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ObjectivesDevelop a digital phenotyping algorithm (PheIndex) using electronic medical records (EMR) data to identify children aged 0-3 who have been diagnosed with genetic disorders or present with illness with an increased risk for genetic disorders from a mother-child cohort.MethodsWe established 13 criteria for the algorithm where two metrics – a quantified score and a classification – were derived. The criteria and the classification were validated by chart review from a pediatrician and clinical geneticist. To demonstrate the utility of our algorithm in real-world evidence applications, we examined the association between size of carrier screening panel (small/≤4 genes [CS-S] vs large/≥100genes [CS-L]) undertaken by mothers prior to delivery, and children classified as presenting with illness with an increased risk for genetic disorders by our algorithm.ResultsThe PheIndex algorithm identified 1,088 such children out of 93,154 live births and achieved 90% sensitivity, 97% specificity, and 94% accuracy by chart review. We found that children whose mothers received CS-L were less likely to be classified as presenting with illness with an increased risk for genetic disorders and a decreased need to have multiple specialist visits and multiple ER visits, compared to children whose mothers received CS-S.ConclusionsThe PheIndex algorithm can help identify when a rare genetic disorder may be present, and has the potential to improve healthcare delivery by alerting providers to consider ordering a diagnostic genetic test and/or referring a patient to a medical geneticist or other specialists.Article SummaryAlgorithm using EMR data to identify children who have been diagnosed with a genetic disorder or present with illness with increased risk of genetic disorders.What’s known on this subjectWith over 7000 Mendelian disorders, identifying children with a specific rare genetic disorder diagnosis through structured EMR data is challenging given incompleteness of records, inaccurate medical diagnosis coding, as well as heterogeneity in clinical symptoms and procedures for specific disorders.What this study addsWe developed a digital phenotyping algorithm using electronic medical records (EMR) data to identify children aged 0-3 who have been diagnosed with genetic disorders or present with illness with an increased risk for genetic disorders from a mother-child cohort.

Detonation is a shock-induced combustion in which chemical reactions are closely coupled with shock waves. The shock wave compresses the reactant with an abrupt increase in temperature and pressure, initiating the reactants to be burnt into products. The intense heat release permits the high propagating speed of the shock wave to be sustained. It is fundamental research related to both the safety industry and propulsion systems. For most explosive mixtures, detonation wave speeds are formulated by Chapman–Jouguet (CJ) theory. Typical detonation velocities for gaseous mixtures generally range from 1400 to 3000 m/s. Behind the shock, the time scale for reactions is commonly on the order of microseconds or even less. Furthermore, the detonation front is intrinsically unstable, forming transient multi-dimensional structures. Many studies revealed that high resolution is necessary to resolve the essential detonation structures. Due to its complex nature and multiple time scales, detonation is thus a challenging problem for solvers on shock-capturing capability, robustness, and computational efficiency. This chapter will present several essential aspects of detonation research by applying the CESE schemes.

In this chapter, some remarks are made on the numerical characteristics of the CESE schemes described in foregoing chapters. Due to the special formulation, rigorous analysis of the CESE schemes will take more efforts than that of traditional finite difference schemes. However, it is possible to extend the widely used modified equation analysis, modified wavenumber analysis, and von Neumann stability analysis to the CESE schemes.

Multi-fluid flows involving shock-accelerated inhomogeneities and shock-induced instability play essential roles in a wide variety of problems including, but not limited to, supersonic combustion [1], inertial confinement fusion [2], and supernova explosion [3]. Numerical simulations of these complex flows prove to be challenging in the presence of moving and deformable material interfaces, especially for fluids with large differences in their densities or thermodynamic properties. Therefore, a discontinuity-capturing, mass-conserving, and positivity-preserving scheme is desirable for compressible multi-fluid simulations.

The previous chapter has shown that the necessary numerical dissipation can be introduced in 1D CESE schemes through either a central or upwind approach.

This chapter is dedicated to the description of high-order CESE schemes. In the second-order CESE schemes.

As depicted in Chap. 2, the interface between the two sub-CEs (CD in Fig. 2.7), belongs to the SE of (j, n). The flux FC needs to be calculated through the Taylor expansion at point (j, n) toward the inverse time direction. As a result, the a scheme is reversible. This violates the second law of thermodynamics. Thus, the non-dissipative core suffers from the unphysical oscillations for practical applications.

This chapter is devoted to demonstrating the basic ideas in the CESE method. These ideas include the adoption of a space–time integral form of governing equations as the starting point of scheme construction, as well as the introduction of conservation element (CE) and solution element (SE) in the discretization of space–time domain. Then, the non-dissipative core scheme of the CESE method will be presented in detail.

With the rapid development of electronic computers, numerical computation has become an important paradigm of scientific discovery as well as a powerful tool for engineering research. Solving complex problems in a computational fashion is more than applying theories, equations, and formulas. Computational methods, also called algorithms or schemes, have strong influences on the outcomes of computations.

In this book, the space–time CESE method is introduced as a novel and distinctive numerical approach to solving conservation equations in engineering sciences. Also, from a historical perspective, the development of the CESE method since the 1990s has been reviewed and the remarkable improvements and extensions of the CESE method in the past few years has been summarized. Various applications of the CESE method have been presented to emphasize its numerical performance under different scenarios, including many research topics in engineering, such as compressible multi-fluid flows and detonations.

We characterize the clinical utility and economic benefits of a comprehensive pan-ethnic carrier screening panel that spans 282 monogenic disease conditions in a large, diverse population of 397,540 reproductive health patients. For 142,049 of these patients, we were able to accurately estimate genetic ancestries across 7 major population groups. We examined individual carrier and at-risk carrier couple (ARCC) rates with respect to self-reported and genetic ancestries across ancestry-specific and pan-ethnic panels. Our results show that this comprehensive panel identified >10-times the ARCCs compared with a two-gene pan-ethnic panel and provided a substantial benefit over ancestry-specific screening panels across the major population groups. Finally, we generated a universal cost-of-care model across the monogenic disease conditions represented on the comprehensive pan-ethnic carrier screening panel to demonstrate potential healthcare savings in addition to the demonstrated clinical benefits that could be realized adopting this type of panel as standard of care for all.

Sesame harbors a large diversity in root morphological and anatomical traits and a high root biomass improves the plant aboveground biomass as well as the seed yield. Sesame provides one of the most nutritious and healthy vegetable oils, sparking an increasing demand of its seeds. However, with the low yield and productivity of sesame, there is still a huge gap between the seed demand and supply. Improving the root system has a high potential to increase crop productivity, but information on the diversity of the sesame root systems is still lacking. In this study, 40 diverse sesame varieties were grown in soil and hydroponics systems and the diversity of the root system was investigated. The results showed that sesame holds a large root morphological and anatomical diversity, which can be harnessed in breeding programmes. Based on the clustering of the genotypes in hydroponics and soil culture systems, we found that similar genotypes were commonly clustered either in the small-root or in the big-root group, indicating that the hydroponics system can be employed for a large-scale root phenotyping. Our results further revealed that the root biomass positively contributes to increased seed yield in sesame, based on multi-environmental trials. By comparing the root transcriptome of two contrasting genotypes, 2897 differentially expressed genes were detected and they were enriched in phenylpropanoid biosynthesis, starch and sucrose metabolism, stilbenoid, diarylheptanoid and gingerol biosynthesis, flavonoid biosynthesis, suggesting that these pathways are crucial for sesame root growth and development. Overall, this study sheds light on the diversity of sesame root system and offers the basis for improving root traits and increasing sesame seed yield.

An extended Zel'dovich–von Neumann–Doring (ZND) model has been proposed to address vibrational nonequilibrium mechanism. To expand the application of this extended ZND model in predicting flow characteristics under thermal nonequilibrium for hydrogen-related detonation simulations, a case of one-dimensional stoichiometric hydrogen-oxygen detonation with argon dilution is adopted for comparative study. A vibrational relaxation timescale is introduced in the extended ZND model together with simplified single-step and two-step chemical reaction models. In addition, a numerical simulation using the conservation element and solution element (CE/SE) algorithm and detailed chemistry with vibrational nonequilibrium coupling is conducted to serve as a benchmark for the model predictions. In this specific case study, predictions of half reaction length are in good agreement with simulations if the single-step Arrhenius model and the characteristic vibrational temperature of hydrogen are used. Compared with the detailed numerical simulations, the current extended ZND model and the simplified chemical models are demonstrated feasible and economical to predict the half reaction thickness under the vibrational nonequilibrium condition and can serve as one of the analytical tools in studying large-scale H2 O2 detonation.

The biosynthesis and storage of lipids in oil crop seeds involve many gene families, such as nonspecific lipid-transfer proteins (nsLTPs). nsLTPs are cysteine-rich small basic proteins essential for plant development and survival. However, in sesame, information related to nsLTPs was limited. Thus, the objectives of this study were to identify the Sesamum indicum nsLTPs (SiLTPs) and reveal their potential role in oil accumulation in sesame seeds. Genome-wide analysis revealed 52 SiLTPs, nonrandomly distributed on 10 chromosomes in the sesame variety Zhongzhi 13. Following recent classification methods, the SiLTPs were divided into nine types, among which types I and XI were the dominants. We found that the SiLTPs could interact with several transcription factors, including APETALA2 (AP2), DNA binding with one finger (Dof), etc. Transcriptome analysis showed a tissue-specific expression of some SiLTP genes. By integrating the SiLTPs expression profiles and the weighted gene co-expression network analysis (WGCNA) results of two contrasting oil content sesame varieties, we identified SiLTPI.23 and SiLTPI.28 as the candidate genes for high oil content in sesame seeds. The presumed functions of the candidate gene were validated through overexpression of SiLTPI.23 in Arabidopsis thaliana. These findings expand our knowledge on nsLTPs in sesame and provide resources for functional studies and genetic improvement of oil content in sesame seeds.

The ETS2 repressor factor (ERF) is a transcription factor in the RAS-MEK-ERK signal transduction cascade that regulates cell proliferation and differentiation, and pathogenic sequence variants in the ERF gene cause variable craniosynostosis inherited in an autosomal dominant pattern. The reported ERF variants are largely loss-of-function, implying haploinsufficiency as a primary disease mechanism; however, ERF gene deletions have not been reported previously. Here we describe three probands with macrocephaly, craniofacial dysmorphology, and global developmental delay. Clinical genetic testing for fragile X and other relevant sequencing panels were negative; however, chromosomal microarray identified heterozygous deletions (63.7–583.2 kb) on Chromosome 19q13.2 in each proband that together included five genes associated with Mendelian diseases (ATP1A3, ERF, CIC, MEGF8, and LIPE). Parental testing indicated that the aberrations were apparently de novo in two of the probands and were inherited in the one proband with the smallest deletion. Deletion of ERF is consistent with the reported loss-of-function ERF variants, prompting clinical copy-number-variant classifications of likely pathogenic. Moreover, the recent characterization of heterozygous loss-of-function CIC sequence variants as a cause of intellectual disability and neurodevelopmental disorders inherited in an autosomal dominant pattern is also consistent with the developmental delays and intellectual disabilities identified among the two probands with CIC deletions. Taken together, this case series adds to the previously reported patients with ERF and/or CIC sequence variants and supports haploinsufficiency of both genes as a mechanism for a variable syndromic cranial phenotype with developmental delays and intellectual disability inherited in an autosomal dominant pattern.

Numerical simulations were performed to investigate the re-initiation mechanism of a diffracted detonation wave near the critical channel width for a weakly unstable gas. Two scenarios were examined: diffraction of a planar detonation wave and of a cellular detonation wave inside the inlet channel. The results revealed that the critical channel width predicted using a cellular detonation wave is smaller than that predicted using a planar detonation wave. The re-initiation mechanisms are described in detail by tracing massless particles along both the plane of symmetry and the re-initiation path. For planar detonation diffractions, a compression wave is formed in the far field behind the diffracted shock. Re-initiation is closely related to the amplification of this compression wave and its coalescence with the diffracted shock. Depending on the inlet channel width, the strength of the reflected rarefaction wave is responsible for weakening the strength of the compression wave and its coalescence with the diffracted shock, consequently hindering the reaction of particles behind the diffracted shock wave. In cellular cases, the continuous collisions of transverse waves, which generate local explosion sites, sustain detonation wave propagation.

Aim: To comprehensively interrogate CYP2D6 by integrating genotyping, copy number analysis and novel strategies to identify CYP2D6*36 and characterize CYP2D6 duplications. Methods: Genotyping of 16 CYP2D6 alleles, multiplex ligation-dependent probe amplification (MLPA) and CYP2D6*36 and duplication allele-specific genotyping were performed on 427 African–American, Asian, Caucasian, Hispanic, and Ashkenazi Jewish individuals. Results: A novel PCR strategy determined that almost half of all CYP2D6*10 (100C>T) alleles are actually *36 (isolated or in tandem with *10) and all identified duplication alleles were characterized. Integrated results from all testing platforms enabled the refinement of genotype frequencies across all studied populations. Conclusion: The polymorphic CYP2D6 gene requires comprehensive interrogation to characterize allelic variation across ethnicities, which was enabled in this study by integrating multiplexed genotyping, MLPA copy number analysis, novel PCR strategies and duplication allele-specific genotyping.

The cover image is based on the Original Article Lessons learned from expanded reproductive carrier screening in self‐reported Ashkenazi, Sephardi, and Mizrahi Jewish patients by Gidon Akler et al., https://doi.org/10.1002/mgg3.1053. [Image: see text]

Discrepancies in detonation cell size are always found between experiments and numerical simulations. The recent numerical simulation by Shi et al. (2016) included the vibrational relaxation effect in molecules and revealed that the vibrational nonequilibrium effect may be one of the reasons for the above discrepancy. In this study, a steady one-dimensional Zel'dovich–von Neumann–Doring (ZND) model is modified to account for the vibrational nonequilibrium effect in gaseous detonation. By introducing a new parameter α, which is defined as the ratio of translational-rotational mode of the specific heat at constant volume to the overall specific heat at constant volume, the translational-rotational energy and the vibrational energy are treated separately in the energy conservation equation. Both the single step and the two step Arrhenius models are used to describe the chemical reaction progress, and the Landau–Teller model and Park's two-temperature model are applied to describe the vibrational energy relaxation and the coupling between the molecular vibration and the chemical reaction, respectively. The parametric study on the modified ZND model is conducted and compared with the conventional ZND one, including the activation energy in chemical model, the ratio of the chemical time scale to the vibrational relaxation time scale and the characteristic vibrational temperature. The results show that the half reaction length is relatively not sensitive to the variation of characteristic vibrational temperature applied in the model (compared with the activation energy and the time ratio), but is increased to a significant extent with the increase of the activation energy and the decrease of the time ratio, when considered the vibrational nonequilibrium. The simulated half reaction lengths in the modified model are in good agreement with those in the conventional model, if the chemical time scale is larger than the vibrational relaxation time scale above a critical ratio when the vibrational nonequilibrium effect is insignificant.

Mosaicism due to somatic mutations can cause multiple diseases including cancer, developmental and overgrowth syndromes, neurodevelopmental disorders, autoinflammatory diseases, and atrial fibrillation. With the increased use of next generation sequencing technology, multiple tools have been developed to identify low-frequency variants, specifically from matched tumor-normal tissues in cancer studies. To investigate whether mosaic variants are implicated in congenital heart disease (CHD), we developed a pipeline using the cancer somatic variant caller MuTect to identify mosaic variants in whole-exome sequencing (WES) data from a cohort of parent/affected child trios (n = 715) and a cohort of healthy individuals (n = 416). This is a novel application of the somatic variant caller designed for cancer to WES trio data. We identified two cases with mosaic KMT2D mutations that are likely pathogenic for CHD, but conclude that, overall, mosaicism detectable in peripheral blood or saliva does not account for a significant portion of CHD etiology.

Multilocus analysis of rare or genetically heterogeneous diseases is a distinct advantage of next-generation sequencing (NGS) over conventional single-gene investigations. Recent studies have begun to uncover an under-recognized prevalence of dual molecular diagnoses in patients with a “blended” phenotype that is the result of 2 clinical diagnoses involving 2 separate genetic loci. This blended phenotype could be mistakenly interpreted as a novel clinical extension of a single-gene disorder. In this study, we ascertained a proband from a large consanguineous Iranian family who manifests postlingual, progressive, moderate hearing loss in addition to suspected Ellis-van Creveld syndrome phenotype. NGS with a customized skeletal dysplasia panel containing over 370 genes and subsequent bioinformatics analysis disclosed 2 homozygous mutations in EVC2 (c.2653C>T; p.Arg885*) and COL11A2 (c.966dup; p.Thr323Hisfs*19), respectively. This study highlights a dual molecular diagnosis in a patient with a blending of 2 distinct phenotypes and illustrates the advantage and importance of this staple technology to facilitate rapid and comprehensive genetic dissection of a heterogeneous phenotype. The differentiation between phenotypic expansion of a genetic disorder and a blended phenotype that is due to more than one distinct genetic aberration is essential in order to reduce the diagnostic odyssey endured by patients.

Background Next‐generation sequencing (NGS)‐based panels have gained traction as a strategy for reproductive carrier screening. Their value for screening Ashkenazi Jewish (AJ) individuals, who have benefited greatly from population‐wide targeted testing, as well as Sephardi/Mizrahi Jewish (SMJ) individuals (an underserved population), has not been fully explored. Methods The clinical utilization by 6,805 self‐reported Jewish individuals of an expanded NGS panel, along with several ancillary assays, was assessed retrospectively. Data were extracted for a subset of 96 diseases that, during the panel design phase, were classified as being AJ‐, SMJ‐, or pan‐Jewish/pan‐ethnic‐relevant. Results 64.6% of individuals were identified as carriers of one or more of these 96 diseases. Over 80% of the reported variants would have been missed by following recommended AJ screening guidelines. 10.7% of variants reported for AJs were in “SMJ‐relevant genes,” and 31.2% reported for SMJs were in “AJ‐relevant genes.” Roughly 2.5% of individuals carried a novel, likely pathogenic variant. One in 16 linked cohort couples was identified as a carrier couple for at least one of these 96 diseases. Conclusion For maximal carrier identification, this study supports using expanded NGS panels for individuals of all Jewish backgrounds. This approach can better empower at‐risk couples for reproductive decision making., This retrospective study examines a specific cohort of 6,805 self‐reported Jewish (Ashkenazi/Sephardi/Mizrahi) patients who underwent carrier screening using NGS‐based expanded panels. Results are presented from an extracted set of 96 genes initially classified as “Jewish‐relevant,” albeit that a majority of the patients (79% of cohort) opted for much larger panels that contained this set of 96. The findings highlight the value of large, universal sequence‐based panels, given that (a) self‐reported ethnic information is often unreliable/complex, and (b) many patients want maximal information for their reproductive decision making.

Here, we report the prenatal detection of a compound heterozygous deletion at chromosome 15q15.3 by clinical chromosomal microarray (CMA) testing that included the CATSPER2 male infertility gene. However, given the low resolution of CMA at this homologous locus, it was unclear if the neighboring STRC hearing loss gene was also affected. Therefore, we developed a novel allele‐specific PCR strategy, which narrowed the proximal breakpoint of the maternally inherited deletion to a 310 bp interval that was 440 bp upstream from the STRC transcription start site.

The ETS2 repressor factor (ERF) is a transcription factor in the RAS-MEK-ERK signal transduction cascade that regulates cell proliferation and differentiation, and pathogenic sequence variants in the ERF gene cause variable craniosynostosis inherited in an autosomal dominant pattern. The reported ERF variants are largely loss-of-function, implying haploinsufficiency as a primary disease mechanism; however, ERF gene deletions have not been reported previously. Here we describe three probands with macrocephaly, craniofacial dysmorphology, and global developmental delay. Clinical genetic testing for fragile X and other relevant sequencing panels were negative; however, chromosomal microarray identified heterozygous deletions (63.7–583.2 kb) on Chromosome 19q13.2 in each proband that together included five genes associated with Mendelian diseases (ATP1A3, ERF, CIC, MEGF8, and LIPE). Parental testing indicated that the aberrations were apparently de novo in two of the probands and were inherited in the one proband with the smallest deletion. Deletion of ERF is consistent with the reported loss-of-function ERF variants, prompting clinical copy-number-variant classifications of likely pathogenic. Moreover, the recent characterization of heterozygous loss-of-function CIC sequence variants as a cause of intellectual disability and neurodevelopmental disorders inherited in an autosomal dominant pattern is also consistent with the developmental delays and intellectual disabilities identified among the two probands with CIC deletions. Taken together, this case series adds to the previously reported patients with ERF and/or CIC sequence variants and supports haploinsufficiency of both genes as a mechanism for a variable syndromic cranial phenotype with developmental delays and intellectual disability inherited in an autosomal dominant pattern.

To resolve the discrepancy between the numerical detonation cell size and experimental observations, simulations are conducted with a detailed thermochemical reaction model for a premixed argon-diluted hydrogen-oxygen mixture. Four different scenarios are considered: (i) The whole system is in thermodynamic equilibrium; (ii) the vibrational relaxation is considered and the translational-rotational temperature is used as the dominant temperature of the chemical reactions; (iii) the same non-equilibrium effect as in the second scenario is used along with Park’s two-temperature model to account for the effect of vibrational temperature on chemical reaction rates; and (iv) a more physically consistent vibration-chemistry-vibration coupling model is adopted. The simulated detonation cell widths for the first and second scenarios are significantly lower than the experimental measurements, whereas reasonable agreement is observed for the third and fourth scenarios. These results confirm that the involvem...

The aim of current research work on micro air vehicles is to realize their autonomous control, i.e. building a library for a lookup table that would apply to micro electronics. In doing so, comprehensive flight tests need to be carried out. In this study, a four-wing flapping MAV is built and a multi-discipline approach is used to design the MAV model. Precision manufacturing technology is introduced here. The finished micro air vehicle has a weight of 8 g and is tested for flight by remote control. The micro air vehicle can perform both hovering and forward flight with high maneuverability. Forward flight is investigated first in this paper. Particle image velocimetry system is employed to examine unsteady aerodynamic performance in selected flight conditions. The study reveals that the micro air vehicle model will provide enough lift at a 30° angle of attack and flapping frequency of 12 Hz, which is consistent with real-life forward flight observations.

The Ashkenazi Jewish (AJ) population has an increased risk for a variety of recessive diseases due to historical founder effects and genetic drift. For some, the disease-causing founder mutations have been identified and well-characterized, but for others, further study is necessary. The purpose of this study is to assess the carrier frequencies of 85 pathogenic variants causative of 29 recessive conditions in the AJ population. Up to 3000 AJ individuals were genotyped by Luminex MagPlex®-TAG™ bead array or Agena Bioscience™ MassARRAY assays. We identified seven conditions with carrier frequencies higher than 1 in 100, nine between 1 in 100 and 1 in 200, and four between 1 in 200 and 1 in 500. Variants in nine conditions had a detected carrier rate of less than 1 in 500 or were not identified in approximately 2000 AJ individuals. We assessed the combined AJ carrier frequency for 18 relatively prevalent diseases to be 1 in 6, and the risk of AJ individuals to be a carrier couple for one of these 18 diseases as 1 in 441. We note additional recessive genetic conditions should be considered for AJ carrier screening panels.

A one-dimensional numerical simulation of detonation propagation is performed with an introduction of the vibrational relaxation mechanism in a single-step chemical model for the first time. This coupling mechanism is constructed based on the energy transfer between the translational-rotational mode and the vibrational mode, together with an averaged two-temperature model in chemical kinetics. A time ratio τ α between the characteristic chemical time scale and the characteristic vibrational time scale is introduced to illustrate whether this coupling effect is crucial in stabilizing the detonation. The simulation is initialized first with an extended steady-state profile and the inclusion of the vibrational energy in the equations. For the particular case considered in this study with a nondimensional heat release Q = 50 , a ratio of specific heat γ = 1.2 , and a nondimensional characteristic vibrational temperature ϑ = 20 , the stability boundary is indicated at an activation energy E a = 26.47 under thermal equilibrium. Two mildly unstable cases for a Chapman-Jouguet (CJ) detonation and an overdriven detonation are then studied with the variation of τ α . The results reveal that the detonation is stabilized by the vibrational nonequilibrium effect with a smaller pulsation amplitude and a longer oscillation period in the shock pressure history, and the neutral stability is shifted. For the CJ detonation case, the critical τ α below which the coupling effect is significant is 7.2. The stabilization of detonation can be attributed to the reduction of the overall chemical reaction rate by vibrational relaxation and thus a shift of the stability limit towards higher activation energy. For an overdriven detonation, the critical τ α is approximately 21 for the studied cases. Since the changes in both overdriven factors f and τ α contributed to the stabilization of detonation, a reduction of the neutral stability limit of f is foreseen when the coupling effect is significant. Lastly, the effect of different ϑ on the stability limit is demonstrated at equilibrium state with vibrational energy included and it is suggested that the shift of stability limit would reach the maximum at around ϑ = 15 . This inaugural work provides a reference on the importance of considering thermal nonequilibrium flow in detonation stability and the implication to the related engine design.

This paper reports a modified steady one-dimensional Zel’dovich–von Neumann–Doring detonation model that considers a vibrational nonequilibrium effect. The Landau–Teller model is adapted for the translational–rotational to vibrational mode exchange rate, and Park’s two-temperature model is applied in the single-step Arrhenius equation. The Millikan and White method is chosen to model the vibrational relaxation time. In this modified model, α is introduced and is defined as the ratio of the specific heat capacity related to the translational–rotational mode only versus the total specific heat capacity at constant pressure. Changes in half-reaction zone length and predicted postshock thermodynamic properties are observed in this modified profile across the postshock state to the Chapman–Jouguet state. The findings agree with a previous numerical simulation of gas detonation with detailed chemistry assessment, in which detonation cell size changes under a vibrational nonequilibrium assumption.

Despite advances by genome-wide association studies (GWAS), much of heritability of common human diseases remains missing, a phenomenon referred to as ‘missing heritability’. One potential cause for ‘missing heritability’ is the rare susceptibility variants overlooked by GWAS. Atrial fibrillation (AF) is the most common arrhythmia seen at hospitals and increases risk of stroke by 5-fold and doubles risk of heart failure and sudden death. Here we studied one large Chinese family with AF and hypertrophic cardiomyopathy (HCM). Whole-exome sequencing analysis identified a mutation in TNNI3, R186Q, that co-segregated with the disease in the family, but did not exist in >1,583 controls, suggesting that R186Q causes AF and HCM. High-resolution melting curve analysis and direct DNA sequence analysis were then used to screen mutations in all exons and exon-intron boundaries of TNNI3 in a panel of 1,127 unrelated AF patients and 1,583 non-AF subjects. Four novel missense variants were identified in TNNI3, including E64G, M154L, E187G and D196G in four independent AF patients, but no variant was found in 1,583 non-AF subjects. All variants were not found in public databases, including the ExAC Browser database with 60,706 exomes. These data suggests that rare TNNI3 variants are associated with AF (P=0.03). TNNI3 encodes troponin I, a key regulator of the contraction-relaxation function of cardiac muscle and was not previously implicated in AF. Thus, this study may identify a new biological pathway for the pathogenesis of AF and provides evidence to support the rare variant hypothesis for missing heritability.

Bardet–Biedl syndrome (BBS) is a recessive disorder characterized by heterogeneous clinical manifestations, including truncal obesity, rod-cone dystrophy, renal anomalies, postaxial polydactyly, and variable developmental delays. At least 20 genes have been implicated in BBS, and all are involved in primary cilia function. We report a 1-year-old male child from Guyana with obesity, postaxial polydactyly on his right foot, hypotonia, ophthalmologic abnormalities, and developmental delay, which together indicated a clinical diagnosis of BBS. Clinical chromosomal microarray (CMA) testing and high-throughput BBS gene panel sequencing detected a homozygous 7p14.3 deletion of exons 1–4 of BBS9 that was encompassed by a 17.5 Mb region of homozygosity at chromosome 7p14.2–p21.1. The precise breakpoints of the deletion were delineated to a 72.8 kb region in the proband and carrier parents by third-generation long-read single molecule real-time (SMRT) sequencing (Pacific Biosciences), which suggested non-homologous end joining as a likely mechanism of formation. Long-read SMRT sequencing of the deletion breakpoints also determined that the aberration included the neighboring RP9 gene implicated in retinitis pigmentosa; however, the clinical significance of this was considered uncertain given the paucity of reported cases with unambiguous RP9 mutations. Taken together, our study characterized a BBS9 deletion, and the identification of this shared haplotype in the parents suggests that this pathogenic aberration may be a BBS founder mutation in the Guyanese population. Importantly, this informative case also highlights the utility of long-read SMRT sequencing to map nucleotide breakpoints of clinically relevant structural variants.

Hoyeraal-Hreidarsson syndrome (HH) is a clinically severe variant of dyskeratosis congenita (DC), characterized by cerebellar hypoplasia, microcephaly, intrauterine growth retardation, and severe immunodeficiency in addition to features of DC. Germline mutations in the RTEL1 gene have recently been identified as causative of HH. In this study, the carrier frequency for five RTEL1 mutations that occurred in individuals of Ashkenazi Jewish descent was investigated in order to advise on including them in existing clinical mutation panels for this population. Our screening showed that the carrier frequency for c.3791G>A (p.R1264H) was higher than expected, 1% in the Ashkenazi Orthodox and 0.45% in the general Ashkenazi Jewish population. Haplotype analyses suggested the presence of a common founder. We recommend that the c.3791G>A RTEL1 mutation be considered for inclusion in carrier screening panels in the Ashkenazi population.

OBJECTIVE Recent genome-wide association studies (GWAS) revealed that a 9p21.3 locus was associated with type 2 diabetes. In this study, we carried out a large-scale case-control study in the GeneID Chinese Han population to 1) further replicate the association of 9p21.3 type 2 diabetes GWAS single nucleotide polymorphisms (SNPs) and 2) assess the association of these SNPs with coronary artery disease. RESEARCH DESIGN AND METHODS Three SNPs (rs2383208, rs10811661, and rs10757283) were genotyped in two GeneID cohorts of 3,167 Chinese Han individuals. Case-control association design was used to determine the association of the SNPs with type 2 diabetes and coronary artery disease. Gensini scores were calculated in the coronary artery disease subjects and were tested for association with the variants. Multivariate logistic regressions were performed on association studies. RESULTS The association between two of the three SNPs and type 2 diabetes was replicated in the GeneID population (rs2383208, P = 0.936; rs10811661-T, P = 0.02, odds ratio [OR] = 1.23; rs10757283-C, P = 0.003, OR = 1.30). The same two SNPs also contributed to the risk of coronary artery disease (CAD) (rs10811661-T, P = 0.002, OR = 1.19; rs10757283-C, P = 0.003, OR = 1.18). In addition, rs10757283 was associated with severity of coronary atherosclerosis estimated by the Gensini scoring system (risk allele C, quantitative-trait regression adjusted P = 0.002). CONCLUSIONS For the first time to our knowledge, our results indicated that the same 9p21.3 locus, represented by SNPs rs10811661 and rs10757283, contributed to the risk of type 2 diabetes and coronary artery disease in our GeneID Chinese Han population.

Background Genetic studies have shown that many slow cardiac myosin regulatory light chain 2 (MYL2) gene mutations can cause hypertrophic cardiomyopathy, which is one of the most common causes of heart failure (HF). But until now there has been no pathological or histological evidence that MYL2 may be associated with HF development. Recent microarray studies indicated that myosin heavy chain expression changed in the pathological process of HF. Because MYL2 is a regulatory component of myosin heavy polypeptide, the role of MYL2 protein in HF needs to be studied. Hypothesis The level of expression of MYL2 may change in the heart tissue of patients with chronic HF. Methods We collected 28 human right auricle samples, 16 from chronic HF patients and 12 from healthy control subjects. Immunohistochemistry was carried out to observe the tissue-expression pattern of the MYL2 protein and Western blot methods were performed to quantify the relative MYL2 expression level. Results In chronic HF patients, the MYL2 protein level decreased significantly compared with normal controls (t test P < 0.05). Among the 16 HF patients, MYL2 expression in the severe HF group (New York Heart Association [NYHA] class III or IV) was even lower than that of the moderate HF group (NYHA class II) (t test P < 0.05). Conclusions MYL2 was down-expressed in HF tissues, and our findings suggested that MYL2 may play a role in the development and progression of chronic HF. Copyright © 2008 Wiley Periodicals, Inc. The first two authors contributed equally to this work. This study was supported by the National Natural Science Foundation of China (30800457, 30900803) and the Natural Science Program of Hubei Province (2009CDZ013). This study has no relationship with any kind of industry. The authors have no other funding, financial relationships, or conflicts of interest to disclose.

Atrial fibrillation (AF) is the most common cardiac rhythm disorder at the clinical setting and accounts for up to 15% of all strokes. Recent genome-wide association studies (GWAS) identified two single nucleotide polymorphisms (SNPs), rs2106261 and rs7193343 in ZFHX3 (zinc finger homeobox 3 gene) and rs13376333 in KCNN3 (encoding a potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3) that showed significant association with AF in multiple populations of European ancestry. Here, we studied a Chinese Han, GeneID cohort consisting of 650 AF patients and 1,447 non-AF controls to test whether the GWAS findings on ZFHX3/KCNN3 and AF can be expanded to a different ethnic population. No significant association was detected for rs7193343 in ZFHX3 and rs13376333 in KCNN3. However, significant association was identified between rs2106261 in ZFHX3 and AF in the GeneID population for both allelic frequencies (P = 0.001 after adjusting for covariates of age, gender, hypertension, coronary artery disease, and diabetes mellitus; OR = 1.32), and genotypic frequencies assuming either an additive or recessive model (OR = 1.29, P = 0.001 and OR = 1.77, P = 0.00018, respectively). When only lone AF cases were analyzed, the association remained significant (OR = 1.50, P = 0.001 for allelic association; OR = 1.45, P = 0.001 for an additive model; OR = 2.24, P = 0.000043 for a recessive model). Our results indicate that rs2106261 in ZFHX3 confers a significant risk of AF in a Chinese Han population. The study expands the association between ZFHX3 and AF to a non-European ancestry population and provides the first evidence of a cross-race susceptibility of the 16q22 AF locus.

X-linked hypohidrotic ectodermal dysplasia (XLHED, OMIM 305100) is a rare congenital disorder that results in the defective development of teeth, hair, nails, and eccrine sweat glands. Previous studies found that mutations in the ectodysplasin A (EDA) gene are associated with XLHED. In the present study, we investigated four Chinese families suffering from classical XLHED and investigated two additional families segregating hypodontia in an X-linked recessive manner. Mutations were characterized respectively in the EDA gene in all families, and five of these mutations were found to be novel. Among these mutations, five were missense (c.200A>T, c.463C>T, c.758T>C, c.926T>G, and c.491A>C) and located in the functional domain of EDA, and one was a splice donor site mutation in intron 5 (c.IVS5 + 1G>A), which may result in an alternative transcript derived from a new cryptic splice site. Our data further confirm that EDA mutations could cause both XLHED and isolated hypodontia and provide evidence that EDA is a strong candidate gene for tooth genesis.

Ellis-van Creveld syndrome (EvC) is a rare autosomal recessive disorder characterized by disproportionate chondrodysplasia, postaxial polydactyly, nail dystrophy, dental abnormalities and in a proportion of patients, congenital cardiac malformations. Weyers acrofacial dysostosis (Weyers) is another dominantly inherited disorder allelic to EvC syndrome but with milder phenotypes. Both disorders can result from loss-of-function mutations in either EVC or EVC2 gene, and phenotypes associated with the two gene mutations are clinically indistinguishable. We present here a clinical and molecular analysis of a Chinese family manifested specific features of EvC syndrome. Sequencing of both EVC and EVC2 identified two novel heterozygous splice site mutations c.384+5G>C in intron 3 and c.1465-1G>A in intron 10 in EVC, which were inherited from mother and father, respectively. In vitro minigene expression assay, RT-PCR and sequencing analysis demonstrated that c.384+5G>C mutation abolished normal splice site and created a new cryptic acceptor site within exon 4, whereas c.1465-1G>A mutation affected consensus splice junction site and resulted in full exon 11 skipping. These two aberrant pre-mRNA splicing processes both produced in-frame abnormal transcripts that possibly led to abolishment of important functional domains. To our knowledge, this is the first report of EVC mutations that cause EvC syndrome in Chinese population. Our data revealed that EVC splice site mutations altered splicing pattern and helped elucidate the pathogenesis of EvC syndrome.