Immunophilins consist of a family of highly conserved proteins binding with immunosuppressive drugs such as FK506, rapamycin and cyclosporin A. FK506-binding protein (FKBP) is one of two major immunophilins and most of FKBP family members bind FK506 and show peptidylprolyl cis/trans isomerase (PPIase) activity. Small size FKBP family members contain only FK506-binding domain, while FKBPs with large molecular weights possess extra domains such as tetratricopeptide repeat domains, calmodulin binding and transmembrane motifs. FKBPs are involved in several biochemical processes including protein folding, receptor signaling, protein trafficking and transcription. FKBP family proteins play important functional roles in the T-cell activation, when complexed with their ligands. The roles of immunophilins in protein transportation and apoptosis through their molecular interactions with receptors or proteins have emerged recently. Moreover, therapeutic implications of immunophilin ligands in treating neurodegenerative disorders have been accumulating. FK506 and its derivatives with no immunosuppressive activities bind to the conserved active sites of the canonical FKBP members such as FKBP12, which shows PPIase activity. These immunophilin ligands show variable efficacy in animal models for Parkinson’s disease, dementia, and spinal cord injury, where the canonical immunophilins function as chaperones and are associate with the protein folding and modulation of oxidative stress. On the other hand, in the noncanonical FKBP members such as FKBP38, FK506-binding site is not conserved and shows neither PPIase activity nor affinity to FK506. Interestingly, the small molecule-mediated inhibition of the noncanonical member of FKBP family appears to cause neuronal protection and induce proliferation of neuronal stem cells in a rat focal cerebral ischemia model. Currently, the mechanisms of actions remain unclear. This review focuses on molecular characteristics of the canonical and noncanonical FKBP family members and the biological functions of their ligands in performing neuroprotective and neurotrophic activities.

No abstract

No abstract

No abstract

61The Tibetan Plateau (TP), known as the "sensible heat pump" and the 62 "atmospheric water tower", modifies monsoon circulations and regional energy and 63 water cycles over Asia (Wu and Zhang 1998; Zhao and Chen 2001a; Wu et al. 2007; 64 Xu et al. 2008b; Zhou et al. 2009). Strong ascent over the TP may transport lower-65 tropospheric water vapor and anthropogenic pollutants into the upper troposphere-66 lower stratosphere (UT-LS), which exerts an influence on the local ozone valley 67 (Zhou et al. 1995; Liu et al. 2003; Bian et al. 2011) and the aerosol-layer 68 enhancements near the tropopause (Tobo et al. 2007; Vernier et al. 2015). The TP also In the 1990s, a longer-term field experiment was conducted over the TP with the 84 support of the Japanese Experiment on Asian Monsoon (JEXAM). It estimated the 2008a; Zhang et al. 2012; Chen et al. 2011 Chen et al. , 2013. It found diurnal variations of et al. 2013; Hu et al. 2014; Zheng et al. 2014 Zheng et al. , 2015a Zheng et al. , b, c, 2016 Guo et al. 2015; 161 Zhuo et al. 2016; Wan et al. 2017). These problems may also cause large uncertainties 162 in reanalysis datasets and satellite products (such as air temperature, soil moisture, 163 surface heat fluxes, and radiation) over the TP (Li et al. 2012; Wang et al. 2012; Zhu 164 et al. 2012; Su et al. 2013; Zeng et al. 2016). 165To promote Tibetan meteorological research, the Third Tibetan Plateau 166Atmospheric Scientific Experiment (TIPEX-III), to continue for eight to ten years, OBJECTIVES. 173The field observational objective of TIPEX-III is to constitute a 3-D observation 174 system of the land surface, PBL, troposphere, and lower stratosphere over the TP. 175This system integrates ground-, air-, and space-based platforms based on the 176 meteorological operational networks, the TIPEX-III network, the existing NIOST (Fig. 1a). Consistent with the operational observations of the 265 CMA, at each site the measurement system measures soil water content ( Fig. 1a). The regional network consists of 33 sites over 270 Naqu (Fig. 1c), which began operating in August 2015, and 17 sites over Shiquanhe This network consists of six additional sites at Bange, Namucuo, Anduo, Nierong, 280Jiali, and Biru, and contributes to integrated research on the high-resolution land-281 surface and PBL processes over the central TP and their effects on mesoscale systems. 282These observations have been conducted at Shiquanhe, Namucuo, Naqu, Anduo, Gongshan (98.67°E, 27.75°N) station on the southeastern slope of the TP (Fig. 1b), a 300 key area for gauging water-vapor transports from the Indian Ocean to East Asia. (Fig. 1b). A primary goal of these observations is to explore the cloud (Fig. 1b). A follow-up field campaign using ground-based radars Tuotuohe, Mangya, Golmud, and Xining meteorological stations (Fig. 1b). Using PRELIMINARY ACHIEVEMENTS OF TIPEX-III. 328The implementation of TIPEX-III has enhanced the monitoring capability for the 380(1) Cloud diurnal variation and warm rain process. 3...

Snow and glacier melting and accumulation are important processes of the hydrological cycle in the cryosphere, e.g., high‐mountain areas. Glaciers and snow cover respond to climate change notably over the Tibetan Plateau (TP) as the Earth's Third Pole where complex topography and lack of ground‐based observations result in knowledge gaps in hydrological processes and large uncertainties in model output. This study develops a snow and glacier melt model for a distributed hydrological model (Coupled Routing and Excess Storage model, CREST) using the Upper Brahmaputra River (UBR) basin in the TP as a case study. Satellite and ground‐based precipitation and land surface temperature are jointly used as model forcing. A progressive two‐stage calibration strategy is developed to derive model parameters, i.e., (1) snow melting processes (stage I) and (2) glacier melting and runoff generation and routing using multisource data (stage II). Stage‐I calibration is performed using the MODIS snow cover area (SCA) product and a blending snow water equivalent (SWE) product combined with partial in situ measurements. Stage‐II calibration is based on Gravity Recovery and Climate Experiment (GRACE) satellite‐derived total water storage (TWS) changes and streamflow observed at a gauging station of the lower reach of the UBR. Results indicate that the developed two‐stage calibration method provides more reliable streamflow, snow (both SCA and SWE), and TWS change simulations against corresponding observations than commonly used methods based on streamflow and/or SCA performance. The simulated TWS time series shows high consistency with GRACE counterparts for the study period 2003–2014, and overestimated melting rates and contributions of glacier meltwater to runoff in previous studies are improved to some degree by the developed model and calibration strategy. Snow and glacier runoff contributed 10.6% and 9.9% to the total runoff, and the depletion rate of glacier mass was ∼ −10 mm/a (∼ −2.4 Gt/a, Gt/a is gigaton (km3 of water) per year) over the UBR basin during the study period. This study is valuable in examining the impacts of climate change on hydrological processes of cryospheric regions and providing an improved approach for simulating more reliable hydrological variables over the UBR basin and potentially similar regions globally.

CpNifS, a cysteine desulfurase required to supply sulfur for ironsulfur cluster biogenesis in Arabidopsis thaliana chloroplasts, belongs to a class of NifS-like enzymes with low endogenous cysteine desulfurase activity. Its bacterial homologue SufS is stimulated by SufE. Here we characterize the Arabidopsis chloroplast protein CpSufE, which has an N-terminal SufE-like domain and a C-terminal BolA-like domain unique to higher plants. CpSufE is targeted to the chloroplast stroma, indicated by green fluorescent protein localization and immunoblot experiments. Like CpNifS, CpSufE is expressed in all major tissues, with higher expression in green parts. Its expression is light-dependent and regulated at the mRNA level. The addition of purified recombinant CpSufE increased the V max for the cysteine desulfurase activity of CpNifS over 40-fold and decreased the K M toward cysteine from 0.1 to 0.043 mM. In contrast, CpSufE addition decreased the affinity of CpNifS for selenocysteine, as indicated by an increase in the K M from 2.9 to 4.17 mM, and decreased the V max for selenocysteine lyase activity by 30%. CpSufE forms dynamic complexes with CpNifS, indicated by gel filtration, native PAGE, and affinity chromatography experiments. A mutant of CpSufE in which the single cysteine was changed to serine was not active in stimulating CpNifS, although it did compete with WT CpSufE. The iron-sulfur cluster reconstitution activity of the CpNifS-CpSufE complex toward apoferredoxin was 20-fold higher than that of CpNifS alone. We conclude that CpNifS and CpSufE together form a cysteine desulfurase required for iron-sulfur cluster formation in chloroplasts.Iron-sulfur (Fe-S) cluster proteins perform a variety of biological roles in electron transfer, catalysis, gene regulation, and sensing of iron and oxygen (1). Iron-sulfur cluster proteins are particularly important to photosynthesis. Measurements of metal ions in Arabidopsis thaliana have indicated that about 70% of the iron in green tissue is present in chloroplasts, and 40% is found in the thylakoids (2). Estimates in other plants indicate that up to 90% of the iron in leaves may be present in the chloroplasts (3). Within the thylakoids, the majority of the iron is found in Fe-S cluster proteins that function in photosynthetic electron transport (4). Next to photosynthetic carbon fixation, other pivotal plastid functions that require Fe-S clusters include nitrogen assimilation, sulfur assimilation, and pigment synthesis (for a review, see Ref. 5). Whereas all plastid types contain a number of important Fe-S cluster proteins, especially the green chloroplasts need to synthesize and maintain a variety of Fe-S proteins with at least five different cluster types (5).In bacteria, three separate Fe-S formation machineries have been characterized (for a review, see Ref. 6). All systems include an NifS-like Cys desulfurase protein, which catalyzes the conversion of cysteine to alanine and elemental sulfur or the conversion of selenocysteine (SeCys) 2 to alanine and elemental selen...

No abstract