Directions of high cycle fatigue cracks emanating from circular notches studied by optical profilometry

Current models for predicting the fatigue endurance of notched solids use the stresses along a straight line, beginning at the notch root, as a simplification of the real crack propagation path. In this work, the experimental crack paths for hollow notched samples were analysed through different microscopy techniques, with the objective of establishing high cycle fatigue crack growth directions in a mild steel. Fully reversed tension–compression fatigue tests of thin-walled tube specimens with a passing-through hole were carried out. The crack paths observed in the outer cylindrical surface were studied in each case, with special attention to the crack initiation point and the crack direction along the first grains. Moreover, the analysis of the fracture surfaces allowed the same analysis to be performed to determine the internal crack paths. It was observed that the crack initiation point was close to the maximum principal stress point at the hole contour as obtained from linear elastic finite element analysis, and the crack direction in its initiation was generally close to Mode I direction, contrary to the conventionally accepted 45 crack growth direction.The authors would like to thank the European Union, the Spanish Government and the Junta de Andalucía for its financial support through grantsDPI2017-84788-PandPID2020-117407GB-I00(FEDER/Ministerio de Ciencia e Innovación - Agencia Estatal de Investigación) and P18-FR- 4306 (‘‘Fondo Europeo de Desarrollo Regional (FEDER) y Consejería de Economía, Conocimiento, Empresas y Universidad de la Junta de Andalucía, dentro del Programa Operativo FEDER 2014-2020’’). N.O. Larrosa would also like to thank the UK Engineering and Physical Sciences Research Council (EPSRC) for its financial support through grant number EP/S012362/1

Reducing chaos in SAT-like search: finding solutions close to a given one

Motivated by our own industrial users, we attack the following challenge that is crucial in many practical planning, scheduling or timetabling applications. Assume that a solver has found a solution for a given hard problem and, due to unforeseen circumstances (e.g., rescheduling), or after an analysis by a committee, a few more constraints have to be added and the solver has to be re-run. Then it is almost always important that the new solution is “close” to the original one. The activity-based variable selection heuristics used by SAT solvers make search chaotic, i.e., extremely sensitive to the initial conditions. Therefore, re-running with just one additional clause added at the end of the input usually gives a completely different solution. We show that naive approaches for finding close solutions do not work at all, and that solving the Boolean optimization problem is far too inefficient: to find a reasonably close solution, state-of-the-art tools typically require much more time than was needed to solve the original problem. Here we propose the first (to our knowledge) approach that obtains close solutions quickly. In fact, it typically finds the optimal (i.e., closest) solution in only 25% of the time the solver took in solving the original problem. Our approach requires no deep theoretical or conceptual innovations. Still, it is non-trivial to come up with and will certainly be valuable for researchers and practitioners facing the same problem.Postprint (published version

Apoptosis resistance in HIV-1 persistently-infected cells is independent of active viral replication and involves modulation of the apoptotic mitochondrial pathway

<p>Abstract</p> <p>Background</p> <p>HIV triggers the decline of CD4⁺T cells and leads to progressive dysfunction of cell-mediated immunity. Although an increased susceptibility to cell death occurs during the acute phase of HIV infection, persistently-infected macrophages and quiescent T-cells seem to be resistant to cell death, representing a potential reservoir for virus production.</p> <p>Results</p> <p>Lymphoid (H9/HTLVIII_Band J1.1) and pro-monocytic (U1) HIV-1 persistently-infected cell lines were treated with hydrogen peroxide (H₂O₂) and staurosporine (STS) for 24 h, and susceptibility to apoptosis was evaluated and compared with uninfected counterparts (H9, Jurkat and U937 respectively). When exposed to different pro-apoptotic stimuli, all persistently-infected cell lines showed a dramatic reduction in the frequency of apoptotic cells in comparison with uninfected cells. This effect was independent of the magnitude of viral replication, since the induction of viral production in lymphoid or pro-monocytic cells by exposure to TNF-α or PMA did not significantly change their susceptibility to H₂O₂- or STS-induced cell death. A mechanistic analysis revealed significant diferences in mitochondrial membrane potential (MMP) and caspase-3 activation between uninfected and persistently-infected cells. In addition, Western blot assays showed a dramatic reduction of the levels of pro-apototic Bax in mitochondria of persistently-infected cells treated with H₂O₂or STS, but not in uninfected cells.</p> <p>Conclusion</p> <p>This study represents the first evidence showing that resistance to apoptosis in persistently-infected lymphoid and monocytic cells is independent of active viral production and involves modulation of the mitochondrial pathway. Understanding this effect is critical to specifically target the persistence of viral reservoirs, and provide insights for future therapeutic strategies in order to promote complete viral eradication.</p

On Tackling the Limits of Resolution in SAT Solving

The practical success of Boolean Satisfiability (SAT) solvers stems from the CDCL (Conflict-Driven Clause Learning) approach to SAT solving. However, from a propositional proof complexity perspective, CDCL is no more powerful than the resolution proof system, for which many hard examples exist. This paper proposes a new problem transformation, which enables reducing the decision problem for formulas in conjunctive normal form (CNF) to the problem of solving maximum satisfiability over Horn formulas. Given the new transformation, the paper proves a polynomial bound on the number of MaxSAT resolution steps for pigeonhole formulas. This result is in clear contrast with earlier results on the length of proofs of MaxSAT resolution for pigeonhole formulas. The paper also establishes the same polynomial bound in the case of modern core-guided MaxSAT solvers. Experimental results, obtained on CNF formulas known to be hard for CDCL SAT solvers, show that these can be efficiently solved with modern MaxSAT solvers

The CD14+/lowCD16+ monocyte subset is more susceptible to spontaneous and oxidant-induced apoptosis than the CD14+CD16− subset

Human monocytes can be classified into two subsets with distinctive characteristics. In this study, we report a difference in apoptotic potential between these two subsets with CD14+/lowCD16+ monocytes being more susceptible than CD14+CD16− monocytes to undergo spontaneous apoptosis and apoptosis induced by reactive oxygen species (ROS). By global transcriptomic and proteomic approaches, we observed that CD14+/lowCD16+ monocytes expressed higher levels of pro-apoptotic genes and proteins such as TNFα, caspase 3, Bax and cytochrome c and showed more caspases 3 and 7 activities. They also exhibited greater aerobic respiration resulting in a higher production of ROS from the mitochondria. CD14+CD16− monocytes, in contrast, showed higher expression of glutathione (GSH)-metabolizing genes such as GSH peroxidase and microsomal GSH S-transferase and were more resistant to oxidative stress than CD14+/lowCD16+ monocytes. The apoptosis of CD14+/lowCD16+ monocytes was ROS dependent as reducing ROS levels significantly reduced cell death. This is the first report of a differential apoptotic propensity of human monocyte subsets, and gaining a better understanding of this process may help to provide a better understanding of the roles of these subsets during homeostasis and under pathological conditions, particularly in situations in which high levels of oxidants are present

Anti-Inflammatory Effects of Resveratrol, Curcumin and Simvastatin in Acute Small Intestinal Inflammation

BACKGROUND: The health beneficial effects of Resveratrol, Curcumin and Simvastatin have been demonstrated in various experimental models of inflammation. We investigated the potential anti-inflammatory and immunomodulatory mechanisms of the above mentioned compounds in a murine model of hyper-acute Th1-type ileitis following peroral infection with Toxoplasma gondii. METHODOLOGY/PRINCIPAL FINDINGS: Here we show that after peroral administration of Resveratrol, Curcumin or Simvastatin, mice were protected from ileitis development and survived the acute phase of inflammation whereas all Placebo treated controls died. In particular, Resveratrol treatment resulted in longer-term survival. Resveratrol, Curcumin or Simvastatin treated animals displayed significantly increased numbers of regulatory T cells and augmented intestinal epithelial cell proliferation/regeneration in the ileum mucosa compared to placebo control animals. In contrast, mucosal T lymphocyte and neutrophilic granulocyte numbers in treated mice were reduced. In addition, levels of the anti-inflammatory cytokine IL-10 in ileum, mesenteric lymph nodes and spleen were increased whereas pro-inflammatory cytokine expression (IL-23p19, IFN-γ, TNF-α, IL-6, MCP-1) was found to be significantly lower in the ileum of treated animals as compared to Placebo controls. Furthermore, treated animals displayed not only fewer pro-inflammatory enterobacteria and enterococci but also higher anti-inflammatory lactobacilli and bifidobacteria loads. Most importantly, treatment with all three compounds preserved intestinal barrier functions as indicated by reduced bacterial translocation rates into spleen, liver, kidney and blood. CONCLUSION/SIGNIFICANCE: Oral treatment with Resveratrol, Curcumin or Simvastatin ameliorates acute small intestinal inflammation by down-regulating Th1-type immune responses and prevents bacterial translocation by maintaining gut barrier function. These findings provide novel and potential prophylaxis and treatment options of patients with inflammatory bowel diseases

The Effects of Vitamin D Receptor Silencing on the Expression of LVSCC-A1C and LVSCC-A1D and the Release of NGF in Cortical Neurons

Recent studies have suggested that vitamin D can act on cells in the nervous system. Associations between polymorphisms in the vitamin D receptor (VDR), age-dependent cognitive decline, and insufficient serum 25 hydroxyvitamin D(3) levels in Alzheimer's patients and elderly people with cognitive decline have been reported. We have previously shown that amyloid β (Aβ) treatment eliminates VDR protein in cortical neurons. These results suggest a potential role for vitamin D and vitamin D-mediated mechanisms in Alzheimer's disease (AD) and neurodegeneration. Vitamin D has been shown to down-regulate the L-type voltage-sensitive calcium channels, LVSCC-A1C and LVSCC-A1D, and up-regulate nerve growth factor (NGF). However, expression of these proteins when VDR is repressed is unknown. The aim of this study is to investigate LVSCC-A1C, LVSCC-A1D expression levels and NGF release in VDR-silenced primary cortical neurons prepared from Sprague-Dawley rat embryos.qRT-PCR and western blots were performed to determine VDR, LVSCC-A1C and -A1D expression levels. NGF and cytotoxicity levels were determined by ELISA. Apoptosis was determined by TUNEL. Our findings illustrate that LVSCC-A1C mRNA and protein levels increased rapidly in cortical neurons when VDR is down-regulated, whereas, LVSCC-A1D mRNA and protein levels did not change and NGF release decreased in response to VDR down-regulation. Although vitamin D regulates LVSCC-A1C through VDR, it may not regulate LVSCC-A1D through VDR.Our results indicate that suppression of VDR disrupts LVSCC-A1C and NGF production. In addition, when VDR is suppressed, neurons could be vulnerable to aging and neurodegeneration, and when combined with Aβ toxicity, it is possible to explain some of the events that occur during neurodegeneration