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Bit error rate (BER) is an important figure of merit to evaluate the performance of a communication system. Analyzing the BER of a linear-time-invariant system has been extensively studied. However, analyzing the BER of nonlinear circuits and systems is challenging because it cannot rely on linear time invariant (LTI) principles, while an exhaustive nonlinear simulation is computationally prohibitive. To find BER, an exhaustive approach requires nonlinear simulations of $2^m$ bit patterns for a channel of m-bit memory, where m can be larger than 100 in today's high-speed and high-performance design. In this work, we develop a fast and accurate method to analyze the BER of large-scale nonlinear circuits. Only O(k) nonlinear simulations are required, with k much less than 2^m and independent of $2^m$ . While performing O(k) nonlinear simulations only, we find a method to determine the probability density function of the nonlinear responses, from which accurate BER results can be obtained. An error assessment method is also developed to evaluate the true error of the nonlinear signaling analysis without the need for knowing the entire nonlinear responses of the channel. Simulations of large-scale real-world nonlinear circuits have demonstrated the accuracy, efficiency, and capacity of the proposed method. A BER as low as $10^{-56}$ is accurately predicted.

BACKGROUND Caused by premature activation of the hypothalamic-pituitary-gonadal axis, there is increasing incidence of central precocious puberty (CPP), especially in girls. Makorin ring finger protein 3 (MKRN3), a maternal imprinted gene with a highly conserved sequence, is the most common genetic etiology associated with CPP. Approximately 50 different mutations in MKRN3 have been found in CPP. CASE SUMMARY This case report involves identical twin sisters presenting with premature thelarche at the age of 6 years. The left hand bone age of both patients revealed advanced age (9 years). Pelvic B ultrasound indicated enlargement of the ovaries. Luteinizing hormone (LH) releasing hormone testing confirmed CPP. Whole-exome sequencing detected the c.841C>T mutation in MKRN3, leading to a single base substitution, in the twins. This mutation was inherited from the father and paternal grandmother. After 3 mo of treatment with a gonadotropin-releasing hormone analog, levels of LH, follicle-stimulating hormone, and estradiol in the proband’s sister returned to normal levels. CONCLUSION Here, we report a rare mutation (c.841C>T) in MKRN3 in identical twin sisters with CPP.

Though central precocious puberty (CPP) as a disease that seriously affects the development of a child is increasing year by year, treatment options remain limited and is the same as the 1980s' method. These are mainly due to the complex pathogenesis of central precocious puberty. Therefore, systems biology approach to identify and explore the multiple factors related to the pathogenesis of central precocious puberty is necessary. Our data established the first proteome profile of CPP revealed 163 down-regulated and 129 were up-regulated differentially expressed proteins. These altered proteins were primarily enriched in three metabolic process including energy metabolism, amino acid metabolism and nitrogenous base metabolism. The identified altered members of the metabolic signaling are valuable and potential novel therapeutic targets of central precocious puberty.

Signaling analysis of nonlinear high-speed circuits is challenging because it cannot rely on linear time-invariant principles, whereas an exhaustive nonlinear simulation is computationally prohibitive for low bit error rates. To find the worst-case eye, an exhaustive approach requires nonlinear simulations of $2^m$ bit patterns for a channel of $m$ -bit memory. In this article, we represent the nonlinear responses to the $2^m$ inputs by a rank- $k$ matrix, where $k$ denotes the number of distinct waveforms in the responses for a prescribed accuracy, which is much smaller than $2^m$ . We further develop a fast full cross approximation algorithm to find the rank- $k$ model with a low complexity independent of $2^m$ . Simulations of large-scale real-world nonlinear circuits with an over 100-bit channel memory demonstrate the accuracy, efficiency, and capacity of the proposed work.

Objectives NPR2 variants are associated with various short stature and bone dysplasia, such as acromesomelic dysplasia Maroteaux tyoe, individuals with a phenotype similar to Léri–Weill syndrome (LWD), and idiopathic short stature (ISS). However, few studies have reported on the relationship between familial short stature (FSS) and NPR2 variants. This study aimed to explore the relationship between FSS and NPR2 variants through the detection and identification of NPR2 variants in children with FSS, phenotypic description, clear treatment plan, and follow-up of treatment effect. Methods Children who met the FSS diagnostic criteria and had informed consent were included in the study. The trio whole-exome sequencing method (trio-WES) was used to detect and evaluate the NPR2 variants. Results A total of 16 children with short stature were included in this study (pretreatment height ≤ −2 standard deviation (SD) in both the patient and the shorter parent, unknown genetic etiology). NPR2 variants were identified in 12.5%(2/16) of the participants. Patient A was a 6-year-old male and 103.7 cm tall (−3.11SD), while Patient B was a 9-year-old female and 123.2 cm tall (−1.88SD). However, their heights increased after recombinant human growth hormone (rhGH) treatment. The height of patient A increased by 0.36SD six months after treatment while that of patient B increased by 1.22SD after one and a half years of treatment. Conclusions NPR2 variant causes FSS. The growth rate of children significantly improved after rhGH treatment. However, further follow-up study is needed to determine the final height after long-term treatment.

Combination treatment with acupoint therapy and conventional medication (CM) has been proposed as a strategy that could improve motor dysfunction in Parkinson's disease (PD). We performed this systematic review and meta-analysis to assess the effects of this combination treatment on motor function in patients with PD.We searched randomized controlled trials (RCTs) from eight databases, comparing combined acupoint therapy and CM and CM (alone or with sham interventions). The quality of the trials was evaluated according to the Cochrane risk of bias. Subgroup and sensitivity analyses were performed on different types of acupoint interventions.Forty-seven trials of 2929 participants were included, with 45 studies used for the meta-analyses. Combination treatment yielded an improved reduction in United Parkinson's disease rating scale (UPDRS) III of -3.85 [95% CI, -4.83 to -2.86] and Webster scale score of -3.17 [95% CI, -4.07 to -2.27]. Further analyses demonstrated that real (compared with sham) intervention was linked to a decreased UPDRS III of -2.02 ([95% CI, -3.60 to -0.44], IAcupoint therapy and CM treatment may improve motor function of patients with PD. Patients with H-Y stage3 could tolerate real acupoint intervention with mild to moderate stimulation for 4-12-week treatment and showed improvement. However, this was demonstrated with low to moderate levels of evidence in statistical description.

A scheme of frequency sweep linearization of semiconductor lasers using a feed-back loop based on amplitude-frequency response is demonstrated in this paper. The beat frequency signal is obtained by self-heterodyne detection. The frequency changes are converted to the envelope of beat frequency signal after amplitude-frequency response. The active frequency sweep linearization is realized by feeding envelope deviations back to the drive currents of the lasers by a feedback loop. A simulation model is built to verify this scheme by Simulink. This scheme does not need high-performance, expensive lasers, complex linearization or tedious post-processing processes, which are of great significance for related applications.

Sky polarization patterns are a relatively new and interesting field of polarized remote sensing. However, most current research mainly focuses on Rayleigh scattering or different conditions of aerosol optical depth. In this study, the sky downward polarization patterns are calculated for both degree of linear polarization and angle of polarization with scattering and absorbing aerosol situations. When coarse-mode aerosol changes from scattering to absorbing, the decreasing trend in the sky downward degree-of-linear-polarization largely slows down when aerosol optical depth increases. For fine-mode aerosol, on the other hand, the change of pattern is not sensitive to the absorbing property of aerosol. Sky downward angle-of-polarization patterns for different levels of aerosol optical depth and aerosol modes are similar, with little change. The results suggest that in order to accurately use sky polarization for remote sensing or bionic navigation, it is necessary to characterize aerosol microphysical properties first, especially when coarse absorbing aerosol exists.

Background: Cornelia de Lange syndrome (CdLS) is a genetic syndrome characterized by intellectual disability, special facial features, growth retardation, feeding difficulties, and multiple organ system abnormalities. NIPBL variants occur in approximately 80% of CdLS cases. Aims: We report a novel de novo heterozygous pathogenic variant in the NIPBL and its association with CdLS. We also examined the key regulatory sequences of the 5′ untranslated region in NIPBL mRNA. Few studies have reported mutation sites in the 5′ untranslated region (UTR) of the NIPBL that result in CdLS. Methods: The patient’s medical history, clinical manifestations, physical examination, laboratory examination, Griffiths development assessment scale—Chinese version, and cardiac B-ultrasound were examined. Mutation screening was conducted using trio whole exome sequencing (trio-WES) and Sanger sequencing. Quantitative PCR was performed to measure the NIPBL expression in peripheral blood mononuclear cells. A Dual-Luciferase reporter assay was conducted to evaluate the transcription of truncated mutants. Results: The proband showed characteristics of CdLS including thick eyebrows, a concave nasal ridge, long and smooth philtrum, downturned corners of the mouth, intellectual disability, postnatal growth retardation, and a short fifth toe. A novel de novo heterozygous pathogenic variant in the NIPBL (c.-467C > T) was identified. A Dual-Luciferase reporter gene assay showed that SPO1 (-490 bp to -360 bp) and SPO3 (-490 bp to -401 bp) induced the highest activity. Conclusions: We found a novel de novo heterozygous pathogenic variant (c.-467C > T) in the NIPBL resulting in CdLS. Our findings expand the spectrum of pathogenic mutations for CdLS. Our in vitro experiments elucidated important regulatory sequences in the 5′ UTR of the NIPBL.

BACKGROUND X-linked agammaglobulinemia is a primary immunodeficiency disease caused by gene mutations of Bruton’s tyrosine kinase (BTK). We found a new mutation point and summarized the correlation analysis and performed a literature review. CASE SUMMARY The proband was a 5-year-old boy. He was admitted to our hospital due to a recurrent cough and a fever that had persisted for a month. He had a history of multiple respiratory infections and sinusitis. There was no immunodeficiency or recurrent infection history among his family members. Agammaglobulinemia was characterized as follows: Immunoglobulin (Ig) A, 90.0 mg/dL (90-450 mg/dL); IgG, 20.0 mg/dL (800-1800 mg/dL); and IgM, 18.0 mg/dL (60-280 mg/dL). Notably, the assessment of IgG subtypes revealed the following very low levels: Subtype 1, 0.26 g/L (3.62-12.28 g/L); subtype 2, 0.10 g/L (0.57-2.9 g/L); subtype 3, 0.009 g/L (0.129-0.789 g/L); and subtype 4, 0.003 g/L (0.013-1.446 g/L). Cellular immunological test results were as follows: CD3, 74.6% (50%-84.0%); CD4, 47.3% (27.0%-51.0%); and CD8, 24.9% (15.0%-44.0%). A de novo hemizygous deletion in BTK was detected: c.902_c.904delAAG/p.E301del. Transcript levels of the mutant BTK were similar to those of the wild-type gene, though overexpression resulted in markedly reduced levels of mutant BTK (9.49% ± 1.58%), relative to the wild-type BTK (75.8% ± 2.98%, P < 0.01). CONCLUSION This case of X-linked agammaglobulinemia was attributed to a de novo hemizygous deletion mutation in BTK (c.902_c.904delAAG/p.E301del). The mutation resulted in markedly reduced BTK protein stability in vitro.

The morbidity of extrahepatic cholangiocarcinoma (CCA) has increased markedly in the past few decades. However, most patients with extrahepatic CCA are diagnosed at an advanced stage and thus cannot receive curative resection in time. To increase the long-term survival probability of nonresectable extrahepatic CCA patients, it is highly desirable to develop alternative treatment strategies. Photodynamic therapy is a highly efficient method for the ablation of cancer cells, but the conventional photosensitizers (PSs) suffer from self-quenching after local accumulation in organelles. To tackle this challenge, we herein develop a mitochondria-anchoring photosensitizer, TTVPHE, with aggregation-induced emission (AIE) characteristics for efficient ablation of extrahepatic CCA cells through the mitochondrial injury pathway. The TTVPHE probe shows significant advantages in terms of fast cell penetration ability, selective mitochondria-targeting ability, and excellent ROS generation ability under white light irradiation. Moreover, the probe can in situ monitor the mitochondrial injury process by translocation from mitochondria to the nuclear membrane. The ultrastructural changes in the morphology of mitochondria under PDT were also characterized using high resolution TEM. This AIE-active probe is promising for the treatment of advanced stage CCA.

Background: This study explored the influences of electroacupuncture combined with dietary intervention on the intestinal flora in perimenopausal patients with abdominal obesity by using the 16s rRNA sequencing technology.Methods: Perimenopausal patients with abdominal obesity were divided into the Electroacupuncture group and the Control group. Patients in the Control group received healthy lifestyle education, while those in the Electroacupuncture group received electroacupuncture combined with dietary intervention. Before and after treatment, the weight, height, waist circumference, hip circumference, waist-height ratio (WHtR), waist to hip ratio (WHR), and body mass index (BMI) of the patients were recorded; the levels of serum triglyceride (TG), total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein cholesterol (HDL-C), fasting insulin (FINS), and fasting blood glucose (FGB) were evaluated; and the abundance, diversity, and species differences of intestinal flora were analyzed using 16s rRNA sequencing technology.Results: The body weight, waist circumference, hip circumference, BMI, WHR, and WHtR of patients in the Electroacupuncture group after treatment were lower than those before treatment. Compared with the Control group, patients in the Electroacupuncture group after treatment displayed lower waist circumference, WHtR, WHR, TG, and LDL levels as well as species abundance, higher species diversity, and lager species difference in the intestinal flora. Besides, the proportions of Klebsiella and Kosakonia in the intestinal flora of patients in the Electroacupuncture group after treatment were larger than those before treatment.Conclusion: Electroacupuncture combined with diet treatment generated a therapeutic effect on abdominal obesity in perimenopausal patients by improving the community structure of intestinal flora.

Signaling analysis of nonlinear circuits is challenging because it cannot rely on linear time invariant principles, while an exhaustive nonlinear simulation is computationally prohibitive for low bit error rates (BER). To find the worst-case eye as well as BER, an exhaustive approach requires nonlinear simulations of 2m bit patterns for a channel of m-bit memory, where $m$ can be larger than 100 in today's high-speed and high-performance design. In this work, we develop fast and accurate algorithms for large-scale signaling analysis of nonlinear circuits, including both worst-case eye and BER analysis. In the proposed algorithms, only O(k) nonlinear simulations are required, with $k$ much less than 2m and independent of 2m. While performing $k$ nonlinear simulations only, we find an accurate and efficient method to determine the probability density function of the nonlinear responses, from which accurate BER results can be obtained. Simulations of large-scale real-world nonlinear circuits demonstrate the accuracy, efficiency, and capacity of the proposed method.

Truck-related accidents account for a substantial portion of traffic accidents. Risky driving behavior is a main cause of traffic accidents. Understanding the risky driving behavior of truck drivers is therefore important in reducing truck-related accidents. This study aimed to propose and validate a research model that integrated a theory of planned behavior, sensation seeking, and risk perception to explain the risky driving behavior of truck drivers. A total of 471 valid data were collected from Chinese truck drivers in this study. Structural equation modeling and mediation analysis were used to examine the influence of factors in the research model on the risky driving behavior of truck drivers. Results showed that sensation seeking and risk perception of truck drivers were influential in shaping their intention to drive riskily with the mediation of attitude toward risky driving. Risk perception and attitude toward risky driving also had a negative influence and positive influence on the intention, respectively. On the basis of the findings, practical recommendations for reducing the risky driving behavior of truck drivers were provided for concerned parties.

This paper studies a UAV receiving system based on multi frequency point automatic search, and displays the received signal through OLED for human-computer interaction. Firstly, the system control chip controls the three channels to automatically search for different signal frequencies and receive the modulated signals transmitted from the transmitter. Then, the received signals are processed by the signal demodulation and low noise amplification of the receiving chip to realize the automatic search of the received signals without cross 24 frequency points. Finally, the RSSI strength is converted into digital quantities by A/D conversion, and the current signal is connected to the OLED display screen, outputting the received frequency data information.

Gestational trophoblastic disease (GTD) is a group of interrelated but distinct diseases and has a serious impact on the reproductive health of women. To analyze the expression of Nanog in GTD and to evaluate its potential to predict the development of gestational trophoblastic neoplasia (GTN).The study included 41 normal first-trimester placentas matched by gestational age to 53 regressed-hydatidiform-moles (rHMs), 56 malignant-HMs (mHMs) and 17 choriocarcinomas (CCAs) and evaluated the Nanog expression by immunohistochemistry. The chi-square test, ANOVA, Fisher's exact test and logistic regression were performed to assess the Nanog expression and clinical prognostic factors in GTD.Compared to normal placenta levels, the Nanog expression was increased in GTD samples (Nanog is an independent predictor of clinical outcomes. It can also be a reliable predictor for GTN development from GTD.

Objective: The aim of this study was to explore the association of dopamine receptor D2 (DRD2) polymorphism and alleviation of obesity in children and adolescents after 8-year follow-up. Methods: This retrospective cohort study included obese children and adolescents with a follow-up period of 8 years. Baseline clinical characteristics and DRD2 polymorphisms (including rs1076562, rs2075654, and rs4586205) were extracted from medical records. A follow-up visit was performed in May 2017 to collect related data including height, weight, diet compliance, and exercise compliance. Results: One hundred and nine obese children and adolescents were included in the current study. Among three DRD2 single nucleotide polymorphisms, only rs2075654 had a statistically significant association with alleviation of obesity, as the alleviation rate for minor allele carriers (68.6% for TC+TT) was higher compared to the major allele homozygote (43.3% for CC). After adjusting for all related factors, the hazard ratio of rs2075654 minor allele carriers for the alleviation of obesity was 3.34 (95% confidence interval (CI): 1.30‒8.58). Conclusions: The rs2075654 polymorphism of DRD2 is related to long-term obesity alleviation in obese Chinese children and adolescents.

microRNA (miR)-590 has been found to serve potential roles in cancer development; however, the expression and function of miR-590 in human gliomas remains to be elucidated. The present study aimed to investigate the expression of miR-590 in human glioma tissues and radioresistant human glioblastoma cells (U251R), and to determine the effect and related molecular mechanism of miR-590-3p on the radiosensitivity of U251R cells in vitro. The results from reverse transcription-quantitative polymerase chain reaction indicated that miR-590-3p was upregulated in human glioma tissues and radioresistant human glioblastoma cells, and that miR-590-3p expression was higher in high grade than in low grade gliomas. In vitro experiments revealed that the miR-590-3p inhibitor enhanced the radiosensitivity of U251R cells by suppressing cell viability, decreasing colony formation capacity and increasing cell apoptosis rate, as demonstrated by MTT, colony formation and flow cytometry analyses. A luciferase reporter assay demonstrated that leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) was a direct target of miR-590-3p. Furthermore, it was demonstrated that the effect of miR-590-3p suppression on cell viability, colony formation capacity and cell apoptosis rate was attenuated by the knockdown of LRIG1 in the U251R cells. In conclusion, the present study revealed that miR-590-3p was upregulated in human glioma tissues and radioresistant human glioblastoma cells, and miR-590-3p contributes to the radioresistance of human glioblastoma cells by directly targeting LRIG1. These findings may provide potential therapeutic strategies to prevent radioresistance in human gliomas.

The aim of this study was to investigate the clinical efficacy of high-intensity focused ultrasound (HIFU) for the treatment of a cesarean scar pregnancy compared with uterine artery embolization (UAE) and intra-arterial methotrexate infusion combined with uterine curettage. In this retrospective cohort study, 31 patients were treated with HIFU (HIFU group), and 45 patients were treated with UAE (UAE group). We compared the treatment and recovery of the patients, including follow-up. After UAE treatment, serum levels of the β subunit of human chorionic gonadotropin declined significantly on the first day, and the residual lesions disappeared in 3–17 wk. One patient underwent hysterectomy; intrauterine adhesions were found by hysteroscopic examination after 6 mo in 2 patients, whose menstrual function did not return to normal. The remainder of the 42 patients recovered normal menstrual functioning during the 3- to 18-wk follow-up. In the patients who underwent HIFU treatment, serum β-HCG levels did not decline rapidly; serum β-HCG levels increased in many patients and then declined to normal steadily within 2–12 wk. Lesions detached in 3–14 wk in all patients, and menstrual functioning was recovered in 3–9 wk without uterine curettage. Compared with the UAE group, the HIFU group had less pain and fewer complications; the patients in the HIFU group were not hospitalized or anesthetized and had lower costs. HIFU is an efficient, tolerable and non-invasive treatment.

In the high-speed design today, equalization (EQ) is one of the key enablers for many interfaces like PCIe and DDR in order to achieve higher data rates, lower power consumption and smaller form factor. Given that there may be multiple equalizers in the system and each of them can have very fine granularity, how to efficiently find out the optimal EQ setting is a very challenging problem for signal integrity engineers even with an linear time invariant (LTI) system. Besides, the circuit implementation of an equalizer like continuous time linear equalizer (CTLE) can be very nonlinear. The strong push for low power design has also inevitably introduced nonlinearity in drivers. Without the simulation capability of handling nonlinear elements and efficiently performing EQ optimization, designers have been forced to make LTI assumptions in their simulations and add cost to guardband for the uncertainty in the simulation predictions. It has eliminated many potentially valuable designs and also added cost and manufacturing complexity to existing designs. In this paper, we propose a new EQ optimization algorithm under the framework of the algorithm developed in [1]. It can avoid the bruteforce simulation of all EQ settings while preserving the nonlinear effects. The proposed method has been validated using a DDR5 example.

Acupoint catgut embedding is a useful therapy for weight management and widely applied in China. This review aimed to systematically evaluate the effects of acupoint catgut embedding on abdominal obesity. We searched the PubMed, Cochrane-Library, Embase, OVID, MEDLINE, ISI (web of science), Wanfang, VIP, CBM, and CNKI for randomized controlled trials that used acupoint catgut embedding to treat abdominal obesity before April 2019 with the language restriction of Chinese and English. The combination subject terms of abdominal obesity (or central obesity) and acupoint catgut embedding (or catgut implantation, catgut embedding) were used. We found 15 studies involving 1584 individuals. When acupoint catgut embedding plus electroacupuncture is compared with electroacupuncture alone, significant reductions in improvement rate (RR = 1.03, 95% CI = 0.99~1.08), body weight (MD = 5.20, 95%CI = 1.16~9.25), body mass index (MD = 1.73, 95%CI = 0.70~2.76), waist circumference (MD = 2.91, 95%CI = 1.36~4.46), and hip circumference (MD = 1.06, 95%CI = -0.18~2.30) were found. Mean values of body weight by acupoint catgut embedding were 1.35 kg compared with electroacupuncture. Less adverse events were reported in all included articles. In summary, pooled outcomes of acupoint catgut embedding presented a tendency of equal effects to other kinds of acupuncture, whereas acupoint catgut embedding plus electroacupuncture is more effective for abdominal obesity. This study is registered with PROSPERO 2017 (CRD42017082357).

In this letter we simulated the top of atmosphere (TOA) polarization patterns with scattering and absorbing aerosol situations through a successive orders of scattering (SOS) radiative transfer model. In the analysis of single scattering properties of aerosol particles, absorbing aerosol has an obvious different pattern from those non-absorbing aerosols. The TOA Degree of Linear Polarization (DoLP) decreases significantly when scattering aerosol optic depth (AOD) increases. While for absorbing aerosol case, the TOA DoLP keep stable or even increases when aerosol absorbing AOD increases, which suggest a way to retrieve absorbing property of aerosol.

Background Gitelman syndrome (GS) is an autosomal recessive disorder and mild variant of classic Bartter syndrome. The latter is caused by defects in the genes CLCNKB and/or CLCNKA (chloride voltage-gated channel Ka and Kb). Patients with GS usually have loss-of-function mutations in SLC12A3. No patient has been reported with compound heterozygous mutations in these genes. We report a girl with GS with a paternally inherited heterozygous mutation in SLC12A3, and maternally inherited heterozygous variants in both CLCNKB and CLCNKA. Case presentation In this report, we reported a female patient (8 y and 10 mo) who had growth retardation (111.8 cm, − 1.62 standard deviation height for age) and normal blood pressure, with persistent hypokalemia, hypomagnesemia, hypocalciuria, hypochloremic alkalosis, and elevated levels of plasma renin and aldosterone. Her younger brother, father, and paternal grandmother all had histories of mild low levels of plasma potassium (3.0–3.5 mmol/L), which were rectified by potassium-rich foods. The genomic DNA of the patient, younger brother, parents, and grandparents were screened for gene variations and pedigree analysis using trio whole exome sequencing (WES). The candidate variants were validated by Sanger sequencing. Protein-protein interaction analysis utilized the following databases: Biogrid, MINT, HPRD, STRING, IntAct, iRefIndex, and ppiTrim. The trio WES screening showed that the patient has paternally inherited SLC12A3 p.N359K, and maternally inherited CLCNKB p.L94I. The paternal grandmother and younger brother are both carriers of SLC12A3 p.N359K. According to the STRING database, SLC12A3 and CLCNKB proteins may interact or coexpress with proteins associated with GS. Conclusions Based on clinical phenotypes, genetic evidence of the pedigree, and previous reported studies, this case of GS indicates a digenetic inheritance of SLC12A3 and CLCNKB that resulted in renal tubular dysfunction perhaps, due to a genetic double-hit mechanism. The putative pathogenicity of the CLCNKB p.L94I variant requires confirmation.

High speed designs often involve transistors operating in linear region, transmission lines, voltage regulator, and other passive electromagnetic (EM) components. Therefore, linear time invariant (LTI) assumption has been prevalent in system analysis for decades. However, ever-increasing signal speed and lower power, area budget are pushing designs to strong nonlinear regimes, e.g., re-drivers (contain limiting amplifiers) have to be used to compensate for the high frequency channel loss. The nonlinear effect is further amplified when the signal is travelling across different physical mediums, resulting in multi-dimensional interaction among transistors, package, motherboard, and external devices. Such nonlinear effects deteriorate system analysis, especially for coupling between device and field. In this paper, we will present system analysis flow and a new approach to fast and accurately simulate such nonlinear high speed designs.

To report on two cases affected with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX).Two unrelated Chinese infants affected with IPEX were investigated. Case 1 was a 4-month-old boy with neonatal diabetes and severe enteropathy. Case 2 was a 6-day newborn boy with neonatal diabetes and ketoacidosis. DNA samples of the two infants and their parents were sequenced for FOXP3 gene mutations. Suspected mutations were verified among 100 unrelated healthy controls. The function of mutations was predicted with bioinformatics software.Both infants had onset of the disease during neonatal period, and manifested insulin-dependent diabetes mellitus, persistent diarrhea, eczema and malnutrition. In case 1, a novel splice site mutation was identified in intron 9 (c.967+3AT) of the FOXP3 gene, for which his mother was a carrier. For case 2, a missense mutation (c.1150GA) was detected in exon 11 of the FOXP3 gene, for which his mother was also a carrier. The IVS9 c.967+3A mutation was not detected among the 100 healthy controls. As predicted with Human Splicing Finder software, the c.967+3AT mutation may influence the splicing of mRNA and affect the function of protein.Both cases had typical clinical manifestation of the IPEX syndrome, among whom a novel splice site mutation (IVS9 c.967+3AT) and a missense mutation (c.1150GA) of the FOXP3 gene were identified. The clinical manifestation of the IPEX syndrome may be variable and the mortality is high. FOXP3 gene sequencing is recommended when insulin-dependent diabetes mellitus is diagnosed during the neonatal period.