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Background: Circular RNAs (circRNAs) exhibit unique patterns of expression and high levels of stability in patient plasma samples such that they represent ideal non-invasive biomarkers that can be leveraged to detect a wide array of diseases including endometrial cancer (EC). This study was designed to identify circRNAs with potential diagnostic utility in serum samples from EC patients while also evaluating the utility of macrophage migration inhibitory factor (MIF) as a biomarker when screening for this form of cancer in the clinic. Methods: Levels of circEPSTI1 and MIF were assessed in the plasma of EC patients and healthy subjects (n=186 each) through qPCR and ELISAs. The diagnostic utility of these biomarkers was assessed with receiver operating characteristic curve (ROC) analyses. Results: Relative to healthy subjects, EC patient serum contained significantly elevated circEPSTI1 and MIF. An association was noted between circEPSTI1 expression in stages, histologic grade, and residual tumor. ROC curves confirmed that serum circEPSTI1 levels distinguished between controls and patients with EC with an Area of 0.835 and serum MIF levels distinguished between controls and patients with EC with an Area of 0.6646. When instead diagnosing patients based on the combination of MIF and circEPSTI1, the Area further rose to 0.8604. Conclusion: Assessing the combination of circEPSTI1 and MIF may be a viable approach to reliably diagnosing EC. [ABSTRACT FROM AUTHOR]

Staphylococcus pseudintermedius can cause severe infections of the skin, ear and other tissues in dogs and cats. Methicillin-resistant S. pseudintermedius (MRSP) has recently become more prevalent, posing a severe threat to companion animals and public health. Therefore, rapid and accurate diagnosis of S. pseudintermedius and MRSP infections in dogs and cats is essential for timely controlling infections. The development of CRISPR/Cas technology offers an innovative solution for rapid diagnosis. Here, we established an assay combining recombinant polymerase amplification (RPA) and CRISPR/Cas12a. By separately detecting the spsJ gene, the specific gene of S. pseudintermedius, and the mecA gene, the methicillin resistance gene, this method allows for the direct detection of methicillin-susceptible S. pseudintermedius (MSSP) and MRSP in clinical samples at 37 °C for a total of 40 min, The results can be directly visualized by the naked eye under blue light. The limits of detection of the RPA-CRISPR/Cas12a assay were 103 copies per reaction for the spsJ gene and 104 copies per reaction for the mecA gene. The RPA-CRISPR/Cas12a detection successfully detected and differentiated clinical isolates of MSSP and MRSP without cross-reactivity with other tested bacteria species. The evaluation of the detection performance of RPA-CRISPR/Cas12a with 47 clinical samples (without culture) from dogs and cats showed that the results of detection were 100% consistent with those of clinical culture and colony sequencing, which was more sensitive than PCR. RPA-CRISPR/Cas12a assay can quickly and sensitively detect S. pseudintermedius and MRSP in clinical samples without expensive instruments, making it suitable for small veterinary clinics. [ABSTRACT FROM AUTHOR]

BMS-932481 was designed to modulate ɣ-secretase activity to produce shorter and less amyloidogenic peptides, potentially averting liabilities associated with complete enzymatic inhibition. Although it demonstrated the intended pharmacology in the clinic, BMS-932481 unexpectedly caused drug-induced liver injury (DILI) in a multiple ascending dose study characterized by dose- and exposure-dependence, delayed onset manifestation, and a high incidence of hepatocellular damage. Retrospective studies investigating the disposition and probable mechanisms of toxicity of BMS-932481 are presented here. These included a mass balance study in bile-duct-cannulated rats and a metabolite profiling study in human hepatocytes, which together demonstrated oxidative metabolism followed by biliary elimination as the primary means of disposition. Additionally, minimal protein covalent binding in hepatocytes and lack of bioactivation products excluded reactive metabolite formation as a probable toxicological mechanism. However, BMS-932481 and 3 major oxidative metabolites were found to inhibit the bile salt export pump (BSEP) and multidrug resistance protein 4 (MRP4) in vitro. Considering human plasma concentrations, the IC50 values against these efflux transporters were clinically meaningful, particularly in the high dose cohort. Active uptake into human hepatocytes in vitro suggested the potential for hepatic levels of BMS-932481 to be elevated further above plasma concentrations, enhancing DILI risk. Conversely, measures of mitochondrial functional decline in hepatocytes treated with BMS-932481 were minimal or modest, suggesting limited contributions to DILI. Collectively, these findings suggested that repeat administration of BMS-932481 likely resulted in high hepatic concentrations of BMS-932481 and its metabolites, which disrupted bile acid transport via BSEP and MRP4, elevating serum biomarkers of liver injury. [ABSTRACT FROM AUTHOR]

During yeast dough fermentation, such as the high-sucrose bread-making process, the yeast cells are subjected to considerable osmotic stress, resulting in poor outcomes. Invertase is important for catalyzing the irreversible hydrolysis of sucrose to free glucose and fructose, and decreasing the catalytic activity of the invertase may reduce the glucose osmotic stress on the yeast. In this study, we performed structural design and site-directed mutagenesis (SDM) on the Saccharomyces cerevisiae invertase (ScInV) in an Escherichia coli expression system to study the catalytic activity of ScInV mutants in vitro. In addition, we generated the same mutation sites in the yeast endogenous genome and tested their invertase activity in yeast and dough fermentation ability. Our results indicated that appropriately reduced invertase activity of yeast ScInV can enhance dough fermentation activity under high-sucrose conditions by 52%. Our systems have greatly accelerated the engineering of yeast endogenous enzymes both in vitro and in yeast, and shed light on future metabolic engineering of yeast. [ABSTRACT FROM AUTHOR]

This study was designed to explore the functional circuitry of the adult zebrafish cerebellum, focusing on its Purkinje cells and using whole‐cell patch recordings and single cell labeling in slice preparations. Following physiological characterizations, the recorded single cells were labeled for morphological identification. It was found that the zebrafish Purkinje cells are surprisingly diverse. Based on their physiology and morphology, they can be classified into at least three subtypes: Type I, a narrow spike cell, which fires only narrow Na+ spikes (<3 ms in duration), and has a single primary dendrite with an arbor restricted to the distal molecular layer; Type II, a broad spike cell, which fires broad Ca2+ spikes (5–7 ms in duration) and has a primary dendrite with limited branching in the inner molecular layer and then further radiates throughout the molecular layer; and Type III, a very broad spike cell, which fires very broad Ca2+ spikes (≥10 ms in duration) and has a dense proximal dendritic arbor that is either restricted to the inner molecular layer (Type IIIa), or radiates throughout the entire molecular layer (Type IIIb). The graded paired‐pulse facilitation of these Purkinje cells' responses to parallel fiber activations and the all‐or‐none, paired‐pulse depression of climbing fiber activation are largely similar to those reported for mammals. The labeled axon terminals of these Purkinje cells end locally, as reported for larval zebrafish. The present study provides evidence that the corresponding functional circuitry and information processing differ from what has been well‐established in the mammalian cerebellum. [ABSTRACT FROM AUTHOR]

The aim of this study was to apply a strategy to express a recombinant CLP peptide and explore its application as a product derived from natural compounds. The amphiphilic CLP peptide was hybridized from three parent peptides (CM4, LL37, and TP5) and was considered to have potent endotoxin-neutralizing activity with minimal cytotoxic and hemolytic activity. To achieve high secretion expression, an expression vector of pPICZαA-HSA-CLP was constructed by the golden gate cloning strategy before being transformed into Pichia pastoris and integrated into the genome. The recombinant CLP was purified through the Ni-NTA affinity chromatography and analyzed by SDS-PAGE and mass spectrometry. The Limulus amebocyte lysate (LAL) test exhibited that the hybrid peptide CLP inhibited lipopolysaccharides (LPS) in a dose-dependent manner and was significantly (p < 0.05) more efficient compared to the parent peptides. In addition, it essentially diminished (p < 0.05) the levels of nitric oxide and pro-inflammatory cytokines (including TNF-α, IL6, and IL-1β) in LPS-induced mouse RAW264.7 macrophages. As an attendant to the control and the parental peptide LL37, the number of LPS-induced apoptotic cells was diminished compared to the control parental peptide LL37 (p < 0.05) with the treatment of CLP. Consequently, we concluded that the hybrid peptide CLP might be used as a therapeutic agent. [ABSTRACT FROM AUTHOR]

In this work, a simple method is proposed to simultaneously reduce the size and cross-polarization level (XPL) of quarter-wave microstrip antennas by reconstructing the magnetic currents along the radiation edges. A design example of five shorted elements is given with a comparison of the quarter-wave microstrip antennas at 1.88 GHz. Measured results show an over 64% size reduction and 17-dB cross-polarization suppression enhancement for the proposed scheme as compared with the conventional one. Moreover, the proposed scheme exhibits good broadside radiation patterns with a gain of 5.4 dBi and the half-power beamwidths of about 104° in the E-plane and 84° in the H-plane. [ABSTRACT FROM AUTHOR]

High-performance miniaturized antennas are one of the goals that have been pursued in the design of wireless communication systems for implantable medical devices. In this article, a 915 MHz novel-shape loop antenna conforming to the inner wall of the capsule is developed by comprehensively adopting meander and symmetrical structure patch, folding technique, and vector current reversal technique. Through electromagnetic simulation, testing, and experimentation, the antenna shows good characteristics such as small size, ultra-wideband, circular polarization, strong robustness, and safety. Specific performances include the following: 1) the size of the developed miniaturized loop conformal antenna is only 30.5 mm $\times $ 4.6 mm $\times $ 0.05 mm and the maximum gain is −21.5 dBi at 915 MHz, which solves the problem of low gain due to the small antenna radiation area; 2) the antenna has a 4.5 GHz ultra-wideband impedance matching bandwidth ($\vert S_{11}\vert < -10$ dB) from 0.5 to 5 GHz. Even if the parameters such as the implantation depth and the thickness of the capsule shell change, or there exists a wireless power transfer system, the antenna can still cover the required frequency band with strong robustness; and 3) the specific absorption rate (SAR) of human tissues radiated by the antenna is far lower than the safety limit in IEEE standards and ICNIRP guidelines. The experimental platform using pork to simulate human tissues was built for antenna performance testing and communication testing. The measurement results verified the good resonance performance, radiation characteristics, and omnidirectionality of the developed antenna. The antenna link loss model is also given, which has been used in wireless communication and localization. [ABSTRACT FROM AUTHOR]

This article studies differential rectangular laminated resonator antenna (LRA) theoretically and experimentally. A theoretical model is proposed to analyze the radiation characteristics of the differential rectangular LRA based on the waveguide excitation theory. Analytical expressions for the inner fields, modal coefficients, radiation fields, directivity, radiation efficiency, and gain are derived. For verification, a prototype of rectangular LRA differentially fed by L-probes is simulated, fabricated, and measured. Acceptable agreements among the calculated, simulated, and measured results are achieved. The theoretical analysis demonstrates that the differential operation can suppress the adjacent high-order modes near the dominant mode and results in low cross-polarization level and a more symmetric radiation pattern. The proposed theoretical model provides physical insight into the operating principle of rectangular LRA and facilitates the design of rectangular LRAs. [ABSTRACT FROM AUTHOR]

Dermatophytosis, an infectious disease caused by several fungi, can affect the hair, nails, and/or superficial layers of the skin and is of global significance. The most common dermatophytes in cats and dogs are Microsporum canis and Trichophyton mentagrophytes. Wood's lamp examination, microscopic identification, and fungal culture are the conventional clinical diagnostic methods, while PCR (Polymerase Chain Reaction) and qPCR (Quantitative PCR) are playing an increasingly important role in the identification of dermatophytes. However, none of these methods could be applied to point-of-care testing (POCT). The recent development of the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) based diagnostic platform promises a rapid, accurate, and portable diagnostic tool. In this paper, we present a Cas12a-fluorescence assay to detect and differentiate the main dermatophytes in clinical samples with high specificity and sensitivity. The Cas12a-based assay was performed with a combination of recombinase polymerase amplification (RPA). The results could be directly visualized by naked eyes under blue light, and all tested samples were consistent with fungal culture and sequencing results. Compared with traditional methods, the RPA-Cas12a-fluorescence assay requires less time (about 30 min) and less complicated equipment, and the visual changes can be clearly observed with naked eyes, which is suitable for on-site clinical diagnosis. [ABSTRACT FROM AUTHOR]

Nrf2-mediated oxidative stress is a promising target of exhaustive exercise-induced fatigue (EEIF). Trilobatin (TLB) is a naturally occurring food additive with antioxidant effect and Nrf2 activation potency. The present study aimed to investigate the effect of TLB on EEIF and elucidate its underlying mechanism. Our results showed that TLB exerted potent anti-EEIF effect, as reflected by the rope climbing test and exhaustive swimming test. Moreover, TLB also effectively reduced the levels of lactate, creatine kinase, and blood urea nitrogen, and increased liver glycogen and skeletal muscle glycogen in mice after EEIF insult. Additionally, TLB also balanced the redox status as evidenced by decreasing the generation of reactive oxygen species and improving the antioxidant enzyme activities including superoxide dismutase, catalase, and glutathione peroxidase, as well as the level of glutathione both in the tissue of muscle and myocardium. Furthermore, TLB promoted nuclear factor erythroid 2-related factor 2 (Nrf2) from the cytoplasm to the nucleus, and upregulated its downstream antioxidant response element (ARE) including quinone oxidoreductase-1 and heme oxygenase-1. Intriguingly, TLB also upregulated the GPx4 protein expression and reduced iron overload in mice after EEIF insult. Encouragingly, the beneficial effect of TLB on EEIF-induced oxidative stress and ferroptosis were substantially abolished in Nrf2-deficient mice. In conclusion, our findings demonstrate, for the first time, that TLB alleviates EEIF-induced oxidative stress through mediating Nrf2/ARE/ferroptosis axis. [ABSTRACT FROM AUTHOR]

In an effort to control the outbreak of the African Swine Fever Virus (ASFV), there is an urgent need to develop an effective method to prevent the pandemic, including vaccines and diagnostic methods. The major capsid protein of ASFV p72 (B646L), which forms a trimer with each monomer adopting a double jelly roll fold, is the main component of the virus particle and major antigen of ASFV. Thus, the p72 protein may be considered an antigen candidate for vaccine and diagnostic development. However, the development of ASFV p72 trimer for the industry application, including veterinary usage, faces unavoidable challenges: firstly, the low cost of the antigen production is required in vaccine and diagnostic application; and, secondly, whether produced antigen folds in its native conformation. Here, based on the information provided by the atomic structure of p72, we have successfully performed rational mutagenesis on p72 trimers and expressed it in Saccharomyces cerevisiae with high yields. The cryo-EM structure of recombinant expressed p72 trimer is determined at 4.18 Å in resolution. The correlation coefficient between this structure and the ASFV virus structure is 0.77, suggesting a highly similar fold of this trimer with the native protein on the virus particle. [ABSTRACT FROM AUTHOR]

This letter studies differential aperture-coupled rectangular laminated resonator antenna (LRA) theoretically and experimentally. A theoretical model is proposed to analyze the resonance and radiation characteristics of the differential aperture-coupled rectangular LRA based on mode matching method. Analytical expressions for the resonant frequencies, Q-factor, impedance bandwidth (BW), radiation fields, directivity, radiation efficiency and gain are first derived. For verification, three prototypes of rectangular LRA with different length-to-height ratios differentially fed by a coupling slot are simulated, fabricated, and measured. Acceptable agreements among the calculated, simulated, and measured results are achieved. The proposed theoretical model provides physical insight into the operating principle of aperture-coupled LRA, which can be applied to predict the performances of rectangular LRAs and to instruct the design of rectangular LRAs. [ABSTRACT FROM AUTHOR]

Compact grid array antennas (GAAs) with the gradient slow-wave structures are designed in this letter. The electrical lengths of slow-wave transmission lines (SW-TLs) with gradient structures are investigated based on the equivalent microwave network. By utilizing SW-TLs with exponential gradient structure on the long sides of GAAs, the proposed antenna achieves an area-reduction factor of 24.4%, with a measured 10 dB impedance bandwidth from 27.50 to 33.86 GHz and a maximum gain of 15.71 dBi. [ABSTRACT FROM AUTHOR]

A novel liquid crystal beam‐steerable antenna is presented. It is a conventional liquid crystal microstrip patch antenna with a bending slot in the middle of the H‐plane. Owing to the introduction of the bending slot, this antenna can work at even mode and odd mode within a frequency band. To obtain the resonant frequencies and radiation characteristics of the two modes, the method of characteristic mode analysis is utilised. It indicates that the resonant frequency of even mode is lower than that of odd mode. Therefore, by choosing liquid crystal as its substrate, this antenna can alter its operating modes by varying the permittivity of liquid crystal. Furthermore, beam steering can be realised since the radiation patterns of the two modes are divergent. An antenna prototype at Ka‐band has been designed, fabricated and measured. The measured results show that the maximum radiation direction can scan from −30° to −2° continuously at 26.5 GHz in the H‐plane. [ABSTRACT FROM AUTHOR]

A shorted patch antenna (SPA) has a major issue of high cross-polarized radiation in the H plane, which has greatly limited its applications. This article presents a simple technique to overcome this fundamental disadvantage of the SPA by creating and exploring the coupled TM0,1/2 mode. The resultant antenna is termed the cross-polarization suppressed SPA (XPS-SPA). A theoretical model is developed to provide physical insight into the reduction of cross-polarized radiation and to determine the optimal width for the coupled elements. Several types of SPAs were designed and fabricated to validate the analysis. Measured results show that the novel antenna not only achieved a reduction of 25 dB in the peak level of cross-polarized radiation but also an enhancement of 1.2 dB in the gain and miniaturization of 22% in the electrical size as compared with those of the conventional SPA. [ABSTRACT FROM AUTHOR]

This article presents the coupled shorted patch antennas (CSPAs), which exhibit dual-band operation of both broadside and conical radiation patterns and successfully overcome the major disadvantage of the large H-plane cross-polarization radiation of conventional shorted patch antennas (SPAs). The basic concept behind this breakthrough innovation is to create and explore the coupled TM0,1/2 modes. It will be shown that the CSPAs provide the horizontally polarized broadside radiation under the odd coupled TM0,1/2 mode for the low band and vertically polarized conical radiation patterns under the even coupled TM0,1/2 mode for the high band, respectively. The CSPAs have smaller resonant sizes when compared with those of the conventional SPAs for broadside radiation. The sum of the two resonant frequencies for the CSPAs is twice of that for the corresponding conventional SPAs based on a single microstrip. The ratio of two resonant frequencies depends on the odd and even mode impedances of the coupled microstrips. The calculated results are validated with the simulated and measured ones. [ABSTRACT FROM AUTHOR]

A novel fan-out wafer-level packaging (FOWLP) technology with double-sided redistribution layers (RDLs) and tall copper vertical interconnects is described. The design of a dual-polarized magnetoelectric (ME) dipole antenna based on this new packaging technology is presented. It is shown that the antenna with a size of $10\times10$ mm2 achieves good impedance matching and a stable radiation pattern over a wide bandwidth from 25 to 43 GHz, which can cover most of the millimeter-wave (mmWave) bands of the fifth-generation (5G) mobile networks in different countries. The measurement results demonstrate that the antenna is well suited for FOWLP technology and can be used for phased-array modules in 5G wireless communication systems. [ABSTRACT FROM AUTHOR]

African swine fever (ASF) is a serious contagious disease that causes fatal haemorrhagic fever in domestic and wild pigs, with high morbidity. It has caused devastating damage to the swine industry worldwide, necessitating the focus of attention on detection of the ASF pathogen, the African swine fever virus (ASFV). In order to overcome the disadvantages of conventional diagnostic methods (e.g. time-consuming, demanding and unintuitive), quick detection tools with higher sensitivity need to be explored. In this study, based on the conserved p72 gene sequence of ASFV, we combined the Cas12a-based assay with recombinase polymerase amplification (RPA) and a fluorophore-quencher (FQ)-labeled reporter assay for rapid and visible detection. Five crRNAs designed for Cas12a-based assay showed specificity with remarkable fluorescence intensity under visual inspection. Within 20 minutes, with an initial concentration of two copies of DNA, the assay can produce significant differences between experimental and negative groups, indicating the high sensitivity and rapidity of the method. Overall, the developed RPA-Cas12a-fluorescence assay provides a fast and visible tool for point-of-care ASFV detection with high sensitivity and specificity, which can be rapidly performed on-site under isothermal conditions, promising better control and prevention of ASF. [ABSTRACT FROM AUTHOR]

Saccharomyces cerevisiae is a widely used cell factory for the production of fuels and chemicals. However, as a non‐oleaginous yeast, S. cerevisiae has a limited production capacity for lipophilic compounds, such as β‐carotene. To increase its accumulation of β‐carotene, we engineered different lipid metabolic pathways in a β‐carotene producing strain and investigated the relationship between lipid components and the accumulation of β‐carotene. We found that overexpression of sterol ester synthesis genes ARE1 and ARE2 increased β‐carotene yield by 1.5‐fold. Deletion of phosphatidate phosphatase (PAP) genes (PAH1, DPP1, and LPP1) also increased β‐carotene yield by twofold. Combining these two strategies resulted in a 2.4‐fold improvement in β‐carotene production compared with the starting strain. These results demonstrated that regulating lipid metabolism pathways is important for β‐carotene accumulation in S. cerevisiae, and may also shed insights to the accumulation of other lipophilic compounds in yeast. [ABSTRACT FROM AUTHOR]

A new method to miniaturize patch antennas is presented by using coupled microstrip patches. A design example is given at 8.45 GHz. The resultant patch antenna has an electrical size of 0.146 × 0.146 × 0.04 λ03, which is about 60% area reduction with respect to a conventional patch antenna. The miniaturized patch antenna shows similar broadside radiation patterns and a lower cross-polarization level as compared with the conventional one. It exhibits a realized gain of 5.4 dBi with the half-power beamwidths of 107° in the E-plane and 87° in the H-plane, respectively. Both simulated and measured results demonstrate that the miniaturized patch antenna exhibits excellent impedance and radiation characteristics and is a promising candidate for highly integrated wireless systems. [ABSTRACT FROM AUTHOR]

In recent years, there has been great interest in millimeter-wave (mmwave) and terahertz (THz) technologies due to an increasing demand for ultrahigh data transfer rate. Two novel solutions, i.e., antenna on chip (AoC) and antenna in package (AiP), have been proposed for the development of highly integrated radio and radar systems [1]-[5]. To measure the antenna characteristics of AoC and AiP, a reliable probe-based mm-wave/THz antenna measurement setup became essential. Over the last 20 years, the world has witnessed the prosperous development of various mmwave/THz antenna measurement setups, most of which can be divided into two types, i.e., probe-station and quasi-in-air based. The former type has a feature that allows the testing equipment to be compactly established on a large metal stage, which has been widely used for near-field based and as part of the farfield-based setups [6]-[10]. The antenna under test (AUT) is maintained on a wafer chuck placed on the stage and thus, only the radiation pattern in the upper half-space is measurable due to the metal stage obstruction. The latter type reduces the defect by using an extended supporting structure to hold the AUT in midair away from the stage so that the radiation patterns in both the upper and lower half-spaces are measurable. Many setups of this type measure antennas at far-field distances, and some of them are also compatible with near-field testing. Compared to probe-station based, quasi-inair based takes up much more space and is less compact. [ABSTRACT FROM AUTHOR]

Post-translational modifications of histone proteins greatly impact gene expression and cell fate decisions in eukaryotes. To study these, it is important to develop a convenient, multiplex, and efficient method to precisely introduce mutations to histones. Because eukaryotic cells usually contain multiple copies of histone genes, it is a challenge to mutate all histones at the same time by the traditional homologous recombination method. Here, we developed a CRISPR-Cas9 based shuffle system in Saccharomyces cerevisiae, to generate point mutations on both endogenous histone H3 and H4 genes in a rapid, seamless and multiplex fashion. Using this method, we generated yeast strains containing histone triple H3–K4R–K36R–K79R mutants and histone combinatorial H3–K56Q–H4–K59A double mutants with high efficiencies (70–80%). This CRISPR-Cas9 based mutagenesis system could be an invaluable tool to the epigenetics field. [ABSTRACT FROM AUTHOR]

Coproporphyrin I (CPI) is an endogenous biomarker of OATP1B activity and associated drug‐drug interactions. In this study, a minimal physiologically‐based pharmacokinetic model was developed to investigate the impact of OATP1B1 genotype (c.521T>C), ethnicity, and sex on CPI pharmacokinetics and interindividual variability in its baseline. The model implemented mechanistic descriptions of CPI hepatic transport between liver blood and liver tissue and renal excretion. Key model parameters (e.g., endogenous CPI synthesis rate, and CPI hepatic uptake clearance) were estimated by fitting the model simultaneously to three independent CPI clinical datasets (plasma and urine data) obtained from white (n = 16, men and women) and Asian‐Indian (n = 26, all men) subjects, with c.521 variants (TT, TC, and CC). The optimized CPI model successfully described the observed data using c.521T>C genotype, ethnicity, and sex as covariates. CPI hepatic active was 79% lower in 521CC relative to the wild type and 42% lower in Asian‐Indians relative to white subjects, whereas CPI synthesis was 23% higher in male relative to female subjects. Parameter sensitivity analysis showed marginal impact of the assumption of CPI synthesis site (blood or liver), resulting in comparable recovery of plasma and urine CPI data. Lower magnitude of CPI‐drug interaction was simulated in 521CC subjects, suggesting the risk of underestimation of CPI‐drug interaction without prior OATP1B1 genotyping. The CPI model incorporates key covariates contributing to interindividual variability in its baseline and highlights the utility of the CPI modeling to facilitate the design of prospective clinical studies to maximize the sensitivity of this biomarker. [ABSTRACT FROM AUTHOR]

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Defects are now recognized to be a useful tool in tailoring the properties of metal–organic frameworks (MOFs). The introduction of missing linker and cluster defects into MOFs provides additional active sites, optimizes the acidity/basicity, improves the conductivity, tailors mechanical responses and creates more pore space to enhance diffusion and mass transfer in MOFs. Structural defects in MOFs have been demonstrated to be beneficial in areas such as catalysis, decontamination, bio-applications, adsorption, separation, energy storage, energy conversion, electronics, magnetics, optical functional materials and others. Defective MOFs are also excellent model materials for the fundamental study of defect chemistry. In this review, we provide a general overview of the commonly available methods that are feasible for the creation and characterization of structural defects in MOF materials. Additionally, recent studies on various applications of defective MOFs are highlighted, aiming to provide new insights into the design and introduction of structural defects to synthesize MOF materials with high performance and to promote the wide application of defective MOFs in various fields. Challenges and future perspectives on defect engineering of MOFs are also addressed. [ABSTRACT FROM AUTHOR]

Background: Expanded carrier screening (ECS) has emerged as an effective approach to identify at‐risk couples (ARCs)—before they initiate attempts at reproduction—who possess a high probability of having a child affected by severe recessive diseases. The objective of this study was to evaluate the clinical utility of ECS in Chinese patients seeking the help of assisted reproductive technology (ART). Methods: An ECS test, which covers 201 genes implicated in 135 recessive (autosomal or X‐linked) diseases, was routinely offered to all ART patients in a single genetics and in vitro fertilization clinic. Additional options for preimplantation or prenatal genetic diagnosis were discussed and offered to all ARCs. All ECS results were aggregated and the clinical decisions of the ARCs were surveyed. Results: A total of 2,923 ART patients, representing 1,462 couples, were screened. Overall, 46.73% of the individuals were found to be the carriers for at least 1 of the 135 diseases. Of the tested couples, 2.26% (n = 33) were identified as ARCs. As of the completion of this study, 21 (63.6%) ARCs have decided to avert an affected pregnancy with the help of preimplantation genetic testing for monogenetic conditions. The cumulative carrier rate of the 187 autosomal recessive genes in the ECS panel for the 2,836 Han Chinese individuals without a family history was estimated to be 45.91%. The estimated at‐risk couple rate indicates that the screening for only the top 31 genes with gene carrier rates >0.5% would identify more than 94% of the ARCs identified by screening all 187 genes. Conclusion: Our study demonstrates that ESC yields a significant clinical value for ART patients in China. In addition, by estimating the yields of the ECS panel, we identify genes that are appropriate for screening the Han population. [ABSTRACT FROM AUTHOR]

TRIM13, a member of the TRIM family, is a RING domain containing E3 ubiquitin ligase which plays critical roles in diverse cellular processes including cell death, cancer and antiviral immunity. However, its expression and molecular mechanism on renal cell carcinoma (RCC) have not been characterized. This study explored the clinical significance and biological function of TRIM13 in human RCC. Western blot analyses and Immunohistochemical were performed in RCC tissues. The clinical relevance of TRIM13 in RCC was evaluated by immunohistochemical staining using tissue microarray. The role of TRIM13 in migration was studied in renal cell carcinoma cell lines of 786-O through knocking down TRIM13 with siRNA and over-expression of TRIM13. The regulation of TRIM13 on migration and invasion were determined by wound-healing and transwell assays. Western blot analyses showed that TRIM13 expression was dramatically decreased in RCC tissues compared with adjacent non-tumorous tissues. Up-regulation of TRIM13 in 786-O cells resulted in decreased NF-kB, MMP-9 and p-AKT levels and the capability for migration and invasion. In contrast, the ectopic expression of TRIM13 decreased the migration and invasion ability of 786-O cells. These findings indicate that TRIM13 decreases RCC metastasis and invasion may serve as a candidate RCC prognostic marker and a potential therapeutic target. [ABSTRACT FROM AUTHOR]

A dual-band differential shifted-feed microstrip grid array antenna (DSF-MGAA) with two parasitic patches is presented in this communication. By moving the feed location, a conventional MGAA (C-MGAA) can be turned into an SF-MGAA for dual-band operation. The high-frequency band of SF-MGAA corresponds to the operation mode of the C-MGAA, and its low-frequency band is similar to that of the patch or meshed patch antenna. A new differential feeding scheme and two parasitic patches are adopted to improve the impedance bandwidth of SF-MGAA. The proposed DSF-MGAA can cover a dual band of 3.7 and 28.5 GHz. The measured −10 dB impedance bandwidths of 3.4% and 4.5%, which correspond to the peak gains of 8.98 and 19.2 dBi, are obtained in the low- and high-frequency bands, respectively. The DSF-MGAA can be a potential candidate for the future dual-band wireless communication. [ABSTRACT FROM AUTHOR]

Antenna-in-package (AiP) technology, in which there is an antenna (or antennas) with a transceiver die (or dies) in a standard surface-mounted device, represents an important antenna and packaging technology achievement in recent years. AiP technology has been widely adopted by chipmakers for 60-GHz radios and gesture radars. It has also found applications in 77-GHz automotive radars, 94-GHz phased arrays, 122-GHz imaging sensors, and 300-GHz wireless links. It is believed that AiP technology will also provide elegant antenna and packaging solutions to the fifth generation and beyond operating in the lower millimeter-wave (mmWave) bands. Thus, one can conclude that AiP technology has emerged as the mainstream antenna and packaging technology for various mmWave applications. This article will provide an overview of the development of AiP technology. It will consider antennas, packages, and interconnects for AiP technology. It will show that the antenna choice is usually based on those popular antennas that can be easily designed for the application, that the package choice is governed for automatic assembly, and that the materials and processes choices involve tradeoffs among constraints, such as electrical performance, thermal–mechanical reliability, compactness, manufacturability, and cost. This article also shows a probe-based setup to measure mmWave AiP impedance and radiation characteristics. It goes on to give AiP examples implemented, respectively, in a low-temperature co-fired ceramic, an embedded wafer level ball grid array process, and a high-density interconnect processes. Finally, this article will summarize and present some recommendations on research topics to further the state of the art of AiP technology. [ABSTRACT FROM AUTHOR]

A ntenna-in-package (AiP) technology integrates an antenna or antennas with a radio or radar transceiver die (or dies) into a standard surface-mount package. AiP technology balances performance, size, and cost well. Thus, it has been widely adopted by chipmakers for radios and radars. Many papers and patents are devoted to AiP technology. However, little is known about the history of this important antenna and packaging technology. This article aims to fill this void with a general description of early efforts that drove the development of AiP technology as we know it today. [ABSTRACT FROM AUTHOR]

Phomopsis asparagi is a fungal pathogen that causes destructive stem blight disease in garden asparagus worldwide. The host-pathogen interactions and molecular mechanisms of its pathogenicity are poorly understood. In this study, a protoplast transformation approach mediated by polyethylene glycol (PEG) was established for P. asparagi, and green fluorescent protein (GFP) expression transformants were successfully obtained. The transformants were mitotically stable when grown on potato dextrose agar (PDA) plates amended with 100 μg mL−1 of hygromycin B after five successive subcultures without selective pressure. All of the analysed transformants were further confirmed by polymerase chain reaction (PCR) amplification with primers specific to the hygromycin B phosphotransferase (hph) gene and Southern blotting. Moreover, these transformants showed similar pathogenicity on garden asparagus spears compared with the wild type, although a difference in growth rate was observed in oatmeal agar (OA) plates. These GFP expression transformants will serve as useful tools for investigating host penetration and the invasive growth of this devastating fungal pathogen, as well as defining the nature of the host-pathogen interaction. [ABSTRACT FROM AUTHOR]

In the present investigations, we evaluate in vitro hepatocyte uptake and partitioning for the prediction of in vivo clearance and liver partitioning. Monkeys were intravenously co-dosed with rosuvastatin and bosentan, substrates of the organic anion transporting polypeptides (OATPs), and metformin, a substrate of organic cation transporter 1 (OCT1). Serial plasma and liver samples were collected over time. Liver and plasma unbound fraction was determined using equilibrium dialysis. In vivo unbound partitioning (Kp) for rosuvastatin, bosentan, and metformin, calculated from total concentrations in the liver and plasma, were 243, 553, and 15, respectively. A physiologically based pharmacokinetic monkey model that incorporates active and passive hepatic uptake was developed to fit plasma and liver concentrations. In addition, a two-compartment model was used to fit in vitro hepatic uptake curves in suspended monkey hepatocyte to determine active uptake, passive diffusion, and intracellular unbound fraction parameters. At steady-state in the model, in vitro Kp was determined. The results demonstrated that in vitro values under-predicted in vivo active uptake for rosuvastatin, bosentan, and metformin by 6.7-, 28-, and 1.5-fold, respectively, while passive diffusion was over-predicted. In vivo Kp values were under-predicted from in vitro data by 30-, 79-, and 3-fold. In conclusion, active uptake and liver partitioning in monkeys for OATP substrates were greatly under-predicted from in vitro hepatocyte uptake, while OCT-mediated uptake and partitioning scaled reasonably well from in vitro, demonstrating substrate- and transporter-dependent scaling factors. The combination of in vitro experimental and modeling approaches proved useful for assessing prediction of in vivo intracellular partitioning. [ABSTRACT FROM AUTHOR]

The garden asparagus stem blight caused by filamentous fungus Phomopsis asparagi exposes a serious threat on asparagus production globally. However, to present, we understand poorly about the molecular mechanisms of fungal pathogenicity. To facilitate functional genomics research of P. asparagi, here we developed a highly efficient and stable Agrobacterium tumefaciens-mediated transformation approach which yielded 150-200 transformants per 1 × 10 conidia. Our results indicated that 25 °C, acetosyringone concentration of 150 μmol/L, and 72 h were recommended as optimal co-cultivation conditions for the transformation. Using this transformation approach, we constructed a T-DNA insertion mutant library containing 1253 strains. Twenty randomly selected T-DNA insertion mutants were able to grow on 0.2 × PDA selective media after five successive subcultures without selective pressure, indicating that the exogenous T-DNA was stably integrated into the P. asparagi genome. We confirmed several randomly selected mutants using PCR with primers specific to the hph gene. Southern blots suggested that three out of the five selected mutants have a single T-DNA insertion. Interestingly, multiple mutant candidates with growth defects were obtained from the growth assay. Moreover, several mutants were selected for further analysis on the T-DNA flanking sequences through TAIL-PCR analysis. A sequence comparison of total junction fragments implied that the insertion of T-DNA within P. asparagi genome appeared to be a random event. The transformation technology and genetic resources developed here will facilitate studies of pathogenic mechanisms in this devastating filamentous fungal pathogen of garden asparagus. [ABSTRACT FROM AUTHOR]

The development of a dual-feed microstrip grid array antenna for either balanced or unbalanced operation to radiate pencil-beam patterns has been described. As an example, the dual-feed microstrip grid array antenna on RT/duroid 5880 substrate with a size of 60 × 60 × 0.787 mm3 or 4.8λ × 4.8λ × 0.063λ at 24 GHz were designed and fabricated. The measured results show that the dual-feed microstrip grid array antenna has achieved excellent performances: 4.85% impedance bandwidth, 9.03% gain bandwidth, and 20.6-dBi gain at 24.15 GHz as a balanced antenna and 6.05% impedance bandwidth, 7.74% gain bandwidth, and 17.8-dBi gain at 24.15 GHz as an unbalanced antenna. The dual-feed microstrip grid array antenna is a suitable antenna candidate for radar and sensor applications. [ABSTRACT FROM AUTHOR]

Objectives The purpose of this study was to evaluate the diagnostic utility of karyotype analysis of amniotic fluid for fetuses with abnormal sonographic findings and to determine the detection rates of abnormal karyotypes. Methods We conducted a retrospective study of 5328 fetuses with abnormal sonographic findings in the first or second trimester enrolled from October 1998 and September 2015. Cytogenetic results from amniotic fluid were obtained in all of these pregnancies. Sonographic abnormalities were stratified according to anatomic system involvement. Results A total of 238 abnormal karyotypes were encountered in the 5328 fetuses (4.5%). The highest rate of chromosomal anomalies was in fetuses with structural abnormalities in multiple organ systems (25.7%), followed by an abnormal amniotic fluid volume (7.9%), structural abnormalities in a single system (7.3%), multiple nonstructural anomalies (7.2%), isolated placental abnormalities (7.1%), and isolated soft markers for aneuploidy (2.4%; P < .01). Among abnormalities in a single system, gastrointestinal and neck/body fluids had particularly high detection rates (26.1% and 26.2%, respectively). A detailed analysis suggested that the probability of an abnormal karyotype among every anatomic system was statistically significant ( P < .01). This study identified several common indications with extremely high abnormal rates: duodenal atresia (53.1%), holoprosencephaly (48.8%), fetal hydrops (39.5%), cerebellar hypoplasia (32.0%), cystic hygroma (31.5%), absent/short nasal bone (11.0%), and bilateral choroid plexus cysts (8.5%). Conclusions Cytogenetic analysis has important clinical utility in a wide range of settings, such as prenatal diagnosis. For fetuses with indications of a highly abnormal detection rate, karyotype analysis should be suggested. [ABSTRACT FROM AUTHOR]

PCR-mediated homologous recombination is a powerful approach to introduce epitope tags into the chromosomal loci at the N-terminus or the C-terminus of targeted genes. Although strategies of C-terminal epitope tagging of target genes at their loci are simple and widely used in yeast, C-terminal epitope tagging is not practical for all proteins. For example, a C-terminal tag may affect protein function or a protein may get cleaved or processed, resulting in the loss of the epitope tag. Therefore, N-terminal epitope tagging may be necessary to resolve these problems. In some cases, an epitope tagging strategy is used to introduce a heterologous promoter with the epitope tag at the N-terminus of a gene of interest. The potential issue with this strategy is that the tagged gene is not expressed at the endogenous level. Another strategy after integration is to excise the selection marker, using the Cre-LoxP system, leaving the epitope tagged gene expressed from the endogenous promoter. However, N-terminal epitope tagging of essential genes using this strategy requires a diploid strain followed by tetrad dissection. Here we present 14 new plasmids for N-terminal tagging, which combines two previous strategies for epitope tagging in a haploid strain. These ' N-ICE' plasmids were constructed so that non-essential and essential genes can be N-terminally 3 × FLAG tagged and expressed from an inducible promoter ( GAL1), constitutive promoters ( CYC1 or PYK1) or the endogenous promoter. We have validated the N-ICE plasmid system by N-terminal tagging two non-essential genes ( SET1 and SET2) and two essential genes ( ERG11 and PKC1). Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A domain of locations of a proton in the perovskite structure is determined by studying the local structure and a hard sphere point charge model. Two intra- and one inter-octahedron processes with different energy barriers of ⟨ E1⟩, ⟨ E2⟩, and ⟨ E3⟩ have been studied, respectively. The order of the energy barriers is predicted as ⟨ E3⟩ > ⟨ E1⟩ ≥ ⟨ E2⟩ by studying both the changes of bonding in these processes and the charge imbalance between the acceptor dopant ion and the B type ion. The inter-octahedron hopping, ⟨ E3⟩, is shown to be a necessary and rate limiting step by using percolation and charge imbalance argument. This result differs with earlier calculations, however, it agrees with the result of quasi-elastic neutron and other experimental results. Through studying the lattice dynamics of a 1D O-H chain and its monomer, we have developed new formulae for a hydrogen bond system and applied them to explain the experimentally observed red-shift and broadening of the O-H vibration peak. These phenomena are revealed as indications of the quasi-free state of a proton instead of the formation of hydrogen bond. [ABSTRACT FROM AUTHOR]

The bile salt export pump (BSEP) is expressed on the canalicular membrane of hepatocytes regulating liver bile salt excretion, and impairment of BSEP function may lead to cholestasis in humans. This study explored drug biliary excretion, as well as serum chemistry, individual bile acid concentrations and liver transporter expressions, in the SAGE Bsep knockout (KO) rat model. It was observed that the Bsep protein in KO rats was decreased to 15% of that in the wild type (WT), as quantified using LC-MS/MS. While the levels of Ntcp and Mrp2 were not significantly altered, Mrp3 expression increased and Oatp1a1 decreased in KO animals. Compared with the WT rats, the KO rats had similar serum chemistry and showed normal liver transaminases. Although the total plasma bile salts and bile flow were not significantly changed in Bsep KO rats, individual bile acids in plasma and liver demonstrated variable changes, indicating the impact of Bsep KO. Following an intravenous dose of deuterium labeled taurocholic acid (D4-TCA, 2 mg/kg), the D4-TCA plasma exposure was higher and bile excretion was delayed by approximately 0.5 h in the KO rats. No differences were observed for the pravastatin plasma concentration-time profile or the biliary excretion after intravenous administration (1 mg/kg). Collectively, the results revealed that these rats have significantly lower Bsep expression, therefore affecting the biliary excretion of endogenous bile acids and Bsep substrates. However, these rats are able to maintain a relatively normal liver function through the remaining Bsep protein and via the regulation of other transporters. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]