Pervasive, Coordinated Protein-Level Changes Driven by Transcript Isoform Switching during Meiosis.

To better understand the gene regulatory mechanisms that program developmental processes, we carried out simultaneous genome-wide measurements of mRNA, translation, and protein through meiotic differentiation in budding yeast. Surprisingly, we observed that the levels of several hundred mRNAs are anti-correlated with their corresponding protein products. We show that rather than arising from canonical forms of gene regulatory control, the regulation of at least 380 such cases, or over 8% of all measured genes, involves temporally regulated switching between production of a canonical, translatable transcript and a 5' extended isoform that is not efficiently translated into protein. By this pervasive mechanism for the modulation of protein levels through a natural developmental program, a single transcription factor can coordinately activate and repress protein synthesis for distinct sets of genes. The distinction is not based on whether or not an mRNA is induced but rather on the type of transcript produced.

Small and Large Ribosomal Subunit Deficiencies Lead to Distinct Gene Expression Signatures that Reflect Cellular Growth Rate.

Levels of the ribosome, the conserved molecular machine that mediates translation, are tightly linked to cellular growth rate. In humans, ribosomopathies are diseases associated with cell-type-specific pathologies and reduced ribosomal protein (RP) levels. Because gene expression defects resulting from ribosome deficiency have not yet been experimentally defined, we systematically probed mRNA, translation, and protein signatures that were either unlinked from or linked to cellular growth rate in RP-deficient yeast cells. Ribosome deficiency was associated with altered translation of gene subclasses, and profound general secondary effects of RP loss on the spectrum of cellular mRNAs were seen. Among these effects, growth-defective 60S mutants increased synthesis of proteins involved in proteasome-mediated degradation, whereas 40S mutants accumulated mature 60S subunits and increased translation of ribosome biogenesis genes. These distinct signatures of protein synthesis suggest intriguing and currently mysterious differences in the cellular consequences of deficiency for small and large ribosomal subunits.

Gate-tunable bolometer based on strongly coupled graphene mechanical resonators.

Bolometers based on graphene have demonstrated outstanding performance with high sensitivity and short response time. In situ adjustment of bolometers is very important in various applications, but it is still difficult to implement in many systems. Here we propose a gate-tunable bolometer based on two strongly coupled graphene nanomechanical resonators. Both resonators are exposed to the same light field, and we can measure the properties of one bolometer by directly tracking the resonance frequency shifts, and indirectly measure the other bolometer through mechanical coupling. We find that the sensitivity and the response bandwidth of both bolometers can be independently adjusted by tuning the corresponding gate voltages. Moreover, the properties of the indirectly measured bolometer show a dependence on the coupling between the two resonators, with other parameters being fixed. Our method has the potential to optimize the design of large-scale bolometer arrays, and open new horizons in infrared/terahertz astronomy and communication systems.

Adrenomedullin Improves Hypertension and Vascular Remodeling partly through the Receptor-Mediated AMPK Pathway in Rats with Obesity-Related Hypertension.

Adrenomedullin (ADM) is a novel cardiovascular peptide with anti-inflammatory and antioxidant properties. Chronic inflammation, oxidative stress and calcification play pivotal roles in the pathogenesis of vascular dysfunction in obesity-related hypertension (OH). Our study aimed to explore the effects of ADM on the vascular inflammation, oxidative stress and calcification in rats with OH. Eight-week-old Sprague Dawley male rats were fed with either a Control diet or a high fat diet (HFD) for 28 weeks. Next, the OH rats were randomly subdivided into two groups as follows: (1) HFD control group, and (2) HFD with ADM. A 4-week treatment with ADM (7.2 µg/kg/day, ip) not only improved hypertension and vascular remodeling, but also inhibited vascular inflammation, oxidative stress and calcification in aorta of rats with OH. In vitro experiments, ADM (10 nM) in A7r5 cells (rat thoracic aorta smooth muscle cells) attenuated palmitic acid (PA, 200 µM) or angiotensin II (Ang II, 10 nM) alone or their combination treatment-induced inflammation, oxidative stress and calcification, which were effectively inhibited by the ADM receptor antagonist ADM22-52 and AMP-activated protein kinase (AMPK) inhibitor Compound C, respectively. Moreover, ADM treatment significantly inhibited Ang II type 1 receptor (AT1R) protein expression in aorta of rats with OH or in PA-treated A7r5 cells. ADM improved hypertension, vascular remodeling and arterial stiffness, and attenuated inflammation, oxidative stress and calcification in OH state partially via receptor-mediated AMPK pathway. The results also raise the possibility that ADM will be considered for improving hypertension and vascular damage in patients with OH.

Accurate Thermodynamic Properties of Ideal Bosons in a Highly Anisotropic 2D Harmonic Potential.

One can derive an analytic result for the issue of Bose-Einstein condensation (BEC) in anisotropic 2D harmonic traps. We find that the number of uncondensed bosons is represented by an analytic function, which includes a series expansion of q-digamma functions in mathematics. One can utilize this analytic result to evaluate various thermodynamic functions of ideal bosons in 2D anisotropic harmonic traps. The first major discovery is that the internal energy of a finite number of ideal bosons is a monotonically increasing function of anisotropy parameter p. The second major discovery is that, when p≥0.5, the changing with temperature of the heat capacity of a finite number of ideal bosons possesses the maximum value, which happens at critical temperature Tc. The third major discovery is that, when 0.1≤p<0.5, the changing with temperature of the heat capacity of a finite number of ideal bosons possesses an inflection point, but when p<0.1, the inflection point disappears. The fourth major discovery is that, in the thermodynamic limit, at Tc and when p≥0.5, the heat capacity at constant number reveals a cusp singularity, which resembles the λ-transition of liquid helium-4. The fifth major discovery is that, in comparison to 2D isotropic harmonic traps (p=1), the singular peak of the specific heat becomes very gentle when p is lowered.

Paracandidimonas lactea sp. nov., a urea-utilizing bacterium isolated from landfill.

A urea-utilizing bacterium, designated Q2-2 T, was isolated from landfill. Cells of strain Q2-2 T were Gram stain-negative, aerobic, short-rod bacteria. Strain Q2-2 T was observed to grow at a temperature range of 15-37℃ (optimum 30 â„ƒ), a pH range of 5.5-9.5 (optimum pH 8.0) and 0-4% (w/v) NaCl (optimum 1%). The major respiratory quinone was Q-8, and the major polar lipids were diphosphatidyl glycerol, phosphatidylethanolamine, phosphatidylmethylethanolamine, and phosphatidyl glycerol. Based on the 16S rRNA gene sequence, strain Q2-2 T had the highest similarity with Paracandidimonas caeni 24 T (98.0%), followed by Pusillimonas soli MJ07T (97.5%), Parapusillimonas granuli Ch07T (97.2%), Pusillimonas ginsengisoli DCY25T (97.1%) and Paracandidimonas soli IMT-305 T (96.4%). The ANI values between strain Q2-2 T and the above related type strains were 71.02%, 73.52%, 74.32%, 74.59% and 72.29%, respectively. The DNA G + C content of strain Q2-2 T was 61.1%. Therefore, strain Q2-2 T represents a novel species of the genus Paracandidimonas, for which the name Paracandidimonas lactea sp. nov. (type strain Q2-2 T = CGMCC 1.19179 T = JCM 34906 T) is proposed.

Caldovatus aquaticus sp. nov., a moderately thermophilic bacterium isolated from hot spring microbial mat.

Two closely related, aerobic, Gram-stain-negative, motile, oval-shaped, non-endospore-forming, moderately thermophilic bacteria, designated strains SYSU G05006T and SYSU G05005, were isolated from a bioreactor enrichment and the original sample was collected from Rehai National Park, Tengchong, Yunnan Province, PR China. The results of phylogenetic analysis based on the 16S rRNA gene sequences indicated that these two strains were closely related to Caldovatus sediminis YIM 72346T (96.75 and 96.89 % sequence similarity, respectively). The whole genome size of strain SYSU G05006T was 3.87 Mbp with a DNA G+C content of 75.33 mol%. The average nucleotide identity (ANI based on the MUMmer algorithm≤90.31 % and ANI based on blast≤89.36 %) and digital DNA-DNA hybridization (≤35.10 %) values between strain SYSU G05006T and other members of the family Acetobacteraceae were all lower than the threshold values recommended for distinguishing novel prokaryotic species. Optimal growth of the strain was observed at 55 °C and pH 6.0. Ubiquinone-10 was the predominant respiratory lipoquinone. The major cellular fatty acids included iso-C14 : 0, C16 : 1 ω5c, summed feature 5 and summed feature 7. The major polar lipids consisted of diphosphatidylglycerol, one unidentified aminolipid, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, two unidentified phospholipids and two unidentified lipids. Based on results of phylogenetic analyses, comparative genomics and phenotypic characteristics, we describe a new species of the genus Caldovatus represented by strain SYSU G05006T (=KCTC 82831T=MCCC 1K06125T), for which we propose the name Caldovatus aquaticus sp. nov.

Positive regulation of ataxia-telangiectasia-mutated protein (ATM) by E2F transcription Factor 1 (E2F-1) in cisplatin-resistant nasopharyngeal carcinoma cells.

OBJECTIVE: To explore the mechanism of E2F transcription Factor 1 (E2F-1)-mediated ataxia-telangiectasia-mutated protein (ATM) in cisplatin (DDP)-resistant nasopharyngeal carcinoma (NPC). METHODS: E2F-1 and ATM expression was assessed in DDP-resistant NPC cell lines (CNE2/DDP and HNE1/DDP) and parental cells. Then, DDP-resistant NPC cells were transfected with control shRNA (short hairpin RNA) or E2F-1 shRNAs with or without ATM lentiviral activation particles. The half maximal inhibitory concentration (IC50) was evaluated by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay, and the cell cycle and cell proliferation were measured by flow cytometry and EdU staining, respectively. In addition, the expression of genes and proteins was quantified by quantitative reverse-transcription polymerase chain reaction (qRT-PCR) and western blotting, respectively. RESULTS: Both E2F-1 and ATM expression in DDP-resistant NPC cells was much higher than that in parental cells. E2F-1 shRNA reduced ATM expression in DDP-resistant NPC cells, but ATM overexpression had no significant effect on E2F-1. ATM overexpression enhanced DDP resistance in DDP-resistant NPC cells with increased IC50 values, which was reversed by E2F-1 inhibition. Meanwhile, ATM overexpression resulted in upregulation of ABCA2 and ABCA5 in DDP-resistant NPC cells, induced elevations in the transition of the cells into S-phase, and increased cell proliferation with enhanced expression of cyclin E1, CDK2, and Ki67, which was reversed by E2F-1 shRNAs. CONCLUSION: Downregulation of E2F-1, possibly by regulating ATM, could block the cell cycle in the G1 phase and reduce the proliferation of CNE2/DDP cells, thereby reversing the resistance of human NPC cells to DDP.

Bioinspired Trinuclear Copper Catalyst for Water Oxidation with a Turnover Frequency up to 20000 s-1.

Solar-powered water splitting is a dream reaction for constructing an artificial photosynthetic system for producing solar fuels. Natural photosystem II is a prototype template for research on artificial solar energy conversion by oxidizing water into molecular oxygen and supplying four electrons for fuel production. Although a range of synthetic molecular water oxidation catalysts have been developed, the understanding of O-O bond formation in this multielectron and multiproton catalytic process is limited, and thus water oxidation is still a big challenge. Herein, we report a trinuclear copper cluster that displays outstanding reactivity toward catalytic water oxidation inspired by multicopper oxidases (MCOs), which provides efficient catalytic four-electron reduction of O2 to water. This synthetic mimic exhibits a turnover frequency of 20000 s-1 in sodium bicarbonate solution, which is about 150 and 15 times higher than that of the mononuclear Cu catalyst (F-N2O2Cu, 131.6 s-1) and binuclear Cu2 complex (HappCu2, 1375 s-1), respectively. This work shows that the cooperation between multiple metals is an effective strategy to regulate the formation of O-O bond in water oxidation catalysis.

Phonon lasing with an atomic thin membrane resonator at room temperature.

Graphene has been considered as one of the best materials to implement mechanical resonators due to their excellent properties such as low mass, high quality factors and tunable resonant frequencies. Here we report the observation of phonon lasing induced by the photonthermal pressure in a few-layer graphene resonator at room temperature, where the graphene resonator and the silicon substrate form an optical cavity. A marked threshold in the oscillation amplitude and a narrowing linewidth of the vibration mode are observed, which confirms a phonon lasing process in the graphene resonator. Our findings will stimulate the studies on phononic phenomena, help to establish new functional devices based on graphene mechanical resonators, and might find potential applications in classical and quantum sensing fields, as well as in information processing.

Inhibitor development of MTH1 via high-throughput screening with fragment based library and MTH1 substrate binding cavity.

MutT Homolog 1 (MTH1) has been proven to hydrolyze oxidized nucleotide triphosphates during DNA repair. It can prevent the incorporation of wrong nucleotides during DNA replication and mitigate cell apoptosis. In a cancer cell, abundant reactive oxygen species can lead to substantial DNA damage and DNA mutations by base-pairing mismatch. MTH1 could eliminate oxidized dNTP and prevent cancer cells from entering cell death. Therefore, inhibition of MTH1 activity is considered to be an anti-cancer therapeutic target. In this study, high-throughput screening techniques were combined with a fragment-based library containing 2,313 compounds, which were used to screen for lead compounds with MTH1 inhibitor activity. Four compounds with MTH1 inhibitor ability were selected, and compound MI0639 was found to have the highest effective inhibition. To discover the selectivity and specificity of this action, several derivatives based on the MTH1 and MI0639 complex structure were synthesized. We compared 14 complex structures of MTH1 and the various compounds in combination with enzymatic inhibition and thermodynamic analysis. Nanomolar-range IC50 inhibition abilities by enzyme kinetics and Kd values by thermodynamic analysis were obtained for two compounds, named MI1020 and MI1024. Based on structural information and compound optimization, we aim to provide a strategy for the development of MTH1 inhibitors with high selectivity and specificity.

Global translation inhibition yields condition-dependent de-repression of ribosome biogenesis mRNAs.

Ribosome biogenesis (RiBi) is an extremely energy intensive process that is critical for gene expression. It is thus highly regulated, including through the tightly coordinated expression of over 200 RiBi genes by positive and negative transcriptional regulators. We investigated RiBi regulation as cells initiated meiosis in budding yeast and noted early transcriptional activation of RiBi genes, followed by their apparent translational repression 1 hour (h) after stimulation to enter meiosis. Surprisingly, in the representative genes examined, measured translational repression depended on their promoters rather than mRNA regions. Further investigation revealed that the signature of this regulation in our data depended on pre-treating cells with the translation inhibitor, cycloheximide (CHX). This treatment, at 1 h in meiosis, but not earlier, rapidly resulted in accumulation of RiBi mRNAs that were not translated. This effect was also seen in with CHX pre-treatment of cells grown in media lacking amino acids. For NSR1, this effect depended on the -150 to -101 region of the promoter, as well as the RiBi transcriptional repressors Dot6 and Tod6. Condition-specific RiBi mRNA accumulation was also seen with translation inhibitors that are dissimilar from CHX, suggesting that this phenomenon might represent a feedback response to global translation inhibition.

Eva-1 homolog A promotes papillary thyroid cancer progression and epithelial-mesenchymal transition via the Hippo signalling pathway.

Recently, the incidence of thyroid cancer is increasing worldwide. Papillary thyroid cancer (PTC) is the most common histological type of thyroid cancer. Whole-transcriptome sequence analysis was performed to further understand the primary molecular mechanisms of the occurrence and progression of PTC. Results showed that Eva-1 homolog A (EVA1A) may be a potential gene for the PTC-associated gene in thyroid cancer. In this work, the role of EVA1A expression in thyroid cancer was investigated. Real-time PCR was performed to detect the expression level of EVA1A in 43 pairs of PTC and four thyroid cancer cell lines. The Cancer Genome Atlas (TCGA) database was used to evaluate the relationship between the expression level of EVA1A and the pathological feature of PTC. The logistic regression analysis of the TCGA data set indicated that the expression of EVA1A was an independent risk factor for tumour, nde and metastasis (TNM) in PTC. This study shows the down-regulation of EVA1A inhibited the colony formation, proliferation, migration and invasion of PTC cell lines. In the protein level, knockdown of EVA1A can regulate the expression of N-cadherin, vimentin, Bcl-xL, Bax, YAP and TAZ. This study indicated that EVA1A was an oncogene associated with PTC.

Simultaneous determination and determination of sildenafil and its active metabolite in human plasma using LC-MS/MS method.

A sensitive and selective high-performance liquid chromatography-tandam mass spectrometry (LC-MS/MS) method was developed and validated for the simultaneous quantification of sildenafil and its metabolite N-desmethyl sildenafil in human plasma. Sildenafil-d8 was used as an internal standard. The analytes were extracted by precipitation extraction and chromatographed on a C18 column using mobile phase A of water (containing 0.1% formic acid) and mobile phase B of acetonitrile (containing 0.1% formic acid) with gradient elution. Quantification was done using multiple reaction monitoring mode to monitor the precursor-to-product ion transitions of m/z 475.4 → m/z 283.3 for sildenafil, m/z 461.4 → m/z 283.2 for N-desmethyl sildenafil and m/z 483.3 → m/z 108.1 for IS in positive ionization mode. The calibration curve was established over the range of 2.00-1,000 ng/ml and the correlation coefficient was >0.99. The intra-day and inter-day relative standard deviations were <6.5% for sildenafil and 6.3% for N-desmethyl sildenafil respectively. Accuracy determinaed at four concentrations was 86.50-105.67% for sildenafil and 96.83-114.40% for N-desmethyl sildenafil. This method was successfully applied to a pharmacokinetic description of sildenafil and the effect of food intake on the pharmacokinetics of sildenafil was also demonstrated in healthy Chinese volunteers.

Impact of treatment modalities on patients with recurrent hepatocellular carcinoma after liver transplantation: Preliminary experience.

BACKGROUND: Post-liver transplantation (LT) hepatocellular carcinoma (HCC) recurrence still occurs in approximately 20% of patients and drastically affects their survival. This study aimed to evaluate the efficacy of various treatments for recurrent HCC after LT in a Chinese population. METHODS: A total of 64 HCC patients with tumor recurrence after LT were enrolled in this study. Univariate and multivariate analyses were performed to identify factors affecting post-recurrence survival. RESULTS: Of the 64 patients with recurrent HCC after LT, those who received radical resection followed by nonsurgical therapy had a median overall survival (OS) of 20.9 months after HCC recurrence, significantly superior to patients who received only nonsurgical therapy (9.4 months) or best supportive care (2.4 months). The one- and two-year OS following recurrence was favorable for patients receiving radical resection followed by nonsurgical therapy (93.8%, 52.6%), poor for patients receiving only nonsurgical therapy (30.8%, 10.8%), and dismal for patients receiving best supportive care (0%, 0%; overall P < 0.001). Median OS in sorafenib-tolerant patients treated with lenvatinib was 19.5 months, far surpassing the patients that discontinued sorafenib or were treated with regorafenib after sorafenib failure (12 months, P < 0.001). Compared with tacrolimus-based immunosuppressive therapy, OS was significantly increased with sirolimus-based therapy at one and two years after HCC recurrence (P = 0.035). Multivariate analysis showed radical resection combined with nonsurgical therapy for recurrent HCC and sorafenib-lenvatinib sequential therapy were independent favorable factors for post-recurrence survival. CONCLUSIONS: Aggressive surgical intervention in well-selected patients significantly improves OS after recurrence. A multidisciplinary treatment approach is required to slow down disease progression for patients with unresectable recurrent HCC.

Safety and efficacy of an integrated endovascular treatment strategy for early hepatic artery occlusion after liver transplantation.

BACKGROUND: Hepatic artery occlusion (HAO) after liver transplantation (LT) is typically comprised of hepatic artery thrombosis (HAT) and stenosis (HAS), both of which are severe complications that coexist and interdependent. This study aimed to evaluate an integrated endovascular treatment (EVT) strategy for the resolution of early HAO and identify the risk factors associated with early HAO as well as the procedural challenge encountered in the treatment strategy. METHODS: Consecutive orthotopic LT recipients (n = 366) who underwent transplantation between June 2017 and December 2018 were retrospectively investigated. EVT was performed using an integrated strategy that involved thrombolytic therapy, shunt artery embolization plus vasodilator therapy, percutaneous transluminal angioplasty, and/or stent placement. Simple EVT was defined as the clinical resolution of HAO by one round of EVT with thrombolytic therapy and/or shunt artery embolization plus vasodilator therapy. Otherwise, it was defined as complex EVT. RESULTS: Twenty-six patients (median age 52 years) underwent EVT for early HAO that occurred within 30 days post-LT. The median interval from LT to EVT was 7 (6-16) days. Revascularization time (OR = 1.027; 95% CI: 1.005-1.050; P = 0.018) and the need for conduit (OR = 3.558; 95% CI: 1.241-10.203, P = 0.018) were independent predictors for early HAO. HAT was diagnosed in eight patients, and four out of those presented with concomitant HAS. We achieved 100% technical success and recanalization by performing simple EVT in 19 patients (3 HAT+/HAS- and 16 HAT-/HAS+) and by performing complex EVT in seven patients (1 HAT+/HAS-, 4 HAT+/HAS+, and 2 HAT-/HAS+), without major complications. The primary assisted patency rates at 1, 6, and 12 months were all 100%. The cumulative overall survival rates at 1, 6, and 12 months were 88.5%, 88.5%, and 80.8%, respectively. Autologous transfusion < 600 mL (94.74% vs. 42.86%, P = 0.010) and interrupted suture for hepatic artery anastomosis (78.95% vs. 14.29%, P = 0.005) were more prevalent in simple EVT. CONCLUSIONS: The integrated EVT strategy was a feasible approach providing effective resolution with excellent safety for early HAO after LT. Appropriate autologous transfusion and interrupted suture technique helped simplify EVT.

[Endoplasmic Reticulum Stress and Mitochondrial Damage in Rat Cardiomyocytes after Acute Myocardial Infarction].

OBJECTIVE: To study the alterations of endoplasmic reticulum (ER) stress and mitochondrial damage after acute myocardial infarction (AMI). METHODS: A total of 40 SD rats were used in this study and 32 of them were subjected to AMI by ligation of left anterior descending artery. The rats were sacrificed and the heart tissues were collected after 1 h, 2 h, 4 h and 6 h of AMI ( n=8 per group). The mRNA levels of activating transcription factor 6 alpha ( ATF6) and immunoglobulin heavy chain binding potein ( BiP), as well as the expression of mitochondrial DNA (mtDNA) in cytoplasm were detected by RT-PCR. The ATP levels in the cardiomyocytes were detected by a commercial ATP assay kit. RESULTS: The mRNA levels of ATF6 and BiP were significantly increased after 1 h of AMI, which were maintained at high level from 2 h of AMI to the end of the experiment ( P<0.05). The ATP concentrations in the cardiomyocytes were significantly elevated after 1 h of AMI but remarkably decreased after 4 h and 6 h of AMI ( P<0.05). The release of mtDNA in cytoplasm was significantly increased after 2 h of AMI, followed by further elevations at 4 h and 6 h after AMI ( P<0.05). CONCLUSION: Mitochondrial damage is secondary to ER stress in AMI.

Flexible degenerate cavity with ellipsoidal mirrors.

Here we present a design of a traveling-wave optical cavity containing four identical ellipsoidal mirrors arranged in a square. The cavity proves to support more than 21 Laguerre-Gaussian modes simultaneously. There is a polarization splitting in the cavity that can be used for polarization filtering with a high isolation level.

An improved LC-MS/MS method for determination of cinacalcet in human plasma and its application to the evaluation of food intake effect on the pharmacokinetics of cinacalcet in healthy volunteers.

A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of cinacalcet in human plasma was developed and validated. This assay was based on liquid-liquid extraction and cinacalcet-d4 was used as an internal standard (IS). Separation was achieved on a C18 column by the mobile phase A of water (containing 0.1% formic acid) and the mobile phase B of acetonitrile-water (95:5, v/v) (containing 0.2% formic acid) with gradient elution. Quantification was done using multiple reaction monitoring mode to monitor the precursor-to-product ion transitions of m/z 358.2 → m/z 155.2 for cinacalcet and m/z 362.3 → m/z 155.0 for IS at positive ionization mode. The calibration curve was established over the range 0.05-20.0 ng/mL and the correlation coefficient was >0.99. The intra- and inter-day relative standard deviations were <5.8%. Accuracy determined at four concentrations ranged between 96.0 and 106.0%. This method was successfully applied to a pharmacokinetic description of oral dose of cinacalcet and the significant effect of food intake on the pharmacokinetics of cinacalcet was first demonstrated in Chinese healthy volunteers.