Stretchable, Programmable and Magnet-Insensitive Protonic Display Based on Integrated Ionic Circuit.

As a new approach to "More than Moore", integrated ionic circuits serve as a possible alternative to traditional electronic circuits, yet the integrated ionic circuit composed of functional ionic elements and ionic connections is still challenging. Herein, a stretchable and transparent ionic display module of the integrated ionic circuit has been successfully prepared and demonstrated by pixelating a proton-responsive hydrogel. It is programmed to excite the hydrogel color change by a Faraday process occurring at the electrode at the specific pixel points, which enables the display of digital information and even color information. Importantly, the display module exhibits stable performance under strong magnetic field conditions (1.7 T). The transparent and stretchable nature of such ionic modules also allows them to be utilized in a broad range of scenarios, which paves the way for integrated ionic circuits.

An active controllable wide-angle and ultra-wideband terahertz absorber/reflector based on VO2 metamaterial.

The use of metamaterials in the design of optics is an important strategy for controlling light fields. Numerous terahertz metamaterial devices have been recently designed; however, their performance is relatively limited. Here, the thermally induced phase change characteristics of vanadium dioxide (VO2) were harnessed to design a perfect wide-angle and ultra-wideband switchable terahertz absorber/reflector with a simple structure and three layers from top to bottom (VO2, SiO2, and Au). The absorption mechanism based on the impedance matching theory and electric field distribution was investigated, and the influence of structural parameters on the absorption rate and performance of the absorber in a wide wave vector range were analyzed. The study findings showed that the device perfectly absorbed a bandwidth of over 6.0 THz (absorption >90%). The absorption (reflection) was modulated from 0.01 to 0.999 with the change of the background temperature. More importantly, the device could switch between complete ultra-wideband reflection and perfect absorption over a wide angle range. This study provides important insights into the design of terahertz functional devices.

[Advances in genetic research on Non-syndromic congenital joint synostosis].

Congenital joint synostosis (CJS) is a functional impairment resulting from failure in joint morphogenesis during embryonic development. Clinically, it may be classified as syndromic (sCJS) and non-syndromic (nsCJS) disorders. Common sCJS include chromosomal disorders such as Klinefelter syndrome and single-gene disorders like Apert/Pfeiffer/Crouzon syndromes, Holt-Oram syndrome, Ehlers-Danlos syndrome, and Radial-ulnar synostosis with thrombocytopenia, presenting with multiple system/organ anomalies. By contrast, nsCJS manifest with only joint abnormalities, affecting one or multiple joints. This review has focused on human nsCJS and its genetic etiology. To date, variants in seven genes (NOG, GDF5, FGF9, GDF6, FGF16, SMAD6, and MECOM) have been identified as causative factors for nsCJS. This review has focused on such genes and provided a comprehensive review for the clinical phenotypes, genetic patterns, common variants, and underlying mechanisms associated with nsCJS based on a literature review. In addition, it has also analyzed other candidate genes for nsCJS within the context of relevant signaling pathways involved in joint morphogenesis.

Novel Loss of Function (G15D) Mutation on RAC2 in a Family with Combined Immunodeficiency and Increased Levels of Immunoglobulin G, A, and E.

Ras-related C3 botulinum toxin substrate 2 (RAC2) is a small guanine nucleotide binding molecule that is exclusively expressed in hematopoietic cell lineages as a switcher. Based on in vivo and/or in vitro model experiments, RAC2 plays important roles in different cells through proliferation, secretion, and phagocytosis. It also performs a suppressing function in immunoglobulin (Ig) switching in Rac2-/- animals or cells. Several RAC2 natural mutations have been described in patients with primary immunodeficiency. RAC2 mutations can be classified into loss-of-function inactivating (LoF-I) and gain-of-function activating mutations according to their functional effects. Only two LoF-I mutations on RAC2 have been reported, including a dominant D57N mutation in several cases that exhibit granulocyte function defects and a recessive D56X mutation in cases with common variable immunodeficiency. Regardless of the type of mutation, most of the reported RAC2 mutant cases have shown reduced IgG, IgA, and IgM levels. Herein, we report on a family with three members that suffer from persistent HPV infection, recurrent respiratory infections, bronchiectasis, and autoimmune disease. The immunologic profile suggests that the family was affected by combined immunodeficiency (CID) with increased serum levels of IgG, IgA, and IgE. Exome sequencing identified a de novo RAC2 mutation (c.44G > A/p.G15D) that was co-segregated with the disease in the family. Gene functional experiments identified that such mutation results in reduced guanosine triphosphate binding activity and RAC2 protein expression. In patients' lymphocytes, impaired aggregation and proliferation effects, decreased mitochondrial membrane potential, and increased levels of cell apoptosis were observed, although no functional abnormalities were detected in neutrophils. To our knowledge, this study was the first to identify a LoF-I mutation of RAC2 affecting lymphocyte function that consequently led to CID and increased levels of serum IgG, IgE, and IgA. This study presents a novel subtype of RAC2-related immune disorder.

Terahertz absorber based on vanadium dioxide with high sensitivity and switching capability between ultra-wideband and ultra-narrowband.

The terahertz perfect absorber can be applied in the control, sensing and modulation of optical fields in micro- and nanostructures. However, they are only single function, complex device structure and low sensing sensitivity. Based on this, by introducing the bound state in the continuum (BIC) with infinite quality factor and field enhancement effect, and taking advantage of the phase transition characteristics of vanadium dioxide (VO2), we designed a terahertz perfect absorber device which can actively switch between ultra-wideband and ultra-narrowband. The absorption mechanism is explained by multipole analysis theory, impedance matching theory and electromagnetic field distribution. The broadband absorption is mainly due to the electric dipole resonance on metallic VO2 materials, and the absorption is more than 99% across 3.64-6.96 THz, and it has excellent characteristics such as robustness. Ultra-narrowband perfect absorption has a quality factor greater than 2200 due mainly to the implementation of symmetrically protected BIC with a sensing sensitivity of 2.575 THz per RIU. Therefore, this research could be widely used in the fields of integrated optical circuits, optoelectronic sensing and perceptual modulation of energy, as well as providing additional design ideas for the design of terahertz multifunctional devices.

Case series of congenital pseudarthrosis of the tibia unfulfilling neurofibromatosis type 1 diagnosis: 21% with somatic NF1 haploinsufficiency in the periosteum.

Up to 84% of patients with congenital pseudarthrosis of the tibia (CPT) present with neurofibromatosis type 1 (NF1) (NF1-CPT). However, the etiology of CPT not fulfilling the NIH diagnostic criteria for NF1 (non-NF1-CPT) is not well understood. Here, we collected the periosteum tissue from the pseudarthrosis (PA) site of 43 non-NF1-CPT patients and six patients with NF1-CPT, together with the blood or oral specimen of trios (probands and unaffected parents). Whole-exome plus copy number variation sequencing, multiplex ligation-dependent probe amplification (MLPA), ultra-high amplicon sequencing, and Sanger sequencing were employed to identify pathogenic variants. The result showed that nine tissues of 43 non-NF1-CPT patients (21%) had somatic mono-allelic NF1 inactivation, and five of six NF1-CPT patients (83.3%) had bi-allelic NF1 inactivation in tissues. However, previous literature involving genetic testing did not reveal somatic mosaicism in non-NF1-CPT patients so far. In NF1-CPT patients, when the results from earlier reports and the present study were combined, 66.7% of them showed somatic NF1 inactivation in PA tissues other than germline inactivation. Furthermore, no diagnostic variants from other known genes (GNAS, AKT1, PDGFRB, and NOTCH3) related to skeletal dysplasia were identified in the nine NF1 positive non-NF1-CPT patients and six NF1-CPT patients. In conclusion, we detected evident somatic mono-allelic NF1 inactivation in the non-NF1-CPT. Thus, for pediatric patients without NF1 diagnosis, somatic mutations in NF1 are important.

MECOM-related disorder: Radioulnar synostosis without hematological aberration due to unique variants.

PURPOSE: The etiology for a considerable proportion of patients with congenital radioulnar synostosis (RUS) remains unclear. This study aimed to investigate the genetic cause of RUS without a known cause. METHODS: Patients with RUS were investigated. Exome sequencing and/or Sanger sequencing was performed. Bioinformatics analysis was also performed. Pathogenicity was evaluated for variants of interest. RESULTS: We identified unique missense variants in MECOM (encodes EVI1) associated with RUS in 8 families. Of them, 6 families had variants in residue R781, including 3 families with R781C (c.2341C>T), 2 families with R781H (c.2342G>A), and 1 family with R781L (c.2342G>T). Another 2 variants included I783T (c.2348T>C) in 1 family and Q777E (c.2329C>G) in 1 family. All these variants were clustered within the ninth zinc finger motif of EVI1. Phenotype evaluation identified that most of these patients with RUS harboring mutant MECOM had finger malformations, but none of them had identifiable hematological abnormalities. Functional experiments showed that MECOM R781C led to alterations in TGF-ß-mediated transcriptional responses. CONCLUSION: This study examined MECOM variants by focusing on RUS instead of hematological abnormalities. The R781 residue in EVI1 is a hotspot for human RUS variants. Mutant MECOM is the second most common cause for familial RUS.

Expanding the genotypes and phenotypes for 19 rare diseases by exome sequencing performed in pediatric intensive care unit.

Phenotypes of some rare genetic diseases are atypical and it is a challenge for pediatric intensive care units (PICUs) to diagnose and manage such patients in an emergency. In this study, we investigated 58 PICU patients (39 deceased and 19 surviving) in critical ill status or died shortly without a clear etiology. Whole exome sequencing was performed of 103 DNA samples from their families. Disease-causing single-nucleotide variants (SNVs) and copy number variants (CNVs) were identified to do genotype-phenotypes analysis. In total, 27 (46.6%) patients received a genetic diagnosis. We identified 34 pathogenic or likely pathogenic SNVs from 26 genes, which are related to at least 19 rare diseases. Each rare disease involved an isolated patient except two patients caused by the same gene ACAT1. The genotypic spectrum was expanded by 23 novel SNVs from gene MARS1, PRRT2, TBCK, TOR1A, ECE1, ARX, ZEB2, ACAT1, CPS1, VWF, NBAS, COG4, and INVS. We also identified two novel pathogenic CNVs. Phenotypes associated with respiratory, multiple congenital anomalies, neuromuscular, or metabolic disorders were the most common. Twenty patients (74.1%) accompanied severe infection, 19 patients (70.1%) died. In summary, our findings expanded the genotypes and phenotypes of 19 rare diseases from PICU with complex characteristics.

Correction: SMAD6 is frequently mutated in nonsyndromic radioulnar synostosis.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

SMAD6 is frequently mutated in nonsyndromic radioulnar synostosis.

PURPOSE: Radioulnar synostosis (RUS) can be syndromic or nonsyndromic. The genetic basis for several RUS syndromes have been reported. However, the genetic cause of nonsyndromic RUS (nsRUS) remains unknown. METHODS: We performed Giemsa (GTG) banding, Sanger sequencing, and exome sequencing on patients (n = 140) and families (n = 11) who suffered from RUS. RESULTS: GTG banding identified 10% RUS sporadic cases affected by sex chromosome aneuploidy. Sanger sequencing on candidate genes revealed noggin (NOG) rarely mutated in nsRUS. Exome sequencing identified 16 loss-of-function (LOF) and 6 missense variants (minor allele frequency [MAF] < 0.0001) in 22/117 nsRUS sporadic patients. Genetic association analysis found a significant association between SMAD6-LOF variants and nsRUS risk (odds ratio [OR] = 430, 95% confidence interval [CI]: 238-780, P < 0.000001). SMAD6 mutated in nsRUS was further confirmed by direct Sanger sequencing of SMAD6-coding regions on other unrelated cohorts of nsRUS cases or families. In summary, we detected 27 SMAD6 rare variants in nsRUS, most of which were LOF variants, 4 were de novo, and 3 were transmitted in families with autosomal dominant inheritance. CONCLUSION: As an intracellular bone morphogenetic protein (BMP) antagonist gene, SMAD6 is frequently mutated in nsRUS. NOG, which encodes an extracellular BMP antagonist, is rarely mutated in nsRUS. This work is the first genetic study on nsRUS.

Case report: two novel VPS13B mutations in a Chinese family with Cohen syndrome and hyperlinear palms.

BACKGROUND: Cohen syndrome (CS) is an uncommon developmental disease with evident clinical heterogeneity. VPS13B is the only gene responsible for CS. Only few sporadic cases of CS have been reported in China. CASE PRESENTATION: A Chinese family with two offspring-patients affected by developmental delay and intellectual disability was investigated in this study. Exome sequencing was performed, and compound heterozygous mutations in VPS13B were segregated for family members with autosomal recessive disorder. Splicing mutation c.3666 + 1G > T (exon 24) and nonsense mutation c. 9844 A > T:p.K3282X (exon 54) were novel. We revisited the family and learned that both patients are affected by microcephaly, developmental delay, neutropenia, and myopia and have a friendly disposition, all of which are consistent with CS phenotypes. We also found that both patients have hyperlinear palms, which their parents do not have. VPS13B mutations reported among the Chinese population were reviewed accordingly. CONCLUSIONS: This study presents two novel VPS13B mutations in CS. The identification of hyperlinear palms in a family affected by CS expands the phenotype spectrum of CS.

Clinical and Genetic Study of Children With Peutz-Jeghers Syndrome Identifies a High Frequency of STK11 De Novo Mutation.

OBJECTIVES: The present study aims to identify the genotype-phenotype correlation in children with Peutz-Jeghers Syndrome (PJS) through the analysis of STK11 gene mutations in the context of clinical and pathological characteristics. METHOD: In this observational cohort study, the clinical characteristics of 18 families diagnosed with pediatric PJS were collected. Genomic DNA from the peripheral blood of affected children and their family members was collected. The coding region of STK11 was amplified by PCR and screened for mutation by Sanger sequencing. The families that were negative for STK11 mutation were further assessed by multiplex ligation-dependent probe amplification (MLPA). RESULT: Initial presentation in affected children was at 1.6 to 14.2 years and included anemia in 8 patients whereas 6 presented for screening by virtue of family history. All patients underwent endoscopy, colonoscopy, and polypectomy. Polyps were distributed throughout the gastrointestinal (GI) tract, including the small intestine, stomach, colon, and rectum.In the 18 pediatric PJS families, STK11 mutations were detected in 8 families by Sanger sequencing, and large deletions were detected in 3 by MLPA, respectively. Nine of the 11 STK11 mutations were de novo, 3 were novel (c.419T>C:p.L140P, c.314T>G:p.L105X), and (c.488_489insACGG p.L164fs). CONCLUSIONS: Although the main clinical features of pediatric PJS were similar to those of PJS cases in adults, a high frequency of STK11 de novo mutations were encountered in our population of patients with PJS.

XRCC2 mutation causes meiotic arrest, azoospermia and infertility.

BACKGROUND: Meiotic homologous recombination (HR) plays an essential role in gametogenesis. In most eukaryotes, meiotic HR is mediated by two recombinase systems: ubiquitous RAD51 and meiosis-specific DMC1. In the RAD51-mediated HR system, RAD51 and five RAD51 paralogues are essential for normal RAD51 function, but the role of RAD51 in human meiosis is unclear. The knockout of Rad51 or any Rad51 paralogue in mice exhibits embryonic lethality. We investigated a family with meiotic arrest, azoospermia and infertility but without other abnormalities. METHODS: Homozygosity mapping and whole-exome sequencing were performed in a consanguineous family. An animal model carrying a related mutation was created by using a CRISPR/Cas9 system. RESULTS: We identified a 1 bp homozygous substitution (c.41T>C/p.Leu14Pro) on a RAD51 paralogue, namely, XRCC2, in the consanguineous family. We did not detect any XRCC2 recessive mutation in a cohort of 127 males with non-obstructive-azoospermia. Knockin mice with Xrcc2-c.T41C/p.Leu14Pro mutation were generated successfully by the CRISPR/Cas9 method. The homozygotes survived and exhibited meiotic arrest, azoospermia, premature ovarian failure and infertility. CONCLUSION: A XRCC2 recessive mutation causing meiotic arrest and infertility in humans was duplicated with knockin mice. Our results revealed a new Mendelian hereditary entity and provided an experimental model of RAD51-HR gene defect in mammalian meiosis.

Trisomy 3 mosaicism in a 5-year-old boy with multiple anomalies: A very rare case.

Trisomy 3 mosaicism in live birth is exceedingly rare. In this study, we report a 5-year-old boy with trisomy 3 mosaicism who exhibits skeletal anomalies, atypical form of ectodermal dysplasias, refractory diarrhea, and normal intelligence. Fluorescence in situ hybridization and microsatellite marker analyses confirmed the existence of trisomy 3 mosaicism and suggested that the parental origin of the additional chromosome 3 in the trisomic cells was maternal. This report further delineated the trisomy 3 mosaicism in live births. The authors propose that both common phenotypes and phenotypic diversity exist on cases with trisomy 3 mosaicism. © 2016 Wiley Periodicals, Inc.

Interstitial deletion 5q14.3q21.3 associated with lethal epilepsy.

The 5q14.3 deletion syndrome is a heterogeneous disorder with remarkable phenotypic diversity ranging from severe to mild manifestation. In this paper, we report on a patient with 5q14.3 q21.3 deletion who exhibited the severe phenotype and died at 5.5 months. This patient can be classified as having sudden unexplained death in epilepsy (SUDEP) [Tomson et al., 2008]. The deleted region (21.02 Mb, Chr.5: 88, 047, 621-109,072,596 × 1 dn), which included MEF2C and EFNA5, was a 16.5 Mb sequence that overlapped with previously reported deletions in a patient with the mild phenotype. This study further demonstrated the complexity of clinical cytogenetic correlation of the 5q14.3 deletion.

Intragenic and extragenic disruptions of FOXL2 mapped by whole genome low-coverage sequencing in two BPES families with chromosome reciprocal translocation.

Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare autosomal dominant disorder that affects craniofacial development and ovarian function. FOXL2 is the only gene known to be responsible for BPES. The majority of BPES patients show intragenic mutations of FOXL2. Recently, a 7.4 kb sequence disruption, which was 283 kb upstream of FOXL2, was identified to independently contribute to the BPES phenotype. Several breakpoints nearing FOXL2 (0 Mb to 1.2 Mb, several of which were distant from the 7.4 kb sequence disruption) have been mapped or deduced through a traditional method in BPES patients with chromosome reciprocal translocation. In this study, two BPES families with chromosome reciprocal translocation were investigated. Intragenic mutations of FOXL2 or pathogenic copy number variations were excluded for the two BPES families. All of the four breakpoints were identified at a base-precise manner using Giemsa banding and whole genome low-coverage sequencing (WGLCS). In family 01, the breakpoints were found at chr1:95,609,998 and chr3:138,879, 114 (213,132 bp upstream of FOXL2). In family 02, the breakpoints were located at chr3:138,665,431 (intragenic disruptions of FOXL2) and chr20:56,924,609. Results indicate that the intragenic and extragenic interruptions of FOXL2 can be accurately and rapidly detected using WGLCS. In addition, both the 213 kb upstream and intragenic interruptions of FOXL2 can cause BPES phenotype.

First report of CTNS mutations in a Chinese family with infantile cystinosis.

Infantile cystinosis (IC) is a rare autosomal recessive disorder characterized by a defect in the lysosomal-membrane transport protein, cystinosin. It serves as a prototype for lysosomal transport disorders. To date, several CTNS mutations have been identified as the cause of the prototypic disease across different ethnic populations worldwide. However, in Asia, the CTNS mutation is very rarely reported. For the Chinese population, no literature on CTNS mutation screening for IC is available to date. In this paper, by using the whole exome sequencing and Sanger sequencing, we identified two novel CTNS splicing deletions in a Chinese IC family, one at the donor site of exon 6 of CTNS (IVS6+1, del G) and the other at the acceptor site of exon 8 (IVS8-1, del GT). These data give information for the genetic counseling of the IC that occurred in Chinese population.