Cell-Cycle-Based Strategies to Drive Myocardial Repair

Cardiomyocytes exhibit robust proliferative activity during development. After birth, cardiomyocyte proliferation is markedly reduced. Consequently, regenerative growth in the postnatal heart via cardiomyocyte proliferation (and, by inference, proliferation of stem-cell-derived cardiomyocytes) is limited and often insufficient to affect repair following injury. Here, we review studies wherein cardiomyocyte cell cycle proliferation was induced via targeted expression of cyclin D2 in postnatal hearts. Cyclin D2 expression resulted in a greater than 500-fold increase in cell cycle activity in transgenic mice as compared to their nontransgenic siblings. Induced cell cycle activity resulted in infarct regression and concomitant improvement in cardiac hemodynamics following coronary artery occlusion. These studies support the notion that cell-cycle-based strategies can be exploited to drive myocardial repair following injury

An Extended Model for the Evolution of Prebiotic Homochirality: A Bottom-Up Approach to the Origin of Life

A generalized autocatalytic model for chiral polymerization is investigated in detail. Apart from enantiomeric cross-inhibition, the model allows for the autogenic (non-catalytic) formation of left and right-handed monomers from a substrate with reaction rates $\epsilon_L$ and $\epsilon_R$, respectively. The spatiotemporal evolution of the net chiral asymmetry is studied for models with several values of the maximum polymer length, N. For N=2, we study the validity of the adiabatic approximation often cited in the literature. We show that the approximation obtains the correct equilibrium values of the net chirality, but fails to reproduce the short time behavior. We show also that the autogenic term in the full N=2 model behaves as a control parameter in a chiral symmetry- breaking phase transition leading to full homochirality from racemic initial conditions. We study the dynamics of the N -> infinity model with symmetric ($\epsilon_L = \epsilon_R$) autogenic formation, showing that it only achieves homochirality for $\epsilon < \epsilon_c$, where $\epsilon_c$ is an N-dependent critical value. For $\epsilon \leq \epsilon_c$ we investigate the behavior of models with several values of N, showing that the net chiral asymmetry grows as tanh(N). We show that for a given symmetric autogenic reaction rate, the net chirality and the concentrations of chirally pure polymers increase with the maximum polymer length in the model. We briefly discuss the consequences of our results for the development of homochirality in prebiotic Earth and possible experimental verification of our findings

Focused Deterrence and the Prevention of Violent Gun Injuries: Practice, Theoretical Principles, and Scientific Evidence

Focused deterrence strategies are a relatively new addition to a growing portfolio of evidence-based violent gun injury prevention practices available to policy makers and practitioners. These strategies seek to change offender behavior by understanding the underlying violence-producing dynamics and conditions that sustain recurring violent gun injury problems and by implementing a blended strategy of law enforcement, community mobilization, and social service actions. Consistent with documented public health practice, the focused deterrence approach identifies underlying risk factors and causes of recurring violent gun injury problems, develops tailored responses to these underlying conditions, and measures the impact of implemented interventions. This article reviews the practice, theoretical principles, and evaluation evidence on focused deterrence strategies. Although more rigorous randomized studies are needed, the available empirical evidence suggests that these strategies generate noteworthy gun violence reduction impacts and should be part of a broader portfolio of violence prevention strategies available to policy makers and practitioners

Electronic Coherence Dephasing in Excitonic Molecular Complexes: Role of Markov and Secular Approximations

We compare four different types of equations of motion for reduced density matrix of a system of molecular excitons interacting with thermodynamic bath. All four equations are of second order in the linear system-bath interaction Hamiltonian, with different approximations applied in their derivation. In particular we compare time-nonlocal equations obtained from so-called Nakajima-Zwanzig identity and the time-local equations resulting from the partial ordering prescription of the cummulant expansion. In each of these equations we alternatively apply secular approximation to decouple population and coherence dynamics from each other. We focus on the dynamics of intraband electronic coherences of the excitonic system which can be traced by coherent two-dimensional spectroscopy. We discuss the applicability of the four relaxation theories to simulations of population and coherence dynamics, and identify features of the two-dimensional coherent spectrum that allow us to distinguish time-nonlocal effects.Comment: 14 pages, 8 figure

Terahertz underdamped vibrational motion governs protein-ligand binding in solution

Low-frequency collective vibrational modes in proteins have been proposed as being responsible for efficiently directing biochemical reactions and biological energy transport. However, evidence of the existence of delocalized vibrational modes is scarce and proof of their involvement in biological function absent. Here we apply extremely sensitive femtosecond optical Kerr-effect spectroscopy to study the depolarized Raman spectra of lysozyme and its complex with the inhibitor triacetylchitotriose in solution. Underdamped delocalized vibrational modes in the terahertz frequency domain are identified and shown to blue-shift and strengthen upon inhibitor binding. This demonstrates that the ligand-binding coordinate in proteins is underdamped and not simply solvent-controlled as previously assumed. The presence of such underdamped delocalized modes in proteins may have significant implications for the understanding of the efficiency of ligand binding and protein–molecule interactions, and has wider implications for biochemical reactivity and biological function

Mining a Cathepsin Inhibitor Library for New Antiparasitic Drug Leads

The targeting of parasite cysteine proteases with small molecules is emerging as a possible approach to treat tropical parasitic diseases such as sleeping sickness, Chagas' disease, and malaria. The homology of parasite cysteine proteases to the human cathepsins suggests that inhibitors originally developed for the latter may be a source of promising lead compounds for the former. We describe here the screening of a unique ∼2,100-member cathepsin inhibitor library against five parasite cysteine proteases thought to be relevant in tropical parasitic diseases. Compounds active against parasite enzymes were subsequently screened against cultured Plasmodium falciparum, Trypanosoma brucei brucei and/or Trypanosoma cruzi parasites and evaluated for cytotoxicity to mammalian cells. The end products of this effort include the identification of sub-micromolar cell-active leads as well as the elucidation of structure-activity trends that can guide further optimization efforts

Na+ imaging reveals little difference in action potential–evoked Na+ influx between axon and soma

Author Posting. © The Authors, 2010. This is the author's version of the work. It is posted here by permission of Nature Publishing Group for personal use, not for redistribution. The definitive version was published in Nature Neuroscience 13 (2010): 852-860, doi:10.1038/nn.2574.In cortical pyramidal neurons, the axon initial segment (AIS) plays a pivotal role in synaptic integration. It has been asserted that this property reflects a high density of Na+ channels in AIS. However, we here report that AP–associated Na+ flux, as measured by high–speed fluorescence Na+ imaging, is about 3 times larger in the rat AIS than in the soma. Spike evoked Na+ flux in the AIS and the first node of Ranvier is about the same, and in the basal dendrites it is about 8 times lower. At near threshold voltages persistent Na+ conductance is almost entirely axonal. Finally, we report that on a time scale of seconds, passive diffusion and not pumping is responsible for maintaining transmembrane Na+ gradients in thin axons during high frequency AP firing. In computer simulations, these data were consistent with the known features of AP generation in these neurons.Supported by US– Israel BSF Grant (2003082), Grass Faculty Grant from the MBL, NIH Grant (NS16295), Multiple Sclerosis Society Grant (PP1367), and a fellowship from the Gruss Lipper Foundation

Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation

NKG2D plays a major role in controlling immune responses through the regulation of natural killer (NK) cells, αβ and γδ T-cell function. This activating receptor recognizes eight distinct ligands (the MHC Class I polypeptide-related sequences (MIC) A andB, and UL16-binding proteins (ULBP)1–6) induced by cellular stress to promote recognition cells perturbed by malignant transformation or microbial infection. Studies into human cytomegalovirus (HCMV) have aided both the identification and characterization of NKG2D ligands (NKG2DLs). HCMV immediate early (IE) gene up regulates NKGDLs, and we now describe the differential activation of ULBP2 and MICA/B by IE1 and IE2 respectively. Despite activation by IE functions, HCMV effectively suppressed cell surface expression of NKGDLs through both the early and late phases of infection. The immune evasion functions UL16, UL142, and microRNA(miR)-UL112 are known to target NKG2DLs. While infection with a UL16 deletion mutant caused the expected increase in MICB and ULBP2 cell surface expression, deletion of UL142 did not have a similar impact on its target, MICA. We therefore performed a systematic screen of the viral genome to search of addition functions that targeted MICA. US18 and US20 were identified as novel NK cell evasion functions capable of acting independently to promote MICA degradation by lysosomal degradation. The most dramatic effect on MICA expression was achieved when US18 and US20 acted in concert. US18 and US20 are the first members of the US12 gene family to have been assigned a function. The US12 family has 10 members encoded sequentially through US12–US21; a genetic arrangement, which is suggestive of an ‘accordion’ expansion of an ancestral gene in response to a selective pressure. This expansion must have be an ancient event as the whole family is conserved across simian cytomegaloviruses from old world monkeys. The evolutionary benefit bestowed by the combinatorial effect of US18 and US20 on MICA may have contributed to sustaining the US12 gene family

An approach for particle sinking velocity measurements in the 3–400 μm size range and considerations on the effect of temperature on sinking rates

The flux of organic particles below the mixed layer is one major pathway of carbon from the surface into the deep ocean. The magnitude of this export flux depends on two major processes—remineralization rates and sinking velocities. Here, we present an efficient method to measure sinking velocities of particles in the size range from approximately 3–400 μm by means of video microscopy (FlowCAM®). The method allows rapid measurement and automated analysis of mixed samples and was tested with polystyrene beads, different phytoplankton species, and sediment trap material. Sinking velocities of polystyrene beads were close to theoretical values calculated from Stokes’ Law. Sinking velocities of the investigated phytoplankton species were in reasonable agreement with published literature values and sinking velocities of material collected in sediment trap increased with particle size. Temperature had a strong effect on sinking velocities due to its influence on seawater viscosity and density. An increase in 9 °C led to a measured increase in sinking velocities of ~40 %. According to this temperature effect, an average temperature increase in 2 °C as projected for the sea surface by the end of this century could increase sinking velocities by about 6 % which might have feedbacks on carbon export into the deep ocean

Perspectives on the Trypanosoma cruzi-host cell receptor interaction

Chagas disease is caused by the parasite Trypanosoma cruzi. The critical initial event is the interaction of the trypomastigote form of the parasite with host receptors. This review highlights recent observations concerning these interactions. Some of the key receptors considered are those for thromboxane, bradykinin, and for the nerve growth factor TrKA. Other important receptors such as galectin-3, thrombospondin, and laminin are also discussed. Investigation into the molecular biology and cell biology of host receptors for T. cruzi may provide novel therapeutic targets