blobs. Finally, a new XMM-Newton observation from 2017 indicates that the system's anomalously soft X-ray spectrum and diminished X-ray luminosity in the wake of the 2016 low state appear to be long-lasting changes compared to pre-2016 observations., peer-reviewed

The tumor suppressor p53 is a key mediator of cellular stress and DNA damage response cascades and is activated after exposure to ionizing radiation. Amplifying wild-type p53 expression by targeting negative regulators such as MDM2 in combination with external beam radiotherapy (EBRT) may result in increased therapeutic effects. The novel stapled peptide PM2 prevents MDM2 from suppressing wild-type p53, and is thus a promising agent for therapeutic combination with EBRT. Effects of PM2 and potential PM2-induced radiosensitivity were assessed in a panel of cancer cell lines using 2D cell viability assays. Western Blot and flow cytometric analyses were used to investigate the mechanisms behind the observed effects in samples treated with PM2 and EBRT. Finally, PM2-treatment combined with EBRT was evaluated in an in vitro 3D spheroid model. PM2-therapy decreased cell viability in wild-type p53, HPV-negative cell lines. Western Blotting and flow cytometry confirmed upregulation of p53, as well as initiation of p53-mediated apoptosis measured by increased cleaved caspase-3 and Noxa activity. Furthermore, 3D in vitro tumor spheroid experiments confirmed the superior effects of the combination, as the only treatment regime resulting in growth inhibition and complete spheroid disintegration. We conclude that PM2 induces antitumorigenic effects in wt p53 HPV-negative cancer cells and potentiates the effects of EBRT, ultimately resulting in tumor eradication in a 3D spheroid model. This strategy shows great potential as a new wt p53 specific tumor-targeting compound, and the combination of PM2 and EBRT could be a promising strategy to increase therapeutic effects and decrease adverse effects from radiotherapy.

Starting from an example of biosphere modelling, the paper considers the contribution of system dynamics to global modelling. The different purposes of modelling approaches are first considered. These are then related to a specific example—which is then seen to derive from the founding works in this area: “World Dynamics” and “The Limits To Growth.” The response to those publications is considered, both the contemporary reactions to them and the myths that have grown up around them. The paper discusses the general cultural acceptance of the perspective offered by these books and the continuing—and decidedly mixed—significance of these works to the field of system dynamics.

Protein flexibility poses a major challenge in binding site identification. Several computational pocket detection methods that utilize small-molecule probes in molecular dynamics (MD) simulations have been developed to address this issue. Although they have proven hugely successful at reproducing experimental structural data, their ability to predict new binding sites that are yet to be identified and characterized has not been demonstrated. Here, we report the use of benzenes as probe molecules in ligand-mapping MD (LMMD) simulations to predict the existence of two novel binding sites on the surface of the oncoprotein MDM2. One of them was serendipitously confirmed by biophysical assays and X-ray crystallography to be important for the binding of a new family of hydrocarbon stapled peptides that were specifically designed to target the other putative site. These results highlight the predictive power of LMMD and suggest that predictions derived from LMMD simulations can serve as a reliable basis for the identification of novel ligand binding sites in structure-based drug design.

This paper concerns the innovative use of a blend of systems thinking ideas in the ‘Munro Review of Child Protection’, a high-profile examination of child protection activities in England, conducted for the Department for Education. We go ‘behind the scenes’ to describe the OR methodologies and processes employed. The circumstances that led to the Review are outlined. Three specific contributions that systems thinking made to the Review are then described. First, the systems-based analysis and visualisation of how a ‘compliance culture’ had grown up. Second the creation of a large, complex systems map of current operations and the effects of past policies on them. Third, how the map gave shape to the range of issues the Review addressed and acted as an organising framework for the systemically coherent set of recommendations made. The paper closes with an outline of the main implementation steps taken so far to create a child protection system with the critically reflective properties of a learning organisation, and methodological reflections on the benefits of systems thinking to support organisational analysis.

I describe the world's first robotic observatory to interact with its observers entirely using the social media platforms Facebook or Twitter. The telescope "tweets" what it's doing, posts live images, and responds to observer commands through a comprehensive command set. Observation requests are queued and observed by a responsive queue engine. Its architecture, social media based image processing capability and several usage examples are also described., Accepted for publication in the proceeding of the Robotic Telescopes, Student Research, and Education Conference, June 2017

Mobile robotic platforms are an indispensable tool for various scientific and industrial applications. Robots are used to undertake missions whose execution is constrained by various factors, such as the allocated time or their remaining energy. Existing solutions for resource constrained multi-robot sensing mission planning provide optimal plans at a prohibitive computational complexity for online application [1],[2],[3]. A heuristic approach exists for an online, resource constrained sensing mission planning for a single vehicle [4]. This work proposes a Genetic Algorithm (GA) based heuristic for the Correlated Team Orienteering Problem (CTOP) that is used for planning sensing and monitoring missions for robotic teams that operate under resource constraints. The heuristic is compared against optimal Mixed Integer Quadratic Programming (MIQP) solutions. Results show that the quality of the heuristic solution is at the worst case equal to the 5% optimal solution. The heuristic solution proves to be at least 300 times more time efficient in the worst tested case. The GA heuristic execution required in the worst case less than a second making it suitable for online execution., 8 pages, 5 figures, accepted for publication in Robotics and Automation Letters (RA-L)

In this piece, I consider the paper by Stouten et al. (2017) in terms of behavioural science. I first consider what, in broad terms, a ‘behavioural turn’ might offer System Dynamics (SD) and then explore in more detail the scope of the territory within which a behavioural approach to SD might be useful.

A number of recent studies suggest that pollinating insects such as bees follow a Lévy random walk in their search for food. Such a strategy has been shown to be more efficient than classical Brownian motion when resources are scarce. However, the models that are currently used to predict the dispersal of pollen by insect pollinators still rely on the Brownian motion assumption and hence likely underestimate the probability of long-range dispersal. In this work, we propose a mechanistic model for pollen dispersal that is based on bee movement through space. The assumption that bees follow a Lévy random walk leads to a model with a fractional-order diffusion term. By numerically solving the model equations, we show that the tails of the stationary pollen distribution decay more slowly than with a classical diffusion model and hence spread over a larger area. The isolation distances required to keep outcrossing below a certain threshold are thus substantially increased. Our results therefore suggest that classical models based on the Brownian motion assumption might seriously underestimate the risk associated with GM pollen outcrossing in conventional crops.

A dominant theme for Friedrich Nietzsche, one that he often employs to punctuate and dramatise key theoretical concerns, is the distinction between truth and lie. While Nietzsche s truth/lie thematic finds expression through a number of concepts on the nature of human deceit, its role within his philosophy may be organised in accordance with three major fields of investigation: morality (where the lie is exaggerated and polemicised), the critique of knowledge (which advances the notion of truth as fiction), and aesthetics (where the lie is recast into a positive sense).Although this tripartite framework is heuristic, its value for the exami-nation of the truth/lie thematic is twofold: it clarifies the essential problems in Nietzsche s philosophical treatment and application of this theme which upon a cursory analysis appear confused and unproductive while at the same time providing a perspective that foregrounds the cumulative effect of his thought a dissolution of the conventional semantic integrity distinguishing truth from lie. This paper examines the semantic innovation in Nietzsche s truth/lie thematic, an approach that calls into question the positions of interpretation adopted in his philosophy.

Single crystals of Cu2ZnSnS4 (CZTS) have been grown by iodine vapor transport with and without addition of NaI. Crystals with tin-rich copper-poor and with zinc-rich copper-poor stoichiometries were obtained. The crystals were characterized by single crystal X-ray diffraction, energy-dispersive X-ray spectroscopy, photocurrent spectroscopy and electroreflectance spectroscopy using electrolyte contacts as well as by spectroscopic ellipsometry, Raman spectroscopy and photoluminescence spectroscopy (PL)/decay. Near-resonance Raman spectra indicate that the CZTS crystals adopt the kesterite structure with near-equilibrium residual disorder. The corrected external quantum efficiency of the p-type crystals measured by photocurrent spectroscopy approaches 100% close to the bandgap energy, indicating efficient carrier collection. The bandgap of the CZTS crystals estimated from the external quantum efficiency spectrum measured using an electrolyte contact was found to be 1.64-1.68 eV. An additional sub-bandgap photocurrent response (Urbach tail) was attributed to sub bandgap defect states. The room temperature PL of the crystals was attributed to radiative recombination via tail states, with lifetimes in the nanosecond range. At high excitation intensities, the PL spectrum also showed evidence of direct band to band transitions at ∼1.6 eV with a shorter decay time. Electrolyte electroreflectance spectra and spectra of the third derivative of the optical dielectric constant in the bandgap region were fitted to two optical transitions at 1.71 and 1.81 eV suggesting a larger valence band splitting than predicted theoretically. The high values of the EER broadening parameters (192 meV) indicate residual disorder consistent with the existence of tail states.

List of plasmids used in the study. (PDF 66 kb)

submittedVersion

p53 is a tetrameric protein with a thermodynamically unstable deoxyribonucleic acid (DNA)‐binding domain flanked by intrinsically disordered regulatory domains that control its activity. The unstable and disordered segments of p53 allow high flexibility as it interacts with binding partners and permits a rapid on/off switch to control its function. The p53 tetramer can exist in multiple conformational states, any of which can be stabilized by a particular modification. Here, we apply the allostery model to p53 to ask whether evidence can be found that the “activating” C‐terminal phosphorylation of p53 stabilizes a specific conformation of the protein in the absence of DNA. We take advantage of monoclonal antibodies for p53 that measure indirectly the following conformations: unfolded, folded, and tetrameric. A double antibody capture enzyme linked‐immunosorbent assay was used to observe evidence of conformational changes of human p53 upon phosphorylation by casein kinase 2 in vitro. It was demonstrated that oligomerization and stabilization of p53 wild‐type conformation results in differential exposure of conformational epitopes PAb1620, PAb240, and DO12 that indicates a reduction in the “unfolded” conformation and increases in the folded conformation coincide with increases in its oligomerization state. These data highlight that the oligomeric conformation of p53 can be stabilized by an activating enzyme and further highlight the utility of the allostery model when applied to understanding the regulation of unstable and intrinsically disordered proteins.