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Abstract Individual optical addressing in chains of trapped atomic ions requires the generation of many small, closely spaced beams with low cross-talk. Furthermore, implementing parallel operations necessitates phase, frequency, and amplitude control of each individual beam. Here, we present a scalable method for achieving all of these capabilities using a high-performance integrated photonic chip coupled to a network of optical fibre components. The chip design results in very low cross-talk between neighbouring channels even at the micrometre-scale spacing by implementing a very high refractive index contrast between the channel core and cladding. Furthermore, the photonic chip manufacturing procedure is highly flexible, allowing for the creation of devices with an arbitrary number of channels as well as non-uniform channel spacing at the chip output. We present the system used to integrate the chip within our ion trap apparatus and characterise the performance of the full individual addressing setup using a single trapped ion as a light-field sensor. Our measurements showed intensity cross-talk below ~10–3 across the chip, with minimum observed cross-talk as low as ~10–5.

Research on positional segregation in sport focuses on mechanisms perpetuating discrepancies in integrated contexts, including in majority-minority sports. However, theoretical explanations for positional segregation should apply to other status groups, such as ethnicity, that may be more salient in monoracial or nearly monoracial settings. We use 2018 to 2019 data on 790 NHL players and executives along with descriptive models previously applied to questions of racial segregation in sport to evaluate if stereotypes have led to ethnicity-based differences in athletes’ outcomes, using on-ice positions, leadership positions, team management positions, and penalty minutes related to stereotypes in playing style. Results show no evidence for ethnic stacking nor barriers to player leadership in the NHL but substantial differences in team management positions and penalty minutes. Our findings illuminate the degree to which theories concerning racial stereotyping mechanisms might be extended to apply in monoracial settings.

This paper shares findings from case study research into how school principals respond to ethical dilemmas. Preliminary research instigated a criteriological inquiry into the nature of schools as systems and findings of that inquiry conclude that schools are complex adaptive social systems rather than the open complicated systems they are unconsciously assumed to be in much of the school leadership literature and professional support. This misrepresentation and misunderstanding of the nature of schools as systems have significant consequences for the effective practice of school leadership and these are particularly poignant in responding to ethical dilemmas. This paper offers an overview of the argument that schools are complex adaptive social systems and identification of leadership work that is compatible and incompatible with that mental model of schools as a system. A finding from the case studies is that the principals act in ways consistent with the nature complexity, without explicit awareness of the mental schemas they are applying. Furthermore, their real life approaches are not reflected in much of the professional learning support and leadership theory currently available to them. The paper identifies principal practices from the case studies that are compatible with the real nature of schools as systems and considers the potential of those features as a framework for critique of policy, professional support and school leadership research and literature. It also proposes that the ways principals understand and respond to real ethical dilemmas challenge the ways schools continue to be defined.

Nuraghi are ubiquitous in the Bronze Age Sardinian landscape, but the reasons for their distribution and wider function remain poorly understood. Here, we evaluate the argument that these megalithic fortified towers were situated for visual control and thus represent nodes of political or coercive power. Using a dataset of 102 nuraghi, we perform a normalized cumulative viewshed to quantify nuraghe visibility in southwestern Sardinia. We analyze the co-occurrence of highly visible areas with variables pertinent to economic control of the landscape using a model comparison approach. The results suggest that there is no underlying structure to the location of the nuraghi that can be related to visual appreciability of the wider environment, indicating that visual control was not an important consideration during the later 2nd millennium b.c. We consider what the driving rationale may have been behind such a predominant site type that is yet apparently unrelated to political control. [ABSTRACT FROM AUTHOR]

Abstract Background The requirement of promyelocytic leukaemia protein (PML) in interferon (IFN)-induced cell apoptosis is well-established. However, the exact mechanisms by which the multiple isoforms of PML protein participate in this process remain not well-understood. We previously demonstrated that PML isoform II (PML-II) positively regulates induced gene expression during a type I IFN response and evaluate here how PML-II contributes to IFNα-induced cell death. Methods HeLa cells were transiently depleted of PML-II by siRNA treatment and the response of these cells to treatment with IFNα assessed by molecular assays of mRNA and proteins associated with IFN and apoptosis responses. Results In HeLa cells, death during IFNα stimulation was reduced by prior PML-II depletion. PML-II removal also considerably decreased the induced expression of pro-apoptotic ISGs such as ISG54 (IFIT2), and substantially impaired or prevented expression of PUMA and TRAIL, proteins that are associated with the intrinsic and extrinsic apoptotic pathways respectively. Thirdly, PML-II depletion enhanced ERK and AKT pro-survival signaling activation suggesting that PML-II normally suppresses signaling via these pathways, and that lack of PML-II hence led to greater than normal activation of AKT signaling upon IFNα stimulation and consequently increased resistance to IFNα-induced apoptosis. Conclusions The positive contribution of PML-II to the expression of various IFNα-induced pro-apoptotic proteins and its inhibition of pro-survival signaling together provide a mechanistic explanation for reduced apoptosis under conditions of PML deficiency and may account for at least part of the role of PML as a tumor suppressor gene. Video Abstract

The world is increasingly characterised by profound income, health and social inequalities (Appadurai, 2000). In recent decades development initiatives aimed at reducing these inequalities have been situated in a context of increasing globalisation with a dominant neo-liberal economic orthodoxy. This paper argues that neo-liberal globalisation contains inherent contradictions regarding choice and uniformity. This is illustrated in this paper through an exploration of the impact of neo-liberal globalisation on population policies and programmes. The dominant neo-liberal economic ideology that has influenced development over the last few decades has often led to alternative global visions being overlooked. Many current population and development debates are characterised by polarised arguments with strongly opposing aims and views. This raises the challenge of finding alternatives situated in more middle ground that both identify and promote the socially positive elements of neo-liberalism and state intervention, but also to limit their worst excesses within the population field and more broadly. This paper concludes with a discussion outlining the positive nature of middle ground and other possible alternatives. (Contains 1 note.)

ABSTRACT Modulation of host cell transcription, translation, and posttranslational modification processes is critical for the ability of many viruses to replicate efficiently within host cells. The human adenovirus (Ad) early region 4 open reading frame 3 (E4-ORF3) protein forms unique inclusions throughout the nuclei of infected cells and inhibits the antiviral Mre11-Rad50-Nbs1 DNA repair complex through relocalization. E4-ORF3 also induces SUMOylation of Mre11 and Nbs1. We recently identified additional cellular targets of E4-ORF3 and found that E4-ORF3 stimulates ubiquitin-like modification of 41 cellular proteins involved in a wide variety of processes. Among the proteins most abundantly modified in an E4-ORF3-dependent manner was the general transcription factor II–I (TFII-I). Analysis of Ad-infected cells revealed that E4-ORF3 induces TFII-I relocalization and SUMOylation early during infection. In the present study, we explored the relationship between E4-ORF3 and TFII-I. We found that Ad infection or ectopic E4-ORF3 expression leads to SUMOylation of TFII-I that precedes a rapid decline in TFII-I protein levels. We also show that E4-ORF3 is required for ubiquitination of TFII-I and subsequent proteasomal degradation. This is the first evidence that E4-ORF3 regulates ubiquitination. Interestingly, we found that E4-ORF3 modulation of TFII-I occurs in diverse cell types but only E4-ORF3 of Ad species C regulates TFII-I, providing critical insight into the mechanism by which E4-ORF3 targets TFII-I. Finally, we show that E4-ORF3 stimulates the activity of a TFII-I-repressed viral promoter during infection. Our results characterize a novel mechanism of TFII-I regulation by Ad and highlight how a viral protein can modulate a critical cellular transcription factor during infection. IMPORTANCE Adenovirus has evolved a number of mechanisms to target host signaling pathways in order to optimize the cellular environment during infection. E4-ORF3 is a small viral protein made early during infection, and it is critical for inactivating host antiviral responses. In addition to its ability to capture and reorganize cellular proteins, E4-ORF3 also regulates posttranslational modifications of target proteins, but little is known about the functional consequences of these modifications. We recently identified TFII-I as a novel target of E4-ORF3 that is relocalized into dynamic E4-ORF3 nuclear structures and subjected to E4-ORF3-mediated SUMO modification. Here, we show that TFII-I is targeted by E4-ORF3 for ubiquitination and proteasomal degradation and that E4-ORF3 stimulates gene expression from a TFII-I-repressed viral promoter. Our findings suggest that the specific targeting of TFII-I by E4-ORF3 is a mechanism to inactivate its antiviral properties. These studies provide further insight into how E4-ORF3 functions to counteract host antiviral responses.

ABSTRACT Protein expression and fatty acid profiles of biofilm cells of chlorhexidine-tolerant Delftia acidovorans (MIC = 15 µg/ml) and its chlorhexidine-susceptible mutant (MIC = 1 µg/ml) were investigated. The chlorhexidine-susceptible mutant (MT51) was derived from the parental strain (WT15) using Tn5 transposon mutagenesis. The disrupted gene was identified as tolQ, a component of the tolQRAB gene cluster known to be involved in outer membrane stability. Proteomic responses of biofilm cells were compared by differential in-gel electrophoresis following exposure to chlorhexidine at sub-MIC (10 µg/ml) and above-MIC (30 µg/ml) concentrations. Numerous changes in protein abundance were observed in biofilm cells following chlorhexidine exposure, suggesting that molecular changes occurred during adaptation to chlorhexidine. Forty proteins showing significant differences (≥1.5-fold; P < 0.05) were identified by mass spectrometry and were associated with various functions, including amino acid and lipid biosynthesis, protein translation, energy metabolism, and stress-related functions (e.g., GroEL, aspartyl/glutamyl-tRNA amidotransferase, elongation factor Tu, Clp protease, and hydroxymyristoyl-ACP dehydratase). Several proteins involved in fatty acid synthesis were affected by chlorhexidine, in agreement with fatty acid analysis, wherein chlorhexidine-induced shifts in the fatty acid profile were observed in the chlorhexidine-tolerant cells, primarily the cyclic fatty acids. Transmission electron microscopy revealed more prominent changes in the cell envelope of chlorhexidine-susceptible MT51 cells. This study suggests that multiple mechanisms involving both the cell envelope (and likely TolQ) and panmetabolic regulation play roles in chlorhexidine tolerance in D. acidovorans. IMPORTANCE Delftia acidovorans has been associated with a number of serious infections, including bacteremia, empyema, bacterial endocarditis, and ocular and urinary tract infections. It has also been linked with a variety of surface-associated nosocomial infections. Biofilm-forming antimicrobial-resistant D. acidovorans strains have also been isolated, including ones displaying resistance to the common broad-spectrum agent chlorhexidine. The mechanisms of chlorhexidine resistance in D. acidovorans are not known; hence, a chlorhexidine-susceptible mutant of the tolerant wild-type strain was obtained using transposon mutagenesis, and the proteome and ultrastructural changes of both strains were compared under chlorhexidine challenge.

Monoclonal antibodies (mAbs) can be potent and highly specific therapeutics, diagnostics and research reagents. Nonetheless, mAb discovery using current in vivo or in vitro approaches can be costly and time-consuming, with no guarantee of success. We have established a platform for rapid discovery and optimization of mAbs ex vivo. This DTLacO platform derives from a chicken B cell line that has been engineered to enable rapid selection and seamless maturation of high affinity mAbs. We have validated the DTLacO platform by generation of high affinity and specific mAbs to five cell surface targets, the receptor tyrosine kinases VEGFR2 and TIE2, the glycoprotein TROP2, the small TNF receptor family member FN14, and the G protein-coupled receptor FZD10. mAb discovery is rapid and humanization is straightforward, establishing the utility of the DTLacO platform for identification of mAbs for therapeutic and other applications.