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Abstract Background Noninvasive prenatal testing (NIPT) has been widely used clinically to detect fetal chromosomal aneuploidy with high accuracy rates, gradually replacing traditional serological screening. However, the application of NIPT for monogenic diseases is still in an immature stage of exploration. The detection of mutations in peripheral blood of pregnant women requires precise qualitative and quantitative techniques, which limits its application. The bioinformatic strategies based on the SNP (single nucleotide polymorphism) linkage analysis are more practical, which can be divided into two types depending on whether proband information is needed. Hidden Markov Mode (HMM) and Sequential probability ratio test (SPRT) are suitable for families with probands. In contrast, methods based on databases and population demographic information are suitable for families without probands. Methods In this study, we proposed a Spearman rank correlation analysis method to infer the fetal haplotypes based on core family information. Allele frequencies of SNPs that were used to construct parental haplotypes were calculated as sets of nonparametric variables, in contrast to their theoretical values represented by a fetal fraction (FF). The effects on the calculation of the fetal concentration of two DNA enrichment methods, multiple‐PCR amplification, and targeted hybrid capture, were compared, and the heterozygosity distribution of SNPs within pedigrees was analyzed to reveal the best conditions for the model application. Results Predictions of the paternal haplotype inheritance were in line with expectations for both DNA library construction methods, while for maternal haplotype inheritance prediction, the rates were 96.55% for method multiple‐PCR amplification and 95.8% for method targeted hybrid capture. Conclusion Positive prediction rates showed that the maternal haplotype prediction was not as accurate as paternal one, due to the large amount of maternal noise in the mother's peripheral blood. Although this model is relatively immature, it provides a new perspective for noninvasive prenatal clinical tests of monogenic diseases.

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]

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]

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]

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]

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]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.comnet.2008.12.004 Byline: Yueping Zhang (a), Saurabh Jain (b), Dmitri Loguinov (c) Keywords: Congestion control; Explicit-feedback; Linux experiment Abstract: Innovative efforts to provide a clean-slate design of congestion control for future high-speed heterogeneous networks have recently led to the development of explicit congestion control. These methods rely on multi-byte router feedback and aim to contribute to the design of a more scalable Internet of tomorrow. However, experimental evaluation and deployment experience with these approaches is still limited to either low bandwidth networks or simple topologies. In addition, all existing implementations are exclusively applicable to either rate- or window-based protocols and are unable to study performance of different protocols on a common platform. This paper aims to fill this void by designing a unified Linux implementation framework for both rate- and window-based methods that does not incur any interference with the system's network stack or applications. Using this implementation, we implement and reveal several key properties of four recent explicit congestion control protocols XCP, JetMax, RCP, and PIQI-RCP using Emulab's gigabit testbed with a ariety of simple yet representative network topologies. Our experiments not only confirm the known behavior of these methods, but also demonstrate their previously undocumented properties (e.g., RCP's transient overshoot under abrupt traffic load changes and JetMax's low utilization in the presence mice flows). Author Affiliation: (a) NEC Laboratories America, Inc., Princeton, NJ 08540, United States (b) Cisco Systems, Inc., San Jose, CA 95134, United States (c) Texas A&M University, College Station, TX 77843, United States Article History: Received 26 March 2008; Revised 8 August 2008; Accepted 8 December 2008 Article Note: (miscellaneous) Responsible Editor: X.S. Shen

Network feedback in a congestion-control system is subject to delay, which can significantly affect stability and performance of the entire system. While most existing stability conditions explicitly depend on delay [D.sub.i] of individual flow i, a recent study [1] shows that the combination of a symmetric Jacobian A and condition p(A) < 1 guarantees local stability of the system regardless of [D.sub.i]. However, the requirement of symmetry is very conservative and no further results have been obtained beyond this point. In this technical note, we proceed in this direction and gain a better understanding of conditions under which congestion-control systems can achieve delay-independent stability. Towards this end, we first prove that if Jacobian matrix A satisfies [parallel] A [parallel] < 1 for any monotonic induced matrix norm [parallel] x [parallel], the system is locally stable under arbitrary diagonal delay [D.sub.i]. We then derive a more generic result and prove that delay-independent stability is guaranteed as long as A is Schur diagonally stable [2], which is also observed to be a necessary condition in simulations. Utilizing these results, we identify several classes of well-known matrices that are stable under diagonal delays if [rho](A) < 1 and prove stability of MKC [1] with arbitrary parameters [[alpha].sub.i] and [[beta].sub.i]. Index Terms--Delay-independent stability, diagonal delay, max-min congestion control.

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]

Stability proofs of nonlinear congestion control systems under heterogeneous feedback delays are usually difficult and involve a fair amount of effort. In this paper, we show that there exist a class of congestion control methods that admit very simple proofs of asymptotic stability and allow control equations to be delay-independent. This is in contrast to most previous work, which requires that each flow land sometimes each router) adapt its control-loop constants based on the feedback delay and/or the length of the corresponding end-to-end path. Our new congestion control method, which we call Max-Min Kelly Control (MKC), builds upon Kelly's original work in [3] and allows end-flows to be stable and fair regardless of network feedback delays or the number of hops in their end-to-end paths. Using basic matrix algebra and discrete control theory, we show MKC's local asymptotic stability under heterogeneous, directional feedback delays. We also offer a simple proof of its global asymptotic stability assuming constant feedback delay. Index Terms--Asymptotic stability, congestion control, delay.