Effect of Leu-enkephalin on the memory reactivation produced by blockade of the benzodiazepine/GABA-chloride ionophore receptor complex

This investigation sought to characterize the interaction between GABA/benzodiazepine and opioid systems in memory retrieval deficit induced by detaining an animal in the training apparatus after acquisition. Mice pretreated with saline or Leu-enkephalin (0.2 mg/kg) were trained in one-trial passive avoidance test with following detention. Pre-testing administration of bicuculline (1 mg/kg), picrotoxin (1 mg/kg), or flumazenil (10 mg/kg) produced the memory-enhancing effect in the saline-pretreated mice. Pretraining treatment with Leu-enkephalin blocked the reactivation of memory produced by bicuculline and picrotoxin, but not flumazenil. The present investigation suggest that both benzodiazepine/GABA and opioid systems are important modulators of memory retrieval and that a specific interaction between these systems is responsible for the observed recovery of impaired memory trace.     

Down syndrome time-clustering in January 1987 in Belarus: link with the Chernobyl accident?

The Chernobyl accident (April 26, 1986) exposed a large part of the Belarus population to ionizing radiation. We analyzed the time trends of Down syndrome (DS) in Belarus to evaluate whether either brief exposure at high dose rates during the plume passage or continuous exposure at low doses and dose rates of the residents of contaminated areas had any detectable impact on DS prevalence at birth. DS data came from the Belarus National Registry of Congenital Malformations (1981–2001). We observed a significant peak of DS in January 1987 (26 cases observed and 9.84 expected; observed/expected ratio = 2.64; 95% CI = 1.72–3.76), but found no positive long-term time trends in contaminated or control areas. The time occurrence of the January peak, high dose rates during the plume passage and experimental data showing a radiosensitive phase of oogenesis around conception time in mammals suggest that the January peak may be linked to the Chernobyl plume.     

Rosuvastatin suppresses the liver microsomal CYP2C11 and CYP2C6 expression in male Wistar rats

The aim was to investigate whether rosuvastatin affect rat cytochrome P450 (CYP) 2C11 and CYP2C6. CYP2C11 and CYP2C6 are considered as counterparts of human CYP2C9, which metabolizes many drugs including S-warfarin, diclofenac or ibuprofen. The male Wistar rats were fed standard laboratory diet (STD) or high cholesterol diet (HCD, 1% of cholesterol, 10% of lard fat) for 21 days. Rosuvastatin administration in STD (0.03% w/w) resulted in decreased mRNA expression of CYP2C11 as well as of CYP2C6 (here significant) and in a significant decrease of the respective protein expression as well as of the enzyme activity of both CYP2C forms. When rosuvastatin was administered in the HCD, the mRNA expression of both CYP2C forms was significantly lowered; the protein and activity parameters did not show significant changes. These results suggest that CYP2C11 as well as CYP2C6 expression and activity are negatively affected by rosuvastatin and may be modulated by high cholesterol high fat diet. Therefore, it should be taken into consideration that drugs metabolized by CYP2C9 in human could interact with rosuvastatin, as it has been already suggested for warfarin (rosuvastatin has increased its anticoagulant effect in human), and for telmisartan, sildenafil and glimepiride.     

Coexistence of vitreous and crystalline phases of H2O at ambient temperature

Formation of vitreous ice during rapid compression of water at room temperature is important for biology and the study of biological systems. Here, we show that Raman spectra of rapidly compressed water at greater than 1 GPa at room temperature exhibits the signature of high-density amorphous ice, whereas the X-ray diffraction (XRD) pattern is dominated by crystalline ice VI. To resolve this apparent contradiction, we used molecular dynamics simulations to calculate full vibrational spectra and diffraction patterns of mixtures of vitreous ice and ice VI, including embedded interfaces between the two phases. We show quantitatively that Raman spectra, which probe the local polarizability with respect to atomic displacements, are dominated by the vitreous phase, whereas a small amount of the crystalline component is readily apparent by XRD. The results of our combined experimental and theoretical studies have implications for detecting vitreous phases of water, survival of biological systems under extreme conditions, and biological imaging. The results provide additional insight into the stable and metastable phases of H₂O as a function of pressure and temperature, as well as of other materials undergoing pressure-induced amorphization and other metastable transitions.

Life as we know it on Earth depends on water. However, water also poses a critical challenge to life when it freezes at atmospheric pressure and low temperatures. The crystallization of H₂O to form hexagonal ice (ice Ih) under these conditions is accompanied by its well-known expansion, which has a dramatic impact on the structure and function of living cells. This crystallization of H₂O disrupts biological membranes and intracellular organization in living organisms and also displaces and concentrates salts and nutrients in the space between crystals (1). Like many liquids, however, rapid cooling of H₂O at ambient pressure to below its glass-transition temperature results in the formation of an amorphous phase known as low-density amorphous ice. Amorphous solid H₂O provides a chance for biological functions to survive where life otherwise cannot exist. Low-density amorphous ice is not the only amorphous form of H₂O. Ice I_h transforms to high-density amorphous (HDA) ice by application of ∼1 GPa of pressure at temperatures below 130 K (2, 3). In addition, a distinct, very-high-density amorphous state (vHDA) can form by isobaric heating and cooling of the HDA (4). low-density amorphous, high-density amorphous, and very-high-density amorphous state ice thus represent the three dominant, solid amorphous forms of H₂O at low temperatures.Solid amorphous phases of H₂O are broadly important in biology and biological applications. That amorphous H₂O which can exist over a broad range of temperatures, from cryogenic conditions to room temperature, is particularly interesting in the context of biological systems. Managing ice crystals is vital for extremophiles to survive damaging effects of H₂O crystallization. These organisms inhibit the growth of ice crystals and regulate the size and shape of the crystals using special antifreeze proteins (5, 6). Additionally, amorphous phases of H₂O are important in preserving biological samples in cryotomography applications. In cryotomography, the amorphous H₂O at low temperature is utilized routinely for sample preparation (7, 8), and significant efforts have been devoted to increase information obtained from cryotomography techniques. The low-temperature regime of amorphous H₂O routinely accessed in cryotomography creates challenges for light microscopy due to freezing of index-matching medium and objectives, which result in lowering the resolution of light microscopy in these applications. Room-temperature amorphous phases of H₂O are, therefore, advantageous for light microscopy applications and further development of techniques such as correlative light and electron microscopy (9–11).While formation of amorphous phases of H₂O below 200 K has been reported in many studies (2, 3, 12–16), a particularly interesting result is the observation of the Raman signature of HDA ice during fast compression of water at room temperature and moderate pressures (17). On the other hand, independent X-ray diffraction (XRD) measurements of H₂O on fast compression could not verify the formation of amorphous H₂O above 200 K (18). Here, we report high-resolution micro-Raman and synchrotron XRD measurements conducted in parallel in rapidly compressed samples of water in diamond anvil cells (DACs). Our findings, that are supported by molecular dynamics simulations, shed light on the nature of the HDA ice at room temperature and reconciled conflicting previous reports.     

High-Entropy Borides under Extreme Environment of Pressures and Temperatures

The high-entropy transition metal borides containing a random distribution of five or more constituent metallic elements offer novel opportunities in designing materials that show crystalline phase stability, high strength, and thermal oxidation resistance under extreme conditions. We present a comprehensive theoretical and experimental investigation of prototypical high-entropy boride (HEB) materials such as (Hf, Mo, Nb, Ta, Ti)B₂ and (Hf, Mo, Nb, Ta, Zr)B₂ under extreme environments of pressures and temperatures. The theoretical tools include modeling elastic properties by special quasi-random structures that predict a bulk modulus of 288 GPa and a shear modulus of 215 GPa at ambient conditions. HEB samples were synthesized under high pressures and high temperatures and studied to 9.5 GPa and 2273 K in a large-volume pressure cell. The thermal equation of state measurement yielded a bulk modulus of 276 GPa, in excellent agreement with theory. The measured compressive yield strength by radial X-ray diffraction technique in a diamond anvil cell was 28 GPa at a pressure of 65 GPa, which is a significant fraction of the shear modulus at high pressures. The high compressive strength and phase stability of this material under high pressures and high temperatures make it an ideal candidate for application as a structural material in nuclear and aerospace fields.     

Reduced coronary flow reserve in the coronary sinus is a predictor of hemodynamically significant stenoses of the left coronary artery territory.

AIM AND METHODS: The role of transesophageal Doppler assessment of coronary flow reserve (CFR) in the coronary sinus (CS) in the diagnostics of significant left coronary artery (LCA) stenoses was studied in 65 CAD patients with angiographically proven >50% stenotic atherosclerosis of the LCA territory (38--with isolated left anterior descending artery (LAD) or left circumflex artery (Cx) stenosis; 27--with both LAD and Cx stenoses) and 31 healthy volunteers (all men). Dipyridamole was used as a stress agent. The antegrade phase of coronary flow in the CS moving into the right atrium was analysed. CFR in the CS was calculated in two ways: (1) as ratio of hyperemic to baseline peak antegrade flow velocity (CFRp); (2) as ratio of hyperemic to baseline volumetric blood flow velocity (CFRv). The level of CFR <2.0 in both ways of calculation was diagnosed as reduced. RESULTS: CAD patients compared with healthy volunteers had significantly lower CFRp (1.51+/-0.44 and 2.57+/-0.79; p<0.001) and CFRv (2.21+/-1.18 and 5.43+/-2.83; p < 0.001) in the CS. CFRp <2.0 in the CS was a predictor of significant stenoses of the LCA with sensitivity of 89% and specificity of 76%, while CFRv <2.0 was a predictor of significant stenoses of the LCA with sensitivity of 49% and specificity of 97%. CFRp <2.0 in the CS was registered in 96% of CAD patients with two-vessel lesion and in 84% of CAD patients with one-vessel lesion, while CFRv <2.0 in the CS was revealed in 85% of CAD patients with two-vessel lesion and only in 26% of CAD patients with one-vessel lesion. Sensitivity and specificity of CFRv <2.0 in the CS in the diagnostics of significant two-vessel lesion of the LCA were 85% and 84%, respectively. CONCLUSIONS: Thus, the reduced CFR in the CS is a sensitive and specific predictor of LCA stenoses. A decrease of both CFRp <2 and CFRv <2.0 in the CS is a predictor of significant two-vessel lesion of the LCA, while a decrease of only CFRp <2.0 in the CS is a predictor of significant one-vessel lesion of the LCA.     

Comblike dendrimers containing Tn antigen modulate natural killing and induce the production of Tn specific antibodies

Comblike glycodendrimers were prepared by the chemoselective ligation of cysteine-modified glycopeptides (1-7) with a 3-maleimidopropionate-modified linear synthetic carrier (8). Glycodendrimers bearing mono-, di-, or tri-Tn clusters (9-11) were tested as inhibitors using plant and mammalian lectins. In the former group, the Codium fragile lectin showed moderate discrimination among 9, 10, and 11. In the latter group, A and B isoforms of rat NKR-P1 lectin strongly discriminated between 9 and 10. 10 caused a 4-fold increase in killing of the NK resistant tumor cell lines at concentrations as low as 10(-8) M. Surprisingly, 11 interacted exclusively with the rat NKR-P1B isoform and inhibited efficiently natural killing in both rats and humans, even in the presence of the activating compounds 9 and 10. Dinitrophenol haptenization or influenza virus hemagglutinin T-cell epitope conjugation increased the immunogenicity of the parent compounds and resulted in the production of Tn specific antibodies.