Counterexample-Preserving Reduction for Symbolic Model Checking

The cost of LTL model checking is highly sensitive to the length of the formula under verification. We observe that, under some specific conditions, the input LTL formula can be reduced to an easier-to-handle one before model checking. In our reduction, these two formulae need not to be logically equivalent, but they share the same counterexample set w.r.t the model. In the case that the model is symbolically represented, the condition enabling such reduction can be detected with a lightweight effort (e.g., with SAT-solving). In this paper, we tentatively name such technique "Counterexample-Preserving Reduction" (CePRe for short), and finally the proposed technquie is experimentally evaluated by adapting NuSMV

Induction of mast cell accumulation, histamine release and skin edema by N49 phospholipase A2

<p>Abstract</p> <p>Background</p> <p>It has been recognized that phospholipase A₂(PLA₂) is a crucial component of snake venom, which contributes greatly to snake venom induced inflammation in man. However, the mechanisms through which N49 PLA₂provoke inflammation remain unclear. Recently, a N49 PLA₂, TM-N49 from <it>Protobothrops mucrosquamatus </it>crude venom was characterized in our laboratory. Since the purification procedure developed is able to supply us with relatively large quantity of highly purified TM-N49, we investigated the ability of TM-N49 in induction of inflammation.</p> <p>Results</p> <p>The results showed that TM-N49 provoked a dose dependent increase in microvascular leakage in the skin of rats. The potency of TM-N49 in induction of skin edema appeared similar potency of bradykinin and histamine. Pretreatment of rats with compound 48/80 diminished TM-N49 induced skin reaction and reduced mast cell numbers in rats. Ginkgolide B and cyproheptadine, but not terfenadine and quinacrine, inhibited TM-N49 elicited microvascular leakage when they were co-injected with the stimulus to rat skin. Moreover, TM-N49 was found to induce histamine release from human colon, lung and tonsil mast cells, and both metabolic inhibitors and pertussis toxin were capable of inhibiting TM-N49 elicited histamine release. TM-N49 induced mast cell accumulation in the peritoneum of mice, which was inhibited by co-injection of ginkgolide B, cyproheptadine and terfenadine. Intravenous injection of monoclonal antibodies against CD18, ICAM-1 and CD11a also blocked TM-N49 induced mast cell accumulation.</p> <p>Conclusion</p> <p>TM-N49 is a potent stimulus for skin edema, mast cell activation and accumulation.</p

Adaptive evolution of the spike gene of SARS coronavirus: changes in positively selected sites in different epidemic groups

BACKGROUND: It is believed that animal-to-human transmission of severe acute respiratory syndrome (SARS) coronavirus (CoV) is the cause of the SARS outbreak worldwide. The spike (S) protein is one of the best characterized proteins of SARS-CoV, which plays a key role in SARS-CoV overcoming species barrier and accomplishing interspecies transmission from animals to humans, suggesting that it may be the major target of selective pressure. However, the process of adaptive evolution of S protein and the exact positively selected sites associated with this process remain unknown. RESULTS: By investigating the adaptive evolution of S protein, we identified twelve amino acid sites (75, 239, 244, 311, 479, 609, 613, 743, 765, 778, 1148, and 1163) in the S protein under positive selective pressure. Based on phylogenetic tree and epidemiological investigation, SARS outbreak was divided into three epidemic groups: 02–04 interspecies, 03-early-mid, and 03-late epidemic groups in the present study. Positive selection was detected in the first two groups, which represent the course of SARS-CoV interspecies transmission and of viral adaptation to human host, respectively. In contrast, purifying selection was detected in 03-late group. These indicate that S protein experiences variable positive selective pressures before reaching stabilization. A total of 25 sites in 02–04 interspecies epidemic group and 16 sites in 03-early-mid epidemic group were identified under positive selection. The identified sites were different between these two groups except for site 239, which suggests that positively selected sites are changeable between groups. Moreover, it was showed that a larger proportion (24%) of positively selected sites was located in receptor-binding domain (RBD) than in heptad repeat (HR)1-HR2 region in 02–04 interspecies epidemic group (p = 0.0208), and a greater percentage (25%) of these sites occurred in HR1–HR2 region than in RBD in 03-early-mid epidemic group (p = 0.0721). These suggest that functionally different domains of S protein may not experience same positive selection in each epidemic group. In addition, three specific replacements (F360S, T487S and L665S) were only found between 03-human SARS-CoVs and strains from 02–04 interspecies epidemic group, which reveals that selective sweep may also force the evolution of S genes before the jump of SARS-CoVs into human hosts. Since certain residues at these positively selected sites are associated with receptor recognition and/or membrane fusion, they are likely to be the crucial residues for animal-to-human transmission of SARS-CoVs, and subsequent adaptation to human hosts. CONCLUSION: The variation of positive selective pressures and positively selected sites are likely to contribute to the adaptive evolution of S protein from animals to humans

The key role for local base order in the generation of multiple forms of China HIV-1 B'/C intersubtype recombinants

BACKGROUND: HIV-1 is a retrovirus with high rate of recombination. Increasing experimental studies in vitro indicated that local hairpin structure of RNA was associated with recombination by favoring RT pausing and promoting strand transfer. A method to estimate the potential to form stem-loop structure by calculating the folding of randomized sequence difference (FORS-D) has been used to investigate the relationship between secondary structure and evolutionary pressure in some genome. It showed that gene regions under strong positive "Darwinian" selection were associated with positive FORS-D values. In the present study, the sequences of HIV-1 subtypes B' and C, both of which represent the parent strains of CRF07_BC, CRF08_BC and China URFs, were selected to investigate the relationship between natural recombination and secondary structure by calculating the FORS-D values. RESULTS: The apparent higher negative FORS-D value region appeared in the gag-pol gene region (nucleotide 0–3000) of HIV-1 subtypes B' and C. Thirteen (86.7 %) of 15 mosaic fragments and 17 (81 %) of 21 recombination breakpoints occurred in this higher negative FORS-D region. This strongly suggested that natural recombination did not occur randomly throughout the HIV genome, and that there might be preferred (or hot) regions or sites for recombination. The FORS-D analysis of breakpoints showed that most breakpoints of recombinants were located in regions with higher negative FORS-D values (P = 0.0053), and appeared to have a higher negative average FORS-D value than the whole genome (P = 0.0007). The regression analysis also indicated that FORS-D values correlated negatively with breakpoint overlap. CONCLUSION: High negative FORS-D values represent high, base order determined stem-loop potentials and influence mainly the formation of stem-loop structures. Therefore, the present results suggested for the first time that occurrence of natural recombination was associated with high base order-determined stem-loop potential, and that local base order might play a key role in the initiation of natural recombination by favoring the formation of stable stem-loop structures

QED contributions to the Ξc−Ξc′\Xi_c-\Xi_c' mixing

We explore the QED corrections to the $\Xi_c-\Xi_c^{\prime}$ mixing within the framework of light-front quark model (LFQM) in the three-quark picture. After explicitly investigating the relation between the $\Xi_c-\Xi_c^{\prime}$ mixing and the flavor $\rm {SU(3)}$ and heavy quark symmetry breaking, we derive the QED contributions to the mixing angle. Numerical results indicate the QED contribution is smaller than the one from the mass difference between the strange and up/down quark provided by a recent Lattice QCD analysis. Adding these contributions together we find that at this stage the $\Xi_c-\Xi_c^{\prime}$ mixing is small and still incapable to account for the large $\rm {SU(3)}$ symmetry breaking in the semi-leptonic $\Xi_c$ decays.Comment: 7 pages, 4figure

Baryons in the light-front approach: the three-quark picture

In this work, a three-quark picture is constructed using a bottom-up approach for baryons in light-front quark model. The shape parameters, which characterize the momentum distribution inside a baryon, are determined with the help of the pole residue of the baryon. The relation between the three-quark picture and the diquark picture is clarified. In model construction, we find that Lorentz boost effect plays an important role, and the bottom-up modeling approach can be generalized to multiquark states. Based on this, a unified theoretical framework for describing multiquark states may be established. As a by-product of model construction, we can easily obtain a new and possibly better definition of baryon interpolating current. The hadron interpolating currents are the starting point of Lattice QCD and QCD sum rules, and therefore have important significance.Comment: 17 page

Dexmedetomidine post-treatment attenuates cardiac ischaemia/reperfusion injury by inhibiting apoptosis through HIF-1α signalling.

Hypoxia-inducible factor 1α (HIF-1α) plays a critical role in the apoptotic process during cardiac ischaemia/reperfusion (I/R) injury. This study aimed to investigate whether post-treatment with dexmedetomidine (DEX) could protect against I/R-induced cardiac apoptosis in vivo and in vitro via regulating HIF-1α signalling pathway. Rat myocardial I/R was induced by occluding the left anterior descending artery for 30 minutes followed by 6-hours reperfusion, and cardiomyocyte hypoxia/reoxygenation (H/R) was induced by oxygen-glucose deprivation for 6 hours followed by 3-hours reoxygenation. Dexmedetomidine administration at the beginning of reperfusion or reoxygenation attenuated I/R-induced myocardial injury or H/R-induced cell death, alleviated mitochondrial dysfunction, reduced the number of apoptotic cardiomyocytes, inhibited the activation of HIF-1α and modulated the expressions of apoptosis-related proteins including BCL-2, BAX, BNIP3, cleaved caspase-3 and cleaved PARP. Conversely, the HIF-1α prolyl hydroxylase-2 inhibitor IOX2 partly blocked DEX-mediated cardioprotection both in vivo and in vitro. Mechanistically, DEX down-regulated HIF-1α expression at the post-transcriptional level and inhibited the transcriptional activation of the target gene BNIP3. Post-treatment with DEX protects against cardiac I/R injury in vivo and H/R injury in vitro. These effects are, at least in part, mediated via the inhibition of cell apoptosis by targeting HIF-1α signalling