Dissolved inorganic carbon budget of two alpine catchments in the central Tibetan Plateau: Glaciation matters.

Dissolved inorganic carbon (DIC) fluxes account for over one-third of the total carbon transported in most rivers. The DIC budget for glacial meltwater of the Tibetan Plateau (TP), however, is still poorly understood, despite the fact, the TP has the largest glacier distribution outside of the Poles. In this study, the Niyaqu and Qugaqie catchments in the central TP were selected to examine the influence of glaciation on the DIC budget in vertical evasion (CO2 exchange rate at the water-air interface) and lateral transport (sources and fluxes) from 2016 to 2018. Significant seasonal variation in DIC concentration was found in the glaciated Qugaqie catchment, but was absent in the not glaciated Niyaqu catchment. δ13CDIC showed seasonal changes for both catchments, with more depleted signatures during the monsoon season. The average CO2 exchange rates in river water of Qugaqie were ~8 times lower compared to Niyaqu with values of -1294.6 ± 438.58 mg/m2/h and -163.4 ± 581.2 mg/m2/h, respectively, indicating that proglacial rivers can act as a substantial CO2 sink due to CO2 consumption by chemical weathering. DIC sources were quantified via the MixSIAR model using δ13CDIC and ionic ratios. During the monsoon season, the contribution from carbonate/silicate weathering driven by atmospheric CO2 was 13-15 % lower, while biogenic CO2 involved in chemical weathering was 9-15 % higher, indicating a seasonal control on weathering agents. Carbonate dissolution driven by H2SO4/HNO3 was the most important contributor to DIC in both catchments (40.7 ± 2.2 % in Niyaqu and 48.5 ± 3.1 % in Qugaqie). The net CO2 consumption rate in the not glaciated Niyaqu catchment was close to 0 (-0.07 ± 0.04 × 105 mol/km2/y), indicating the carbon sink effect caused by chemical weathering in this area was weak. The net CO2 consumption rate in the glaciated Qugaqie catchment, however, was much lower than that in the not glaciated catchment with a value of -0.28 ± 0.05 × 105 mol/km2/y. This study highlights that chemical weathering in small glaciated catchments of the central TP plays an active role in releasing CO2 to the atmosphere.

Pharmacokinetics and safety of dasatinib and its generic: a phase I bioequivalence study in healthy Chinese subjects.

BACKGROUND: Dasatinib (Sprycel®) is a tyrosine kinase inhibitor for treating chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. RESEARCH DESIGN & METHODS: We designed a clinical study to demonstrate that the dasatinib tablet (YiNiShu®) (Chia Tai Tianqing Pharmaceutical Group Co., Ltd) and Dasatinib (Bristol Myers Squibb) were bioequivalent under fasting and fed conditions. The whole study was structured into the fasting trial and the postprandial trial. Each period, subjects were given 50 mg dasatinib or its generic. The RSABE (reference scale average bioequivalence) and ABE (average bioequivalence) methods were employed to assess bioequivalence by pharmacokinetics (PK) parameters for a highly variable drug. RESULTS: 32 and 24 eligible volunteers were enrolled in the fasting and postprandial trials, respectively. In the fasting trial, the RSABE method was performed, and point estimates of Cmax, AUC0-t, and AUC0-∞ met the bioequivalence criteria. In the postprandial trial, the ABE method was performed, and the 90% CI of the geometric mean ratio (GMR) for PK parameters met the requirements of bioequivalence standards. CONCLUSION: The results proved that the PK parameters of the two drugs were similar and bioequivalent, indicating that both drugs had a good safety profile. CLINICAL TRIAL REGISTRATION: This trial was registered in ClinicalTrials.gov (Number: NCT05640804) and Drug Clinical Trial Registration and Information Disclosure Platform (Number: CTR20181708).

A randomized, open-label, two-cycle, two-crossover phase I clinical trial comparing the bioequivalence and safety of afatinib and Giotrif® in healthy Chinese subjects.

OBJECTIVE: Afatinib is an oral, irreversible ErbB family blocker. It binds covalently to the kinase domains of epidermal growth factor (EGFR), HER2 and HER4, resulting in irreversible inhibition of tyrosine kinase autophosphorylation. Our trial compared the bioequivalence and safety between afatinib produced by Chia Tai Tianqing Pharmaceutical Group Co., Ltd. and Giotrif® produced by Boehringer Ingelheim. METHODS: Healthy Chinese subjects (N = 36) were randomly divided into two groups at a ratio of 1:1. There was a single dose per period of afatinib and Giotrif®. The washout was set as 14 days. Plasma drug concentrations of afatinib and Giotrif® were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Statistical analysis of major pharmacokinetic (PK) parameters was conducted to assess drug bioequivalence. In addition, we evaluated the safety of the drugs throughout the trial. RESULTS: The geometric mean ratios (GMRs) of Cmax, AUC0-t, and AUC0-∞ for afatinib and Giotrif® were 102.80%, 101.83%, and 101.58%, respectively. The 90% confidence intervals (CIs) were all within 80%-125%, meeting the bioequivalence standards. In addition, both drugs showed a good safety profile during the trial. CONCLUSION: This study showed that afatinib was bioequivalent to Giotrif® in healthy Chinese subjects with well safety. CHINESE CLINICAL TRIAL REGISTRY: This trial is registered at the Chinese Clinical Trial website ( http://www.chinadrugtrials.org.cn/index.html # CTR20171160).

Aberrant expression of FBXO22 is associated with propofol-induced synaptic plasticity and cognitive dysfunction in adult mice.

Recent observation demonstrated that prolonged anesthesia modifies brain synaptic architecture in all ages, including adult. Propofol is the most commonly utilized anesthetics at clinic. Whether repeated administration of propofol modulates cognitive impairment in adults and changes synaptic plasticity remains, however, to be explored. In this study, we first discovered that repeated and prolonged exposure to propofol-induced cognitive impairment in adult rodents. Then, we examined the property of hippocampal primary neurons and slices after propofol treatment in mice, including synaptic protein profile, dendritic spine density, as well as synaptic transmission. We found the distinctive change of the F-box only protein 22 (FBXO22), an F-box E3 ligase, during this process and further explored its role. Knockdown experiments showed the downregulation of FBXO22 restored the changes by propofol treatment on hippocampal primary neurons and attenuated propofol-induced hippocampal dependent cognitive dysfunction. Our results showed that FBXO22 is involved in the regulation of repeated propofol treatment induced changes of synaptic plasticity and cognitive dysfunction in adult mice. Repeated propofol treatment leads to cognitive dysfunction by regulating FBXO22 in adult rodents.

A randomized, double-blind, single-dose, parallel phase I clinical trial to compare the bioequivalence, immunogenicity, and safety of bevacizumab biosimilar and bevacizumab in healthy Chinese subjects.

BACKGROUND: Bevacizumab, a humanized monoclonal antibody against VEGF, can be used as a target therapy for colorectal cancer. A phase I clinical trial was conducted to compare the bioequivalence, immunogenicity, and safety of bevacizumab biosimilar (Chia Tai Tianqing Pharmaceutical Group Co., Ltd.) and Bevacizumab (Roche Diagnostics GmbH) in healthy Chinese males. RESEARCH DESIGN & METHOD: Healthy Chinese subjects (N = 98) were randomly divided into two groups. A single-dose bevacizumab biosimilar or Bevacizumab was given per cycle. Plasma drug concentrations were detected by liquid chromatography-tandem mass spectrometry (LC-MC/MS) assay. We detected the levels of anti-drug antibody (ADA) to evaluate drug immunogenicity and the safety of drugs throughout the study. RESULTS: The geometric mean ratios (GMRs) of AUC0-t, Cmax, and AUC0-∞ for bevacizumab biosimilar and Bevacizumab were 96.27%, 93.69%, and 97.01%, respectively. The 90% CIs were all within 80-125%, meeting the bioequivalence standards. The levels of ADA were similar. In addition, the two drugs both demonstrated excellent safety in the trial. CONCLUSION: This study showed that bevacizumab biosimilar and Bevacizumab had similar pharmacokinetics (PK) parameters and safety in healthy Chinese subjects.

How do precipitation events modify the stable isotope ratios in leaf water at Lhasa on the southern Tibetan Plateau?

Serving as a medium between source water and cellulose, leaf water contributes to the isotope ratios (δ18O, δ2H) of plant organic matter, which can be used for paleoclimate reconstruction. This study is the first to examine the diurnal variations in the δ18O and δ2H of leaf water on the southern Tibetan Plateau. The δ18O and δ2H of leaf water were relatively low when precipitation events occurred. In particular, 18O and 2H of leaf water became extremely depleted 5 h after the precipitation event. Our findings demonstrate that precipitation can modify the isotope ratios of leaf water from external and internal causes. First, precipitation events affect meteorological elements, lead to decreases in leaf transpiration, and immediately weaken the isotope enrichment of leaf water ('rapid effect' of precipitation). Second, precipitation events affect the internal plant-soil water cycle process, causing the plant to preferentially use deeper soil water, and the corresponding isotope ratios of leaf water exhibit extremely low values 5 h after precipitation events ('delay effect' of precipitation). This study suggests that researchers need to be cautious in separating the signals of precipitation and hydrological processes when interpreting isotope records preserved in tree-ring cellulose archives from the Tibetan Plateau.

Different patterns and origins between northwestern and southeastern Tibetan ice core glaciochemical records over the past century.

Atmospheric circulation systems differ between the northern and southern Tibetan Plateau (TP) and are characterized by prevailing westerly winds and the Indian monsoon, respectively. This leads to spatial differences between glaciochemical records in the northwestern and southeastern TP. We compared the spatial differences in major soluble ion concentrations (Ca2+, SO42-, NO3-, NH4+, Cl-, Na+, K+, and Mg2+) during the last century in the Aru (northwestern TP) and East Rongbuk (ER; southeastern TP) ice cores. Ca2+ exhibited the largest difference between the ice cores (2371 ppb in the Aru ice core and 65 ppb in the ER ice core), indicating that crustal processes were more dominant in the Aru ice core. NH4+ accounted for 17% of the total ion concentration in the ER ice core but only 3% in the Aru ice core, which may be related to the Indian monsoon traveling over NH3 emission zones in southern Asia. The major soluble ion concentrations exhibited decreasing trends in the Aru ice core but increasing trends in the ER ice core (P < 0.01). Empirical orthogonal function and backward trajectory analyses indicated that the major soluble ions in the Aru ice core originated from crustal sources in central Asia; those in the ER ice core had crustal, anthropogenic, and oceanic sources from southern Asia. The results from the Aru ice core suggest that dust events and enhanced prevailing westerly winds promoted the deposition of dust aerosols from the Taklamakan Desert and arid and semi-arid regions of central Asia. Contrastingly, the results from the ER ice core suggest that the Indian monsoon transported crustal and anthropogenic sources from southern Asia and oceanic sources from the Bay of Bengal and Arabian Sea. This study contributes to the comprehensive understanding of the differences in glaciochemical records and their causes between the northwestern and southeastern TP.

Demonstration of a memory calibration method in water isotope measurement by laser spectroscopy.

RATIONALE: Measuring δ18 O and δ2 H values in water using wavelength-scanned cavity ring down spectroscopy (WS-CRDS) requires multiple injections of up to six (and sometimes eight or more) of one sample to remove the memory effect, which decreases the sample throughput and increases the consumables cost. Thus, improved methods for removing the memory effect are required. METHODS: We calculated the memory coefficients by sequential WS-CRDS measurement of two lab standard waters with isotopic differences, and used them to establish calibration equations. We then used these equations to correct the measured δ18 O and δ2 H values by removing the memory effect, instead of using multiple injections in the routine daily measurements. RESULTS: By using this method, the number of injections per sample was reduced to one. The reproducibility (one standard deviation) of the δ18 O and δ2 H values obtained for quality control sample was less than 0.05‰ and 0.5‰ for an annual average, respectively. CONCLUSIONS: By measuring the memory coefficients and establishing the calibration equations, a highly effective method was developed for determining the δ18 O and δ2 H values of water, which could significantly improve sample throughput for liquid water dual isotope measurement without sacrificing the precision.

Mercury speciation and distribution in a glacierized mountain environment and their relevance to environmental risks in the inland Tibetan Plateau.

Glacierized mountain environments can preserve and release mercury (Hg) and play an important role in regional Hg biogeochemical cycling. However, the behavior of Hg in glacierized mountain environments and its environmental risks remain poorly constrained. In this research, glacier meltwater, runoff and wetland water were sampled in Zhadang-Qugaqie basin (ZQB), a typical glacierized mountain environment in the inland Tibetan Plateau, to investigate Hg distribution and its relevance to environmental risks. The total mercury (THg) concentrations ranged from 0.82 to 6.98ng·L-1, and non-parametric pairwise multiple comparisons of the THg concentrations among the three different water samples showed that the THg concentrations were comparable. The total methylmercury (TMeHg) concentrations ranged from 0.041 to 0.115ng·L-1, and non-parametric pairwise multiple comparisons of the TMeHg concentrations showed a significant difference. Both the THg and MeHg concentrations of water samples from the ZQB were comparable to those of other remote areas, indicating that Hg concentrations in the ZQB watershed are equivalent to the global background level. Particulate Hg was the predominant form of Hg in all runoff samples, and was significantly correlated with the total suspended particle (TSP) and not correlated with the dissolved organic carbon (DOC) concentration. The distribution of mercury in the wetland water differed from that of the other water samples. THg exhibited a significant correlation with DOC as well as TMeHg, whereas neither THg nor TMeHg was associated with TSP. Based on the above findings and the results from previous work, we propose a conceptual model illustrating the four Hg distribution zones in glacierized environments. We highlight that wetlands may enhance the potential hazards of Hg released from melting glaciers, making them a vital zone for investigating the environmental effects of Hg in glacierized environments and beyond.

The influence of memory, sample size effects, and filter paper material on online laser-based plant and soil water isotope measurements.

RATIONALE: The recent development of isotope ratio infrared spectroscopy (IRIS) was quickly followed by the addition of online extraction and analysis systems, making it faster and easier to measure soil and plant water isotopes. However, memory and sample size effects limit the efficiency and accuracy of these new setups. In response, this study presents a scheme dedicated to estimating and eliminating these two effects. METHODS: Memory effect was determined by injecting two standard waters alternately. Each standard was injected nine times in a row and analyzed using induction module cavity ring-down spectroscopy (IM-CRDS). Memory coefficients were calculated using a new "multistage jump" algorithm. Sample size effects were evaluated by injecting water volumes ranging from 1 µL to 6 µL. Finally, the influence of cellulose filter paper on the isotopic measurements, the memory, and the sample size effect was evaluated by comparing it with glass filter paper. RESULTS: Memory effects were detected for both δ18 O and δ2 H values, with the latter being stronger. Isotopic differences between replicates of the same plant or soil sample showed a clear decrease after memory correction. A small water volume effect was found only when the injected water volume was larger than 3 µL. However, while the correction method performed well for laboratory-made samples, it did not for field samples, due to the heterogeneity of the isotopic composition of the samples. Stronger memory and water volume effects were found for cellulose filter paper. CONCLUSIONS: The memory coefficients and the water volume-isotope relationship improved the consistency and accuracy of both laboratory and field data. Our results indicate that cellulose filter paper may not be a suitable medium to measure standard waters and evaluate memory and water volume effects. Finally, a detailed correction and calibration protocol is suggested, along with notes on best practices to obtain good-quality IM-CRDS data. Copyright © 2017 John Wiley & Sons, Ltd.

The Interventional Effect of Remote Ischemic Preconditioning on Cerebral Small Vessel Disease: A Pilot Randomized Clinical Trial.

BACKGROUND: Remote ischemic preconditioning (RIPC) of the limb has been shown to induce ischemic tolerance in basic and clinical studies that focused on sustained large artery occlusion rather than small vessel disease (SVD). This study aimed to evaluate the protective effects of brief repetitive limb RIPC on patients with cerebral SVD. METHODS: Seventeen patients with cerebral SVD were enrolled. Patients underwent 5 ischemia-reperfusion cycles of preconditioning/sham preconditioning on both upper limbs twice a day for 1 year. Cerebral hemodynamic indexes, brain lesions, cognitive functions and assessment outcomes of dizziness handicap inventory (DHI) were analyzed. RESULTS: In the RIPC group, the mean flow velocity (MFV) of the left middle cerebral artery (MCA) was accelerated (57.33 (52.33-61.34) vs. 51.33 (48.83-58.33), respectively; p = 0.038), and the post-treatment DHI score was reduced (18 (13-19) vs. 34 (21-45), respectively; p = 0.043). The post-treatment volume of the white matter lesions (WMLs) was also reduced (4.19 (2.96-7.25) vs. 6.06 (4.67-10.95), respectively; p = 0.050). There was no remarkable difference between the 2 groups either before or after treatment. CONCLUSION: The present study indicates that RIPC has potential beneficial effects on cerebral SVD by increasing the MFV of MCA, decreasing the DHI score as well as the volume of WMLs in patients with SVD.

The E3 ligase APC/C-Cdh1 regulates MEF2A-dependent transcription by targeting SUMO-specific protease 2 for ubiquitination and degradation.

Activity-dependent stimuli induced a calcineurin-mediated dephosphorylation of the transcriptional factor MEF2A at serine408 and promoted a switch from SUMOylation to acetylation at lysine403 which led to MEF2A transcriptional activation. We previously identified SENP2 is the de-SUMOylation enzyme for MEF2A and promotes MEF2A-dependent transcription. We report here a requirement for APC(Cdh1)-SENP2-MEF2A axis in the regulation of MEF2A transcriptional activation. APC(Cdh1) interacts with and targets SENP2 for ubiquitination and destruction in the cytoplasm by recognizing a conserved canonical D-box motif in SENP2. Moreover, Cdh1 regulates the transcriptional activity of MEF2A in a SENP2 dependent manner. Activity-dependent stimuli prevented APC(Cdh1)-induced SENP2 ubiquitination, promoted SENP2 nuclear accumulations, and caused MEF2A de-SUMOylation and MEF2A acetylation, leading to MEF2A transcriptional activation. Thus, our findings defined a post-transcriptional mechanism underlying activity-dependent stimuli-induced MEF2A transcriptional activation.

A single amino acid change in Ca(v)1.2 channels eliminates the permeation and gating differences between Ca(2+) and Ba(2+).

Glutamate scanning mutagenesis was used to assess the role of the calcicludine binding segment in regulating channel permeation and gating using both Ca(2+) and Ba(2+) as charge carriers. As expected, wild-type Ca(V)1.2 channels had a Ba(2+) conductance ~2x that in Ca(2+) (G(Ba)/G(Ca) = 2) and activation was ~10 mV more positive in Ca(2+) vs. Ba(2+). Of the 11 mutants tested, F1126E was the only one that showed unique permeation and gating properties compared to the wild type. F1126E equalized the Ca(V)1.2 channel conductance (G(Ba)/G(Ca) = 1) and activation voltage dependence between Ca(2+) and Ba(2+). Ba(2+) permeation was reduced because the interactions among multiple Ba(2+) ions and the pore were specifically altered for F1126E, which resulted in Ca(2+)-like ionic conductance and unitary current. However, the high-affinity block of monovalent cation flux was not altered for either Ca(2+) or Ba(2+). The half-activation voltage of F1126E in Ba(2+) was depolarized to match that in Ca(2+), which was unchanged from that in the wild type. As a result, the voltages for half-activation and half-inactivation of F1126E in Ba(2+) and Ca(2+) were similar to those of wild-type in Ca(2+). This effect was specific to F1126E since F1126A did not affect the half-activation voltage in either Ca(2+) or Ba(2+). These results indicate that residues in the outer vestibule of the Ca(V)1.2 channel pore are major determinants of channel gating, selectivity, and permeation.

[The effects of general anesthesia combined with epidural anesthesia on the stress response in thoracic surgery].

OBJECTIVE: To study the effects of general anesthesia combined with epidural anesthesia (GEA) and pure general anesthesia (GA) on the surgical stress response and cytokines in pulmonary surgery. METHODS: Twenty patients submitted to elective pulmonary surgery were randomly divided into 2 groups of 10 patients: GEA group receiving general anesthesia combined with thoracic epidural analgesia and GA group receiving only general anesthesia. Blood samples were taken before induction, at incision, 2 h, 4 h, 6 h following the incision, and in the 1st and 3rd postoperative day. IL-6, ACTH and cortisol were detected with radioimmunoassay. RESULTS: (1). The concentration of ACTH was similar in the 2 groups before operation, was remarkably increased 2 hours postoperatively (P < 0.05), reached the peak values 2 approximately 4 hours after the incision in most patients (P < 0.01), and returned to the preoperative levels one day after operation without a significant difference at every time point between the two groups. (2). The concentration of cortisol decreased transiently during incision in the GEA group (P < 0.05), then increased gradually, was significantly higher than the preoperative level (P < 0.01), and remained at the high level till the morning of the 1st day after operation (P < 0.01). In the GA group the cortisol concentration was higher than that before operation 2 hours after incision (P < 0.01), and remained at the level higher than that before operation 4 h and 6 h after incision (P < 0.01), and returned to the normal level by the morning of the 3rd day. The cortisol concentration 2 hours after incision in GEA group was significantly lower than that in GA group (P < 0.05), however, the peak concentrations of these 2 groups were not significantly different (P > 0.05). In the GA group the IL-6 concentration began to increase after operation, became significantly different from that before operation 4 hours after operation (P < 0.01), reached the peak level in the morning of the first postoperative day (P < 0.05), and returned to the preoperative level in the third day. In the GEA group the IL-6 concentration began to increase 2 hours after operation (P < 0.05), and returned to the preoperative level in the morning of the first postoperative day. The concentration of IL-6 was positively correlated with that of cortisol (r = 0.231). CONCLUSION: Pulmonary surgery performed with two different anesthetic techniques causes inflammatory cytokine responses. The additional epidural anesthesia doesn't influence cytokine production. It incompletely inhibits the stress response in the early phase. IL-6 and cortisol may have some effects on each other.