Chemical, Physical and Biological Triggers of Evolutionary Conserved Bcl-xL-Mediated Apoptosis

Background: The evidence that pan-Bcl-2 or Bcl-xL-specific inhibitors prematurely kill virus-infected or RNA/DNA-transfected cells provides rationale for investigating these apoptotic inducers further. We hypothesized that not only invasive RNA or DNA (biological factors) but also DNA/RNA-damaging chemical or physical factors could trigger apoptosis that have been sensitized with pan-Bcl-2 or Bcl-xL-specific agents; Methods: We tested chemical and physical factors plus Bcl-xL-specific inhibitor A-1155463 in cells of various origins and the small roundworms (C. elegans); Results: We show that combination of a A-1155463 along with a DNA-damaging agent, 4-nitroquinoline-1-oxide (4NQO), prematurely kills cells of various origins as well as C. elegans. The synergistic effect is p53-dependent and associated with the release of Bad and Bax from Bcl-xL, which trigger mitochondrial outer membrane permeabilization. Furthermore, we found that combining Bcl-xL-specific inhibitors with various chemical compounds or physical insults also induced cell death; Conclusions: Thus, we were able to identify several biological, chemical and physical triggers of the evolutionarily conserved Bcl-xL-mediated apoptotic pathway, shedding light on strategies and targets for novel drug development

Equivalent Circuit Model of Low-Frequency Magnetoelectric Effect in Disk-Type Terfenol-D/PZT Laminate Composites Considering a New Interface Coupling Factor

This paper describes the modeling of magnetoelectric (ME) effects for disk-type Terfenol-D (Tb0.3Dy0.7Fe1.92)/PZT (Pb(Zr,Ti)O3) laminate composite at low frequency by combining the advantages of the static elastic model and the equivalent circuit model, aiming at providing a guidance for the design and fabrication of the sensors based on magnetoelectric laminate composite. Considering that the strains of the magnetostrictive and piezoelectric layers are not equal in actual operating due to the epoxy resin adhesive bonding condition, the magnetostrictive and piezoelectric layers were first modeled through the equation of motion separately, and then coupled together with a new interface coupling factor kc, which physically reflects the strain transfer between the phases. Furthermore, a theoretical expression containing kc for the transverse ME voltage coefficient αv and the optimum thickness ratio noptim to which the maximum ME voltage coefficient corresponds were derived from the modified equivalent circuit of ME laminate, where the interface coupling factor acted as an ideal transformer. To explore the influence of mechanical load on the interface coupling factor kc, two sets of weights, i.e., 100 g and 500 g, were placed on the top of the ME laminates with the same thickness ratio n in the sample fabrication. A total of 22 T-T mode disk-type ME laminate samples with different configurations were fabricated. The interface coupling factors determined from the measured αv and the DC bias magnetic field Hbias were 0.11 for 500 g pre-mechanical load and 0.08 for 100 g pre-mechanical load. Furthermore, the measured optimum thickness ratios were 0.61 for kc = 0.11 and 0.56 for kc = 0.08. Both the theoretical ME voltage coefficient αv and optimum thickness ratio noptim containing kc agreed well with the measured data, verifying the reasonability and correctness for the introduction of kc in the modified equivalent circuit model

A Case Study on Optimization and Control Techniques for Entry Stability in Non-Pillar Longwall Mining

In order to reduce large deformation failure occurrences in non-pillar longwall mining entries due to roof weighting behaviors, a case study in Halagou coal mine was conducted on optimization and control techniques for entry stability in non-pillar longwall mining. The Universal Discrete Element Code (UDEC) modeling was adopted to study entry stability in non-pillar mining, and the characteristics of deformation and stress and crack propagation were revealed. The large deformation transmission between the entry-immediate roof and the gob-immediate roof could be eliminated by optimizing the entry roof structure through a directional roof-cutting method. The localized tensile stresses generated in the entry-surrounding rock caused the generation of coalescent macroscopic fractures, which resulted in the instability of the entry. The tensile stress state could be inhibited by an active flexible support system through enhancing the confining pressure on the surrounding rock. Serious rotation subsidence occurs in the entry roof due to periodic weighting of the main roof, which could be greatly reduced by a passive rigid support pattern. The numerical and field test results both showed that the roof weighting pressure was offloaded by the technique and that the deformation of the entry surrounding the rock in non-pillar mining was quite small. Thus, the technique can effectively ensure the stability of the gob-side entry, which can provide references for entry stability control in non-pillar longwall mining

Mitophagy and Neuroprotection

Neurodegenerative diseases are strongly age-related and currently cannot be cured, with a surge of patient numbers in the coming decades in view of the emerging worldwide ageing population, bringing healthcare and socioeconomic challenges. Effective therapies are urgently needed, and are dependent on new aetiological mechanisms. In neurons, efficient clearance of damaged mitochondria, through the highly evolutionary conserved cellular process termed mitophagy, plays a fundamental role in mitochondrial and metabolic homeostasis, energy supply, neuronal survival, and health. Conversely, defective mitophagy leads to accumulation of damaged mitochondria and cellular dysfunction, contributing to ageing and age-predisposed neurodegeneration. Here, we discuss the contribution of defective mitophagy in these diseases, and underlying molecular mechanisms, and highlight novel therapeutics based on new discovered mitophagy-inducing strategies

Numerical analysis on heat transfer process in the coke oven with the multi-chamber coupling mathematical model

The influence of the thermal conductivity of silica bricks on the coking process as an important component of the coking and combustion chambers is still unclear. A multi-chamber coupling mathematical model of a coke oven is developed to investigate the energy-saving effect of using high thermal conductivity silica bricks in the coke oven. The model is validated using measured temperatures of coal and flue gas bed in a coke oven in operation for a coking cycle. Temperature variation and its distribution in the coking chamber, combustion chamber, and heating wall are simulated for the coke oven using silica bricks with different thermal conductivities. The obtained results showed that compared with the use of common silica bricks, coking time of one cycle can be reduced by ∼60 min, with a decreased consumption of fuel gas by ∼4.9%. The enhancement of heat transfer from the flue gas to the heating wall and the heating wall to coal using silicon bricks with high thermal conductivity can effectively shorten not only the temperature difference between the two sides of the heating wall but also reduce the mean flue temperature of the flue gas by ∼24.5 °C

Nogo-66 promotes β-amyloid protein secretion via NgR/ROCK-dependent BACE1 activation

The generation of β‑amyloid protein (Aβ) is considered a key step in the pathogenesis of Alzheimer's disease (AD) and the regulation of its production is an important therapeutic strategy. It was hypothesized in the present study that Nogo‑A may be involved in AD and may regulate the generation of Aβ. Nogo‑A is known to act as a major inhibitor of neuron regeneration in the adult central nervous system. A recent study indicated that Nogo‑A is associated with AD; however, the underlying effect and molecular mechanisms remain largely elusive. In the present study, the potential effects of Nogo‑A on AD were investigated. ELISA was used to detect the levels of Aβ, enzymatic activity detection kits were used to determine the activity of secretase enzymes in amyloid precursor protein (APP) metabolism, and western blot analysis was used to detect the expression levels of proteins associated with the APP processing and Nogo‑A/Nogo‑66 receptor (NgR) signaling pathways. The results revealed that Nogo‑66, the major inhibitory region of Nogo‑A, promoted neuronal Aβ secretion by increasing the activity of β‑secretase 1 via the NgR/Rho‑associated coiled‑coil containing kinases pathway in a dose‑dependent manner. The present data suggested that Nogo‑A may facilitate the onset and development of AD by promoting Aβ secretion, providing information on a potential novel target for AD therapy