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Objective: Mitochondrial complex‐I deficiency, nuclear type 16, is a rare autosomal recessive disorder caused by biallelic pathogenic variants in NDUFAF5 (C20orf7) (OMIM 618238). The aim of this study was to describe a severe early prenatal manifestation of this disorder, which was previously considered to occur only postnatally. Methods: This was a multicenter retrospective case series including five fetuses from three non‐related families, which shared common sonographic abnormalities, including brain cysts, corpus callosal malformations, non‐immune hydrops fetalis and growth restriction. Genetic evaluation included chromosomal microarray analysis and exome sequencing. Two fetuses from the same family were also available for pathology examination, including electron microscopy. Results: Chromosomal microarray analysis revealed no chromosomal abnormality in any of the tested cases. Trio exome sequencing demonstrated that three affected fetuses from three unrelated families were compound heterozygous or homozygous for likely pathogenic variants in NDUFAF5. No other causative variants were detected. The association between NDUFAF5 variants and fetal malformations was further confirmed by segregation analysis. Histological evaluation of fetal tissues and electron microscopy of the skeletal muscle, liver, proximal tubules and heart demonstrated changes that resembled postmortem findings in patients with mitochondrial depletion disorders as well as previously undescribed findings. Conclusions: Mitochondrial complex‐I deficiency and specifically biallelic mutations in NDUFAF5 have a role in abnormal fetal development, presenting with severe congenital malformations. Mitochondrial complex‐I disorders should be considered in the differential diagnosis of corpus callosal malformations and brain cysts, especially when associated with extracranial abnormalities, such as fetal growth restriction and non‐immune hydrops fetalis. © 2023 International Society of Ultrasound in Obstetrics and Gynecology. Linked article: There is a comment on this article by Finsterer. Click here to view the Correspondence. [ABSTRACT FROM AUTHOR]

Objectives: To determine the incremental diagnostic yield of exome sequencing (ES) after negative chromosomal microarray analysis (CMA) in cases of prenatally diagnosed agenesis of the corpus callosum (ACC) and to identify the associated genes and variants. Methods: A systematic search was performed to identify relevant studies published up until June 2022 using four databases: PubMed, SCOPUS, Web of Science and The Cochrane Library. Studies in English reporting on the diagnostic yield of ES following negative CMA in prenatally diagnosed partial or complete ACC were included. Authors of cohort studies were contacted for individual participant data and extended cohorts were provided for two of them. The increase in diagnostic yield with ES for pathogenic/likely pathogenic (P/LP) variants was assessed in all cases of ACC, isolated ACC, ACC with other cranial anomalies and ACC with extracranial anomalies. To identify all reported genetic variants, the systematic review included all ACC cases; however, for the meta‐analysis, only studies with ≥ three ACC cases were included. Meta‐analysis of proportions was employed using a random‐effects model. Quality assessment of the included studies was performed using modified Standards for Reporting of Diagnostic Accuracy criteria. Results: A total of 28 studies, encompassing 288 prenatally diagnosed ACC cases that underwent ES following negative CMA, met the inclusion criteria of the systematic review. We classified 116 genetic variants in 83 genes associated with prenatal ACC with a full phenotypic description. There were 15 studies, encompassing 268 cases, that reported on ≥ three ACC cases and were included in the meta‐analysis. Of all the included cases, 43% had a P/LP variant on ES. The highest yield was for ACC with extracranial anomalies (55% (95% CI, 35–73%)), followed by ACC with other cranial anomalies (43% (95% CI, 30–57%)) and isolated ACC (32% (95% CI, 18–51%)). Conclusions: ES demonstrated an incremental diagnostic yield in cases of prenatally diagnosed ACC following negative CMA. While the greatest diagnostic yield was observed in ACC with extracranial anomalies and ACC with other central nervous system anomalies, ES should also be considered in cases of isolated ACC. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

The authors of the article titled "Unique prenatal manifestations of biallelic NDUFAF5 variants: expansion of phenotype" respond to comments made by Dr. Finsterer. They clarify that their study did not report on cases of intrauterine fetal death, but rather on cases of termination due to fetal anomalies. They also explain that functional or biochemical testing is not mandatory for determining variant pathogenicity according to the American College of Medical Genetics and Genomics guidelines. The authors provide evidence supporting the pathogenicity of the NDUFAF5 variants they studied and acknowledge the need for further research on one of the variants. They assert that their study contributes to the understanding of prenatal presentations of NDUFAF5-associated disorders and emphasize the challenges of studying prenatal phenotypes. The authors address Dr. Finsterer's mention of other possible abnormalities associated with NDUFAF5 variants and state that the lack of demonstration does not negate their assumption that these variants are causative of the congenital anomalies described in their study. They also clarify that family history and parental carrier status were included in their original manuscript. [Extracted from the article]

This article, titled "EP18.14: The fetal brain in RASopathies: Noonan genes revisited," explores the neurodevelopmental variability and brain imaging features of patients with RASopathies. The study focuses on describing the fetal brain and associated features of fetuses with confirmed RASopathies. The researchers conducted a retrospective study that included four patients with variants in RIT1, LZTR1, RRAS-2, and PTPN11. The findings highlight the range of features observed in fetal brain imaging and emphasize the importance of prenatal assessment for accurate diagnosis and counseling. [Extracted from the article]

Objective: Prenatally detected central nervous system (CNS) anomalies present a diagnostic challenge. In this study, we compared the diagnostic yield of exome sequencing (ES) and chromosomal microarray analysis (CMA) in fetuses with a major CNS anomaly.Methods: This was a retrospective study of 114 cases referred for genetic evaluation following termination of pregnancy (TOP) due to a major CNS anomaly detected on prenatal ultrasound. All fetuses were first analyzed by CMA. All CMA-negative cases were offered ES. CMA-positive cases were reanalyzed using ES to assess its ability to detect copy-number variants (CNVs).Results: CMA identified a pathogenic or likely pathogenic (P/LP) CNV in 11/114 (10%) cases. Eighty-six CMA-negative cases were analyzed using ES, which detected P/LP sequence variants in 38/86 (44%). Among recurrent cases (i.e. cases with a previously affected pregnancy), the incidence of P/LP sequence variants was non-significantly higher compared with non-recurrent ones (12/19 (63%) vs 26/67 (39%); P = 0.06). Among the 38 cases with an ES diagnosis, 20 (53%) were inherited and carried a significant risk of recurrence. Reanalysis of 10 CMA-positive cases by ES demonstrated that the bioinformatics pipeline used for sequence variant analysis also detected all P/LP CNVs, as well as three previously known non-causative CNVs.Conclusions: In our study, ES provided a high diagnostic yield (> 50%) in fetuses with severe CNS structural anomalies, which may have been partly due to the highly selected case series that included post-TOP cases from a specialist referral center. These data suggest that ES may be considered as a first-tier test for the prenatal diagnosis of major fetal CNS anomalies, detecting both P/LP sequence variants and CNVs. This is of particular importance given the time constraints of an ongoing pregnancy and the risk of recurrence in future pregnancies. © 2022 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology. [ABSTRACT FROM AUTHOR]

This article discusses a case study involving a non-consanguineous Jewish couple who terminated a pregnancy due to multiple brain malformations. The couple sought genetic counseling, and trio exome sequencing revealed a heterozygous de-novo likely pathogenic variant in the KIDINS220 gene. This gene encodes a protein that plays a crucial role in embryonic neuronal differentiation and the maturation of axonal/dendritic processes. Heterozygous variants in KIDINS220 have been linked to a syndrome characterized by spastic paraplegia, intellectual disability, nystagmus, and obesity. The report emphasizes the importance of additional investigations in cases of non-isolated ventriculomegaly and expands the prenatal phenotype associated with KIDINS220 variants. [Extracted from the article]

This has been discussed in detail in a recent systematic review by Mellis I et al i .[2], demonstrating that the incremental diagnostic yield of ES over CMA/karyotyping was 15% for non-selected fetal anomalies, 42% for selected anomalies and 17% for CNS anomalies. While patients were offered concurrent chromosomal microarray analysis (CMA) and exome sequencing (ES), most opted for termination of pregnancy even before receiving a genetic test result due to the severity of anomalies and because ES in pregnancy is currently not covered by the Israeli healthcare system. Even if the fetal phenotype may not appear to be severe enough to warrant termination of pregnancy, a genetic test result may point to a severe neurodevelopmental issue that has only mild physical manifestations. [Extracted from the article]

We describe the use of a novel, computerized, multiple outdoor microalgal growth system to achieve conditions maximizing high photosynthesis and biomass production rates. We applied this system to determine the effects of multiple environmental and culture parameters such as light, temperature, pH, and mode of mixing and CO2 supply, and their combinations on the rates of algal photosynthesis, respiration, and growth. We continuously monitored the following parameters: pH, temperature, dissolved oxygen, and light, concomitantly with algal growth and biomass production rates. In particular, we likewise monitored and determined the dramatic effects of CO2 supply, mixing by paddle wheel or bubbling air modes, on algal biomass production. The isolated and synergistic effects of each factor and operation regime were measured and are discussed. We found that the diel range of maxima to minimal pH and oxygen levels strongly correlated with container performance, and were controllable by CO2 supply and mixing regime. We conclude that mixing by bubble aeration was the most important growth-rate controlling factor. It limited the build-up of high oxygen and pH levels that reduce photosynthesis that were measured by O2 evolution. In this study, OD measurements calibrated with biomass concentrations were used to calculate growth rates and estimate the photosynthetic rates of the microalgae. The potential of algae as a source of food, feed, biofuel, and fine chemicals has been widely recognized, but their competitiveness depends on areal yields. Our results allow us to recommend culture parameters that increase areal biomass yields, regardless of the algal species, thereby bringing microalgal mass culture closer to economic viability.

OC12.05: Early second trimester diagnosis of fetal midbrain-hindbrain malformations: a transvaginal neurosonographic study To describe the clinical and neurosonographic features of fetal midbrain-hindbrain (MBHB malformation diagnosed at 14-18 weeks. The MBHB abnormalities include; kinking of the brainstem (KBS) (n = 3), Joubert syndrome (JS) (n = 2), aqueductal stenosis (AS) (n = 11), rhombencephalosynapsis (RES) (n = 3), "open" fourth ventricle (OFV) (n = 6), and Mobius syndrome (MS) (n = 1). [Extracted from the article]

In addition to ventriculomegaly, abnormal corpus callosum and adducted thumbs, fetal MRI has also detected diencephalic and midbrain-hindbrain malformations in most fetuses affected by the L1 syndrome. L1 syndrome includes a spectrum of X-linked disorders caused by pathogenic variants of L1CAM gene, which encodes a cell adhesion molecule involved in the central nervous system (CNS) development. In addition to the evaluation of lateral ventricles, corpus callosum and cortical development, thalami and midbrain-hindbrain were investigated. [Extracted from the article]

High-speed optical communication systems may suffer from a combination of impairments such as memory effect and nonlinear behavior of the optoelectronic components. Nonlinear digital pre-distortion (DPD) is one of the well-known technique to alleviate these effects. As typical implementation of Volterra-based DPD is considered complex and consumes high power, more efficient orthogonal-based Volterra series representation has been proposed. Previous works offered ways to perform efficient grading of the most dominant dimensions based on the combination of the dimensions variances and the signal projection. Here, it is shown that normalization of the data dynamic range further improves this method and decreases significantly the number of required dimensions. Using normalization combined with the previous methods, maximizes the DPD performance by means of error vector magnitude (EVM) and bit error rate (BER), while minimizing the DPD complexity in the terms of required series dimensions. Extensive simulation and lab measurements indicate a potential saving of up to 87% in the number of dimensions with a negligible performance penalty.

The Asymmetric Simple Inclusion Process (ASIP) is an n-site tandem stochastic network with a Poisson arrival influx into the first site. Each site has an unlimited buffer with a gate in front of it. Each gate opens, independently of all other gates, following a site-dependent Exponential inter-opening time. When a site’s gate opens, all particles occupying the site move simultaneously to the next site. In this paper, a Generalized ASIP network is analyzed where the influx is to all sites, while gate openings are determined by a general renewal process. A compact matrix approach—instead of the conventional (and tedious) successive substitution method—is constructed for the derivation of the multidimensional probability-generating function (PGF) of the site occupancies. It is shown that the set of (2nn) linear equations required to obtain the PGF of an n-site network can be first cut by half into a set of 2n−1n equations, and then further reduced to a set of 2n−n+1 equations. The latter set can be additionally split into several smaller triangular subsets. It is also shown how the PGF of an n+1-site network can be derived from the corresponding PGF of an n-site system. Explicit results for networks with n=3 and n=4 sites are obtained. The matrix approach is utilized to explicitly calculate the probability that site k k=1,2,…,n is occupied. We show that, in the case where arrivals occur to the first site only, these probabilities are functions of both the site’s index and the arrival flux and not solely of the site’s index. Consequently, refined formulas for the latter probabilities and for the mean conditional site occupancies are derived. We further show that in the case where the arrival process to the first site is Poisson with rate λ, the following interesting property holds: Psite k is occupied | λ=1=Psite k+1 is occupied | λ→∞. The case where the inter-gate opening intervals are Gamma distributed is investigated and explicit formulas are obtained. Mean site occupancy and mean total load of the first k sites are calculated. Numerical results are presented.

Optical communication systems often include nonlinear components, such as Mach-Zehnder modulators (MZMs). The components' nonlinearity may have a deleterious effect on the system performance, especially when the memory effect is included. One of the most common methods to mitigate the resultant distortion effects is digital predistortion (DPD) based on the Volterra polynomial model. Typically, the DPD coefficients are extracted using the least squares approach. However, naive implementation of the Volterra polynomial model usually introduces significant complexity due to the large number of model coefficients. Here, we propose the use of orthogonal polynomial basis functions for efficient DPD implementation. The orthogonal basis enables the estimation of each coefficient separately, which provides a significant computational gain. Furthermore, the amount of dominant terms in the orthogonal basis representation is significantly lower, which leads to dramatic relaxation in the DPD implementation. In addition to the analytical modeling approach, a nonparametric method is developed by applying eigenvalue decomposition on the correlation matrix, which is required for the case of dependent random variables, or for the case of unknown probability distribution functions. MZM-based lab experiments and simulations were performed, which indicated a potential saving of 50%-80% in the amount of useful dimensions.

Variants of unknown significance (VUS) poses a dilemma in prenatal genetic testing and counselling. Methods Cases were selected from a cohort of 87 patients who underwent TOP for major CNS anomalies and presented VUS either in genetic assessment. [Extracted from the article]

Performance measures are studied for a generalized n-site asymmetric simple inclusion process (G-ASIP), where a general process controls intervals between gate-opening instants. General formulae are obtained for the Laplace–Stieltjes transform, as well as the means, of the (i) traversal time, (ii) busy period, and (iii) draining time. The PGF and mean of (iv) the system’s overall load are calculated, as well as the probability of an empty system, along with (v) the probability that the first occupied site is site k (k = 1, 2, …, n). Explicit results are derived for the wide family of gamma-distributed gate inter-opening intervals (which span the range between the exponential and the deterministic probability distributions), as well as for the uniform distribution. It is further shown that a homogeneous system, where at gate-opening instants gate j opens with probability pj=1n, is optimal with regard to (i) minimizing mean traversal time, (ii) minimizing the system’s load, (iii) maximizing the probability of an empty system, (iv) minimizing the mean draining time, and (v) minimizing the load variance. Furthermore, results for these performance measures are derived for a homogeneous G-ASIP in the asymptotic cases of (i) heavy traffic, (ii) large systems, and (iii) balanced systems.

This paper provides a detailed description of the general design space for metadata storage capabilities. The design space considers issues of metadata identification, typing and representation, dynamic behavior, predefined and user-defined metadata, schema discovery/update, operations, API packaging/marshalling, searching, and versioning. The design space is used to structure a retrospective analysis of the three major alternative metadata designs considered during the design of the WebDAV distributed authoring protocol. Deployment experience with WebDAV properties is also discussed, with the most successful use occurring in custom client/server pairs and in protocol extensions. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Investigates the mediation of epigenetic regulation of vernalization (VRN) in arabidopsis by VRN2. Analysis of plant growth conditions, vernalization treatments and flowering time; Administration of genetic and physical mapping; Prediction and identification of genes.

Fetal imaging findings (US, MRI or both) of fetuses with copy number variants (CNVs) or pathogenic/likely pathogenic sequence variants (SVs) were compared to the classical phenotype described by the literature. OC01.02: Genotype-phenotype correlation in fetuses with major brain malformations using whole-exome sequencing When performing fetal ultrasound (US) we are confronted with the difficult task of finding a correlation between imaging findings, diagnosis and prognosis. [Extracted from the article]

Objective: We evaluated the value of all 3 common biochemical serum markers, maternal serum alpha-fetoprotein, beta-human chorionic gonadotropin, and unconjugated estriol, and combinations thereof as predictors of pregnancy outcome.Study Design: A total of 60,040 patients underwent maternal serum screening. All patients had maternal serum alpha-fetoprotein measurements; beta-human chorionic gonadotropin was measured in 45,565 patients, and 24,504 patients had determination of all 3 markers, including unconjugated estriol. The incidences of various pregnancy outcomes were evaluated according to the serum marker levels by using clinically applied cutoff points.Results: In confirmation of previous observations, increased maternal serum alpha-fetoprotein levels (>2.5 multiples of the median) were found to be significantly associated with pregnancy-induced hypertension, miscarriage, preterm delivery, intrauterine growth restriction, intrauterine fetal death, oligohydramnios, and abruptio placentae. Increased beta-human chorionic gonadotropin levels (>2.5 multiples of the median [MoM]) were significantly associated with pregnancy-induced hypertension, miscarriage, preterm delivery, and intrauterine fetal death. Finally, decreased unconjugated estriol levels (<0.5 MoM) were found to be significantly associated with pregnancy-induced hypertension, miscarriage, intrauterine growth restriction, and intrauterine fetal death. As with increased second-trimester maternal serum alpha-fetoprotein levels, increased serum beta-human chorionic gonadotropin and low unconjugated estriol levels are significantly associated with adverse pregnancy outcomes. These are most likely attributed to placental dysfunction.Conclusion: Multiple-marker screening can be used not only for the detection of fetal anomalies and aneu-ploidy but also for detection of high-risk pregnancies. [ABSTRACT FROM AUTHOR]