High affinity binding of H3K14ac through collaboration of bromodomains 2, 4 and 5 is critical for the molecular and tumor suppressor functions of PBRM1.

Polybromo-1 (PBRM1) is an important tumor suppressor in kidney cancer. It contains six tandem bromodomains (BDs), which are specialized structures that recognize acetyl-lysine residues. While BD2 has been found to bind acetylated histone H3 lysine 14 (H3K14ac), it is not known whether other BDs collaborate with BD2 to generate strong binding to H3K14ac, and the importance of H3K14ac recognition for the molecular and tumor suppressor function of PBRM1 is also unknown. We discovered that full-length PBRM1, but not its individual BDs, strongly binds H3K14ac. BDs 2, 4, and 5 were found to collaborate to facilitate strong binding to H3K14ac. Quantitative measurement of the interactions between purified BD proteins and H3K14ac or nonacetylated peptides confirmed the tight and specific association of the former. Interestingly, while the structural integrity of BD4 was found to be required for H3K14ac recognition, the conserved acetyl-lysine binding site of BD4 was not. Furthermore, simultaneous point mutations in BDs 2, 4, and 5 prevented recognition of H3K14ac, altered promoter binding and gene expression, and caused PBRM1 to relocalize to the cytoplasm. In contrast, tumor-derived point mutations in BD2 alone lowered PBRM1\u27s affinity to H3K14ac and also disrupted promoter binding and gene expression without altering cellular localization. Finally, overexpression of PBRM1 variants containing point mutations in BDs 2, 4, and 5 or BD2 alone failed to suppress tumor growth in a xenograft model. Taken together, our study demonstrates that BDs 2, 4, and 5 of PBRM1 collaborate to generate high affinity to H3K14ac and tether PBRM1 to chromatin. Mutations in BD2 alone weaken these interactions, and this is sufficient to abolish its molecular and tumor suppressor functions

Multiple tumor suppressors regulate a HIF-dependent negative feedback loop via ISGF3 in human clear cell renal cancer.

Whereas VHL inactivation is a primary event in clear cell renal cell carcinoma (ccRCC), the precise mechanism(s) of how this interacts with the secondary mutations in tumor suppressor genes, including PBRM1, KDM5C/JARID1C, SETD2, and/or BAP1, remains unclear. Gene expression analyses reveal that VHL, PBRM1, or KDM5C share a common regulation of interferon response expression signature. Loss of HIF2α, PBRM1, or KDM5C in VHL-/-cells reduces the expression of interferon stimulated gene factor 3 (ISGF3), a transcription factor that regulates the interferon signature. Moreover, loss of SETD2 or BAP1 also reduces the ISGF3 level. Finally, ISGF3 is strongly tumor-suppressive in a xenograft model as its loss significantly enhances tumor growth. Conversely, reactivation of ISGF3 retards tumor growth by PBRM1-deficient ccRCC cells. Thus after VHL inactivation, HIF induces ISGF3, which is reversed by the loss of secondary tumor suppressors, suggesting that this is a key negative feedback loop in ccRCC. © 2018, Liao et al

An invisibility cloak using silver nanowires

In this paper, we use the parameter retrieval method together with an analytical effective medium approach to design a well-performed invisible cloak, which is based on an empirical revised version of the reduced cloak. The designed cloak can be implemented by silver nanowires with elliptical cross-sections embedded in a polymethyl methacrylate host. This cloak is numerically proved to be robust for both the inner hidden object as well as incoming detecting waves, and is much simpler thus easier to manufacture when compared with the earlier proposed one [Nat. Photon. 1, 224 (2007)].Comment: 7 pages, 4 figures, 2 table

Asymptotically Lifshitz wormholes and black holes for Lovelock gravity in vacuum

Static asymptotically Lifshitz wormholes and black holes in vacuum are shown to exist for a class of Lovelock theories in d=2n+1>7 dimensions, selected by requiring that all but one of their n maximally symmetric vacua are AdS of radius l and degenerate. The wormhole geometry is regular everywhere and connects two Lifshitz spacetimes with a nontrivial geometry at the boundary. The dynamical exponent z is determined by the quotient of the curvature radii of the maximally symmetric vacua according to n(z^2-1)+1=(l/L)^2, where L corresponds to the curvature radius of the nondegenerate vacuum. Light signals are able to connect both asymptotic regions in finite time, and the gravitational field pulls towards a fixed surface located at some arbitrary proper distance to the neck. The asymptotically Lifshitz black hole possesses the same dynamical exponent and a fixed Hawking temperature given by T=z/(2^z pi l). Further analytic solutions, including pure Lifshitz spacetimes with a nontrivial geometry at the spacelike boundary, and wormholes that interpolate between asymptotically Lifshitz spacetimes with different dynamical exponents are also found.Comment: 19 pages, 1 figur

The Design and Implementation of Functional Blocks for Process Control

Diplomová práce se zabývá řešením a přípravou funkčních bloků pro řízení procesu. Konkrétně se jedná o modernizaci řízení vysoké pece. Práce se zabývá řídicím systémem a jeho hardwarovým vybavením, konfiguračním a vizualizačním prostředím a samotný závěr práce se týká tvorby simulace vysoké pece a částečné vizualizace některých obrazovek a prvků. Práce je zakončena aplikováním všech získaných poznatků naprogramováním řízení dvoucívkového ventilu v prostředí Step 7 a jeho otestování v simulačním prostředí WinMOD.This thesis deals with design and preparation of functional blocks for control of the process. Specifically, it is a modernization of blast furnace control. The thesis deals with the control system and its hardware equipment, configuration and visualization environment, and the conclusion of the thesis itself concerns the creation of blast furnace simulation and partial visualization of some screens and elements. The work is completed by applying all the knowledge gained by programming the two-coil valve control in the Step 7 environment and testing it in the WinMOD simulation environment.352 - Katedra automatizační techniky a řízenívelmi dobř

Acupuncture Enhances the Synaptic Dopamine Availability to Improve Motor Function in a Mouse Model of Parkinson's Disease

Parkinson's disease (PD) is caused by the selective loss of dopaminergic neurons in the substantia nigra (SN) and the depletion of striatal dopamine (DA). Acupuncture, as an alternative therapy for PD, has beneficial effects in both PD patients and PD animal models, although the underlying mechanisms therein remain uncertain. The present study investigated whether acupuncture treatment affected dopamine neurotransmission in a PD mouse model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We found that acupuncture treatment at acupoint GB34 improved motor function with accompanying dopaminergic neuron protection against MPTP but did not restore striatal dopamine depletion. Instead, acupuncture treatment increased dopamine release that in turn, may lead to the enhancement of dopamine availability in the synaptic cleft. Moreover, acupuncture treatment mitigated MPTP-induced abnormal postsynaptic changes, suggesting that acupuncture treatment may increase postsynaptic dopamine neurotransmission and facilitate the normalization of basal ganglia activity. These results suggest that the acupuncture-induced enhancement of synaptic dopamine availability may play a critical role in motor function improvement against MPTP

Holographic GB gravity in arbitrary dimensions

We study the properties of the holographic CFT dual to Gauss-Bonnet gravity in general $D \ge 5$ dimensions. We establish the AdS/CFT dictionary and in particular relate the couplings of the gravitational theory to the universal couplings arising in correlators of the stress tensor of the dual CFT. This allows us to examine constraints on the gravitational couplings by demanding consistency of the CFT. In particular, one can demand positive energy fluxes in scattering processes or the causal propagation of fluctuations. We also examine the holographic hydrodynamics, commenting on the shear viscosity as well as the relaxation time. The latter allows us to consider causality constraints arising from the second-order truncated theory of hydrodynamics.Comment: 48 pages, 9 figures. v2: New discussion on free fields in subsection 3.3 and new appendix B on conformal tensor fields. Added comments on the relation between the central charge appearing in the two-point function and the "central charge" characterizing the entropy density in the discussion. References adde

Using biomarkers to predict TB treatment duration (Predict TB): a prospective, randomized, noninferiority, treatment shortening clinical trial

Background : By the early 1980s, tuberculosis treatment was shortened from 24 to 6 months, maintaining relapse rates of 1-2%. Subsequent trials attempting shorter durations have failed, with 4-month arms consistently having relapse rates of 15-20%. One trial shortened treatment only among those without baseline cavity on chest x-ray and whose month 2 sputum culture converted to negative. The 4-month arm relapse rate decreased to 7% but was still significantly worse than the 6-month arm (1.6%, P<0.01).  We hypothesize that PET/CT characteristics at baseline, PET/CT changes at one month, and markers of residual bacterial load will identify patients with tuberculosis who can be cured with 4 months (16 weeks) of standard treatment.Methods: This is a prospective, multicenter, randomized, phase 2b, noninferiority clinical trial of pulmonary tuberculosis participants. Those eligible start standard of care treatment. PET/CT scans are done at weeks 0, 4, and 16 or 24. Participants who do not meet early treatment completion criteria (baseline radiologic severity, radiologic response at one month, and GeneXpert-detectable bacilli at four months) are placed in Arm A (24 weeks of standard therapy). Those who meet the early treatment completion criteria are randomized at week 16 to continue treatment to week 24 (Arm B) or complete treatment at week 16 (Arm C). The primary endpoint compares the treatment success rate at 18 months between Arms B and C.Discussion: Multiple biomarkers have been assessed to predict TB treatment outcomes. This study uses PET/CT scans and GeneXpert (Xpert) cycle threshold to risk stratify participants. PET/CT scans are not applicable to global public health but could be used in clinical trials to stratify participants and possibly become a surrogate endpoint. If the Predict TB trial is successful, other immunological biomarkers or transcriptional signatures that correlate with treatment outcome may be identified. TRIAL REGISTRATION: NCT02821832

Causality constraints in AdS/CFT from conformal collider physics and Gauss-Bonnet gravity

We explore the relation between positivity of the energy constraints in conformal field theories and causality in their dual gravity description. Our discussion involves CFTs with different central charges whose description, in the gravity side, requires the inclusion of quadratic curvature corrections. It is enough, indeed, to consider the Gauss-Bonnet term. We find that both sides of the AdS/CFT correspondence impose a restriction on the Gauss-Bonnet coupling. In the case of 6d supersymmetric CFTs, we show the full matching of these restrictions. We perform this computation in two ways. First by considering a thermal setup in a black hole background. Second by scrutinizing the scattering of gravitons with a shock wave in AdS. The different helicities provide the corresponding lower and upper bounds. We generalize these results to arbitrary higher dimensions and comment on some hints and puzzles they prompt regarding the possible existence of higher dimensional CFTs and the extent to which the AdS/CFT correspondence would be valid for them.Comment: 31 pages, 5 figures; v2: typos fixed, cosmetic amendments and references adde

A gravitational lensing detection of filamentary structures connecting luminous red galaxies

We present a weak lensing detection of filamentary structures in the cosmic web, combining data from the Kilo-Degree Survey, the Red Cluster Sequence Lensing Survey, and the Canada-France-Hawaii Telescope Lensing Survey. The line connecting luminous red galaxies with a separation of 3 − 5 h−1 Mpc was chosen as a proxy for the location of filaments. We measured the average weak lensing shear around ∼11 000 candidate filaments selected in this way from the Sloan Digital Sky Survey. After nulling the shear induced by the dark matter haloes around each galaxy, we reported a 3.4σ detection of an anisotropic shear signal from the matter that connects them. Adopting a filament density profile, motivated from N-body simulations, the average density at the centre of these filamentary structures was found to be 15 ± 4 times the critical density