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The different olivine fabrics in ultramafic rocks have been widely used to discuss past tectonic settings, given that the olivine fabrics vary with pressure, temperature and water content. However, there are no research related to whether and how the olivine fabrics transform at different metamorphic stages in a natural rock during the process of deep subduction and exhumation. Yinggelisayi garnet lherzolites from South Altyn have experienced deep continental subduction and exhumation. The garnet lherzolites contain well‐preserved residual protolith minerals, and near‐peak (M1), granulite‐facies retrograde (M2), and amphibolite‐facies retrograde (M3) metamorphic mineral assemblages. Olivine grains in M1 formed at P‐T conditions of 2.52–3.08 GPa, 1,095–1,136°C and low water contents (183–213 ppm H/Si), and showed [010] axes sub‐normal to the foliation and [001] axes subparallel to the lineation, which is characteristic of B‐type fabric ((010)[001]). Olivine grains in M2 formed at P‐T conditions of 1.31–1.80 GPa, 851–893°C and also low water contents (93–139 ppm H/Si), and exhibited [010] axes sub‐normal to the foliation and [100] axes subparallel to the lineation, which is characteristic of A‐type fabric ((010)[100]). These observations suggest that olivine fabrics in high pressure‐ultrahigh pressure metamorphosed ultramafic rocks are different in the near‐peak and retrograde metamorphic stages, and also that the olivine fabrics can be transformed during deep continental subduction and exhumation. Therefore, the dispersed or no clear olivine fabric is probably caused by multi‐stage deformation and metamorphism, and the distinct olivine fabrics can also be used as a clue to identify geological processes and better understand metamorphism and deformation during subduction and exhumation. Plain Language Summary: According to the previous research that different olivine fabrics developed under various temprerature, pressure, stress and water content, we try to discuss the transformation of olivine fabric at different metamorphic stages with different P‐T conditions in metamorphic ultramafic rocks. The Yinggelisayi garnet lherzolites from South Altyn, NW China contain residual protolith minerals, and three stages of metamorphic minerals which include the near‐peak (M1), granulite‐facies (M2) retrograde, and amphibolite‐facies (M3) retrograde metamorphic minerals base on the petrography and mineral composition. And then, we analyzed olivine fabrics in the near‐peak (M1) and early retrograde metamorphic stages (M2). Results showed that the olivine in M1 during deep subduction of the continental crust developed the B‐type olivine fabric and the olivine in M2 during exhumation developed the A‐type olivine fabric. Key Points: Yinggelisayi garnet lherzolites contain residual protolith inclusions and three stages of metamorphic mineralsOlivine in the garnet lherzolites exhibited different fabrics during deep subduction and exhumation of the continental crustOlivine fabrics will be dispersed at multi‐stage deformation and metamorphism [ABSTRACT FROM AUTHOR]

Two types of retrograded eclogite (phengite‐bearing eclogite and garnet pyroxenite) within eclogite‐facies granitic gneisses are reported for the first time from the Younusisayi area of the South Altyn high to ultrahigh pressure (HP–UHP) metamorphic belt. These eclogites were studied using petrology, mineral chemistry, phase equilibrium modelling, and geochronology. The phengite‐bearing eclogite records five stages of metamorphism: (1) early prograde (Grt + Cpx + Amp + Rt + Qz) at conditions of P = 11.50–17.5 kbar, T = 665–740°C; (2) peak eclogite‐facies (Grt + Omp + Ph + Rt + Qz) at conditions of P > 24.2 kbar, T = 710–1000°C; (3) overprinting during retrograde transition to HP granulite‐facies conditions (Grt + Cpx ± Kfs + Pl + Rt + Qz) at P = 12.1–16.9 kbar and T = 760–890°C; (4) retrogression at granulite‐facies conditions (Grt + Cpx + Amp + Pl + Ilm + Qz) of P = 9.1–11.4 kbar, T = 730–840°C; and (5) amphibolite‐facies metamorphism (Amp + Pl + Ilm + Qz) during cooling and decompression. The garnet pyroxenite records four stages of metamorphism: (1) eclogite‐facies at conditions of P > 23.2 kbar, T = 775–965°C; (2) HP granulite‐facies conditions of P = 13.2–17.8 kbar and T = 836–912°C; (3) granulite‐facies conditions of P = 8.6–9.7 kbar, T = 739–783°C; and (4) amphibolite‐facies metamorphism. Zircon U–Pb dating and trace element analysis constrain eclogite‐facies metamorphism to c. 500 Ma, consistent with the age of the surrounding eclogite‐facies granitic gneiss (497.8 ± 2.7 Ma). Retrograde metamorphism ages of c. 460 Ma are interpreted as recording zircon growth after granulite‐facies metamorphism. The P–T–t path defines the integrated process of deep subduction and multistage exhumation and places constraints on the early Palaeozoic geodynamics of the South Altyn belt. Well‐preserved major and trace element zoning of garnets in the Ph‐bearing eclogites lacks evidence of significant thermal diffusion and may record garnet growth during deep subduction, immediately followed by very rapid exhumation. [ABSTRACT FROM AUTHOR]

Summary: Chemotherapy has always been the first therapeutic option for patients with advanced non-small cell lung cancer (NSCLC) with untreatable oncogenic mutations. However, chemotherapy has demonstrated limited success and is associated with severe side effects. This research aimed to investigate the antitumor efficacy and cytotoxic safety of the conjugate ZHER2:V2-pemetrexed, a novel targeted chemotherapeutic drug. In this context, human epidermal growth factor receptor 2 (HER2) + A549 lung xenografts were treated using ZHER2:V2-pemetrexed, pemetrexed or physiological saline. Therapeutic efficacy was monitored by single photon emission computed tomography (SPECT) imaging using the 99mTc-labeled ZHER2:V2-pemetrexed conjugate and further confirmed by performing apoptosis assays using flow cytometry analysis and hematoxylin-eosin (H&E) staining. To evaluate the expression of HER2 in tumor tissues, immunohistochemistry was performed, accompanied by quantitative analysis using flow cytometry. A toxicological evaluation was also conducted. Imaging with 99mTc-ZHER2:V2-pemetrexed demonstrated that in HER2+ A549 models, ZHER2:V2-pemetrexed showed better antineoplastic effects than pemetrexed. Compared with pemetrexed, the results from the pathological and flow cytometry analyses also revealed that ZHER2:V2-pemetrexed exhibits high antitumor activity against A549 tumors, inducing necrosis, apoptosis and cell cycle arrest. In addition, the clinical signs of toxicity in the ZHER2:V2-pemetrexed treated group were reduced compared with those in the pemetrexed treated group. These data revealed that the ZHER2:V2-pemetrexed conjugate encompasses promising targeted antitumor activity against HER2-positive lung adenocarcinoma, with reduced side effects compared with pemetrexed. Thus, the ZHER2:V2-pemetrexed conjugate may serve as a novel molecular agent with tremendous clinical breakthrough potential in the diagnosis and treatment of HER2-positive lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

A lot of previous experimental studies on ultramafic rocks (SiO2 unsaturated system) (Ringwood and Major, 1971; Irifune et al., 1986; Gasparik, 1989; Ono and Yasuda, 1996) have demonstrated that characteristics of Si‐rich and Al‐deficient in garnet are resulted from coupled substitution of SiVI+MVI=AlVI+AlVI and SiVI+NaVII=AlVI+MVII (M=Mg, Fe, Ca) at ultrahigh pressures (UHP) (>5 GPa). The degree of substitution will be enhanced by increasing pressure which has a positive correlation with the content of SiVI, but a negative correlation with the content of AlVI in supersilic garnet. These experimental results established a theoretical foundation for further understanding the formation mechanism of the exsolution of pyroxene in garnet observed in deep mantle xenoliths and some ultrahigh pressure rocks, and also for estimating the pressure conditions of the formation of supersilic garnet before exsolution (Haggerty and Sautter, 1990; Sautter et al., 1991; van Roermund et al., 1998; Ye et al., 2000). Although some experimental studies on SiO2 saturated system have been reported (Irifune et al., 1994; Ono., 1998; Dobrazhinetskya and Green., 2007; Wu et al., 2009), the stability conditions of supersilic garnet are still lack of unified understanding. Therefore, HP‐HT experiments were carried out on felsic rocks under conditions of 6–12GPa and 1000°C–1400°C. Combined with previous experimental data, we try to figure out the minimum stable pressure and geological significants of supersilic garnet in SiO2 saturated system. Our experimental results from SiO2 saturated system show the minimum stable pressure of supersilic garnet should be ≥10 GP of stishovite stability field. These results are similar as that from experiments using starting composition similar to average upper continental crust reported by Irifune et al (1994) who yielded that garnet gradually became supersilic and Al‐deficient as pressures increased above 10 GPa, especially in a pressure interval between 13 and 18 GPa. Moreover, experiments with different starting materials (Ono, 1998; Dobrazhinetskya and Green, 2007; Wu et al. 2009) also indicate the stable pressure condition of supersilic garnet is mainly ≥9 –10 GPa in SiO2 saturated system if data of small‐size grains at low temperature are ignored due to measuring errors. Thus, it can be concluded that the minimum stable pressure of supersilic garnet in SiO2 saturated system is distinctly different from that in SiO2 unsaturated ultramafic rock system. The minimum pressure of the former is ≥9–10 GPa of stishovite stability field, while that of the latter is >5 GPa. Therefore, whether independent SiO2 phase exist or rock system is SiO2 saturated must be taken into considered when estimating the peak pressure of exsolutions in supersilic garnet in UHP rocks. Furthermore, pressure of >5 GPa directly estimated by supersilic garnet based on conclusion from SiO2 unsaturation system rather than SiO2 saturation in previous sdudies may have been underestimated and need to be re‐estimated. Supersilic garnets have been recognized by interior exsolutions of clinopyroxene in garnet pyroxene from Yinggelisayi South Altyn (Liu et al., 2005), and exsolutions of rodlike quartz+rutile in felsic gneiss from Songshugou North Qinling (Liu et al., 2003). According to the experimental results from SiO2 unsaturated system, the peak metamorphic pressure of the both SiO2 saturated rocks have been estimated to be >7Gpa and >5Gpa, respectively. However, combined with the new experimental results above, we re‐estimated that the peak metamorphic pressure of these SiO2 saturated rocks should be≥9 –10 GPa at least, implying an ultra‐deep subduction to mantle depth of stishovite stability field. This research, together with previous findings (Liu et al., 2007, 2018), shows that continental subduction to mantle depth (300km) of stishovite stability field and then exhumation to the surface is obviously more common than previously thought, and the rock types are also diverse. At the same time, it provides a new indicator and thought for recognizing the subduction to the mantle depth of stishovite stability field in UHP metamorphic belt. [ABSTRACT FROM AUTHOR]

In this study, a series of chitosan films with different protonation degrees were prepared by deacidification with NaOH aqueous or ethanol solutions. The films were then used as a model to investigate the effects of the positive charge of chitosan on blood coagulation. The results showed that the positive charge of chitosan acted as a double-edged sword, in that it promoted erythrocyte adhesion, fibrinogen adsorption, and platelet adhesion and activation, but inhibited activation of the contact system. In contrast to prevailing views, we found that the positive charge of chitosan retarded thrombin generation and blood coagulation on these films. At least two reasons were responsible for this phenomenon. First, the positive charge inhibited the contact activation, and second, the positive charge could not significantly promote the activation of non-adherent platelets in the bulk phase during the early stage of coagulation. The present findings improve our understanding of the events leading to blood coagulation on chitosan films, which will be useful for the future development of novel chitosan-based hemostatic devices. [ABSTRACT FROM PUBLISHER]

Abstract: Huperzine A (Hup A) is a lycopodium alkaloid from Huperzia serrata, which has been used as a therapeutic agent in several neurological disorders. Despite the diverse pharmacological activities Hup A has, its role in hippocampal neurogenesis remains to be established. This study showed that Hup A not only promoted the proliferation of cultured mouse embryonic hippocampal neural stem cells (NSCs), but also increased the newly generated cells in the subgranular zone (SGZ) of the hippocampus in adult mice. Furthermore, the in vitro findings indicated that low concentrations of Hup A stimulated the proliferation of cultured NSCs, whereas extremely high concentration of it decreased the cell proliferation. Hup A activated mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway, which was a well-known regulator of biological processes including cell proliferation and differentiation. ERK inhibitor dramatically inhibited the proliferative effect of Hup A on NSCs. Administration of Hup A to adult mice significantly enhanced the cell proliferation in dentate gyrus of hippocampus, and increased the remaining newborn cells 4 weeks after the drug administration. Moreover, the newly generated BrdU+/NeuN+ neurons were also increased by Hup A treatment. These findings suggest a novel role of Hup A in neurogenesis and provide a new insight into its therapeutic effects in neurological disorders via a neurogenesis-related mechanism. [Copyright &y& Elsevier]

Abstract: Mitochondrial malfunction and calcium dyshomeostasis are early pathological events considered as important features of the Alzheimer’s disease (AD) brain. Recent studies have suggested mitochondrion as an active regulator of Ca2+ signaling based on its calcium buffering capacity. Herein, we investigated the mitochondrial involvement in the modulation of store-operated calcium entry (SOCE) in neural 2a (N2a) transgenic AD model cells. Results showed that SOCE was significantly depressed in N2a cells transfected with wild-type human APP695 (N2a APPwt) compared with empty vector control (N2a WT) cells. Pharmacological manipulation with mitochondrial function blockers, such as FCCP, RuR, or antimycin A/oligomycin, could inhibit mitochondrial calcium handling, and then impair SOCE pathway in N2a WT cells. Furthermore, mitochondria of N2a APPwt cells exhibited more severe swelling in response to Ca2+, which is an indication of mitochondrial membrane permeability transition (MPT), than the wild-type controls. Additionally, treatment with cyclosporin A, a potent inhibitor of cyclophilin D, which can block MPT, could significantly restore the attenuated SOCE in N2a APPwt cells. Therefore, inhibition of cyclophilin D might be a therapeutic strategy for Alzheimer’s disease. [Copyright &y& Elsevier]

Abstract: Oxidative stress has been demonstrated to be involved in the pathogenesis of Alzheimer''s disease (AD). Thus, antioxidant therapy may represent a promising avenue for the treatment of AD. Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a potent free radical scavenger and has been shown to provide neuroprotection in both animal models of cerebral ischemia and stroke patients. In the present study, we investigated the protective effect of edaravone against AD-relevant insults in neuroblastoma N2a cells and explored the potential mechanisms involved. N2a/Swe.Δ9 cells were used as the AD model cells, which exhibited reduced cell viability, increased apoptosis and oxidative stress as well as decreased mitochondrial membrane potential compared with N2a/Wt cells. All of these phenotypes were significantly reversed by edaravone treatment. Edaravone treatment significantly elevated cell viability, reduced apoptotic rate, attenuated oxidative stress and improved mitochondrial membrane potential in N2a/Swe.Δ9 cells. Furthermore, edaravone treatment inhibited mitochondria-dependent apoptosis pathways in N2a/Swe.Δ9 cells through decreasing the Bax/Bcl-2 ratio, attenuating cytochrome c release and suppressing the activation of caspase-3. These results demonstrate that edaravone provides neuroprotection in an AD-related in vitro model and therefore, may be a potential complement for AD therapy. [Copyright &y& Elsevier]

Abstract: β- and γ-secretase cleave the amyloid precursor protein (APP) to release the amyloidogenic β-amyloid peptides (Aβ) and the APP intracellular domain (AICD). Aβ has been widely believed to initiate pathogenic cascades culminating in Alzheimer''s disease (AD). However, the physiological functions of the AICD remain elusive. In this study, we found the AICD to strongly inhibit Wnt-induced transcriptional reporter activity, and to counteract Wnt-induced c-Myc expression. Loss of the AICD resulted in an increased responsiveness to Wnt/β-catenin-mediated transcription. Mechanically, the AICD was found to interact with glycogen synthase kinase 3 beta (GSK3β) and promote its kinase activity. The subsequent AICD-strengthened Axin–GSK3β complex potentiates β-catenin poly-ubiquitination. Functional studies in N2a mouse neuroblastoma cells, rat pheochromocytoma PC12 cells and primary neurons showed that the AICD facilitated neurite outgrowth. And AICD antagonised Wnt3a-suppressed growth arrest and neurite outgrowth in N2a and PC12 cells. Taken together, our results identify the AICD as a novel inhibitory factor of the canonical Wnt signalling pathway and suggest its regulatory role in neuronal cell proliferation and differentiation. [Copyright &y& Elsevier]

Background: Endoplasmic reticulum (ER) stress is a therapeutic target in cancer given its regulation of bioenergetics and cell death. Methodology & results: We synthesized 14 ER stress-triggered anthraquinone derivatives by introducing an amino group at the 3-position side chain of the lead compound obtained previously. Most of the anthraquinone derivatives exhibited good antitumor activity due to their ability to induce ER damage through cytoplasmic vacuoles. The mechanisms of ER stress caused by compound KA-4c were related to increasing the expression levels of the ATF6 and Bip proteins and upregulating CHOP and cleaved PARP. Conclusion: Compound KA-4c triggers ER stress response and induces apoptosis via the ATF6-CHOP signaling pathway.

Chemotherapy has always been the first therapeutic option for patients with advanced non-small cell lung cancer (NSCLC) with untreatable oncogenic mutations. However, chemotherapy has demonstrated limited success and is associated with severe side effects. This research aimed to investigate the antitumor efficacy and cytotoxic safety of the conjugate Z HER2:V2 -pemetrexed, a novel targeted chemotherapeutic drug. In this context, human epidermal growth factor receptor 2 (HER2) + A549 lung xenografts were treated using Z HER2:V2 -pemetrexed, pemetrexed or physiological saline. Therapeutic efficacy was monitored by single photon emission computed tomography (SPECT) imaging using the 99m Tc-labeled Z HER2:V2 -pemetrexed conjugate and further confirmed by performing apoptosis assays using flow cytometry analysis and hematoxylin-eosin (H&E) staining. To evaluate the expression of HER2 in tumor tissues, immunohistochemistry was performed, accompanied by quantitative analysis using flow cytometry. A toxicological evaluation was also conducted. Imaging with 99m Tc-Z HER2:V2 -pemetrexed demonstrated that in HER2+ A549 models, Z HER2:V2 -pemetrexed showed better antineoplastic effects than pemetrexed. Compared with pemetrexed, the results from the pathological and flow cytometry analyses also revealed that Z HER2:V2 -pemetrexed exhibits high antitumor activity against A549 tumors, inducing necrosis, apoptosis and cell cycle arrest. In addition, the clinical signs of toxicity in the Z HER2:V2 -pemetrexed treated group were reduced compared with those in the pemetrexed treated group. These data revealed that the Z HER2:V2 -pemetrexed conjugate encompasses promising targeted antitumor activity against HER2-positive lung adenocarcinoma, with reduced side effects compared with pemetrexed. Thus, the Z HER2:V2 -pemetrexed conjugate may serve as a novel molecular agent with tremendous clinical breakthrough potential in the diagnosis and treatment of HER2-positive lung adenocarcinoma.

Recent studies suggest that transplantation of mesenchymal stem cells might have therapeutic effects in preventing pathogenesis of several neurodegenerative disorders. Adipose-derived mesenchymal stem cells (ADSCs) are a promising new cell source for regenerative therapy. However, whether transplantation of ADSCs could actually ameliorate the neuropathological deficits in Alzheimer's disease (AD) and the mechanisms involved has not yet been established. Here, we evaluated the therapeutic effects of intracerebral ADSC transplantation on AD pathology and spatial learning/memory of APP/PS1 double transgenic AD model mice. Results showed that ADSC transplantation dramatically reduced β-amyloid (Aβ) peptide deposition and significantly restored the learning/memory function in APP/PS1 transgenic mice. It was observed that in both regions of the hippocampus and the cortex there were more activated microglia, which preferentially surrounded and infiltrated into plaques after ADSC transplantation. The activated microglia exhibited an alternatively activated phenotype, as indicated by their decreased expression levels of proinflammatory factors and elevated expression levels of alternative activation markers, as well as Aβ-degrading enzymes. In conclusion, ADSC transplantation could modulate microglial activation in AD mice, mitigate AD symptoms, and alleviate cognitive decline, all of which suggest ADSC transplantation as a promising choice for AD therapy. This manuscript is published as part of the International Association of Neurorestoratology (IANR) supplement issue of Cell Transplantation.

Mitochondrial malfunction and calcium dyshomeostasis are early pathological events considered as important features of the Alzheimer's disease (AD) brain. Recent studies have suggested mitochondrion as an active regulator of Ca(2+) signaling based on its calcium buffering capacity. Herein, we investigated the mitochondrial involvement in the modulation of store-operated calcium entry (SOCE) in neural 2a (N2a) transgenic AD model cells. Results showed that SOCE was significantly depressed in N2a cells transfected with wild-type human APP695 (N2a APPwt) compared with empty vector control (N2a WT) cells. Pharmacological manipulation with mitochondrial function blockers, such as FCCP, RuR, or antimycin A/oligomycin, could inhibit mitochondrial calcium handling, and then impair SOCE pathway in N2a WT cells. Furthermore, mitochondria of N2a APPwt cells exhibited more severe swelling in response to Ca(2+), which is an indication of mitochondrial membrane permeability transition (MPT), than the wild-type controls. Additionally, treatment with cyclosporin A, a potent inhibitor of cyclophilin D, which can block MPT, could significantly restore the attenuated SOCE in N2a APPwt cells. Therefore, inhibition of cyclophilin D might be a therapeutic strategy for Alzheimer's disease., (Copyright © 2012 Elsevier Inc. All rights reserved.)