Blood soluble drag-reducing polymers prevent lethality from hemorrhagic shock in acute animal experiments

Over the past several decades, blood-soluble drag reducing polymers (DRPs) have been shown to significantly enhance hemodynamics in various animal models when added to blood at nanomolar concentrations. In the present study, the effects of the DRPs on blood circulation were tested in anesthetized rats exposed to acute hemorrhagic shock. The animals were acutely resuscitated either with a 2.5% dextran solution (Control) or using the same solution containing 0.0005% or 5 parts per million (ppm) concentration of one of two blood soluble DRPs: high molecular weight (MW=3500 kDa) polyethylene glycol (PEG-3500) or a DRP extracted from Aloe vera (AVP). An additional group of animals was resuscitated with 0.0075% (75 ppm) polyethylene glycol of molecular weight of 200 kDa (PEG-200), which possesses no drag-reducing ability. All of the animals were observed for two hours following the initiation of fluid resuscitation or until they expired. We found that infusion of the DRP solutions significantly improved tissue perfusion, tissue oxygenation, and two-hour survival rate, the latter from 19% (Control) and 14% (PEG-200) to 100% (AVP) and 100% (PEG-3500). Furthermore, the Control and PEG-200 animals that survived required three times more fluid to maintain their blood pressure than the AVP and PEG-3500 animals. Several hypotheses regarding the mechanisms underlying these observed beneficial hemodynamic effects of DRPs are discussed. Our findings suggest that the drag-reducing polymers warrant further investigation as a potential clinical treatment for hemorrhagic shock and possibly other microcirculatory disorders.     

Genetically encoded fluorescent indicator for intracellular hydrogen peroxide

We developed a genetically encoded, highly specific fluorescent probe for detecting hydrogen peroxide (H(2)O(2)) inside living cells. This probe, named HyPer, consists of circularly permuted yellow fluorescent protein (cpYFP) inserted into the regulatory domain of the prokaryotic H(2)O(2)-sensing protein, OxyR. Using HyPer we monitored H(2)O(2) production at the single-cell level in the cytoplasm and mitochondria of HeLa cells treated with Apo2L/TRAIL. We found that an increase in H(2)O(2) occurs in the cytoplasm in parallel with a drop in the mitochondrial transmembrane potential (DeltaPsi) and a change in cell shape. We also observed local bursts in mitochondrial H(2)O(2) production during DeltaPsi oscillations in apoptotic HeLa cells. Moreover, sensitivity of the probe was sufficient to observe H(2)O(2) increase upon physiological stimulation. Using HyPer we detected temporal increase in H(2)O(2) in the cytoplasm of PC-12 cells stimulated with nerve growth factor.     

MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals

MDC1 functions in checkpoint activation and DNA repair following DNA damage. To address the physiological role of MDC1, we disrupted the MDC1 gene in mice. MDC1-/- mice recapitulated many phenotypes of H2AX-/- mice, including growth retardation, male infertility, immune defects, chromosome instability, DNA repair defects, and radiation sensitivity. At the molecular level, H2AX, MDC1, and ATM form a positive feedback loop, with MDC1 directly mediating the interaction between H2AX and ATM. MDC1 binds phosphorylated H2AX through its BRCT domain and ATM through its FHA domain. Through these interactions, MDC1 accumulates activated ATM flanking the sites of DNA damage, facilitating further ATM-dependent phosphorylation of H2AX and the amplification of DNA damage signals. In the absence of MDC1, many downstream ATM signaling events are defective. These results suggest that MDC1, as a signal amplifier of the ATM pathway, is vital in controlling proper DNA damage response and maintaining genomic stability.     

Extracting surface activation time from the optically recorded action potential in three-dimensional myocardium

Optical mapping has become an indispensible tool for studying cardiac electrical activity. However, due to the three-dimensional nature of the optical signal, the optical upstroke is significantly longer than the electrical upstroke. This raises the issue of how to accurately determine the activation time on the epicardial surface. The purpose of this study was to establish a link between the optical upstroke and exact surface activation time using computer simulations, with subsequent validation by a combination of microelectrode recordings and optical mapping experiments. To simulate wave propagation and associated optical signals, we used a hybrid electro-optical model. We found that the time of the surface electrical activation (t(E)) within the accuracy of our simulations coincided with the maximal slope of the optical upstroke (t(F)*) for a broad range of optical attenuation lengths. This was not the case when the activation time was determined at 50% amplitude (t(F50)) of the optical upstroke. The validation experiments were conducted in isolated Langendorff-perfused rat hearts and coronary-perfused pig left ventricles stained with either di-4-ANEPPS or the near-infrared dye di-4-ANBDQBS. We found that t(F)* was a more accurate measure of t(E) than was t(F50) in all experimental settings tested (P = 0.0002). Using t(F)* instead of t(F50) produced the most significant improvement in measurements of the conduction anisotropy and the transmural conduction time in pig ventricles.     

Individual typological profiles for human heart rate under local cold and hypoxic exposures

1. Examining male residents of the Russian Far-East, changes in their heart rate structures and temperature variations on the hand surfaces under hypoxic and local cold factor were studied.

2. Reliable differences in statistical and spectral-wave indices of human heart rate and hand surface thermal pattern depending on the level of nonspecific resistance.

3. It is possible to select persons resistant to low temperature and oxygen deficiency by their heart rate responses to hypoxia and local cold impacts.     

Analysis of DsRed Mutants. Space around the fluorophore accelerates fluorescence development.

Earlier mutagenesis of the red fluorescent protein drFP583, also called DsRed, resulted in a mutant named Fluorescent Timer (Terskikh, A., Fradkov, A., Ermakova, G., Zaraisky, A., Tan, P., Kajava, A. V., Zhao, X., Lukyanov, S., Matz, M., Kim, S., Weissman, I., and Siebert, P. (2000) Science 290, 1585--1588). Further mutagenesis generated variants with novel and improved fluorescent properties. The mutant called AG4 exhibits only green fluorescence. The mutant, called E5up (V105A), shows complete fluorophore maturation, eventually eliminating residual green fluorescence present in DsRed. Finally, the mutant, called E57 (V105A, I161T, S197A), matures faster than DsRed as demonstrated in vitro with purified protein and in vivo with recombinant protein expressed in Escherichia coli and Xenopus leavis. Comparative analysis of the mutants in the context of the crystal structure of DsRed suggests that mutants with free space around the fluorophore mature faster and more completely.     

High‐Performance and Stable All‐Polymer Solar Cells Using Donor and Acceptor Polymers with Complementary Absorption

To explore the advantages of emerging all‐polymer solar cells (all‐PSCs), growing efforts have been devoted to developing matched donor and acceptor polymers to outperform fullerene‐based PSCs. In this work, a detailed characterization and comparison of all‐PSCs using a set of donor and acceptor polymers with both conventional and inverted device structures is performed. A simple method to quantify the actual composition and light harvesting contributions from the individual donor and acceptor is described. Detailed study on the exciton dissociation and charge recombination is carried out by a set of measurements to understand the photocurrent loss. It is unraveled that fine‐tuned crystallinity of the acceptor, matched donor and acceptor with complementary absorption and desired energy levels, and device architecture engineering can synergistically boost the performance of all‐PSCs. As expected, the PBDTTS‐FTAZ:PNDI‐T10 all‐PSC attains a high and stable power conversion efficiency of 6.9% without obvious efficiency decay in 60 d. This work demonstrates that PNDI‐T10 can be a potential alternative acceptor polymer to the widely used acceptor N2200 for high‐performance and stable all‐PSCs.     

8.0% Efficient All‐Polymer Solar Cells with High Photovoltage of 1.1 V and Internal Quantum Efficiency near Unity

In very recent years, growing efforts have been devoted to the development of all‐polymer solar cells (all‐PSCs). One of the advantages of all‐PSCs over the fullerene‐based PSCs is the versatile design of both donor and acceptor polymers which allows the optimization of energy levels to maximize the open‐circuit voltage (V_oc). However, there is no successful example of all‐PSCs with both high V_oc over 1 V and high power conversion efficiency (PCE) up to 8% reported so far. In this work, a combination of a donor polymer poly[4,8‐bis(5‐(2‐octylthio)thiophen‐2‐yl)benzo[1,2‐b:4,5‐b′]dithiophene‐2,6‐diyl‐alt‐(5‐(2‐ethylhexyl)‐4H‐thieno[3,4‐c]pyrrole‐4,6(5H)‐dione)‐1,3‐diyl] (PBDTS‐TPD) with a low‐lying highest occupied molecular orbital level and an acceptor polymer poly[[N,N′‐bis(2‐octyldodecyl)‐naphthalene‐1,4,5,8‐bis(dicarboximide)‐2,6‐diyl]‐alt‐thiophene‐2,5‐diyl] (PNDI‐T) with a high‐lying lowest unoccupied molecular orbital level is used, realizing high‐performance all‐PSCs with simultaneously high V_oc of 1.1 V and high PCE of 8.0%, and surpassing the performance of the corresponding PC₇₁BM‐based PSCs. The PBDTS‐TPD:PNDI‐T all‐PSCs achieve a maximum internal quantum efficiency of 95% at 450 nm, which reveals that almost all the absorbed photons can be converted into free charges and collected by electrodes. This work demonstrates the advantages of all‐PSCs by incorporating proper donor and acceptor polymers to boost both V_oc and PCEs.