Mammals have become “an environment” for enterobacterial phage life cycles. Therefore it could be expected that bacteriophages adapt to them. This adaptation must comprise bacteriophage proteins.Gp ...Hoc seems to have significance neither for phage particle structure nor for phage antibacterial activity. It is evidently not necessary for the “typical” antibacterial actions of bacteriophages. But the rules of evolution make it improbable that gp Hoc really has no function, and non-essential genes of T4-type phages are probably important for phages’ adaptation to their particular lifestyle. More interesting is the eukaryotic origin of gp Hoc: a resemblance to immunoglobulin-like proteins that reflects their evolutionary relation. Substantial differences in biological activity between T4 and a mutant that lacks gp Hoc were observed in a mammalian system. Hoc protein seems to be one of the molecules predicted to interact with mammalian organisms and/or modulate these interactions.
Calcineurin inhibitors (CNIs) are immunosuppressive drugs used to prevent graft rejection after organ transplant. Common side effects include renal magnesium wasting and hypomagnesemia, which may ...contribute to new‐onset diabetes mellitus, and hypercalciuria, which may contribute to post‐transplant osteoporosis. Previous work suggested that CNIs reduce the abundance of key divalent cation transport proteins, expressed along the distal convoluted tubule, causing renal magnesium and calcium wasting. It has not been clear, however, whether these effects are specific for the distal convoluted tubule, and whether these represent off‐target toxic drug effects, or result from inhibition of calcineurin. The CNI tacrolimus can inhibit calcineurin only when it binds with the immunophilin, FKBP12; we previously generated mice in which FKBP12 could be deleted along the nephron, to test whether calcineurin inhibition is involved, these mice are normal at baseline. Here, we confirmed that tacrolimus‐treated control mice developed hypomagnesemia and urinary calcium wasting, with decreased protein and mRNA abundance of key magnesium and calcium transport proteins (NCX‐1 and Calbindin‐D28k). However, qPCR also showed decreased mRNA expression of NCX‐1 and Calbindin‐D28k, and TRPM6. In contrast, KS‐FKBP12−/− mice treated with tacrolimus were completely protected from these effects. These results indicate that tacrolimus affects calcium and magnesium transport along the distal convoluted tubule and strongly suggests that inhibition of the phosphatase, calcineurin, is directly involved.
We showed that deletion of the tacrolimus‐binding protein, necessary for tacrolimus to inhibit calcineurin, completely prevented the effects on divalent ion metabolism. This was associated with protection of transport proteins in the distal convoluted tubule.
One of the greatest challenges in cancer therapy is to develop methods to deliver chemotherapy agents to tumor cells while reducing systemic toxicity to noncancerous cells. A promising approach to ...localizing drug release is to employ drug-loaded nanoparticles with coatings that release the drugs only in the presence of specific triggers found in the target cells such as pH, enzymes, or light. However, many parameters affect the nanoparticle distribution and drug release rate, and it is difficult to quantify drug release in situ. In this work, we show proof-of-principle for a “smart” radioluminescent nanocapsule with an X-ray excited optical luminescence (XEOL) spectrum that changes during release of the optically absorbing chemotherapy drug, doxorubicin. XEOL provides an almost background-free luminescent signal for measuring drug release from particles irradiated by a narrow X-ray beam. We study in vitro pH-triggered release rates of doxorubicin from nanocapsules coated with a pH-responsive polyelectrolyte multilayer using HPLC and XEOL spectroscopy. The doxorubicin was loaded to over 5% by weight and released from the capsule with a time constant in vitro of ∼36 days at pH 7.4 and 21 h at pH 5.0, respectively. The Gd2O2S:Eu nanocapsules are also paramagnetic at room temperature with similar magnetic susceptibility and similarly good MRI T 2 relaxivities to Gd2O3, but the sulfur increases the radioluminescence intensity and shifts the spectrum. Empty nanocapsules did not affect cell viability up to concentrations of at least 250 μg/mL. These empty nanocapsules accumulated in a mouse liver and spleen following tail vein injection and could be observed in vivo using XEOL. The particles are synthesized with a versatile template synthesis technique which allows for control of particle size and shape. The XEOL analysis technique opens the door to noninvasive quantification of drug release as a function of nanoparticle size, shape, surface chemistry, and tissue type.
Stereophotogrammetry as a method for the surface scanning can be used to capture some properties of the human body parts. The objective of this study is to quantify the foot stress distribution in 3D ...during its quasi-static stand using a footprint into an imprinting material when knowing its mechanical properties. One foot of a female, having the mass of 65kg, was chosen for the FEM foot model construction. After obtaining her foot imprint to the dental imprinting material, its positive plaster cast was created, whose surface was possible to scan using stereophotogrammetry. The imprint surface digital model was prepared with the help of the Konica-Minolta Vivid 9i triangulation scanner. This procedure provides the measured object models in a high resolution. The resulting surface mesh of the foot imprint involved 9.600 nodes and 14.000 triangles, approximately, after reduction due to the FEM analysis. Simulation of foot imprint was solved as the 3D time dependent nonlinear mechanical problem in the ADINA software. The sum of vertical reactions calculated at the contact area nodes was 320.5 N, which corresponds to the mass of 32.67 kg. This value is in a good agreement with the subject half weight – the load of one foot during its quasi-static stand. The partial pressures resulting from this mathematical model match the real pressures on the interface of the foot and imprinting material quite closely. Principally, these simulations can be used to assess the contact pressures in practical cases, e.g., between a foot and its footwear.
Bacteriophage T4 is a virus with well-known genetics, structure, and biology. Such techniques as X-ray crystallography, cryo-EM, and three-dimensional (3D) image reconstruction allowed describing its ...structure very precisely. The genome of this bacteriophage was completely sequenced, which opens the way for the use of many molecular techniques, such as site-specific mutagenesis, which was widely applied,
e.g.
, in investigating the functions of some essential T4 proteins. The phage-display method, which is commonly applied in bacteriophage modifications, was successfully used to display antigens (PorA protein, VP2 protein of vvIBDV, and antigens of anthrax and HIV) on T4’s capsid platform. As first studies showed, the phage-display system as well as site-specific mutagenesis may also be used to modify interactions between phage particles and mammalian cells or to obtain phages infecting species other than the host bacteria. These may be used, among others, in the constantly developing bacteriophage therapy. All manipulations of this popular bacteriophage may enable the development of vaccine technology, phage therapy, and other branches of biological and medical science.
(ProQuest: ... denotes formulae and/or non-USASCII text omitted; see image) The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in ...proton-proton collision data at a centre-of-mass energy of ... corresponding to an integrated luminosity of 38 pb^sup -1^. Jets are reconstructed with the anti-k ^sub t^ algorithm with distance parameters R=0.4 or R=0.6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta p ^sub T^greater than or equal to20 GeV and pseudorapidities |eta|<4.5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2.5 % in the central calorimeter region (|eta|<0.8) for jets with 60less than or equal top ^sub T^<800 GeV, and is maximally 14 % for p ^sub T^<30 GeV in the most forward region 3.2less than or equal to|eta|<4.5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon p ^sub T^, the sum of the transverse momenta of tracks associated to the jet, or a system of low-p ^sub T^ jets recoiling against a high-p ^sub T^ jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-p ^sub T^ jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined.
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