1] To better constrain the ongoing rates of deformation in northern Tibet, the ages of fluvial and glacial geomorphic markers left-laterally displaced by the Altyn Tagh Fault have been determined by radiocarbon and 10 Be-26 Al cosmic ray exposure dating. Two sites were investigated: Cherchen He and Sulamu Tagh, both near Tura ($37.6°N, 86.6°E). The sites are geomorphologically distinct with Cherchen He dominated by fluvial processes and the Sulamu Tagh by glacial action. Nine offsets ranging from 166 to 3660 m with ages between 6 and 113 ka yield an average slip rate of 26.9 ± 6.9 mm/yr. Landscape evolution appears to have been modulated by climate change and is temporally consistent with the d 18 O record from the Guliya ice cap in the West Kunlun; the features of interest were all formed by glacial and fluvial processes subsequent to marine isotope stage 5e, with the youngest features having formed during the early Holocene Optimum. This ''near-field,'' morphochronological slip rate is averaged over many earthquake cycles and is hence little affected by interseismic strain. It is kinematically consistent with other, somewhat lower, geomorphic slip rate measurements to the east. The average rate, and lower bounds obtained from alternate interpretational models, 18.4 mm/yr, cannot be reconciled with the most rece geodetic measurements ($7 mm/yr), suggesting that interseismic strain and interactions with adjacent faults may lead to disparate geologic and geodetic rate estimates. This late Pleistocene-Holocene, morphochronologic rate would imply that, at this longitude, the Altyn Tagh Fault, on the north edge of Tibet, might absorb almost as much of India's convergence relative to Siberia as the Himalayan Main Frontal Thrust does on the southern edge of the plateau.

In vivo experience induces changes in synaptic NMDA receptor (NMDAR) subunit components, which are correlated with subsequent modifications of synaptic plasticity. However, little is known about how these subunit changes regulate the induction threshold of subsequent plasticity. At hippocampal Schaffer collateral-CA1 synapses, we first examined whether a recent history of neuronal activity could affect subsequent synaptic plasticity through its actions on NMDAR subunit components. We found that prior activity history produced by priming stimulations (PSs) across a wide range of frequencies (1-100 Hz) could induce bidirectional changes in the NR2A/NR2B ratio, which governs the threshold for subsequent long-term potentiation/long-term depression (LTP/LTD). Manipulating the NR2A/NR2B ratio through partial NR2 subunit blockade mimicked the PS regulation of the LTP/LTD threshold. Our results demonstrate that activity-dependent changes in the NR2A/NR2B ratio can be critical factors in metaplastic regulation of the LTP/LTD threshold.

Hepatocellular carcinoma (HCC) is an aggressive malignancy and the second leading cause of cancer-related deaths worldwide. Conventional biomarkers exhibit poor performance in the surveillance, diagnosis, and prognosis of HCC. MicroRNAs (miRNAs) are a class of evolutionarily conserved small non-coding RNAs that are involved in the regulation of gene expression and protein translation, and they play critical roles in cell growth, differentiation, and the development of various types of cancers, including HCC. Recent evidence revealed the role of miRNAs as potential novel and ideal biomarkers for HCC. miRNAs are released to extracellular spaces, and they are extremely stable in bodily fluids, including serum or plasma, where they are packaged into various microparticles or associated with RNA-binding proteins. Numerous studies have demonstrated that circulating miRNAs have potential applications as minimally invasive biomarkers for HCC diagnosis and prognosis. The present review highlights current understanding of miRNA biogenesis and the origins and types of circulating miRNAs. We summarize recent progress in the use of circulating miRNAs as diagnostic and prognostic biomarkers for HCC. We also discuss the challenges and perspectives of the clinical utility of circulating miRNAs in HCC.

The mammalian target of rapamycin (mTOR) plays a critical role for cell growth and survival in many cell types. While substantial progress has been made in understanding the abnormal activation of mTORC1 in the pathogenesis of kidney disease, little is known about mTORC2 in kidney disease such as acute kidney injury (AKI). To study this, we generated a mouse model with tubule-specific deletion of Rictor (Tubule-Rictor-/-). The knockouts were born normal and no obvious kidney dysfunction or kidney morphologic abnormality was found within 2 months of birth. However, ablation of Rictor in the tubular cells exacerbated cisplatin-induced AKI compared to that in the control littermates. As expected, tubular cell apoptosis, Akt phosphorylation (Ser473), and autophagy were induced in the kidneys from the control littermates by cisplatin treatment. Less cell autophagy or Akt phosphorylation and more cell apoptosis in the kidneys of the knockout mice were identified compared with those in the control littermates. In NRK-52E cells in vitro, Rictor siRNA transfection sensitized cell apoptosis to cisplatin but with reduced cisplatin-induced autophagy. Metformin, an inducer of autophagy, abolished cell death induced by Rictor siRNA and cisplatin. Thus, endogenous Rictor/mTORC2 protects against cisplatin-induced AKI, probably mediated by promoting cell survival through Akt signaling activation and induction of autophagy.

Regulation of neuronal NMDA receptor (NMDAR) is critical in synaptic transmission and plasticity. Protein kinase C (PKC) promotes NMDAR trafficking to the cell surface via interaction with NMDAR-associated proteins (NAPs). Little is known, however, about the NAPs that are critical to PKC-induced NMDAR trafficking. Here, we showed that calcium/calmodulin-dependent protein kinase II (CaMKII) could be a NAP that mediates the potentiation of NMDAR trafficking by PKC. PKC activation promoted the level of autophosphorylated CaMKII and increased association with NMDARs, accompanied by functional NMDAR insertion, at postsynaptic sites. This potentiation, along with PKC-induced long term potentiation of the AMPA receptor-mediated response, was abolished by CaMKII antagonist or by disturbing the interaction between CaMKII and NR2A or NR2B. Further mutual occlusion experiments demonstrated that PKC and CaMKII share a common signaling pathway in the potentiation of NMDAR trafficking and longterm potentiation (LTP) induction. Our results revealed that PKC promotes NMDA receptor trafficking and induces synaptic plasticity through indirectly triggering CaMKII autophosphorylation and subsequent increased association with NMDARs.The NMDA receptor (NMDAR) 3 plays a critical role in neural development, learning and memory, sensory perception, and synaptic plasticity (1, 2). Therefore, regulation of neuronal NMDARs is of great importance to synaptic transmission. PKC increases the NMDA channel opening rate and delivers new NMDARs to the plasma membrane through regulated exocytosis (3, 4). This potentiation of NMDAR trafficking is not due to phosphorylation of the NMDAR by PKC (5), suggesting that PKC indirectly exerts its effect through interaction with NMDAR-associated signaling and/or trafficking protein(s) (3, 4). Very recently, two elegant studies revealed that a SNARE protein, either SNAP-23 or SNAP-25, is such an NMDAR-associated trafficking protein that is critical to the promotion of NMDAR trafficking by PKC (6, 7). The PKC-dependent activation of the Src family of non-receptor protein kinases enhances NMDAR function mainly through increasing NMDAR channel gating (3, 8 -11). It is still uncertain, however, whether an NMDAR-associated signaling protein that interacts with PKC displays a similar enhancing effect in NMDAR trafficking.Numerous studies performed as early as the late 1980s support the idea of functional and positive cross-talk between CaMKII and PKC (12-15). One speculation based on these findings is that PKC and CaMKII act in series and share, at least partially, a common pathway by convergence in regulating certain common substrates. Interestingly, NMDAR could be such a common molecular target. Both PKC and CaMKII have phosphorylation sites on NMDAR. CaMKII is associated with both NR2A and NR2B NMDAR subunits (16 -18). PKC potentiates NMDAR gating and in turn enhances Ca 2ϩ influx and intracellular Ca 2ϩ /camodulin, which could trigger CaMKII autophosphorylation and increase association with NR2A and NR2B sub...

Although an increasing number of studies have demonstrated the plasticity of NMDA receptor-mediated synaptic transmission, little is known about the molecular mechanisms that underlie this neurologically important process. In a study of NMDAR-mediated synaptic responses in hippocampal Schaffer-CA1 synapses whose AMPA receptor (AMPAR) activity is totally blocked, we uncovered differences between the trafficking mechanisms that underlie the long-term potentiation (LTP) and long-term depression (LTD) that can be induced in these cells under these conditions. The LTP-producing protocol failed to induce a change in the amplitude of NMDAR-mediated postsynaptic currents (NMDAR EPSCs) in the first 5-10 min, but induced gradual enhancement of NMDAR EPSCs thereafter that soon reached a stable magnitude. This "slow" LTP of NMDAR EPSCs (LTP(NMDA)) was blocked by inhibiting exocytosis or actin polymerization in postsynaptic cells. By contrast, LTD of NMDAR EPSCs (LTD(NMDA)) was immediately inducible, and, although it was blocked by the actin stabilizer, it was unaffected by exocytosis or endocytosis inhibitors. Furthermore, concomitant changes in the decay time of NMDAR EPSCs suggested that differential switches in NR2 subunit composition accompanied LTP(NMDA) and LTD(NMDA), and these changes were blocked by the calcium buffer BAPTA or an mGluR antagonist. Our results suggest that LTP(NMDA) and LTD(NMDA) utilize different NMDAR trafficking pathways and express different ratios of NMDAR subunits on the postsynaptic surface.

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It has been reported that human mesenchymal stem cells are able to inhibit T lymphocyte activation; however, the discrepancy among different sources of MSCs is not well documented. In this study, we have compared the MSCs from bone marrow (BM), adipose tissue (AT), placenta (PL), and umbilical cord (UC) to determine which one displayed the most efficient immunosuppressive effects on phytohemagglutinin-induced T cell proliferation. Among them we found that hUC-MSC has the strongest effects on inhibiting T cell proliferation and is chosen to do the further study. We observed that T lymphocyte spontaneously released abundant IFN-γ. And IFN-γ secreted by T lymphocyte could induce the expression of indoleamine 2, 3-dioxygenase (IDO) in hUC-MSCs. IDO was previously reported to induce T lymphocyte apoptosis and cell cycle arrest in S phase. When cocultured with hUC-MSCs, T lymphocyte expression of caspase 3 was significantly increased, while Bcl2 and CDK4 mRNA expression decreased dramatically. Addition of 1-methyl tryptophan (1-MT), an IDO inhibitor, restored T lymphocyte proliferation, reduced apoptosis, and induced resumption of the cell cycle. In addition, the changes in caspase 3, CDK4, and Bcl2 expression were reversed by 1-MT. These findings demonstrate that hUC-MSCs induce T lymphocyte apoptosis and cell cycle arrest by expressing abundant IDO and provide an explanation for some of the immunomodulatory effects of MSCs.