Development of a non-intercepting weak beam current measurement electronics for Heavy Ion Accelerator Facility in Lanzhou.

Non-destructive measurements of low-intensity charged particle beams are particularly challenging for beam diagnostics. At the Heavy Ion Accelerator Facility in Lanzhou (HIRFL), beams with weak currents below 1 µA are often provided for experiments. The detection of such low beam current is below the threshold of typical standard beam current transformers. Therefore, a low-intensity monitoring system is developed by using a sensitive capacitive pick-up (PU) and low-noise electronics. This device measures beam currents by digitally analyzing the amplitude of the PU signals using a homodyne detection scheme. During lab tests, the amplitude nonlinearity is <0.5% in the operational range of 1 nA-45 µA and the amplitude resolution is 0.94 nA. At present, four measurement systems for low beam currents are installed at HIRFL for the monitoring of standard operating conditions with low beam currents below 1 µA. After an absolute calibration with a Faraday cup, it can be used for accurate beam intensity measurement with a current resolution of about 1 nA.

Genotype-phenotype correlation study of structural abnormalities in a fetal brain caused by a novel KDM4B variant.

BACKGROUND: Fetal ventriculomegaly (VM), a common brain structure malformation detected during prenatal ultrasound diagnosis, is associated with an increased risk of neurodevelopmental disorders (NDDs) after birth. KDM4B encodes a lysine-specific demethylase that interacts with histone H3K23me3. Variations in KDM4B are reportedly associated with human NDDs; however, only 11 such patients have been reported. Herein, we report a fetus with VM and agenesis of the corpus callosum (ACC), which suggests that KDM4B plays an important role in fetal brain development. METHODS: Fetal skin tissue and parental peripheral venous blood samples were collected. Whole-exome and Sanger sequencing were performed to analyze fetal germline variants. Human 293T cells transfected with wild-type or mutant KDM4B were used for western blotting (WB) to analyze protein expression levels. RESULTS: An insertion variant of KDM4B, NM_015015.3: c.2889_2890insGAGAGCATCACGGTGAGCTGTGGGGTGGGGCAGGGGGCGGGGGGAGGCTGGGAGCACAGTGACAACCTGTACCCC, was identified in the fetal tissue; however, the parents carried the wild-type gene. The WB results indicated significantly reduced expression of the mutant protein, likely owing to decreased stability. CONCLUSIONS: The structural abnormalities in the brain of the studied fetus may be attributed to an insertion variant of KDM4B. This study highlights the importance of screening for KDM4B variants and considering potential copy number variations when observing VM or ACC in prenatal ultrasound imaging.

Case report: "Major fetal cardiac pathology associated with a novel CTNND1 mutation".

Background: The p120-ctn protein, encoded by CTNND1, is involved in intercellular connections and regulates epithelial-mesenchymal transformation. CTNND1 mutations can lead to blepharocheilodontic syndrome (BCDS). Increasing evidence shows that although BCDS mainly manifests as craniofacial and oral deformities, it can also present as congenital heart disease, limb deformities, and neurodevelopmental disorders. Case description: We report a prenatal case of a major cardiac malformation at 24+3 weeks of gestation. Ultrasound examination revealed a hypoplastic left ventricular, aortic coarctation, and a ventricular septal defect. Genetic analysis of the fetal tissues showed the presence of a novel mutation in CTNND1 (NM_001085458.2: c.566_c.567insG; p.Pro190fs*15), which may lead to premature termination of protein coding, while both the parents harbored wild-type CTNND1. To date, only 15 CTNND1 mutations have been reported in 19 patients worldwide, of which approximately 31% (6/19) had a cardiac phenotype. Conclusion: To the best of our knowledge, this is the first case report of fetal complicated cardiac malformations caused by this CTNND1 mutation. Our findings provide new clinical references for prenatal diagnosis and suggest an important role for CTNND1 in early cardiac development.

COL7A1 Homozygous Arg2471Ter Mutation Leads to the Severe Phenotype of Autosomal Recessive Dystrophic Epidermolysis Bullosa in the Fetus.

Introduction: Autosomal recessive dystrophic epidermolysis bullosa (RDEB) is a rare disease with an early onset and severe phenotype. The pathogenic mechanism associated with mutations in the gene COL7A1 has been widely studied and many related cases have been reported, but prenatal cases are rare. Here, we report the prenatal diagnosis of a sporadic case of RDEB. Methods: In this study, the fetus with abnormal skin manifestations, which were determined during a prenatal ultrasound, was evaluated based on the ultrasound and autopsy findings and the results of molecular diagnostic analyses. Samples of the fetus and the parents were subjected to trio whole-exome sequencing, and in vitro functional analyses were conducted to analyze the pathogenicity of the detected mutation. Results: During the conventional prenatal ultrasound, the fetus showed abnormal epidermal lines on both lower limbs and the plantar skin as well as an interruption of the continuity of the lateral epidermal line below the ankle of the right lower limb. Gene testing revealed a homozygous nonsense mutation in COL7A1 (c.7411C>T, p.Arg2471Ter), which gave rise to RDEB in the fetus. Further, the results of the in vitro functional experiments confirmed that the mutation might lead to protein degradation. Conclusion: Most prenatal diagnoses of RDEB are the result of targeted molecular analyses carried out based on family history, and prenatal ultrasound reports of severe RDEB phenotypes are extremely rare. Our case suggests that the observation of abnormal epidermal lines should be given due consideration during prenatal diagnosis, as they may be a sign of possible epidermolysis bullosa.

Prenatal case report of Barth syndrome caused by novel TAFAZZIN mutation: Clinical characteristics of fetal dilated cardiomyopathy with ascites.

Barth syndrome (BTHS) is a rare X-linked recessive genetic disease, which appears in infancy with myocardial and skeletal muscle diseases, neutropenia, growth retardation, and other clinical features. TAFAZZIN is the pathogenic gene of BTHS, which encodes the tafazzin protein of the inner membrane of the mitochondria, a phosphatidyltransferase involved in cardiolipin remodeling and functional maturation. At present, BTHS has been widely reported, but prenatal cases are rare. We report a 24+4-week fetus with clinical manifestations including left ventricular insufficiency and ascites. After induced labor, whole exome sequencing detection of fetal skin tissue showed that TAFAZZIN had the mutation c.311A > C/p.His104Pro and that his mother was the carrier. This His104Pro mutation has hitherto not been reported, and it is rated as likely to be pathogenic according to the American College of Medical Genetics and Genetics guidelines. Molecular dynamics and protein expression experiments on the His104Pro mutation showed that the stability of the local protein structure and protein expression were reduced. In conclusion, the case presented in this study enriches our knowledge of the TAFAZZIN mutation spectrum and suggests that His104Pro may lead to cardiac structural abnormalities in the early embryo. The possibility of BTHS should be considered when an abnormal cardiac structure or ascites appear in a prenatal ultrasound.

A new digital beam position and phase measurement implementation based on a field programmable gate array for the high intensity heavy-ion accelerator iLinac.

A new digital beam position and phase measurement (BPM) system was designed for the ion-Linac accelerator at the high intensity heavy ion accelerator facility. The fundamental and second harmonic signals are retrieved from the BPM electrodes to simultaneously calculate their respective beam positions and phases. All data acquisition and digital signal processing algorithm routines are performed in a field programmable gate array (FPGA). The position and phase information are obtained by using the in-phase and quadrature demodulation method. A practical and straightforward method is used to generate the second harmonic reference signal for processing the second harmonic beam signal. The reconfigurable filters are integrated into the FPGA to allow the measurement of short beam pulse length. The laboratory test results show that the achieved phase resolution is better than 0.2° and 0.03° when the input signal is -60 and -45 dBm, respectively. A position resolution better than 30 µm was achieved for an input power level of approximately -60 dBm, and it can reach 7 µm with the input power higher than -45 dBm. The entire execution time of the algorithm is accomplished within 3.4 µs, which provides a sufficient reaction time for the fast beam interlock signal to the machine protection system. The performance of this newly designed prototype BPM electronics was evaluated with the online proton beam.

Prenatal ultrasound findings of ectodermal dysplasia: a case report.

BACKGROUND: Ectodermal Dysplasia is a diverse group of inherited disorders characterized by a congenital defect in two or more ectodermal structures. Due to a fairly low incidence, to the best of our knowledge there are few clues that can assist in making an effective prenatal ultrasound diagnosis. Currently, the prenatal diagnosis of ectodermal dysplasia depends on a fetal genetic test combined with the family history. In this case report, we present a fetal case of ectodermal dysplasia with a remarkable prenatal ultrasound image, genetic testing, family history, and relevant exams of the stillbirth. CASE PRESENTATION: A multipara with a 22-week singleton male pregnancy undergoing a fetal ultrasound examination. The image showed a hypoplastic maxilla and mandible. Subsequently, the ectodermal dysplasia was defined using a family history and genetic testing. The skin pathology from the aborted fetus demonstrated a hypohidrotic type. The computed tomography (CT) reconstruction after induced labor confirmed the prenatal ultrasound findings of the maxilla and mandible. CONCLUSIONS: This case suggested that prenatal ultrasound may provide a valuable clue of ectodermal dysplasia. The diagnosis can be established using further prenatal genetic testing and a family history.

Prenatal ultrasound-assisted identification of multiple malformations caused by a deletion in the long-arm end of chromosome 7 and review of the literature.

Clinical cases of chromosome 7 long-arm end deletion are rare. Generally, 7q terminal deletion syndrome results in complex clinical phenotypes, such as microcephaly, growth and development retardation, holoprosencephaly, and sacral hypoplasia. Herein, we report the genetic and clinical features of a fetus with multiple malformations observed by prenatal ultrasound. The results showed that there was a large fragment deletion of approximately 27.7 Mb in 7q32.3-qter. The induced fetus showed facial abnormalities of cleft lip and palate, and some organ structural abnormalities (such as diaphragmatic hernia and polycystic renal dysplasia) were observed by autopsy and pathology. To provide more reliable information for disease diagnosis and genetic counseling, we reviewed and analyzed the reported cases of isolated 7q terminal syndrome.

Modular arrangements of sequence motifs determine the functional diversity of KDM proteins.

Histone lysine demethylases (KDMs) play a vital role in regulating chromatin dynamics and transcription. KDM proteins are given modular activities by its sequence motifs with obvious roles division, which endow the complex and diverse functions. In our review, according to functional features, we classify sequence motifs into four classes: catalytic motifs, targeting motifs, regulatory motifs and potential motifs. JmjC, as the main catalytic motif, combines to Fe2+ and α-ketoglutarate by residues H-D/E-H and S-N-N/Y-K-N/Y-T/S. Targeting motifs make catalytic motifs recognize specific methylated lysines, such as PHD that helps KDM5 to demethylate H3K4me3. Regulatory motifs consist of a functional network. For example, NLS, Ser-rich, TPR and JmjN motifs regulate the nuclear localization. And interactions through the CW-type-C4H2C2-SWIRM are necessary to the demethylase activity of KDM1B. Additionally, many conservative domains that have potential functions but no deep exploration are reviewed for the first time. These conservative domains are usually amino acid-rich regions, which have great research value. The arrangements of four types of sequence motifs generate that KDM proteins diversify toward modular activities and biological functions. Finally, we draw a blueprint of functional mechanisms to discuss the modular activity of KDMs.

Multi-substrate selectivity based on key loops and non-homologous domains: new insight into ALKBH family.

AlkB homologs (ALKBH) are a family of specific demethylases that depend on Fe2+ and α-ketoglutarate to catalyze demethylation on different substrates, including ssDNA, dsDNA, mRNA, tRNA, and proteins. Previous studies have made great progress in determining the sequence, structure, and molecular mechanism of the ALKBH family. Here, we first review the multi-substrate selectivity of the ALKBH demethylase family from the perspective of sequence and structural evolution. The construction of the phylogenetic tree and the comparison of key loops and non-homologous domains indicate that the paralogs with close evolutionary relationship have similar domain compositions. The structures show that the lack and variations of four key loops change the shape of clefts to cause the differences in substrate affinity, and non-homologous domains may be related to the compatibility of multiple substrates. We anticipate that the new insights into selectivity determinants of the ALKBH family are useful for understanding the demethylation mechanisms.