Effects of Wnt and different TLR stimulations on microglia-induced invasion of breast cancer cells

Seit einigen Jahren steht die Rolle der benignen Zellen eines Primärtumors im Fokus der Forschung. In diesem Zusammenhang konnte bereits gezeigt werden, dass vor allem aus dem Blut eingewanderte Makrophagen die Tumorprogression fördern können. Die Rolle der residenten Makrophagen während der Metastasierung von Tumorzellen, insbesondere der zerebralen Metastasierung, wurde jedoch erst wenig untersucht. Aufgrund der stark eingeschränkten Therapiemöglichkeiten zerebraler Metastasierung, analysierten wir die Rolle der Mikroglia in diesem Prozess. Um die direkte Interaktion zwischen Karzinomzellen und dem lebenden Hirngewebe besser untersuchen zu können, etablierten wir ein neuartiges Ko-Kulturmodell, das einen murinen organotypischen Hirnschnitt und einen angrenzenden Tumorplug umfasste. Wir zeigten, dass Mikroglia die Invasion und Kolonisation von Mammakarzinomzellen fördern indem sie als aktive Transporter dienen. Proinvasive Mikroglia zeigten eine veränderte Morphologie jedoch keine gesteigerte Expression von Cytokinen des M2-Phänotyps noch eine veränderte Genexpression. Die Aktivierung des Toll-like Rezeptor (TLR) 4 Signalwegs durch bakterielles Lipopolysaccharid (LPS) induzierte einen klassischen M1-Phänotyp in Mikroglia, die durch Tumorzellen beeinflusst wurden, und auf diese Weise eine Hemmung der proinvasiven Funktion. Ein ähnlicher Effekt auf die Invasion der Tumorzellen wurde durch die Hemmung der Mikroglia mittels Clodronat oder die Inaktivierung des WNT Signalwegs durch Hemmung des Rezeptors oder des WNT Zielgens CXCR4 erreicht. Eine wesentliche Erkenntnis war, dass TLR (4) sowie Stickstoffoxid (NO) eine vielseitige Funktion aufwiesen, die über die Adaptorproteine MyD88 und TRIF des TLR Signalwegs vermittelt wurde. Während der Signalweg über MyD88 in Mikroglia für die Tumor fördernden Effekte erforderlich war, konnte die (zusätzliche) Aktivierung des Signalwegs über TRIF das Resultat umkehren. Zusammenfassend zeigten unsere Daten, dass Mikroglia eine Schlüsselfunktion in der Tumorprogression aufweisen, wobei sowohl der WNT Signalweg als auch der TLR Signalweg aber auch bestimmte gemeinsame Ziele entscheidende Funktionen in diesem Prozess vermitteln

Topological phases and edge modes of an uneven ladder

We investigate the topological properties of a two-chain quantum ladder with uneven legs, i.e. the two chains differ in their periods by a factor of two. Such an uneven ladder presents rich band structures classified by the closure of either direct or indirect bandgaps. It also provides opportunities to explore fundamental concepts concerning band topology and edge modes, including the difference of intracellular and intercellular Zak phases, and the role of the inversion symmetry (IS). We calculate the Zak phases of the two kinds and find excellent agreement with the dipole moment and extra charge accumulation, respectively. We also find that configurations with IS feature a pair of degenerate two-side edge modes emerging as the closure of the direct bandgap, while configurations without IS feature one-side edge modes emerging as not only the closure of both direct and indirect bandgap but also within the band continuum. Furthermore, by projecting to the two sublattices, we find that the effective Bloch Hamiltonian corresponds to that of a generalized Su-Schrieffer-Heeger model or Rice-Mele model whose hopping amplitudes depend on the quasimomentum. In this way, the topological phases can be efficiently extracted through winding numbers. We propose that uneven ladders can be realized by spin-dependent optical lattices and their rich topological characteristics can be examined by near future experiments.Comment: 17 pages with 15 figure

Loss of vesicular dopamine release precedes tauopathy in degenerative dopaminergic neurons in a Drosophila model expressing human tau.

While a number of genome-wide association studies have identified microtubule-associated protein tau as a strong risk factor for Parkinson's disease (PD), little is known about the mechanism through which human tau can predispose an individual to this disease. Here, we demonstrate that expression of human wild-type tau is sufficient to disrupt the survival of dopaminergic neurons in a Drosophila model. Tau triggers a synaptic pathology visualized by vesicular monoamine transporter-pHGFP that precedes both the age-dependent formation of tau-containing neurofibrillary tangle-like pathology and the progressive loss of DA neurons, thereby recapitulating the pathological hallmarks of PD. Flies overexpressing tau also exhibit progressive impairments of both motor and learning behaviors. Surprisingly, contrary to common belief that hyperphosphorylated tau could aggravate toxicity, DA neuron degeneration is alleviated by expressing the modified, hyperphosphorylated tau(E14). Together, these results show that impairment of VMAT-containing synaptic vesicle, released to synapses before overt tauopathy may be the underlying mechanism of tau-associated PD and suggest that correction or prevention of this deficit may be appropriate targets for early therapeutic intervention

PbSe Nanorod Field-Effect Transistors:Room- and Low-Temperature Performance

Lead chalcogenides with large exciton Bohr radius display strong quantum confinement, which make them applicable in a wide range of optoelectronic devices such as solar cells and photodetectors. Especially, 1D PbSe nanocrystals attract much attention with their potential for multiple exciton generation. However, very little is known on their charge transport properties. In this study well performing field-effect transistors based on PbSe nanorods with an inorganic iodide-based ligand are presented for the first time. The transistors at room temperature display ambipolar characteristics with electron mobility of approximate to 0.1 cm(2) V-1 s(-1) and hole mobility of 1.1 x 10(-4) cm(2) V-1 s(-1) in the ultraclean environment. Low temperature investigation reveals a transition around 200 K between nearest-neighbor and variable-range hopping mechanism. Below 200 K, the transport properties are dominated by the severe disorder

Carcinoma cells misuse the host tissue damage response to invade the brain

The metastatic colonization of the brain by carcinoma cells is still barely understood, in particular when considering interactions with the host tissue. The colonization comes with a substantial destruction of the surrounding host tissue. This leads to activation of damage responses by resident innate immune cells to protect, repair, and organize the wound healing, but may distract from tumoricidal actions. We recently demonstrated that microglia, innate immune cells of the CNS, assist carcinoma cell invasion. Here we report that this is a fatal side effect of a physiological damage response of the brain tissue. In a brain slice coculture model, contact with both benign and malignant epithelial cells induced a response by microglia and astrocytes comparable to that seen at the interface of human cerebral metastases. While the glial damage response intended to protect the brain from intrusion of benign epithelial cells by inducing apoptosis, it proved ineffective against various malignant cell types. They did not undergo apoptosis and actually exploited the local tissue reaction to invade instead. Gene expression and functional analyses revealed that the C-X-C chemokine receptor type 4 (CXCR4) and WNT signaling were involved in this process. Furthermore, CXCR4-regulated microglia were recruited to sites of brain injury in a zebrafish model and CXCR4 was expressed in human stroke patients, suggesting a conserved role in damage responses to various types of brain injuries. Together, our findings point to a detrimental misuse of the glial damage response program by carcinoma cells resistant to glia-induced apoptosis

The CDEX-1 1 kg Point-Contact Germanium Detector for Low Mass Dark Matter Searches

The CDEX Collaboration has been established for direct detection of light dark matter particles, using ultra-low energy threshold p-type point-contact germanium detectors, in China JinPing underground Laboratory (CJPL). The first 1 kg point-contact germanium detector with a sub-keV energy threshold has been tested in a passive shielding system located in CJPL. The outputs from both the point-contact p+ electrode and the outside n+ electrode make it possible to scan the lower energy range of less than 1 keV and at the same time to detect the higher energy range up to 3 MeV. The outputs from both p+ and n+ electrode may also provide a more powerful method for signal discrimination for dark matter experiment. Some key parameters, including energy resolution, dead time, decay times of internal X-rays, and system stability, have been tested and measured. The results show that the 1 kg point-contact germanium detector, together with its shielding system and electronics, can run smoothly with good performances. This detector system will be deployed for dark matter search experiments.Comment: 6 pages, 8 figure

Intralesional TLR4 agonist treatment strengthens the organ defense against colonizing cancer cells in the brain

Brain metastasis in breast cancer remains difficult to treat and its incidence is increasing. Therefore, the development of new therapies is of utmost clinical relevance. Recently, toll-like receptor (TLR) 4 was correlated with IL6 expression and poor prognosis in 1 215 breast cancer primaries. In contrast, we demonstrated that TLR4 stimulation reduces microglia-assisted breast cancer cell invasion. However, the expression, prognostic value, or therapeutic potential of TLR signaling in breast cancer brain metastasis have not been investigated. We thus tested the prognostic value of various TLRs in two brain-metastasis gene sets. Furthermore, we investigated different TLR agonists, as well as MyD88 and TRIF-deficient microenvironments in organotypic brain-slice ex vivo co-cultures and in vivo colonization experiments. These experiments underline the ambiguous roles of TLR4, its adapter MyD88, and the target nitric oxide (NO) during brain colonization. Moreover, analysis of the gene expression datasets of breast cancer brain metastasis patients revealed associations of TLR1 and IL6 with poor overall survival. Finally, our finding that a single LPS application at the onset of colonization shapes the later microglia/macrophage reaction at the macro-metastasis brain-parenchyma interface (MMPI) and reduces metastatic infiltration into the brain parenchyma may prove useful in immunotherapeutic considerations

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data