Cell Cycle Entry Control in Naïve and Memory CD8⁺ T Cells

CD8+ T cells play important roles in immunity and immuno-oncology. Upon antigen recognition and co-stimulation, naïve CD8+ T cells escape from dormancy to engage in a complex programme of cellular growth, cell cycle entry and differentiation, resulting in rapid proliferation cycles that has the net effect of producing clonally expanded, antigen-specific cytotoxic T lymphocytes (CTLs). A fraction of activated T cells will re-enter dormancy by differentiating into memory T cells, which have essential roles in adaptive immunity. In this review, we discuss the current understanding of cell cycle entry control in CD8+ T cells and crosstalk between these mechanisms and pathways regulating immunological phenotypes

The Use Of Automated Telephone Interfaces With Customers By Local Organizations: Best Practices And Exploratory Investigation Of Usage

Automated telephone systems (ATS) have been criticized by customers as a frustrating way to interact with an organization.  This study seeks to discover ATS best practices, assess how many local organizations (as opposed to 1-800 call centers) are utilizing various ATSs, and determine which ATS best practices these local organizations are adopting.  A list of 35 best practices were found.  An exploratory examination of 400 organizations in a mid-sized mid-western city revealed that very few use an advanced ATS, with 51% using a simple answering machine. The adoption of best practices by these organizations was quite varied.  Managerial recommendations as well as future research suggestions are offered

Discerning population connectivity and natal origins of Pacific herring (Clupea pallasi): inferences on population structure from otolith chemistry

Pacific herring, Clupea pallasi, undertake annual migrations between feeding and spawning grounds that link life stages, habitats, populations, communities, and ecosystems. However, movement patterns of these highly mobile fish are poorly understood. Declines in Pacific herring abundance and slow population recoveries in the absence of fishing pressure have elevated concerns over the status of this ecologically, economically, and culturally important species. Pacific herring spawn on substrate in nearshore habitats where eggs and larvae develop for approximately two weeks before hatching. Early development within discrete spawning grounds could facilitate the incorporation of distinctive chemical signatures within otoliths that could be used as intrinsic markers to trace movements and mixing among groups or regions. Identifying the direction and strength of connectivity among groups can reveal source populations and promote the development of population- and ecosystem-based management strategies that reflect ecologically relevant spatial scales. We applied otolith microchemistry data to: 1) test the utility of elemental signatures to distinguish the natal origins of larval herring; 2) evaluate inter-annual variation in natal signatures within spawning sites; and 3) assess the similarity of edge and natal signatures of adult herring within and among spawning sites. In 2015 and 2016, we sampled actively spawning adult herring and their offspring in the northern Salish Sea and across British Columbia, Canada. Otoliths were extracted, aged, and their elemental composition analyzed using laser ablation inductively coupled plasma mass spectrometry. Cohort-specific analyses were applied to assess consistency among elemental signatures and broader, age-specific movement patterns. Our analyses show that otolith elemental signatures of Pacific herring can provide insight into complex population structure at scales of 10s – 1000 kms to inform and enhance spatially-explicit approaches to conservation and management

A Colorimetric Chemosensor Based on a Nozoe Azulene That Detects Fluoride in Aqueous/Alcoholic Media

Colorimetry is an advantageous method for detecting fluoride in drinking water in a resource-limited context, e. g., in parts of the developing world where excess fluoride intake leads to harmful health effects. Here we report a selective colorimetric chemosensor for fluoride that employs an azulene as the reporter motif and a pinacolborane as the receptor motif. The chemosensor, NAz-6-Bpin, is prepared using the Nozoe azulene synthesis, which allows for its rapid and low-cost synthesis. The chemosensor gives a visually observable response to fluoride both in pure organic solvent and also in water/alcohol binary solvent mixtures

Measuring the Pharmacodynamic Effects of a Novel Hsp90 Inhibitor on HER2/neu Expression in Mice Using 89Zr-DFO-Trastuzumab

The positron-emitting radionuclide (89)Zr (t(1/2) = 3.17 days) was used to prepare (89)Zr-radiolabeled trastuzumab for use as a radiotracer for characterizing HER2/neu-positive breast tumors. In addition, pharmacodynamic studies on HER2/neu expression levels in response to therapeutic doses of PU-H71 (a specific inhibitor of heat-shock protein 90 [Hsp90]) were conducted.Trastuzumab was functionalized with desferrioxamine B (DFO) and radiolabeled with [(89)Zr]Zr-oxalate at room temperature using modified literature methods. ImmunoPET and biodistribution experiments in female, athymic nu/nu mice bearing sub-cutaneous BT-474 (HER2/neu positive) and/or MDA-MB-468 (HER2/neu negative) tumor xenografts were conducted. The change in (89)Zr-DFO-trastuzumab tissue uptake in response to high- and low-specific-activity formulations and co-administration of PU-H71 was evaluated by biodistribution studies, Western blot analysis and immunoPET. (89)Zr-DFO-trastuzumab radiolabeling proceeded in high radiochemical yield and specific-activity 104.3+/-2.1 MBq/mg (2.82+/-0.05 mCi/mg of mAb). In vitro assays demonstrated >99% radiochemical purity with an immunoreactive fraction of 0.87+/-0.07. In vivo biodistribution experiments revealed high specific BT-474 uptake after 24, 48 and 72 h (64.68+/-13.06%ID/g; 71.71+/-10.35%ID/g and 85.18+/-11.10%ID/g, respectively) with retention of activity for over 120 h. Pre-treatment with PU-H71 was followed by biodistribution studies and immunoPET of (89)Zr-DFO-trastuzumab. Expression levels of HER2/neu were modulated during the first 24 and 48 h post-administration (29.75+/-4.43%ID/g and 41.42+/-3.64%ID/g, respectively). By 72 h radiotracer uptake (73.64+/-12.17%ID/g) and Western blot analysis demonstrated that HER2/neu expression recovered to baseline levels.The results indicate that (89)Zr-DFO-trastuzumab provides quantitative and highly-specific delineation of HER2/neu positive tumors, and has potential to be used to measure the efficacy of long-term treatment with Hsp90 inhibitors, like PU-H71, which display extended pharmacodynamic profiles

CATH: comprehensive structural and functional annotations for genome sequences.

The latest version of the CATH-Gene3D protein structure classification database (4.0, http://www.cathdb.info) provides annotations for over 235,000 protein domain structures and includes 25 million domain predictions. This article provides an update on the major developments in the 2 years since the last publication in this journal including: significant improvements to the predictive power of our functional families (FunFams); the release of our 'current' putative domain assignments (CATH-B); a new, strictly non-redundant data set of CATH domains suitable for homology benchmarking experiments (CATH-40) and a number of improvements to the web pages

New functional families (FunFams) in CATH to improve the mapping of conserved functional sites to 3D structures.

CATH version 3.5 (Class, Architecture, Topology, Homology, available at http://www.cathdb.info/) contains 173 536 domains, 2626 homologous superfamilies and 1313 fold groups. When focusing on structural genomics (SG) structures, we observe that the number of new folds for CATH v3.5 is slightly less than for previous releases, and this observation suggests that we may now know the majority of folds that are easily accessible to structure determination. We have improved the accuracy of our functional family (FunFams) sub-classification method and the CATH sequence domain search facility has been extended to provide FunFam annotations for each domain. The CATH website has been redesigned. We have improved the display of functional data and of conserved sequence features associated with FunFams within each CATH superfamily

The Sydney-AAO Multi-object Integral field spectrograph (SAMI)

We demonstrate a novel technology that combines the power of the multi-object spectrograph with the spatial multiplex advantage of an integral field spectrograph (IFS). The Sydney-AAO Multi-object IFS (SAMI) is a prototype wide-field system at the Anglo-Australian Telescope (AAT) that allows 13 imaging fibre bundles ("hexabundles") to be deployed over a 1-degree diameter field of view. Each hexabundle comprises 61 lightly-fused multimode fibres with reduced cladding and yields a 75 percent filling factor. Each fibre core diameter subtends 1.6 arcseconds on the sky and each hexabundle has a field of view of 15 arcseconds diameter. The fibres are fed to the flexible AAOmega double-beam spectrograph, which can be used at a range of spectral resolutions (R=lambda/delta(lambda) ~ 1700-13000) over the optical spectrum (3700-9500A). We present the first spectroscopic results obtained with SAMI for a sample of galaxies at z~0.05. We discuss the prospects of implementing hexabundles at a much higher multiplex over wider fields of view in order to carry out spatially--resolved spectroscopic surveys of 10^4 to 10^5 galaxies.Comment: 24 pages, 16 figures. Accepted by MNRA

The CATH domain structure database: new protocols and classification levels give a more comprehensive resource for exploring evolution

We report the latest release (version 3.0) of the CATH protein domain database (). There has been a 20% increase in the number of structural domains classified in CATH, up to 86 151 domains. Release 3.0 comprises 1110 fold groups and 2147 homologous superfamilies. To cope with the increases in diverse structural homologues being determined by the structural genomics initiatives, more sensitive methods have been developed for identifying boundaries in multi-domain proteins and for recognising homologues. The CATH classification update is now being driven by an integrated pipeline that links these automated procedures with validation steps, that have been made easier by the provision of information rich web pages summarising comparison scores and relevant links to external sites for each domain being classified. An analysis of the population of domains in the CATH hierarchy and several domain characteristics are presented for version 3.0. We also report an update of the CATH Dictionary of homologous structures (CATH-DHS) which now contains multiple structural alignments, consensus information and functional annotations for 1459 well populated superfamilies in CATH. CATH is directly linked to the Gene3D database which is a projection of CATH structural data onto ∼2 million sequences in completed genomes and UniProt