Chromophore-labelled, luminescent platinum complexes: syntheses, structures, and spectroscopic properties

Ligands based upon 4-carboxamide-2-phenylquinoline derivatives have been synthesised with solubilising octyl hydrocarbon chains and tethered aromatic chromophores to give naphthyl (HL2), anthracenyl (HL3) and pyrenyl (HL4) ligand variants, together with a non-chromophoric analogue (HL1) for comparison. 1H NMR spectroscopic studies of the ligands showed that two non-interchangeable isomers exist for HL2 and HL4 while only one isomer exists for HL1 and HL3. Supporting DFT calculations on HL4 suggest that the two isomers may be closely isoenergetic with a relatively high barrier to exchange of ca. 100 kJ mol−1. These new ligands were cyclometalated with Pt(II) to give complexes [Pt(L1–4)(acac)] (acac = acetylacetonate). The spectroscopically characterised complexes were studied using multinuclear NMR spectroscopy including 195Pt{1H} NMR studies which revealed δPt ca. −2785 ppm for [Pt(L1–4)(acac)]. X-ray crystallographic studies were undertaken on [Pt(L3)(acac)] and [Pt(L4)(acac)], each showing the weakly distorted square planar geometry at Pt(II); the structure of [Pt(L3)(acac)] showed evidence for intermolecular Pt–Pt interactions. The UV-vis. absorption studies show that the spectral profiles for [Pt(L2–4)(acac)] are a composite of the organic chromophore centred bands and a broad 1MLCT (5d → π*) band (ca. 440 nm) associated with the complex. Luminescence studies showed that complexes [Pt(L2–4)(acac)] are dual emissive with fluorescence characteristic of the tethered fluorophore and long-lived phosphorescence attributed to 3MLCT emission. In the case of the pyrenyl derivative, [Pt(L4)(acac)], the close energetic matching of the 3MLCT and 3LCpyr excited states led to an elongation of the 3MLCT emission lifetime (τ = 42 μs) under degassed solvent conditions, suggestive of energy transfer processes between the two states

TH17 cells require ongoing classic IL-6 receptor signaling to retain transcriptional and functional identity

Acting in concert with TGF-b, IL-6 signaling induces Th17 cell development by programming Th17-related genes via STAT3. A role for IL-6 signaling beyond the inductive phase of Th17 cell development has not been defined, as IL-23 signaling downstream of Th17 cell induction also activates STAT3 and is thought responsible for Th17 cell maintenance. Here, we find that IL-6 signaling is required for both induction and maintenance of Th17 cells; IL-6Ra–deficient Th17 cells rapidly lost their Th17 phenotype and did not cause disease in two models of colitis. Cotransfer of WT Th17 cells with IL-6Ra–deficient Th17 cells induced colitis but was unable to rescue phenotype loss of the latter. High IL-6 in the colon promoted classic, or cis, rather than trans receptor signaling that was required for maintenance of Th17 cells. Thus, ongoing classic IL6 signaling underpins the Th17 program and is required for Th17 cell maintenance and function

Human Cortical Neural Stem Cells Expressing Insulin‐Like Growth Factor‐I: A Novel Cellular Therapy for Alzheimer’s Disease

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/135291/1/sct3201653379.pd

Water soluble, cyclometalated Pt(II)–Ln(III) conjugates towards novel bimodal imaging agents

Facile conjugation of a luminescent cyclometalated PtII complex with a DO3A-derived GdIII moiety yields a hybrid species with visible luminescence and enhanced relaxivity

Photon Dominated Regions in NGC 3603

Aims: We aim at deriving the excitation conditions of the interstellar gas as well as the local FUV intensities in the molecular cloud surrounding NGC 3603 to get a coherent picture of how the gas is energized by the central stars. Methods: The NANTEN2-4m submillimeter antenna is used to map the [CI] 1-0, 2-1 and CO 4-3, 7-6 lines in a 2' x 2' region around the young OB cluster NGC 3603 YC. These data are combined with C18O 2-1 data, HIRES-processed IRAS 60 and 100 micron maps of the FIR continuum, and Spitzer/IRAC maps. Results: The NANTEN2 observations show the presence of two molecular clumps located south-east and south-west of the cluster and confirm the overall structure already found by previous CS and C18O observations. We find a slight position offset of the peak intensity of CO and [CI], and the atomic carbon appears to be further extended compared to the molecular material. We used the HIRES far-infrared dust data to derive a map of the FUV field heating the dust. We constrain the FUV field to values of \chi = 3 - 6 \times 10^3 in units of the Draine field across the clouds. Approximately 0.2 to 0.3 % of the total FUV energy is re-emitted in the [CII] 158 {\mu}m cooling line observed by ISO. Applying LTE and escape probability calculations, we derive temperatures (TMM1 = 43 K, TMM2 = 47 K), column densities (N(MM1) = 0.9 \times 10^22 cm^-2, N(MM2) = 2.5 \times 10^22 cm^-2) and densities (n(MM1) = 3 \times 10^3 cm^-3, n(MM2) = 10^3 -10^4 cm^-3) for the two observed molecular clumps MM1 and MM2. Conclusions: The cluster is strongly interacting with the ambient molecular cloud, governing its structure and physical conditions. A stability analysis shows the existence of gravitationally collapsing gas clumps which should lead to star formation. Embedded IR sources have already been observed in the outskirts of the molecular cloud and seem to support our conclusions.Comment: 13 pages, 10 figures, accepted for publication by A&

Self-Organizing Networks in Complex Infrastructure Projects

While significant importance is given to establishing formal organizational and contractual hierarchies, existing project management techniques neglect the management of self-organizing networks in large-infrastructure projects. We offer a case-specific illustration of self-organization using network theory as an investigative lens. The findings have shown that these networks exhibit a high degree of sparseness, short path lengths, and clustering in dense “functional” communities around highly connected actors, thus demonstrating the small-world topology observed in diverse real-world self-organized networks. The study underlines the need for these non-contractual functions and roles to be identified and sponsored, allowing the self-organizing network the space and capacity to evolve

Interleukin-17D and Nrf2 mediate initial innate immune cell recruitment and restrict MCMV infection.

Innate immune cells quickly infiltrate the site of pathogen entry and not only stave off infection but also initiate antigen presentation and promote adaptive immunity. The recruitment of innate leukocytes has been well studied in the context of extracellular bacterial and fungal infection but less during viral infections. We have recently shown that the understudied cytokine Interleukin (IL)-17D can mediate neutrophil, natural killer (NK) cell and monocyte infiltration in sterile inflammation and cancer. Herein, we show that early immune cell accumulation at the peritoneal site of infection by mouse cytomegalovirus (MCMV) is mediated by IL-17D. Mice deficient in IL-17D or the transcription factor Nuclear factor (erythroid-derived 2)-like 2 (Nrf2), an inducer of IL-17D, featured an early decreased number of innate immune cells at the point of viral entry and were more susceptible to MCMV infection. Interestingly, we were able to artificially induce innate leukocyte infiltration by applying the Nrf2 activator tert-butylhydroquinone (tBHQ), which rendered mice less susceptible to MCMV infection. Our results implicate the Nrf2/IL-17D axis as a sensor of viral infection and suggest therapeutic benefit in boosting this pathway to promote innate antiviral responses

The BARD1 Cys557Ser Variant and Breast Cancer Risk in Iceland

BACKGROUND: Most, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer. METHODS AND FINDINGS: The Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.11–3.01, p = 0.014). The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22–4.75, p = 0.015). Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16–8.40, p = 0.046) in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors of contemporary carriers lived in a single county in the southeast of Iceland and that all carriers shared a SNP haplotype, which is suggestive of a founder event. Cys557Ser was found on the same SNP haplotype background in the HapMap Project CEPH sample of Utah residents. CONCLUSIONS: Our findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation

Whole genome characterization of sequence diversity of 15,220 Icelanders

Understanding of sequence diversity is the cornerstone of analysis of genetic disorders, population genetics, and evolutionary biology. Here, we present an update of our sequencing set to 15,220 Icelanders who we sequenced to an average genome-wide coverage of 34X. We identified 39,020,168 autosomal variants passing GATK filters: 31,079,378 SNPs and 7,940,790 indels. Calling de novo mutations (DNMs) is a formidable challenge given the high false positive rate in sequencing datasets relative to the mutation rate. Here we addressed this issue by using segregation of alleles in three-generation families. Using this transmission assay, we controlled the false positive rate and identified 108,778 high quality DNMs. Furthermore, we used our extended family structure and read pair tracing of DNMs to a panel of phased SNPs, to determine the parent of origin of 42,961 DNMs.Peer Reviewe

Germline sequence variants in TGM3 and RGS22 confer risk of basal cell carcinoma.

To access publisher's full text version of this article. Please click on the hyperlink in Additional Links field.To search for new sequence variants that confer risk of cutaneous basal cell carcinoma (BCC), we conducted a genome-wide association study of 38.5 million single nucleotide polymorphisms (SNPs) and small indels identified through whole-genome sequencing of 2230 Icelanders. We imputed genotypes for 4208 BCC patients and 109 408 controls using Illumina SNP chip typing data, carried out association tests and replicated the findings in independent population samples. We found new BCC susceptibility loci at TGM3 (rs214782[G], P = 5.5 × 10(-17), OR = 1.29) and RGS22 (rs7006527[C], P = 8.7 × 10(-13), OR = 0.77). TGM3 encodes transglutaminase type 3, which plays a key role in production of the cornified envelope during epidermal differentiation.Red Tematica de Investigacion Cooperative en Cancer RD06/0020/1054 Danish Cancer Society "Europe Against Cancer": European Prospective Investigation into Cancer and Nutrition (EPIC) deCODE Genetics/AMGE