66 research outputs found
Tuning the magnetic ground state of a novel tetranuclear Nickel(II) molecular complex by high magnetic fields
Electron spin resonance and magnetization data in magnetic fields up to 55 T
of a novel multicenter paramagnetic molecular complex [L_2Ni_4(N_3)(O_2C
Ada)_4](Cl O_4) are reported. In this compound, four Ni centers each having a
spin S = 1 are coupled in a single molecule via bridging ligands (including a
\mu_4-azide) which provide paths for magnetic exchange. Analysis of the
frequency and temperature dependence of the ESR signals yields the relevant
parameters of the spin Hamiltonian, in particular the single ion anisotropy gap
and the g factor, which enables the calculation of the complex energy spectrum
of the spin states in a magnetic field. The experimental results give
compelling evidence for tuning the ground state of the molecule by magnetic
field from a nonmagnetic state at small fields to a magnetic one in strong
fields owing to the spin level crossing at a field of ~25 T.Comment: revised version, accepted for publication in Physical Review
Antiferromagnetic Dimers of Ni(II) in the S=1 Spin-Ladder Na_2Ni_2(C_2O_4)_3(H_2O)_2
We report the synthesis, crystal structure and magnetic properties of the S=1
2-leg spin-ladder compound Na_2Ni_2(C_2O_4)_3(H_2O)_2. The magnetic properties
were examined by magnetic susceptibility and pulsed high field magnetization
measurements. The magnetic excitations have been measured in high field high
frequency ESR. Although the Ni(II) ions form structurally a 2-leg ladder, an
isolated dimer model consistently describes the observations very well. The
analysis of the temperature dependent magnetization data leads to a magnetic
exchange constant of J=43 K along the rungs of the ladder and an average value
of the g-factor of 2.25. From the ESR measurements, we determined the single
ion anisotropy to D=11.5 K. The validity of the isolated dimer model is
supported by Quantum Monte Carlo calculations, performed for several ratios of
interdimer and intradimer magnetic exchange and taking into account the
experimentally determined single ion anisotropy. The results can be understood
in terms of the different coordination and superexchange angles of the oxalate
ligands along the rungs and legs of the 2-leg spin ladder.Comment: 8 pages, 10 figure
High field level crossing studies on spin dimers in the low dimensional quantum spin system NaT(CO)(HO) with T=Ni,Co,Fe,Mn
In this paper we demonstrate the application of high magnetic fields to study
the magnetic properties of low dimensional spin systems. We present a case
study on the series of 2-leg spin-ladder compounds
NaT(CO)(HO) with T = Ni, Co, Fe and Mn. In all
compounds the transition metal is in the high spin configuation. The
localized spin varies from S=1 to 3/2, 2 and 5/2 within this series. The
magnetic properties were examined experimentally by magnetic susceptibility,
pulsed high field magnetization and specific heat measurements. The data are
analysed using a spin hamiltonian description. Although the transition metal
ions form structurally a 2-leg ladder, an isolated dimer model consistently
describes the observations very well. This behaviour can be understood in terms
of the different coordination and superexchange angles of the oxalate ligands
along the rungs and legs of the 2-leg spin ladder. All compounds exhibit
magnetic field driven ground state changes which at very low temperatures lead
to a multistep behaviour in the magnetization curves. In the Co and Fe
compounds a strong axial anisotropy induced by the orbital magnetism leads to a
nearly degenerate ground state and a strongly reduced critical field. We find a
monotonous decrease of the intradimer magnetic exchange if the spin quantum
number is increased
Genetics and beyond - the transcriptome of human monocytes and disease susceptibility
BACKGROUND: Variability of gene expression in human may link gene sequence variability and phenotypes; however, non-genetic variations, alone or in combination with genetics, may also influence expression traits and have a critical role in physiological and disease processes. METHODOLOGY/PRINCIPAL FINDINGS: To get better insight into the overall variability of gene expression, we assessed the transcriptome of circulating monocytes, a key cell involved in immunity-related diseases and atherosclerosis, in 1,490 unrelated individuals and investigated its association with >675,000 SNPs and 10 common cardiovascular risk factors. Out of 12,808 expressed genes, 2,745 expression quantitative trait loci were detected (P<5.78x10(-12)), most of them (90%) being cis-modulated. Extensive analyses showed that associations identified by genome-wide association studies of lipids, body mass index or blood pressure were rarely compatible with a mediation by monocyte expression level at the locus. At a study-wide level (P<3.9x10(-7)), 1,662 expression traits (13.0%) were significantly associated with at least one risk factor. Genome-wide interaction analyses suggested that genetic variability and risk factors mostly acted additively on gene expression. Because of the structure of correlation among expression traits, the variability of risk factors could be characterized by a limited set of independent gene expressions which may have biological and clinical relevance. For example expression traits associated with cigarette smoking were more strongly associated with carotid atherosclerosis than smoking itself. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that the monocyte transcriptome is a potent integrator of genetic and non-genetic influences of relevance for disease pathophysiology and risk assessment
Pharmacological and pre-clinical safety profile of rSIV.F/HN, a hybrid lentiviral vector for cystic fibrosis gene therapy
RATIONALE AND OBJECTIVE: Cystic fibrosis (CF) is caused by mutations in the CF Transmembrane Conductance Regulator (CFTR) gene. CFTR modulators offer significant improvements, but approximately 10% of patients remain nonresponsive or are intolerant. This study provides an analysis of rSIV.F/HN, a lentiviral vector optimized for lung delivery, including CFTR protein expression, functional correction of CFTR defects and genomic integration site analysis in preparation for a first-in-human clinical trial.METHODS: Air-liquid interface cultures of primary human bronchial epithelial cells (HBEC) from CF patients (F508del/F508del), as well as a CFTR-deficient immortalized human lung epithelial cell line mimicking Class I (CFTR-null) homozygous mutations, were used to assess transduction efficiency. Quantification methods included a novel proximity ligation assay (PLA) for CFTR protein expression. For assessment of CFTR channel activity, Ussing chamber studies were conducted. The safety profile was assessed using integration site analysis and in vitro insertional mutagenesis studies.RESULTS: rSIV.F/HN expressed CFTR and restored CFTR-mediated chloride currents to physiological levels in primary F508del/F508del HBECs as well as in a Class I cells. In contrast, the latter could not be achieved by small-molecule CFTR modulators, underscoring the potential of gene therapy for this mutation class. Combination of rSIV.F/HN-CFTR with the potentiator ivacaftor showed a greater than additive effect. The genomic integration pattern showed no site predominance (frequency of occurrence ≤10%), and a low risk of insertional mutagenesis was observed in an in vitro immortalization assay.CONCLUSIONS: The results underscore rSIV.F/HN as a promising gene therapy vector for CF, providing a mutation-agnostic treatment option.</p
Clonogenic growth of human breast cancer cells co-cultured in direct contact with serum-activated fibroblasts
INTRODUCTION: Accumulating evidence suggests that fibroblasts play a pivotal role in promoting the growth of breast cancer cells. The objective of the present study was to characterize and validate an in vitro model of the interaction between small numbers of human breast cancer cells and human fibroblasts. METHODS: We measured the clonogenic growth of small numbers of human breast cancer cells co-cultured in direct contact with serum-activated, normal human fibroblasts. Using DNA microarrays, we also characterized the gene expression profile of the serum-activated fibroblasts. In order to validate the in vivo relevance of our experiments, we then analyzed clinical samples of metastatic breast cancer for the presence of myofibroblasts expressing α-smooth muscle actin. RESULTS: Clonogenic growth of human breast cancer cells obtained directly from in situ and invasive tumors was dramatically and consistently enhanced when the tumor cells were co-cultured in direct contact with serum-activated fibroblasts. This effect was abolished when the cells were co-cultured in transwells separated by permeable inserts. The fibroblasts in our experimental model exhibited a gene expression signature characteristic of 'serum response' (i.e. myofibroblasts). Immunostaining of human samples of metastatic breast cancer tissue confirmed that myofibroblasts are in direct contact with breast cancer cells. CONCLUSION: Serum-activated fibroblasts promote the clonogenic growth of human breast cancer cells in vitro through a mechanism that involves direct physical contact between the cells. This model shares many important molecular and phenotypic similarities with the fibroblasts that are naturally found in breast cancers
Next-generation insights into regulatory T cells: expression profiling and FoxP3 occupancy in Human
Regulatory T-cells (Treg) play an essential role in the negative regulation of immune answers by developing an attenuated cytokine response that allows suppressing proliferation and effector function of T-cells (CD4+ Th). The transcription factor FoxP3 is responsible for the regulation of many genes involved in the Treg gene signature. Its ablation leads to severe immune deficiencies in human and mice. Recent developments in sequencing technologies have revolutionized the possibilities to gain insights into transcription factor binding by ChiP-seq and into transcriptome analysis by mRNA-seq. We combine FoxP3 ChiP-seq and mRNA-seq in order to understand the transcriptional differences between primary human CD4+ T helper and regulatory T-cells, as well as to study the role of FoxP3 in generating those differences. We show, that mRNA-seq allows analyzing the transcriptomal landscape of T-cells including the expression of specific splice variants at much greater depth than previous approaches, whereas 50% of transcriptional regulation events have not been described before by using diverse array technologies. We discovered splicing patterns like the expression of a kinase-dead isoform of IRAK1 upon T-cell activation. The immunoproteasome is up-regulated in both Treg and CD4+ Th cells upon activation, whereas the ‘standard’ proteasome is up-regulated in Tregs only upon activation
Next-generation insights into regulatory T cells: expression profiling and FoxP3 occupancy in Human
Regulatory T-cells (Treg) play an essential role in the negative regulation of immune answers by developing an attenuated cytokine response that allows suppressing proliferation and effector function of T-cells (CD4+ Th). The transcription factor FoxP3 is responsible for the regulation of many genes involved in the Treg gene signature. Its ablation leads to severe immune deficiencies in human and mice. Recent developments in sequencing technologies have revolutionized the possibilities to gain insights into transcription factor binding by ChiP-seq and into transcriptome analysis by mRNA-seq. We combine FoxP3 ChiP-seq and mRNA-seq in order to understand the transcriptional differences between primary human CD4+ T helper and regulatory T-cells, as well as to study the role of FoxP3 in generating those differences. We show, that mRNA-seq allows analyzing the transcriptomal landscape of T-cells including the expression of specific splice variants at much greater depth than previous approaches, whereas 50% of transcriptional regulation events have not been described before by using diverse array technologies. We discovered splicing patterns like the expression of a kinase-dead isoform of IRAK1 upon T-cell activation. The immunoproteasome is up-regulated in both Treg and CD4+ Th cells upon activation, whereas the ‘standard’ proteasome is up-regulated in Tregs only upon activation
Typing Late Prehistoric Cows and Bulls—Osteology and Genetics of Cattle at the Eketorp Ringfort on the Öland Island in Sweden
Human management of livestock and the presence of different breeds have been discussed in archaeozoology and animal breeding. Traditionally osteometrics has been the main tool in addressing these questions. We combine osteometrics with molecular sex identifications of 104 of 340 morphometrically analysed bones in order to investigate the use of cattle at the Eketorp ringfort on the Öland island in Sweden. The fort is dated to 300–1220/50 A.D., revealing three different building phases. In order to investigate specific patterns and shifts through time in the use of cattle the genetic data is evaluated in relation to osteometric patterns and occurrence of pathologies on cattle metapodia. Males were genotyped for a Y-chromosomal SNP in UTY19 that separates the two major haplogroups, Y1 and Y2, in taurine cattle. A subset of the samples were also genotyped for one SNP involved in coat coloration (MC1R), one SNP putatively involved in resistance to cattle plague (TLR4), and one SNP in intron 5 of the IGF-1 gene that has been associated to size and reproduction
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