Structure and Function of a Mycobacterial NHEJ DNA Repair Polymerase

Non homologous end-joining (NHEJ)-mediated repair of DNA double-strand breaks in prokaryotes requires Ku and a specific multidomain DNA ligase (LigD). We present crystal structures of the primase/polymerisation domain (PolDom) of Mycobacterium tuberculosis LigD, alone and complexed with nucleotides. The PolDom structure combines the general fold of the archaeo-eukaryotic primase (AEP) superfamily with additional loops and domains that together form a deep cleft on the surface, likely used for DNA binding. Enzymatic analysis indicates that the PolDom of LigD, even in the absence of accessory domains and Ku proteins, has the potential to recognise DNA end-joining intermediates. Strikingly, one of the main signals for the specific and efficient binding of PolDom to DNA is the presence of a 5'-phosphate group, located at the single/double-stranded junction at both gapped and 3'-protruding DNA molecules. Although structurally unrelated, Pol lambda and Pol mu, the two eukaryotic DNA polymerases involved in NHEJ, are endowed with a similar capacity to bind a 5'-phosphate group. Other properties that are beneficial for NHEJ, such as the ability to generate template distortions and realignments of the primer, displayed by Pol lambda and Pol mu, are shared by the PolDom of bacterial LigD. In addition, PolDom can perform non-mutagenic translesion synthesis on termini containing modified bases. Significantly, ribonucleotide insertion appears to be a recurrent theme associated with NHEJ, maximised in this case by the deployment of a dedicated primase, although its in vivo relevance is unknown

PIP5KIβ Selectively Modulates Apical Endocytosis in Polarized Renal Epithelial Cells

Localized synthesis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] at clathrin coated pits (CCPs) is crucial for the recruitment of adaptors and other components of the internalization machinery, as well as for regulating actin dynamics during endocytosis. PtdIns(4,5)P2 is synthesized from phosphatidylinositol 4-phosphate by any of three phosphatidylinositol 5-kinase type I (PIP5KI) isoforms (α, β or γ). PIP5KIβ localizes almost exclusively to the apical surface in polarized mouse cortical collecting duct cells, whereas the other isoforms have a less polarized membrane distribution. We therefore investigated the role of PIP5KI isoforms in endocytosis at the apical and basolateral domains. Endocytosis at the apical surface is known to occur more slowly than at the basolateral surface. Apical endocytosis was selectively stimulated by overexpression of PIP5KIβ whereas the other isoforms had no effect on either apical or basolateral internalization. We found no difference in the affinity for PtdIns(4,5)P2-containing liposomes of the PtdIns(4,5)P2 binding domains of epsin and Dab2, consistent with a generic effect of elevated PtdIns(4,5)P2 on apical endocytosis. Additionally, using apical total internal reflection fluorescence imaging and electron microscopy we found that cells overexpressing PIP5KIβ have fewer apical CCPs but more internalized coated structures than control cells, consistent with enhanced maturation of apical CCPs. Together, our results suggest that synthesis of PtdIns(4,5)P2 mediated by PIP5KIβ is rate limiting for apical but not basolateral endocytosis in polarized kidney cells. PtdIns(4,5)P2 may be required to overcome specific structural constraints that limit the efficiency of apical endocytosis. © 2013 Szalinski et al

Extracellular Matrix Aggregates from Differentiating Embryoid Bodies as a Scaffold to Support ESC Proliferation and Differentiation

Embryonic stem cells (ESCs) have emerged as potential cell sources for tissue engineering and regeneration owing to its virtually unlimited replicative capacity and the potential to differentiate into a variety of cell types. Current differentiation strategies primarily involve various growth factor/inducer/repressor concoctions with less emphasis on the substrate. Developing biomaterials to promote stem cell proliferation and differentiation could aid in the realization of this goal. Extracellular matrix (ECM) components are important physiological regulators, and can provide cues to direct ESC expansion and differentiation. ECM undergoes constant remodeling with surrounding cells to accommodate specific developmental event. In this study, using ESC derived aggregates called embryoid bodies (EB) as a model, we characterized the biological nature of ECM in EB after exposure to different treatments: spontaneously differentiated and retinoic acid treated (denoted as SPT and RA, respectively). Next, we extracted this treatment-specific ECM by detergent decellularization methods (Triton X-100, DOC and SDS are compared). The resulting EB ECM scaffolds were seeded with undifferentiated ESCs using a novel cell seeding strategy, and the behavior of ESCs was studied. Our results showed that the optimized protocol efficiently removes cells while retaining crucial ECM and biochemical components. Decellularized ECM from SPT EB gave rise to a more favorable microenvironment for promoting ESC attachment, proliferation, and early differentiation, compared to native EB and decellularized ECM from RA EB. These findings suggest that various treatment conditions allow the formulation of unique ESC-ECM derived scaffolds to enhance ESC bioactivities, including proliferation and differentiation for tissue regeneration applications. © 2013 Goh et al

Out-of-equilibrium physics in driven dissipative coupled resonator arrays

Coupled resonator arrays have been shown to exhibit interesting many- body physics including Mott and Fractional Hall states of photons. One of the main differences between these photonic quantum simulators and their cold atoms coun- terparts is in the dissipative nature of their photonic excitations. The natural equi- librium state is where there are no photons left in the cavity. Pumping the system with external drives is therefore necessary to compensate for the losses and realise non-trivial states. The external driving here can easily be tuned to be incoherent, coherent or fully quantum, opening the road for exploration of many body regimes beyond the reach of other approaches. In this chapter, we review some of the physics arising in driven dissipative coupled resonator arrays including photon fermionisa- tion, crystallisation, as well as photonic quantum Hall physics out of equilibrium. We start by briefly describing possible experimental candidates to realise coupled resonator arrays along with the two theoretical models that capture their physics, the Jaynes-Cummings-Hubbard and Bose-Hubbard Hamiltonians. A brief review of the analytical and sophisticated numerical methods required to tackle these systems is included.Comment: Chapter that appeared in "Quantum Simulations with Photons and Polaritons: Merging Quantum Optics with Condensed Matter Physics" edited by D.G.Angelakis, Quantum Science and Technology Series, Springer 201

Sri Lankan tsunami refugees: a cross sectional study of the relationships between housing conditions and self-reported health

BACKGROUND: On the 26th December 2004 the Asian tsunami devastated the Sri Lankan coastline. More than two years later, over 14,500 families were still living in transitional shelters. This study compares the health of the internally displaced people (IDP), living in transitional camps with those in permanent housing projects provided by government and non-government organisations in Sri Lanka. METHODS: This study was conducted in seven transitional camps and five permanent housing projects in the south west of Sri Lanka. Using an interviewer-led questionnaire, data on the IDPs' self-reported health and housing conditions were collected from 154 participants from transitional camps and 147 participants from permanent housing projects. Simple tabulation with non-parametric tests and logistic regression were used to identify and analyse relationships between housing conditions and the reported prevalence of specific symptoms. RESULTS: Analysis showed that living conditions were significantly worse in transitional camps than in permanent housing projects for all factors investigated, except 'having a leaking roof'. Transitional camp participants scored significantly lower on self-perceived overall health scores than those living in housing projects. After controlling for gender, age and marital status, living in a transitional camp compared to a housing project was found to be a significant risk factor for the following symptoms; coughs OR: 3.53 (CI: 2.11-5.89), stomach ache 4.82 (2.19-10.82), headache 5.20 (3.09-8.76), general aches and pains 6.44 (3.67-11.33) and feeling generally unwell 2.28 (2.51-7.29). Within transitional camp data, the only condition shown to be a significant risk factor for any symptom was household population density, which increased the risk of stomach aches 1.40 (1.09-1.79) and headaches 1.33 (1.01-1.77). CONCLUSION: Internally displaced people living in transitional camps are a vulnerable population and specific interventions need to be targeted at this population to address the health inequalities that they report to be experiencing. Further studies need to be conducted to establish which aspects of their housing environment predispose them to poorer health

The functional head of the Cambrian radiodontan (stem-group Euarthropoda) Amplectobelua symbrachiata

© The Author(s). 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. The attached file is the published version of the article

Two-orbital SU(N) magnetism with ultracold alkaline-earth atoms

Fermionic alkaline-earth atoms have unique properties that make them attractive candidates for the realization of novel atomic clocks and degenerate quantum gases. At the same time, they are attracting considerable theoretical attention in the context of quantum information processing. Here we demonstrate that when such atoms are loaded in optical lattices, they can be used as quantum simulators of unique many-body phenomena. In particular, we show that the decoupling of the nuclear spin from the electronic angular momentum can be used to implement many-body systems with an unprecedented degree of symmetry, characterized by the SU(N) group with N as large as 10. Moreover, the interplay of the nuclear spin with the electronic degree of freedom provided by a stable optically excited state allows for the study of spin-orbital physics. Such systems may provide valuable insights into strongly correlated physics of transition metal oxides, heavy fermion materials, and spin liquid phases.Comment: 15 pages, 10 figures. V2: extended experimental accessibility and Kondo sections in the main text (including new Fig. 5b) and in the Methods; reorganized other parts; added reference

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

Measuring multipartite entanglement via dynamic susceptibilities

Entanglement plays a central role in our understanding of quantum many body physics, and is fundamental in characterising quantum phases and quantum phase transitions. Developing protocols to detect and quantify entanglement of many-particle quantum states is thus a key challenge for present experiments. Here, we show that the quantum Fisher information, representing a witness for genuinely multipartite entanglement, becomes measurable for thermal ensembles via the dynamic susceptibility, i.e., with resources readily available in present cold atomic gas and condensed-matter experiments. This moreover establishes a fundamental connection between multipartite entanglement and many-body correlations contained in response functions, with profound implications close to quantum phase transitions. There, the quantum Fisher information becomes universal, allowing us to identify strongly entangled phase transitions with a divergent multipartiteness of entanglement. We illustrate our framework using paradigmatic quantum Ising models, and point out potential signatures in optical-lattice experiments.Comment: 5+5 pages, 3+2 figure

Critical Thinking in Nursing Education: Literature Review

The need for critical thinking in nursing has been accentuated in response to the rapidly changing health care environment. Nurses must think critically to provide effective care whilst coping with the expansion in role associated with the complexities of current health care systems. This literature review will present a history of inquiry into critical thinking and research to support the conclusion that critical thinking is necessary not only in the clinical practice setting, but also as an integral component of nursing education programs to promote the development of nurses’ critical thinking abilities. The aims of this paper are: (a) to review the literature on critical thinking; (b) to examine the dimensions of critical thinking; (c) to investigate the various critical thinking strategies for their appropriateness to enhance critical thinking in nurses, and; (d) to examine issues relating to evaluation of critical thinking skills in nursing.</ul