The role of cardiac troponin T quantity and function in cardiac development and dilated cardiomyopathy

Background: Hypertrophic (HCM) and dilated (DCM) cardiomyopathies results from sarcomeric protein mutations, including cardiac troponin T (cTnT, TNNT2). We determined whether TNNT2 mutations cause cardiomyopathies by altering cTnT function or quantity; whether the severity of DCM is related to the ratio of mutant to wildtype cTnT; whether Ca2+ desensitization occurs in DCM; and whether absence of cTnT impairs early embryonic cardiogenesis. Methods and Findings: We ablated Tnnt2 to produce heterozygous Tnnt2+/ mice, and crossbreeding produced homozygous null Tnnt2-/-embryos. We also generated transgenic mice overexpressing wildtype (TGWT) or DCM mutant (TGK210Δ) Tnnt2. Crossbreeding produced mice lacking one allele of Tnnt2, but carrying wildtype (Tnnt2+/-/TGWT) or mutant (Tnnt2+/-/TGK210Δ) transgenes. Tnnt2+/-mice relative to wildtype had significantly reduced transcript (0.82 ± 0.06 [SD] vs. 1.00 ± 0.12 arbitrary units; p = 0.025), but not protein (1.01 ± 0.20 vs. 1.00 ± 0.13 arbitrary units; p = 0.44). Tnnt2+/-mice had normal hearts (histology, mass, left ventricular end diastolic diameter [LVEDD], fractional shortening [FS]). Moreover, whereas Tnnt2+/-/ TGK210Δ mice had severe DCM, TGK210Δ mice had only mild DCM (FS 18 ± 4 vs. 29 ± 7%; p < 0.01). The difference in severity of DCM may be attributable to a greater ratio of mutant to wildtype Tnnt2 transcript in Tnnt2+/-/TGK210Δ relative to TGK210Δ mice (2.42±0.08, p = 0.03). Tnnt2+/-/TGK210Δ muscle showed Ca2+ desensitization (pCa50 = 5.34 ± 0.08 vs. 5.58 ± 0.03 at sarcomere length 1.9 μm. p<0.01), but no difference in maximum force generation. Day 9.5 Tnnt2-/-embryos had normally looped hearts, but thin ventricular walls, large pericardial effusions, noncontractile hearts, and severely disorganized sarcomeres. Conclusions: Absence of one Tnnt2 allele leads to a mild deficit in transcript but not protein, leading to a normal cardiac phenotype. DCM results from abnormal function of a mutant protein, which is associated with myocyte Ca2+ desensitization. The severity of DCM depends on the ratio of mutant to wildtype Tnnt2 transcript. cTnT is essential for sarcomere formation, but normal embryonic heart looping occurs without contractile activity. © 2008 Ahmad et al

Kinetic Theory Approach to Modeling of Cellular Repair Mechanisms under Genome Stress

Under acute perturbations from outer environment, a normal cell can trigger cellular self-defense mechanism in response to genome stress. To investigate the kinetics of cellular self-repair process at single cell level further, a model of DNA damage generating and repair is proposed under acute Ion Radiation (IR) by using mathematical framework of kinetic theory of active particles (KTAP). Firstly, we focus on illustrating the profile of Cellular Repair System (CRS) instituted by two sub-populations, each of which is made up of the active particles with different discrete states. Then, we implement the mathematical framework of cellular self-repair mechanism, and illustrate the dynamic processes of Double Strand Breaks (DSBs) and Repair Protein (RP) generating, DSB-protein complexes (DSBCs) synthesizing, and toxins accumulating. Finally, we roughly analyze the capability of cellular self-repair mechanism, cellular activity of transferring DNA damage, and genome stability, especially the different fates of a certain cell before and after the time thresholds of IR perturbations that a cell can tolerate maximally under different IR perturbation circumstances

The programming of sequences of saccades

Saccadic eye movements move the high-resolution fovea to point at regions of interest. Saccades can only be generated serially (i.e., one at a time). However, what remains unclear is the extent to which saccades are programmed in parallel (i.e., a series of such moments can be planned together) and how far ahead such planning occurs. In the current experiment, we investigate this issue with a saccade contingent preview paradigm. Participants were asked to execute saccadic eye movements in response to seven small circles presented on a screen. The extent to which participants were given prior information about target locations was varied on a trial-by-trial basis: participants were aware of the location of the next target only, the next three, five, or all seven targets. The addition of new targets to the display was made during the saccade to the next target in the sequence. The overall time taken to complete the sequence was decreased as more targets were available up to all seven targets. This was a result of a reduction in the number of saccades being executed and a reduction in their saccade latencies. Surprisingly, these results suggest that, when faced with a demand to saccade to a large number of target locations, saccade preparation about all target locations is carried out in paralle

The effect of S-substitution at the O6-guanine site on the structure and dynamics of a DNA oligomer containing a G:T mismatch

The effect of S-substitution on the O6 guanine site of a 13-mer DNA duplex containing a G:T mismatch is studied using molecular dynamics. The structure, dynamic evolution and hydration of the S-substituted duplex are compared with those of a normal duplex, a duplex with Ssubstitution on guanine, but no mismatch and a duplex with just a G:T mismatch. The S-substituted mismatch leads to cell death rather than repair. One suggestion is that the G:T mismatch recognition protein recognises the S-substituted mismatch (GS:T) as G:T. This leads to a cycle of futile repair ending in DNA breakage and cell death. We find that some structural features of the helix are similar for the duplex with the G:T mismatch and that with the S-substituted mismatch, but differ from the normal duplex, notably the helical twist. These differences arise from the change in the hydrogen-bonding pattern of the base pair. However a marked feature of the S-substituted G:T mismatch duplex is a very large opening. This showed considerable variability. It is suggested that this enlarged opening would lend support to an alternative model of cell death in which the mismatch protein attaches to thioguanine and activates downstream damage-response pathways. Attack on the sulphur by reactive oxygen species, also leading to cell death, would also be aided by the large, variable opening

Shoulder pain due to cervical radiculopathy: an underestimated long-term complication of herpes zoster virus reactivation?

Purpose To evaluate if herpes zoster virus (HZV) reactivation may be considered in the aetiology of cervical radiculopathy. Methods The study group was composed of 110 patients (52 M-58F;mean age ± SD:46.5 ± 6.12; range:40-73) with a clinical diagnosis of cervical radiculopathy. Patients with signs of chronic damage on neurophysiological studies were submitted to an X-ray and to an MRI of the cervical spine in order to clarify the cause of the cervical radiculopathy and were investigated for a possible reactivation of HZV; HZV reactivation was considered as “recent” or “antique” if it occurs within or after 24 months from the onset of symptoms, respectively. Data were submitted to statistics. Results Thirty-eight patients (34,5%,16 M-22F) had a history of HZV reactivation: four (2 M-2F) were “recent” and 34 (14 M-20F) were “antique”. In 68 of 110 participants (61,8%,30 M-38F), pathological signs on X-ray and/or MRI of the cervical spine appeared; in the remaining 42 (38,2%,22 M-20F) X-ray and MRI resulted as negative. Among patients with HZV reactivation, seven (18,4%) had a “positive” X-ray-MRI while in 31 (81,6%) the instrumental exams were considered as negative. The prevalence of “antique” HZV reactivations was statistically greater in the group of patients with no pathological signs on X-ray/MRI of the cervical spine with respect to the group with a pathological instrumental exam (p < 0.01). Conclusions It may be useful to investigate the presence of a positive history of HZV reactivation and to consider it as a long-term complication of a cervical root inflammation especially in patients in which X-ray and MRI of the cervical spine did not show pathological findings

Traffic-related pollution and asthma prevalence in children. Quantification of associations with nitrogen dioxide.

Ambient nitrogen dioxide is a widely available measure of traffic-related air pollution and is inconsistently associated with the prevalence of asthma symptoms in children. The use of this relationship to evaluate the health impact of policies affecting traffic management and traffic emissions is limited by the lack of a concentration-response function based on systematic review and meta-analysis of relevant studies. Using systematic methods, we identified papers containing quantitative estimates for nitrogen dioxide and the 12 month period prevalence of asthma symptoms in children in which the exposure contrast was within-community and dominated by traffic pollution. One estimate was selected from each study according to an a priori algorithm. Odds ratios were standardised to 10 μg/m(3) and summary estimates were obtained using random- and fixed-effects estimates. Eighteen studies were identified. Concentrations of nitrogen dioxide were estimated for the home address (12) and/or school (8) using a range of methods; land use regression (6), study monitors (6), dispersion modelling (4) and interpolation (2). Fourteen studies showed positive associations but only two associations were statistically significant at the 5 % level. There was moderate heterogeneity (I(2) = 32.8 %) and the random-effects estimate for the odds ratio was 1.06 (95 % CI 1.00 to 1.11). There was no evidence of small study bias. Individual studies tended to have only weak positive associations between nitrogen dioxide and asthma prevalence but the summary estimate bordered on statistical significance at the 5 % level. Although small, the potential impact on asthma prevalence could be considerable because of the high level of baseline prevalence in many cities. Whether the association is causal or indicates the effects of a correlated pollutant or other confounders, the estimate obtained by the meta-analysis would be appropriate for estimating impacts of traffic pollution on asthma prevalence

Minimal Flavour Violation for Leptoquarks

Scalar leptoquarks, with baryon and lepton number conserving interactions, could have TeV scale masses, and be produced at colliders or contribute to a wide variety of rare decays. In pursuit of some insight as to the most sensitive search channels, We assume that the leptoquark-lepton-quark coupling can be constructed from the known mass matrices. We estimate the rates for selected rare processes in three cases: leptoquarks carrying lepton and quark flavour, leptoquarks with quark flavour only, and unflavoured leptoquarks. We find that leptoquark decay to top quarks is an interesting search channel.Comment: 17 pages, 2 figures, minor changes and references adde

Towards a Systematic Construction of Realistic D-brane Models on a del Pezzo Singularity

A systematic approach is followed in order to identify realistic D-brane models at toric del Pezzo singularities. Requiring quark and lepton spectrum and Yukawas from D3 branes and massless hypercharge, we are led to Pati-Salam extensions of the Standard Model. Hierarchies of masses, flavour mixings and control of couplings select higher order del Pezzo singularities, minimising the Higgs sector prefers toric del Pezzos with dP3 providing the most successful compromise. Then a supersymmetric local string model is presented with the following properties at low energies: (i) the MSSM spectrum plus a local B-L gauge field or additional Higgs fields depending on the breaking pattern, (ii) a realistic hierarchy of quark and lepton masses and (iii) realistic flavour mixing between quark and lepton families with computable CKM and PMNS matrices, and CP violation consistent with observations. In this construction, kinetic terms are diagonal and under calculational control suppressing standard FCNC contributions. Proton decay operators of dimension 4, 5, 6 are suppressed, and gauge couplings can unify depending on the breaking scales from string scales at energies in the range 10^{12}-10^{16} GeV, consistent with TeV soft-masses from moduli mediated supersymmetry breaking. The GUT scale model corresponds to D3 branes at dP3 with two copies of the Pati-Salam gauge symmetry SU(4)\timesSU(2)R\timesSU(2)L. D-brane instantons generate a non-vanishing mu-term. Right handed sneutrinos can break the B-L symmetry and induce a see-saw mechanism of neutrino masses and R-parity violating operators with observable low-energy implications.Comment: 27 pages plus 5 appendices (42 pages total), 9 figures. v3: equation refs and citation correcte