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Background Bile acids (BAs) conduct crucial signals in human metabolism. Correlations between changes in plasma BA concentrations, insulin secretion defects, and progression of type 2 diabetes mellitus (T2DM) in humans have not been sufficiently investigated. This study explored the trajectories of changes in human plasma BA concentrations and their association with insulin secretion dynamics during a two-step hyperglycemic clamp. Methods Eleven healthy subjects with normal glucose tolerance (NGT) and 33 drug-naive T2DM subjects were enrolled in the study. The two-step hyperglycemic clamp consisted of a classic clamp as Step 1 with fasting, followed by a Step 2 clamp after ingestion of a carbohydrate meal, illustrating basal and incretin-amplified insulin responses to glucose. Plasma BA were assayed using liquid chromatography-tandem mass spectrometry. Nine T2DM subjects were followed-up, and the two-step clamp was repeated after 3 months sulfonylurea treatment. Results Ursodeoxycholic acid (UDCA) was lower and lithocholic acid (LCA) and taurocholic acid (TCA) were higher in T2DM compared with NGT subjects. The dynamics of plasma UDCA concentrations and the UDCA/LCA ratio was positively correlated with insulin secretion in T2DM subjects and were corrected after treatment. Moreover, fasting ratios of UDCA/LCA and unconjugated/conjugated BAs were correlated with the first phase of insulin secretion in T2DM subjects. Conclusion The abnormal BA composition in T2DM subjects and its correlation with insulin secretion during the clamp suggest an interaction between BA signals and insulin secretion capacity, and the potential to use fasting plasma BA composition indices to predict and evaluate the progression and prognosis of T2DM.

An increasing amount of evidence suggests that the delayed effect of antibiotics (abx) on gut microbiota after its cessation is not as favorable as its immediate effect on host metabolism. However, it is not known how the diverse abx-dependent metabolic effects influence diabetic subjects and how gut microbiota is involved. Here, we treated db/db mice with abx cocktail for 12 days and discontinued for 24 days. We found that db/db mice showed decreased body weight and blood glucose after abx treatment, which rapidly caught up after abx cessation. Twenty-four days after abx withdrawal, db/db mice exhibit increased plasma, hepatic total cholesterol (TC) levels and liver weight. The gut microbiota composition at that time showed decreased relative abundances (RAs) of Desulfovibrionaceae and Rikenellaceae, increased RA of Erysipelotrichaceae and Mogibacteriaceae, which were correlating with the reduced short-chain fatty acids (SCFAs) in gut content, such as propionic acid and valeric acid and with the elevated fecal taurine-conjugated bile acids (BAs) levels. The molecular biology studies showed inhibited hepatic BA synthesis from cholesterol, impeded intracellular transportation and biliary excretion of cholesterol that all conferred to liver TC accumulation. The associations among alterations of gut microbiota composition, microbial metabolite profiles and host phenotypes suggested the existence of gut microbiota-linked mechanisms that mediate the unfavorable delayed effects of abx on db/db mice cholesterol metabolism. Thus, we call upon the caution of applying abx in diabetic animal models for studying microbiota-host interaction and in type 2 diabetes subjects for preventing chronic cardiovascular consequences.

Sulfonylureas are one of the commonly used drugs in type 2 diabetes mellitus (T2DM) but with considerable incidence of monotherapy failure. However, the mechanism of patients' drug response is unclear, and suitability evaluation biomarkers are in urgent need for precision medicine. In this study, a pseudotargeted gas chromatography-mass spectrometry method was employed to investigate the serum metabolic profiling of 66 significant responders and 24 nonsignificant responders at baseline and 16 weeks after gliclazide modified-release (MR) monotherapy. Clinical improvements in blood glucose level and insulin sensitivity were closely associated with the alterations of TCA cycle, ketone body metabolism, lipid oxidation, branched-chain amino acid catabolism, and gut flora metabolism. The different baseline metabolic profiling observed in the two groups implied that patients with lower dyslipidemia level may be more suitable for sulfonylurea therapy. The biomarker panel consisting of HbA1c, 5,8,11,14,17-eicosapentaenoic acid, methyl 8,11,14-eicosatrienoate, and methyl hexadecanoate shows a very good prediction ability for the suitability of gliclazide treatment, and it may be meaningful in personalized medicine of T2DM patients by sulfonylurea therapy.

PRINCE is a 64-bit lightweight block cipher with a 128-bit key published at ASIACRYPT 2012. Assuming one nibble fault is injected, previous different fault analysis (DFA) on PRINCE adopted the technique from DFA on AES and current results are different. This paper aims to make a comprehensive study of algebraic fault analysis (AFA) on PRINCE. How to build the equations for PRINCE and faults are explained. Extensive experiments are conducted. Under nibble-based fault model, AFA with three or four fault injections can succeed within 300 seconds with a very high probability. Under other fault models such as byte-based, half word-based, word-based fault models, the faults become overlapped in the last round and previous DFAs are difficult to work. Our results show that AFA can still succeed to recover the full master key. To evaluate security of PRINCE against fault attacks, we utilize AFA to calculate the reduced entropy of the secret key for given amount of fault injections. The results can interpret and compare the efficiency of previous work. Under nibble-based fault model, the master key of PRINCE can be reduced to 29.69 and 236.10 with 3 and 2 fault injections on average, respectively.

The therapeutic benefit of physical activity to prevent and treat type 2 diabetes is commonly accepted. However, the impact of the disease on the acute metabolic response is less clear. To this end, we investigated the effect of type 2 diabetes on exercise-induced plasma metabolite changes and the muscular transcriptional response using a complementary metabolomics/transcriptomics approach.We analysed 139 plasma metabolites and hormones at nine time points, and whole genome expression in skeletal muscle at three time points, during a 60 min bicycle ergometer exercise and a 180 min recovery phase in type 2 diabetic patients and healthy controls matched for age, percentage body fat and maximal oxygen consumption (VO2).Pathway analysis of differentially regulated genes upon exercise revealed upregulation of regulators of GLUT4 (SLC2A4RG, FLOT1, EXOC7, RAB13, RABGAP1 and CBLB), glycolysis (HK2, PFKFB1, PFKFB3, PFKM, FBP2 and LDHA) and insulin signal mediators in diabetic participants compared with controls. Notably, diabetic participants had normalised rates of lactate and insulin levels, and of glucose appearance and disappearance, after exercise. They also showed an exercise-induced compensatory regulation of genes involved in biosynthesis and metabolism of amino acids (PSPH, GATM, NOS1 and GLDC), which responded to differences in the amino acid profile (consistently lower plasma levels of glycine, cysteine and arginine). Markers of fat oxidation (acylcarnitines) and lipolysis (glycerol) did not indicate impaired metabolic flexibility during exercise in diabetic participants.Type 2 diabetic individuals showed specific exercise-regulated gene expression. These data provide novel insight into potential mechanisms to ameliorate the disturbed glucose and amino acid metabolism associated with type 2 diabetes.

FLUSH+RELOAD attack is recently proposed as a new type of Cache timing attacks. There are three essential factors in this attack, which are monitored instructions, threshold and waiting interval. However, existing literature seldom exploit how and why they could affect the system. This paper aims to study the impacts of these three parameters, and the method of how to choose optimal values. The complete rules for choosing the monitored instructions based on necessary and sufficient condition are proposed. How to select the optimal threshold based on Bayesian binary signal detection principal is also proposed. Meanwhile, the time sequence model of monitoring is constructed and the calculation of the optimal waiting interval is specified. Extensive experiments are conducted on RSA implemented with binary square-and-multiply algorithm. The results show that the average success rate of full RSA key recovery is 89.67%.

The dependence of terahertz (THz) emission power on the thickness of series $\hbox{Bi}_{2}\hbox{Sr}_{2} \hbox{CaCu }_{2} \hbox{O} _{8}$ (BSCCO) mesas is studied in this letter. An intrinsic Josephson junction (IJJ) array with two BSCCO mesas in series is proposed. The current–voltage characteristics of the IJJs, the powers, and Fourier spectra of the THz emission are measured for different thicknesses of the mesas, which is gradually mounted by the argon ion beam milling. Experiment results indicate that the THz emission power grows as the thickness of the mesas is increasing. The power reaches a maximum value of about 0.502 $\mu\hbox{W}$ at a frequency of 0.708 THz when the thickness is 1200 nm. However, the THz emission power decreases while the thickness of the mesas keeps increasing. This nonlinearity between the THz emission power and the thickness of the mesas is due to the cavity resonance of the mesas and the self-heating generated by the IJJs in the mesas. The structure of connecting two mesas in series can be extended to form an IJJ array of multiple series mesas, which could further improve the THz emission power.

Major depressive disorder (MDD) is a debilitating mental disease with a pronounced impact on the quality of life of many people; however, it is still difficult to diagnose MDD accurately. In this study, a nontargeted metabolomics approach based on ultra-high-performance liquid chromatography equipped with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to find the differential metabolites in plasma samples from patients with MDD and healthy controls. Furthermore, a validation analysis focusing on the differential metabolites was performed in another batch of samples using a targeted approach based on the dynamic multiple reactions monitoring method. Levels of acyl carnitines, ether lipids, and tryptophan pronouncedly decreased, whereas LPCs, LPEs, and PEs markedly increased in MDD subjects as compared with the healthy controls. Disturbed pathways, mainly located in acyl carnitine metabolism, lipid metabolism, and tryptophan metabolism, were clearly brought to light in MDD subjects. The binary logistic regression result showed that carnitine C10:1, PE-O 36:5, LPE 18:1 sn-2, and tryptophan can be used as a combinational biomarker to distinguish not only moderate but also severe MDD from healthy control with good sensitivity and specificity. Our findings, on one hand, provide critical insight into the pathological mechanism of MDD and, on the other hand, supply a combinational biomarker to aid the diagnosis of MDD in clinical usage.

Deuterium neutral beam injection is employed for assistant heating of plasma on experimental advanced superconducting tokamak (EAST). A set of infrared pyrometers is used for fast interlock protection system on EAST neutral beam injector. Typical experimental results are presented to illustrate the performance of beam shine through. During the high power injection, the maximal surface temperature will reach up to about 600 °C. If the temperature is higher than the limited value, the beam pulse is interrupted in about 20 ms. The shine through power is explained qualitatively with the performance of the plasma.

Metabolic profiling of silkworm, especially the factors that affect silk synthesis at the metabolic level, is little known. Herein, metabolomic method based on gas chromatography-mass spectrometry was applied to identify key metabolic changes in silk synthesis deficient silkworms. Forty-six differential metabolites were identified in Nd group with the defect of silk synthesis. Significant changes in the levels of glycine and uric acid (up-regulation), carbohydrates and free fatty acids (down-regulation) were observed. The further metabolomics of silk synthesis deficient silkworms by decreasing silk proteins synthesis using knocking out fibroin heavy chain gene or extirpating silk glands operation showed that the changes of the metabolites were almost consistent with those of the Nd group. Furthermore, the increased silk yields by supplying more glycine or its related metabolite confirmed that glycine is a key metabolite to regulate silk synthesis. These findings provide important insights into the regulation between metabolic profiling and silk synthesis.

Bile acids (BAs) conduct crucial signals in human metabolism. Correlations between changes in plasma BA concentrations, insulin secretion defects, and progression of type 2 diabetes mellitus (T2DM) in humans have not been sufficiently investigated. This study explored the trajectories of changes in human plasma BA concentrations and their association with insulin secretion dynamics during a two-step hyperglycemic clamp.Eleven healthy subjects with normal glucose tolerance (NGT) and 33 drug-naïve T2DM subjects were enrolled in the study. The two-step hyperglycemic clamp consisted of a classic clamp as Step 1 with fasting, followed by a Step 2 clamp after ingestion of a carbohydrate meal, illustrating basal and incretin-amplified insulin responses to glucose. Plasma BA were assayed using liquid chromatography-tandem mass spectrometry. Nine T2DM subjects were followed-up, and the two-step clamp was repeated after 3 months sulfonylurea treatment.Ursodeoxycholic acid (UDCA) was lower and lithocholic acid (LCA) and taurocholic acid (TCA) were higher in T2DM compared with NGT subjects. The dynamics of plasma UDCA concentrations and the UDCA/LCA ratio was positively correlated with insulin secretion in T2DM subjects and were corrected after treatment. Moreover, fasting ratios of UDCA/LCA and unconjugated/conjugated BAs were correlated with the first phase of insulin secretion in T2DM subjects.The abnormal BA composition in T2DM subjects and its correlation with insulin secretion during the clamp suggest an interaction between BA signals and insulin secretion capacity, and the potential to use fasting plasma BA composition indices to predict and evaluate the progression and prognosis of T2DM.

Recent lightweight cryptographic algorithms are vulnerable to side channel attacks (SCA), requiring a careful design of implementations. In this paper, we carefully investigate the “Low-Entropy Masking Scheme” (LEMS) on the block cipher LED in the context of resource-constrained environments. We propose an improved LEMS called “iM-LED”, so as to satisfy two different yet unified design goals: to maintain the entropy of the masking at one bit, meanwhile, to enhance first-order SCA-resistance against advanced SCAs such as correlation-enhanced collision attack (CCA). The security of the implementation has been evaluated based on the SASEBO-W board, which proves that iM-LED has boosted its mitigation against SCA with limited overheads.

Genetic alterations drive metabolic reprograming to meet increased biosynthetic precursor and energy demands for cancer cell proliferation and survival in unfavorable environments. A systematic study of gene-metabolite regulatory networks and metabolic dysregulation should reveal the molecular mechanisms underlying prostate cancer (PCa) pathogenesis. Herein, we performed gas chromatography-mass spectrometry (GC-MS)-based metabolomics and RNA-seq analyses in prostate tumors and matched adjacent normal tissues (ANTs) to elucidate the molecular alterations and potential underlying regulatory mechanisms in PCa. Significant accumulation of metabolic intermediates and enrichment of genes in the tricarboxylic acid (TCA) cycle were observed in tumor tissues, indicating TCA cycle hyperactivation in PCa tissues. In addition, the levels of fumarate and malate were highly correlated with the Gleason score, tumor stage and expression of genes encoding related enzymes and were significantly related to the expression of genes involved in branched chain amino acid degradation. Using an integrated omics approach, we further revealed the potential anaplerotic routes from pyruvate, glutamine catabolism and branched chain amino acid (BCAA) degradation contributing to replenishing metabolites for TCA cycle. Integrated omics techniques enable the performance of network-based analyses to gain a comprehensive and in-depth understanding of PCa pathophysiology and may facilitate the development of new and effective therapeutic strategies.

Liquid chromatography-mass spectrometry (LC-MS) is an important analytical platform for metabolomics study. Peak alignment of metabolomics dataset is one of the keys for a successful metabolomics study. In this work, a MS/MS-based peak alignment method for LC-MS metabolomics data was developed. A rigorous strategy for screening endogenous reference variables was proposed. Firstly, candidate endogenous reference variables were selected based on MS, MS/MS and retention time in all samples. Multiple robust endogenous reference variables were obtained through further evaluation and confirmation. Then retention time of each metabolite feature was corrected by local linear regression using the four nearest neighbor robust reference variables. Finally, peak alignment was carried out based on corrected retention time, MS and MS/MS. Comparing with the other two peak alignment methods, the developed method showed a good performance and was suitable for metabolomics data with larger retention time drift. Our approach provides a simple and robust alignment method which is reliable to align LC-MS metabolomics dataset.

Fault analysis is a very powerful technique to break cryptographic implementations. In particular, bit-level fault analysis (BLFA), where faults are injected by flipping one or a few isolated bits, are among the most efficient of the lot. BLFA requires both precise fault injection capabilities and sophisticated key extraction skills. Algebraic fault analysis (AFA) is a good analysis technique for BLFA. Compared with differential fault analysis (DFA), AFA relies on the automation from machine solvers. Since it fully utilizes the leakages along propagation paths, it can extract the whole key when there is only one or a few bits infected, and when the injection is into the much deeper rounds. In practice, it is very difficult to inject precise bit-level faults and expensive equipments are indeed required. However, if the underlying cryptographic hardware is maliciously modified, BLFA can be easily achieved. This recent security threat is popularly known as Hardware trojan horse (HTH). HTH is a by-product of much popular and economically necessary outsourcing trend in semiconductors. A well designed HTH can precisely inject any type of faults to enable AFA and bypass detections, by having low cost and with low activation rate. Accepted version

HIGHT is a lightweight block cipher which has been adopted as a standard block cipher. In this paper, we present a bit-level algebraic fault analysis (AFA) of HIGHT, where the faults are perturbed by a stealthy HT. The fault model in our attack assumes that the adversary is able to insert a HT that flips a specific bit of a certain intermediate word of the cipher once the HT is activated. The HT is realized by merely 4 registers and with an extremely low activation rate of about 0.000025. We show that the optimal location for inserting the designed HT can be efficiently determined by AFA in advance. Finally, a method is proposed to represent the cipher and the injected faults with a merged set of algebraic equations and the master key can be recovered by solving the merged equation system with an SAT solver. Our attack, which fully recovers the secret master key of the cipher in 12572.26 seconds, requires three times of activation on the designed HT. To the best of our knowledge, this is the first Trojan attack on HIGHT.

In this study, a novel and efficient fuzzy logic control (FLC) -based local coordinated ramp metering strategy is studied for networked freeway traffic control. Local traffic measurements are exchanged among neighbouring controllers. Based on both local and exchanged traffic measurement, the FLC based coordinated decision-making algorithms determine the reference mainstream densities, which are consequently tracked by local controllers using feedback control-based strategy. The parameters of the FLC algorithm are adjusted by a simple and efficient simultaneous perturbation stochastic approximation based parameter learning algorithm, which finds the optimal coordinated decision-making policies without interruption to normal freeway operations. Due to the limited communication among neighbouring controllers, communication cost is reduced compared with existing centralised control-based strategies. Furthermore, the structure of the proposed strategy is simple without involvement of complex model-based calculation. Case studies show the potential of the proposed strategy for coordinated freeway ramp metering problems with significantly improved system efficiency. In particular, using the proposed local coordinated ramp metering strategy, the system cost function is reduced by over 48% compared with no control case, and by over 18% compared with uncoordinated feedback control-based ramp metering case. The queue volumes at the on-ramp links are well balanced both temporally and spatially.

Lung cancer is currently the leading cause of cancer-related mortality worldwide. It is, therefore, important to enhance understanding and add a new auxiliary detection tool of lung cancer. In this work, serum metabolic characteristics of lung cancer were investigated with a non-targeted metabolomics method. The metabolic profiling of 23 patients with lung cancer and 23 healthy controls were analyzed using ultra high performance liquid chromatography/quadrupole time of flight mass spectrometry (UPLC/Q-TOF MS). Partial least squares discriminant analysis (PLS-DA) model of the metabolic data allowed the clear separation of the lung cancer patients from the healthy controls. In total, 27 differential metabolites were identified, which were mostly related to the perturbation of lipid metabolism, including choline, free fatty acids, lysophosphatidylcholines, etc. Choline and linoleic acid were defined as one combinational biomarker using binary logistic regression, which was supported by the validation with a smaller sample-set (9 patients and 9 healthy controls). These findings show that LC/MS-based serum metabolic profiling has potential application in complementary identification of lung cancer patients, and could be a powerful tool for cancer research.

The voltage-biased current-voltage (I–V) characteristics of intrinsic Josephson junctions (IJJs), which are fabricated with misaligned high temperature superconducting Tl2Ba2CaCu2O8 (Tl-2212) thin film, are investigated experimentally. Three characteristic regions in the I–V curve are observed at 47 K. In the low voltage part, the current firstly increases and then decreases slowly with increasing the biased voltage, which is shown as a bump. In the next region, the current slightly increases with increasing the biased voltage until a sudden decrease of the current appears. Thereafter, branch structure forms with increasing the voltage on the I–V characteristic. The influence of the self-heating on the I–V characteristics is investigated and the temperature dependence of the I–V characteristics is measured to explore these characteristics in detail.

We report the circuit simulations and experiments of millimeter-wave radiation from a high temperature superconducting (HTS) bicrystal Josephson junction (BJJ) array. To study the effects of junction characteristic parameters on radiation properties, new radiation circuit models are proposed in this paper. The series resistively and capacitively shunted junction (RCSJ) models are packaged into a Josephson junction array (JJA) model in the simulation. The current-voltage characteristics (IVCs) curve and radiation peaks are simulated and analyzed by circuit models, which are also observed from the experiment at liquid nitrogen temperature. The experimental radiation linewidth and power are in good agreement with simulated results. The presented circuit models clearly demonstrate that the inconsistency of the JJA will cause a broad linewidth and a low detected power. The junction radiation properties are also investigated at the optimal situation by circuit simulation. The results further confirm that the consistent JJA characteristic parameters can successfully narrow the radiation linewidth and increase the power of junction radiation.

TlBa2Ca2Cu3O9 (Tl-1223) films have promising applications due to their high critical temperature and strong magnetic flux pinning. Nevertheless, the preparation of pure phase Tl-1223 film is still a challenge. We successfully fabricate Tl-1223 thin films on LaAlO3 (001) substrates using dc magnetic sputtering and a post annealing two-step method in argon atmosphere. The crystallization temperature of Tl-1223 films in argon is reduced by 100°C compared to that in oxygen. This greatly reduces the volatilization of Tl and improves the surface morphology of films. The lower annealing temperature can effectively improve the repeatability of the Tl-1223 film preparation. In addition, pure Tl-1223 phase can be obtained in a broad temperature zone, from 790°C to 830°C. In our study, the films show homogenous and dense surface morphology using the presented method. The best critical temperature of Tl-1223 films is characterized to be 110 K, and the critical current J c (77 K, 0 T) is up to 2.13 × 106 A/cm2.

Sphingolipids are a family of bioactive molecules with high structural diversity and complexity. They not only serve as integral components of cellular membrane, but also play pivotal roles in signaling and other cellular events. It is desirable for the development of sensitive, robust and structural-specific analytical approaches enabling rapid determination of as many sphingolipid species as possible. Herein we present an analytical method for large-scaled profiling of sphigolipids in human serum, which consisted of an improved extraction protocol using tert -butyl methyl ether combined with mild alkaline hydrolysis, and an ultra high performance reversed-phase liquid chromatography-dynamic multiple reaction monitoring-mass spectrometric (RPLC-dynamic MRM-MS) method. In total 84 endogenous sphingolipid species covering six subcategories (i.e. free sphingoid base, dihydroceramide, ceramide, hexosylceramide, lactosylceramide, and sphingomyelin), were separated and quantified in a single run within 10 min. A broad linear range over 2.5–4 orders of magnitude ( r 2 > 0.99), a limit of detection of 0.01–0.17 pmol/mL, and a limit of quantitation of 0.02–0.42 pmol/mL were obtained for each subcategory. Average recovery of each subcategory was within 85.6–95.6%. Median values of coefficient of variation (CV) of all detected 84 sphingolipids were 3.9% and 6.8% for intraday and interday precision, respectively. This method was exemplarily applied in a study regarding dysregulated sphingolipid homeostasis in hepatocellular carcinoma. The establishment of this method provides a useful tool for serum-based high throughput screening of sphingolipid biomarkers and mechanism investigation of sphingolipid metabolic regulation in human disease.

A common challenge for scientists working with animal tissue or human biopsy samples is the limitation of material and consequently, the difficulty to perform comprehensive metabolic profiling within one experiment. Here, we present a novel approach to simultaneously perform targeted and non-targeted metabolomics as well as lipidomics from one small piece of liver or muscle tissue by ultra-high performance liquid chromatography/mass spectrometry (UHPLC/MS) following a methyl tert-butyl ether (MTBE)-based extraction. Equal relative amounts of the resulting polar and non-polar fractions were pooled, evaporated and reconstituted in the appropriate solvent for UHPLC/MS analysis. This mix was comparable or superior in yield and reproducibility to a standard 80% methanol extraction for the profiling of polar and lipophilic metabolites (free carnitine, acylcarnitines and FFA). The mix was also suitable for non-targeted metabolomics, an easy measure to increase the metabolite coverage by 30% relative to using the polar fraction alone. Lipidomics was performed from an aliquot of the non-polar fraction. This novel strategy could successfully be applied to one mouse soleus muscle with a dry weight of merely 2.5 mg. By enabling a simultaneous profiling of lipids and metabolites with mixed polarity while saving material for molecular, biochemical or histological analyses, our approach may open up new perspectives toward a comprehensive investigation of small, valuable tissue samples.

BACKGROUND Metabolomics is a powerful tool that is increasingly used in clinical research. Although excellent sample quality is essential, it can easily be compromised by undetected preanalytical errors. We set out to identify critical preanalytical steps and biomarkers that reflect preanalytical inaccuracies. METHODS We systematically investigated the effects of preanalytical variables (blood collection tubes, hemolysis, temperature and time before further processing, and number of freeze–thaw cycles) on metabolomics studies of clinical blood and plasma samples using a nontargeted LC-MS approach. RESULTS Serum and heparinate blood collection tubes led to chemical noise in the mass spectra. Distinct, significant changes of 64 features in the EDTA-plasma metabolome were detected when blood was exposed to room temperature for 2, 4, 8, and 24 h. The resulting pattern was characterized by increases in hypoxanthine and sphingosine 1-phosphate (800% and 380%, respectively, at 2 h). In contrast, the plasma metabolome was stable for up to 4 h when EDTA blood samples were immediately placed in iced water. Hemolysis also caused numerous changes in the metabolic profile. Unexpectedly, up to 4 freeze–thaw cycles only slightly changed the EDTA-plasma metabolome, but increased the individual variability. CONCLUSIONS Nontargeted metabolomics investigations led to the following recommendations for the preanalytical phase: test the blood collection tubes, avoid hemolysis, place whole blood immediately in ice water, use EDTA plasma, and preferably use nonrefrozen biobank samples. To exclude outliers due to preanalytical errors, inspect the biomarker signal intensities reflecting systematic as well as accidental and preanalytical inaccuracies before processing the bioinformatics data.

The side-channel cube attack (SCCA) is a powerful cryptanalysis technique that combines the side-channel and cube attack. This paper proposes several advanced techniques to improve the Hamming weight-based SCCA (HW-SCCA) on the block cipher PRESENT. The new techniques utilize non-linear equations and an iterative scheme to extract more information from leakage. The new attacks need only 2^8^.^9^5 chosen plaintexts to recover 72 key bits of PRESENT-80 and 2^9^.^7^8 chosen plaintexts to recover 121 key bits of PRESENT-128. To the best of our knowledge, these are the most efficient SCCAs on PRESENT-80/128. To show the feasibility of the proposed techniques, real attacks have been conducted on PRESENT on an 8-bit microcontroller, which are the first SCCAs on PRESENT on a real device. The proposed HW-SCCA can successfully break PRESENT implementations even if they have some countermeasures such as random delay and masking.

In this study, the problem of optimal freeway local ramp metering is address by using fuzzy logic control (FLC)-based ramp metering. The objective of optimal freeway local ramp metering is to minimise a weighted total-time spent-(WTTS)-based cost function, which measures the performance of freeway local ramp metering in terms of the WTTS by vehicles on both the freeway mainstream and on-ramp link. A simple and efficient local ramp metering algorithm based on Takagi-Sugeno type FLC algorithm is proposed. The input membership functions of the FLC controller are predefined, and human expert knowledge on freeway traffic flow behaviours is utilised to reduce the size of fuzzy rule base. The consequent parameters are fine-tuned by particle swarm optimisation and microscopic traffic simulations. Simulation studies with PARAMICS traffic simulation platform show the potential of the proposed approach in obtaining the optimal freeway local ramp metering strategies to strike a balance between traffic conditions on the mainstream and the on-ramp link.

High temperature superconducting (HTS) Josephson junction arrays (JJAs) fabricated on bicrystal substrate were embedded in a Fabry–Perot (F–P) resonator. We detected the radiation from the JJAs at about 74.08 GHz. By investigating the Current–Voltage (I–V) characteristics of the JJAs, the influence of the substrate on height of the Shapiro steps was studied. The result showed that the JJAs located at different positions of the substrate had different coupling strength. Also, the influence of the substrate was explored by presenting the comparison of radiation at different frequencies. Electromagnetic simulation was used to explain the experiment results.

In a non-hypothesis driven metabolomics approach plasma samples collected at six different time points (before, during and after an exercise bout) were analyzed by gas chromatography-time of flight mass spectrometry (GC-TOF MS). Since independent component analysis (ICA) does not need a priori information on the investigated process and moreover can separate statistically independent source signals with non-Gaussian distribution, we aimed to elucidate the analytical power of ICA for the metabolic pattern analysis and the identification of key metabolites in this exercise study. A novel approach based on descriptive statistics was established to optimize ICA model. In the GC-TOF MS data set the number of principal components after whitening and the number of independent components of ICA were optimized and systematically selected by descriptive statistics. The elucidated dominating independent components were involved in fuel metabolism, representing one of the most affected metabolic changes occurring in exercising humans. Conclusive time dependent physiological changes of the metabolic pattern under exercise conditions were detected. We conclude that after optimization ICA can successfully elucidate key metabolite pattern as well as characteristic metabolites in metabolic processes thereby simplifying the explanation of complex biological processes. Moreover, ICA is capable to study time series in complex experiments with multi-levels and multi-factors.

In this paper, we present a wideband mobile antenna with two modes that can produce dual-polarized omni-directional radiation patterns using a segmented loop element. The two different modes are designed to operate at neighbouring frequencies to realize the wideband property. The segmented loop itself induces one mode and radiates H-polarized radiation pattern. In the meantime, the loop element excites the ground plane which operates as a radiator and radiates V-polarized radiation pattern. The results confirm that the proposed antenna covers the WiMAX and WLAN bands with a 10-dB impedance bandwidth of 0.74 GHz (2.12 GHz – 2.86 GHz). The mobile antenna achieves the average realized gain and radiation efficiency of 2.9 dBi and 84% over the entire operating bands, respectively.

Emerging evidence has linked the gut microbiome to human obesity. We performed a metagenome-wide association study and serum metabolomics profiling in a cohort of lean and obese, young, Chinese individuals. We identified obesity-associated gut microbial species linked to changes in circulating metabolites. The abundance of Bacteroides thetaiotaomicron, a glutamate-fermenting commensal, was markedly decreased in obese individuals and was inversely correlated with serum glutamate concentration. Consistently, gavage with B. thetaiotaomicron reduced plasma glutamate concentration and alleviated diet-induced body-weight gain and adiposity in mice. Furthermore, weight-loss intervention by bariatric surgery partially reversed obesity-associated microbial and metabolic alterations in obese individuals, including the decreased abundance of B. thetaiotaomicron and the elevated serum glutamate concentration. Our findings identify previously unknown links between intestinal microbiota alterations, circulating amino acids and obesity, suggesting that it may be possible to intervene in obesity by targeting the gut microbiota.

Metabolomics studies of human plasma demonstrate a correlation of lower plasma lysophosphatidylcholines (LPC) concentrations with insulin resistance, obesity, and inflammation. This relationship is not unraveled on a molecular level. Here we investigated the effects of the abundant LPC(16:0) and LPC(18:1) on human skeletal muscle cells differentiated to myotubes. Transcriptome analysis of human myotubes treated with 10μM LPC for 24h revealed enrichment of up-regulated peroxisome proliferator-activated receptor (PPAR) target transcripts, including ANGPTL4, PDK4, PLIN2, and CPT1A. The increase in both PDK4 and ANGPTL4 RNA expression was abolished in the presence of either PPARδ antagonist GSK0660 or GSK3787. The induction of PDK4 by LPCs was blocked with siRNA against PPARD. The activation of PPARδ transcriptional activity by LPC was shown as PPARδ-dependent luciferase reporter gene expression and enhanced DNA binding of the PPARδ/RXR dimer. On a functional level, further results show that the LPC-mediated activation of PPARδ can reduce fatty acid-induced inflammation and ER stress in human skeletal muscle cells. The protective effect of LPC was prevented in the presence of the PPARδ antagonist GSK0660. Taking together, LPCs can activate PPARδ, which is consistent with the association of high plasma LPC levels and PPARδ-dependent anti-diabetic and anti-inflammatory effects.

Major depressive disorder (MDD) is a grave debilitating mental disease with a high incidence and severely impairs quality of life. Therefore, its physiopathological basis study and diagnostic biomarker discovery are extremely valuable. In this study, a non-targeted lipidomics strategy using ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was performed to reveal differential lipids between MDD (n = 60) and healthy controls (HCs, n = 60). Validation of changed lipid species was performed in an independent batch including 75 MDD and 52 HC using the same lipidomic method. Pronouncedly changed lipid species in MDD were discovered, which mainly were lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), 1-O-alkyl-2-acyl-PE (PE O), 1-O-alkyl-2-acyl-PC (PC O), sphingomyelin (SM), diacylglycerol (DG), and triacylglycerol (TG). Among these lipid species, LPC, LPE, PC, PE, PI, TG, etc. remarkably increased in MDD and showed pronounced positive relationships with depression severity, while 1-O-alkyl-2-acyl-PE and SM with odd summed carbon number significantly decreased in MDD and demonstrated negative relationships with depression severity. A combinational lipid panel including LPE 20:4, PC 34:1, PI 40:4, SM 39:1, 2, and TG 44:2 was defined as potential diagnostic biomarker with a good sensitivity and specificity for distinguishing MDD from HCs. Our study brings insights into lipid metabolism disorder in MDD and provides a specific potential biomarker for MDD diagnose.

Roux-en-Y gastric bypass (RYGB) is one of the most effective treatments for long-term weight loss and diabetes remission; however, the mechanisms underlying these changes are not clearly understood. In this study, the serum metabolic profiles of 23 remission and 12 nonremission patients with type 2 diabetes mellitus (T2DM) were measured at baseline, 6- and 12-months after RYGB. A metabolomics analysis was performed based on ultra-performance liquid chromatography-mass spectrometry. Clinical improvements in insulin sensitivity, energy metabolism, and inflammation were related to metabolic alterations of free fatty acids (FFAs), acylcarnitines, amino acids, bile acids, and lipids species. Differential metabolic profiles were observed between the two T2DM subgroups, and patients with severity fat accumulation and oxidation stress may be more suitable for RYGB. Baseline levels of tryptophan, bilirubin, and indoxyl sulfate measured prior to surgery as well as levels of FFA 16:0, FFA 18:3, FFA 17:2, and hippuric acid measured at 6 months after surgery best predicted the suitability and efficacy of RYGB for patients with T2DM. These metabolites represent potential biomarkers that may be clinically helpful in individualized treatment for T2DM patients by RYGB.

Circulating trimethylamine N-Oxide (TMAO) levels predict cardiovascular disease (CVD), possibly by impacting on cholesterol metabolism and oxidative stress. Because hepatic TMAO production is regulated by insulin signalling and it is unclear whether and to what extent circulating TMAO levels associate with CVD risk, independently of insulin resistance and its important determinants fatty liver and visceral obesity, we have now addressed this question in 220 subjects who participated in the Tübingen Lifestyle Intervention Program. Visceral fat mass (r = 0.40, p 20%). We provide novel information that increased serum TMAO levels associate with increased cIMT, independently of established cardiovascular risk markers, including insulin resistance, visceral obesity and fatty liver. Furthermore, the decrease of cIMT during a lifestyle intervention may be related to the decrease of TMAO levels.

Algebraic fault analysis (AFA), which combines algebraic cryptanalysis with fault attacks, has represented serious threats to the security of lightweight block ciphers. Inspired by an earlier framework for the analysis of side-channel attacks presented at EUROCRYPT 2009, a new generic framework is proposed to analyze and evaluate algebraic fault attacks on lightweight block ciphers. We interpret AFA at three levels: 1) the target; 2) the adversary; and 3) the evaluator. We describe the capability of an adversary in four parts: 1) the fault injector; 2) the fault model describer; 3) the cipher describer; and 4) the machine solver. A formal fault model is provided to cover most of current fault attacks. Different strategies of building optimal equation set are also provided to accelerate the solving process. At the evaluator level, we consider the approximate information metric and the actual security metric. These metrics can be used to guide adversaries, cipher designers, and industrial engineers. To verify the feasibility of the proposed framework, we make a comprehensive study of AFA on an ultra-lightweight block cipher called LBlock. Three scenarios are exploited, which include injecting a fault to encryption, to key scheduling, or modifying the round number or counter. Our best results show that a single fault injection is enough to recover the master key of LBlock within the affordable complexity in each scenario. To verify the generic feature of the proposed framework, we apply AFA to three other block ciphers, i.e., Data Encryption Standard, PRESENT, and Twofish. The results demonstrate that our framework can be used for different ciphers with different structures.

We measure the current–voltage (I–V) curves of intrinsic Josephson junctions (IJJs) in misaligned Tl2Ba2CaCu2O8 thin films embedded in a Fabry–Perot (F-P) resonator at liquid nitrogen temperature. Regarding the substrate as a dielectric resonator, electromagnetic coupling between the intrinsic Josephson junctions is improved. By adjusting the location of the substrate in the F-P resonator, the critical current of the IJJs under microwave irradiation (75.6 GHz) is suppressed almost to zero. Two pairs of symmetrical radiation (75.6 GHz) peaks are detected. Possible explanations for this experimental result are discussed.

A new circuit model for designing and manufacturing an S-band low noise amplifier (LNA) with the software, Advanced Design System (ADS), is introduced in this paper. The proposed model involves shunted impedance at the grid to achieve a stable LNA without measuring the S-parameters of transistors at low temperatures. The LNA was measured over the operation band of 2.2–2.3 GHz, which has input and output standing wave ratios below 1.2. The noise figure of the manufactured LNA was about 0.2 dB and the gain was above 22 dB, which indicated that our LNA worked well at 77 K.

A synthesized design method is proposed to design microstrip band-pass filters. The impact of the box structure to the filter performance is considered besides the structure of microstrip. An X-band high temperature superconducting (HTS) microstrip filter for deep space network is designed using this method. The six-pole microstrip band-pass filter at frequency of 9500 ± 500 MHz is realized using TBCCO HTS thin film grown on 0.5 mm thick LaAlO3 substrate. The filter shows very high rejection of 90 dB in the stopband and extremely low loss less than 0.2 dB. The measured results are close to the simulated results without any post-production tuning.

This paper represents the development of a high temperature superconducting (HTS) filter, the highest operating temperature of which is up to 93 K. The filter is designed for S band with 4% fractional bandwidth and fabricated using thallium-barium-calcium-copper oxide (Tl2Ba2CaCu2O8) thin films. At 93 K, the measurements of the filter show that the insertion loss in the passband is less than 0.22 dB, the return loss is better than 20 dB, and the out-of-band rejection is more than 80 dB. The analysis on the characteristics of the filter operating at different temperatures shows that the filter can work well at temperatures around 90 K. The temperature of 93 K is the highest among the previous reports for HTS filters. The result reported in this paper is significant for HTS filters to be used in the field of microwave communication requiring high sensitivity.

Xindi soft capsule is a traditional Chinese medicine preparation which consists of sea buckthorn flavonoids and sea buckthorn berry oil. In this study, a urinary metabonomics method based on the ultra-performance liquid chromatography combined with quadrupole time-of-flight tandem mass spectrometry (UPLC Q-TOF MS) was used to evaluate the efficacy and study the mechanism of traditional Chinese medicine preparation to blood stasis. With pattern recognition analysis (principal component analysis and partial least squares-discriminate analysis) of urinary metabolites, a clear separation of acute blood stasis model group and healthy control group was achieved, the dose groups were located between acute blood stasis model group and healthy control group showing a tendency of recovering to healthy control group, high dose and middle dose were more effective than low dose. Some significantly changed metabolites like cholic acid, phenylalanine and kynurenic acid have been found and identified and used to explain the mechanism. The work shows that the metabonomics method is a valuable tool in the research mechanism of traditional Chinese medicine.

In this study we developed and optimized a column-switching high-performance liquid chromatographic (HPLC) system for the complementary analysis of polar and apolar compounds in complex samples. The polar compounds are separated on a hydrophilic interaction chromatographic (HILIC) column; the part of the sample non-retained on HILIC is transferred into and separated on a reversed-phase (RP) column through an interface, thus preventing the loss of analytes eluting at dead time in common single-column mode. The signals are in turn recorded in the same chromatogram either by a UV or by a mass spectrometric detector. Applying a mixture of 25 standard compounds (12 hydrophilic and 13 hydrophobic) the system proves to be reliable, robust and easy-operating. The investigation of urine revealed an increase in the detected metabolite ion masses compared to the single-column HILIC-electrospray ionization (ESI)-MS analysis. Utilizing online the complementary selectivity of HILIC and RPLC in a fully automatic mode, this approach holds out the prospect to enlarge the number of detectable compounds in non-targeted "-omics" studies and sophisticated target-driven approaches by a single injection.

Abnormal savda is a special symptom in Uigur medicine. The understanding of its metabolic origins is of great importance for the subsequent treatment. Here, a metabonomic study of this symptom was carried out using LC-MS based human serum metabolic profiling. Orthogonal signal correction partial least-squares discriminant analysis (OSC-PLS-DA) was used for the classification and prediction of abnormal savda. Potential biomarkers from metabonomics were also identified for a metabolic understanding of abnormal savda. As a result, our OSC-PLS-DA model had a satisfactory ability for separation and prediction of abnormal savda. The potential biomarkers including bilirubin, bile acids, tryptophan, phenylalanine and lyso-phosphatidylcholines indicated that abnormal savda could be related to some abnormal metabolisms within the body, including energy metabolism, absorption of nutrition, metabolism of lecithin on cell membrane, etc. To the best of our knowledge, this is the first study of abnormal savda based on serum metabolic profiling. The LC/MS-based metabonomic platform could be a powerful tool for the classification of symptoms and for the development of this traditional medicine into an evidence-based one.

A high-temperature superconducting (HTS) filter subsystem consisting of a 10-pole HTS filter with group delay self-equalization, a cryogenic low noise amplifier (LNA), and a cooling device is presented in this paper. The HTS filter has a 0.51% fractional bandwidth at 1955 MHz, simulated in Sonnet, and is fabricated using double-sided Tl2Ba2CaCu2O8 films on 0.5 mm thick LaAlO3 substrate. Measured responses show that the minimum insertion loss of the filter is 0.16 dB, and the out-of-band rejection is better than 75 dB. The slope is 27 dB MHz−1 at the low band edge and 22 dB MHz−1 at the upper band edge. The HTS filter subsystem has a gain of 19.3 dB and a noise figure (NF) of 0.8 dB. Furthermore, the phase distortion of HTS filters is considered, and an efficient design approach for self-equalized HTS filters is proposed.