Borane adducts of punicine and of its dehydroxy derivatives (pyridinium-1-yl)-2-and 3-phenolates

The natural product punicine (Punica granatum) exists in two tautomeric forms, the cross-conjugated mesomeric betaine 1-(pyridinium-1-yl)-2-hydroxy-phenyl-5-olate and the conjugated mesomeric betaine 1-(pyridinium-1-yl)-5-hydroxy-phenyl-2-olate. Punicine as well as its picoline derivatives reacted with tris(pentafluorophenyl)borane exclusively at the 2'-olate group to form zwitterionic borates. Correspondingly, the 5'-dehydroxy derivate of punicine, the conjugated heterocyclic mesomeric betaine 1-(pyridinium-1-yl)-phenyl-2-olate and its picoline derivatives also gave borates, whereas analogous reactions of the cross-conjugated isomer 2'-dehydroxypunicine [1-(pyridinium-1-yl)-phenyl-3-olatel did not result in the formation of stable adducts. (C) 2020 Elsevier Ltd. All rights reserved.Peer reviewe

RNA-protein correlation of liver toxicity markers in HepaRG cells

The liver is a main target organ for the toxicity of many different compounds. While in general, in vivo testing is still routinely used for assessing the hepatotoxic potential of test chemicals, the use of in vitro models offers advantages with regard to throughput, consumption of resources, and animal welfare aspects. Using the human hepatoma cell line HepaRG, we performed a comparative evaluation of a panel of hepatotoxicity marker mRNAs and proteins after exposure of the cells to 30 different pesticidal active compounds comprising herbizides, fungicides, insecticides, and others. The panel of hepatotoxicity markers included nuclear receptor target genes, key players of fatty acid and bile acid metabolism-related pathways, as well as recently identified biomarkers of drug-induced liver injury. Moreover, marker genes and proteins were identified, for example, S100P, ANXA10, CYP1A1, and CYP7A1. These markers respond with high sensitivity to stimulation with chemically diverse test compounds already at non-cytotoxic concentrations. The potency of the test compounds, determined as an overall parameter of their ability to deregulate marker expression in vitro, was very similar between the mRNA and protein levels. Thus, this study does not only characterize the response of human liver cells to 30 different pesticides but also demonstrates that hepatotoxicity testing in human HepaRG cells yields well comparable results at the mRNA and protein levels. Furthermore, robust hepatotoxicity marker genes and proteins were identified in HepaRG cells

Critical Casimir effect in films for generic non-symmetry-breaking boundary conditions

Systems described by an O(n) symmetrical $\phi^4$ Hamiltonian are considered in a $d$-dimensional film geometry at their bulk critical points. A detailed renormalization-group (RG) study of the critical Casimir forces induced between the film's boundary planes by thermal fluctuations is presented for the case where the O(n) symmetry remains unbroken by the surfaces. The boundary planes are assumed to cause short-ranged disturbances of the interactions that can be modelled by standard surface contributions $\propto \bm{\phi}^2$ corresponding to subcritical or critical enhancement of the surface interactions. This translates into mesoscopic boundary conditions of the generic symmetry-preserving Robin type $\partial_n\bm{\phi}=\mathring{c}_j\bm{\phi}$. RG-improved perturbation theory and Abel-Plana techniques are used to compute the $L$-dependent part $f_{\mathrm{res}}$ of the reduced excess free energy per film area $A\to\infty$ to two-loop order. When $d<4$, it takes the scaling form $f_{\mathrm{res}}\approx D(c_1L^{\Phi/\nu},c_2L^{\Phi/\nu})/L^{d-1}$ as $L\to\infty$, where $c_i$ are scaling fields associated with the surface-enhancement variables $\mathring{c}_i$, while $\Phi$ is a standard surface crossover exponent. The scaling function $D(\mathsf{c}_1,\mathsf{c}_2)$ and its analogue $\mathcal{D}(\mathsf{c}_1,\mathsf{c}_2)$ for the Casimir force are determined via expansion in $\epsilon=4-d$ and extrapolated to $d=3$ dimensions. In the special case $\mathsf{c}_1=\mathsf{c}_2=0$, the expansion becomes fractional. Consistency with the known fractional expansions of D(0,0) and $\mathcal{D}(0,0)$ to order $\epsilon^{3/2}$ is achieved by appropriate reorganisation of RG-improved perturbation theory. For appropriate choices of $c_1$ and $c_2$, the Casimir forces can have either sign. Furthermore, crossovers from attraction to repulsion and vice versa may occur as $L$ increases.Comment: Latex source file, 40 pages, 9 figure

Clinicopathologic and molecular analysis of embryonal rhabdomyosarcoma of the genitourinary tract: evidence for a distinct DICER1-associated subgroup.

Embryonal rhabdomyosarcoma (ERMS) of the uterus has recently been shown to frequently harbor DICER1 mutations. Interestingly, only rare cases of extrauterine DICER1-associated ERMS, mostly located in the genitourinary tract, have been reported to date. Our goal was to study clinicopathologic and molecular profiles of DICER1-mutant (DICER1-mut) and DICER1-wild type (DICER1-wt) ERMS in a cohort of genitourinary tumors. We collected a cohort of 17 ERMS including nine uterine (four uterine corpus and five cervix), one vaginal, and seven urinary tract tumors. DNA sequencing revealed mutations of DICER1 in 9/9 uterine ERMS. All other ERMS of our cohort were DICER1-wt. The median age at diagnosis of patients with DICER1-mut and DICER1-wt ERMS was 36 years and 5 years, respectively. Limited follow-up data (available for 15/17 patients) suggested that DICER1-mut ERMS might show a less aggressive clinical course than DICER1-wt ERMS. Histological features only observed in DICER1-mut ERMS were cartilaginous nodules (6/9 DICER1-mut ERMS), in one case accompanied by foci of ossification. Recurrent mutations identified in both DICER1-mut and DICER1-wt ERMS affected KRAS, NRAS, and TP53. Copy number analysis revealed similar structural variations with frequent gains on chromosomes 2, 3, and 8, independent of DICER1 mutation status. Unsupervised hierarchical clustering of array-based whole-genome DNA methylation data of our study cohort together with an extended methylation data set including different RMS subtypes from genitourinary and extra-genitourinary locations (n = 102), revealed a distinct cluster for DICER1-mut ERMS. Such tumors clearly segregated from the clusters of DICER1-wt ERMS, alveolar RMS, and MYOD1-mutant spindle cell and sclerosing RMS. Only one tumor, previously diagnosed as ERMS arising in the maxilla of a 6-year-old boy clustered with DICER1-mut ERMS of the uterus. Subsequent sequencing analysis identified two DICER1 mutations in the latter case. Our results suggest that DICER1-mut ERMS might qualify as a distinct subtype in future classifications of RMS

Seeding and transgenic overexpression of alpha-synuclein triggers dendritic spine pathology in the neocortex

Although misfolded and aggregated alpha-synuclein (alpha-syn) is recognized in the disease progression of synucleinopathies, its role in the impairment of cortical circuitries and synaptic plasticity remains incompletely understood. We investigated how alpha-synuclein accumulation affects synaptic plasticity in the mouse somatosensory cortex using two distinct approaches. Long-term in vivo imaging of apical dendrites was performed in mice overexpressing wild-type human alpha-synuclein. Additionally, intracranial injection of preformed alpha-synuclein fibrils was performed to induce cortical alpha-syn pathology. We find that alpha-synuclein overexpressing mice show decreased spine density and abnormalities in spine dynamics in an age-dependent manner. We also provide evidence for the detrimental effects of seeded alpha-synuclein aggregates on dendritic architecture. We observed spine loss as well as dystrophic deformation of dendritic shafts in layer V pyramidal neurons. Our results provide a link to the pathophysiology underlying dementia associated with synucleinopathies and may enable the evaluation of potential drug candidates on dendritic spine pathology in vivo

Development of a GEM-TPC prototype

The use of GEM foils for the amplification stage of a TPC instead of a con- ventional MWPC allows one to bypass the necessity of gating, as the backdrift is suppressed thanks to the asymmetric field configuration. This way, a novel continuously running TPC, which represents one option for the PANDA central tracker, can be realized. A medium sized prototype with a diameter of 300 mm and a length of 600 mm will be tested inside the FOPI spectrometer at GSI using a carbon or lithium beam at intermediate energies (E = 1-3AGeV). This detector test under realistic experimental conditions should allow us to verify the spatial resolution for single tracks and the reconstruction capability for displaced vertexes. A series of physics measurement implying pion beams is scheduled with the FOPI spectrometer together with the GEM-TPC as well.Comment: 5 pages, 4 figures, Proceedings for 11th ICATTP conference in como (italy

Neutrophils are required for both the sensitization and elicitation phase of contact hypersensitivity

Allergic contact dermatitis and its animal model, contact hypersensitivity (CHS), are T cell-mediated inflammatory skin diseases induced by contact allergens. Though numerous cellular and molecular players are known, the mechanism of chemical-induced sensitization remains poorly understood. Here, we identify neutrophils as crucial players in the sensitization phase of CHS. Genetic deficiency of neutrophils caused by myeloid-specific deletion of Mcl-1 or antibody-mediated depletion of neutrophils before sensitization abrogated the CHS response. Neutrophil deficiency reduced contact allergen-induced cytokine production, gelatinase release, and reactive oxygen species production in naive mice. Mast cell deficiency inhibited neutrophil accumulation at the site of sensitization. In turn, neutrophils were required for contact allergen-induced release of further neutrophil-attracting chemokines, migration of DCs to the draining lymph nodes, and priming of allergen-specific T cells. Lymph node cells from mice sensitized in the absence of neutrophils failed to transfer sensitization to naive recipients. Furthermore, no CHS response could be induced when neutrophils were depleted before elicitation or when normally sensitized lymph node cells were transferred to neutrophil-deficient recipients, indicating an additional role for neutrophils in the elicitation phase. Collectively, our data identify neutrophils to be critically involved in both the sensitization and elicitation phase of CHS

Azimuthal and Single Spin Asymmetries in Hard Scattering Processes

In this article we review the present understanding of azimuthal and single spin asymmetries for inclusive and semi-inclusive particle production in unpolarized and polarized hadronic collisions at high energy and moderately large transverse momentum. After summarizing the experimental information available, we discuss and compare the main theoretical approaches formulated in the framework of perturbative QCD. We then present in some detail a generalization of the parton model with inclusion of spin and intrinsic transverse momentum effects. In this context, we extensively discuss the phenomenology of azimuthal and single spin asymmetries for several processes in different kinematical configurations. A comparison with the predictions of other approaches, when available, is also given. We finally emphasize some relevant open points and challenges for future theoretical and experimental investigation.Comment: 70 pages, 34 ps figures. Invited review paper to be published in Progress in Particle and Nuclear Physic