[Analysis of clinical features and genetic variant in a child with Cowden syndrome 1].

OBJECTIVE: To explore the genetic etiology of a child with Cowden syndrome 1 (CS1). METHODS: A child who had visited the Ningbo Women and Children's Hospital on August 26, 2022 was selected as the study subject. Clinical information of the child was collected. Genomic DNA was extracted from peripheral blood samples of the child and his family members and subjected to whole exome sequencing (WES). Candidate variant was verified by Sanger sequencing. RESULTS: The child, a 13-year-old boy, had manifested with severe mental retardation, hyperactivity, autistic behavior, sparse and prominent teeth, macrocephaly, and skin freckles on the penis. His mother had presented with multiple papules, hamartomatous polyps, thyroid adenoma and macrocephaly. WES results revealed that the child has harbored a nonsense c.781C>T (p.Q261*) variant of the PTEN gene, which was inherited from his mother. Based on the guidelines from the American College of Medical Genetics and Genomics, the c.781C>T variant was classified as likely pathogenic (PVS1+PM2_Supporting). CONCLUSION: The c.781C>T variant of the PTEN gene probably underlay the pathogenesis in the child and his mother. Above finding has facilitated genetic counseling for this family.

[Clinical phenotype and genetic analysis of a fetus with Cardiac valvular dysplasia type 1].

OBJECTIVE: To explore the genetic basis for a fetus with Cardiac valvular dysplasia type 1 (CVDP1). METHODS: A CVDP1 fetus identified at the Ningbo Women and Children's Hospital on July 7, 2022 was selected as the study subject. Clinical data of the fetus was collected. The fetus and its parents were subjected to trio-whole exome sequencing (trio-WES), and candidate variants were verified by Sanger sequencing. RESULTS: The fetus had exhibited generalized edema, complex cardiac malformation, abdominal effusion, and enhanced intestinal and renal parenchymal echoes. Trio-WES revealed that it has harbored compound heterozygous variants of the PLD1 gene, namely c.2977C>T (p.R993*) and c.1460G>A (p.W487*), which were respectively inherited from its father and mother. Neither variant was reported previously. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.2977C>T (p.R993*) variant was evaluated to be likely pathogenic (PVS1_Moderate+PM2_Supporting+PM3+PP4), whilst the c.1460G>A (p.W487*) variant was evaluated to be pathogenic (PVS1+PM2_Supporting+PP4). CONCLUSION: The c.2977C>T (p.R993*) and c.1460G>A (p.W487*) compound heterozygous variants of the PLD1 gene probably underlay the CVDP1 in the fetus. Above discovery has enriched the mutational spectrum of the PLD1 gene and provided a guidance for genetic counseling and prenatal diagnosis in this family.

A novel 268 kb deletion combined with a splicing variant in IL7R causes of severe combined immunodeficiency in a Chinese family: a case report.

BACKGROUND: Severe combined immunodeficiency (SCID) is a group of fatal primary immunodeficiencies characterized by the severe impairment of T-cell differentiation. IL7R deficiency is a rare form of SCID that usually presents in the first months of life with severe and opportunistic infections, failure to thrive, and a high risk of mortality unless treated. Although recent improvements in early diagnosis have been achieved through newborn screening, few IL7R-related SCID patients had been reported in the Chinese population. CASE PRESENTATION: Here, we retrospectively analyzed a case of SCID in a 5-month-old girl with symptoms, including severe T-cell depletion, recurrent fever, oral ulcers, pneumonia, hepatosplenomegaly, bone marrow hemophagocytosis, and bacterial and viral infections. Whole-exome sequencing (WES), quantitative PCR (qPCR), and chromosome microarray analysis (CMA) were performed to identify the patient's genetic etiology. We identified a 268 kb deletion and a splicing variant, c.221 + 1G > A, in the proband. These two variants of IL7R were inherited from the father and mother. CONCLUSIONS: To our knowledge, this is the first report of whole IL7R gene deletion in combination with a pathogenic splicing variant in a patient with SCID. This deletion also expands the pathogenic variation spectrum of SCID caused by IL7R. The incorporation of exome-based copy number variant analysis makes WES a powerful molecular diagnostic technique for the clinical diagnosis of pediatric patients.

α 2 -ADRENORECEPTOR ANTAGONIST AMELIORATES SEPSIS-ASSOCIATED PULMONARY FIBROSIS BY SUPPRESSING NOREPINEPHRINE-MEDIATED FIBROBLAST DIFFERENTIATION VIA INHIBITING PKC ACTIVATION.

ABSTRACT: Pulmonary fibrosis is an important factor affecting the prognosis of severe septic patients with acute lung injury. The objective of this study was to explore the effect of norepinephrine (NE) and α 2 -adrenoreceptor (AR) on sepsis-associated pulmonary fibrosis and the mechanism underlying these effects. We found pulmonary fibrotic changes, and increased NE production and α 2A -AR expression in the pulmonary tissue of mice subjected to cecal ligation and puncture surgery. Reserpine and yohimbine alleviated pulmonary fibrosis in mice with sepsis by exhausting NE derived from the lung's adrenergic nerve and blocking α 2 -AR, respectively. There was no significant difference in the expression of the three α 1 -AR subtypes. The effect of NE on promoting pulmonary fibroblast differentiation in vitro was suppressed by yohimbine. Both the protein and mRNA expression levels of α 2A -AR were increased in pulmonary fibroblasts treated with LPS. Clonidine, a selective α 2 -AR agonist, enhanced LPS-induced differentiation in pulmonary fibroblasts, as indicated by the increase in α-smooth muscle actin and collagen I/III, which was mitigated by inhibiting PKC and p38. Further in vivo results indicated that yohimbine alleviated pulmonary fibrosis and inhibited the phosphorylation of PKC, p38, and Smad2/3 in lung tissue of mice exposed to LPS for 4 weeks. Clonidine showed the opposite effect to yohimbine, which aggravated LPS-induced pulmonary fibrosis. These findings demonstrated that the sepsis-induced increase in NE promoted fibroblast differentiation via activating α 2 -AR. Blockage of α 2 -AR effectively ameliorated sepsis-associated pulmonary fibrosis by abolishing NE-induced lung fibroblast differentiation and inhibiting the PKC-p38-Smad2/3 pathway.

[Clinical and genetic analysis of a rare fetus with Protein C deficiency due to compound heterozygous variants of PROC gene].

OBJECTIVE: To explore the genetic etiology for a fetus with hydrocephalus and intraventricular hemorrhage. METHODS: Trio whole exome sequencing was carried out. Candidate variants were verified by Sanger sequencing of the fetus and its parents. RESULTS: The fetus was found to harbor c.818G>A (p.W273X) and c.833T>C (p.L278P) compound heterozygous variants of the PROC gene, which were respectively inherited from its mother and father. Based on the guidelines of the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be likely pathogenic (PVS1_Strong+PM2_Supporting+PP4; PM2_Supporting+PM3+PP1+PP3+PP4). CONCLUSION: The fetus was diagnosed with Protein C deficiency due to the c.818G>A (p.W273X) and c.833T>C (p.L278P) compound heterozygous variants of the PROC gene. Above finding has enriched the spectrum of PROC gene variants and enabled genetic counseling and prenatal diagnosis for the family.

Quantum generative adversarial learning in photonics.

Quantum generative adversarial networks (QGANs), an intersection of quantum computing and machine learning, have attracted widespread attention due to their potential advantages over classical analogs. However, in the current era of noisy intermediate-scale quantum (NISQ) computing, it is essential to investigate whether QGANs can perform learning tasks on near-term quantum devices usually affected by noise and even defects. In this Letter, using a programmable silicon quantum photonic chip, we experimentally demonstrate the QGAN model in photonics for the first time to our knowledge and investigate the effects of noise and defects on its performance. Our results show that QGANs can generate high-quality quantum data with a fidelity higher than 90%, even under conditions where up to half of the generator's phase shifters are damaged, or all of the generator and discriminator's phase shifters are subjected to phase noise up to 0.04π. Our work sheds light on the feasibility of implementing QGANs on the NISQ-era quantum hardware.

[Clinical and genetic analysis of two children with Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language due to de novo variants of MEF2C gene].

OBJECTIVE: To explore the clinical characteristics and genetic etiology for two children with Neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language (MEDHSIL). METHODS: Two children who had visited the Ningbo Women and Children's Hospital on October 15, 2021 were selected as the study subjects. Whole exome sequencing (WES) was carried out for both patients. Candidate variants were verified by Sanger sequencing of their family members. RESULTS: The two children were respectively found to harbor a heterozygous c.138delC (p.Ile47Serfs*42) variant and a c.833del (p.L278*) variant of the MEF2C gene. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were predicted to be pathogenic (PVS1+PS2+PM2_Supporting). CONCLUSION: The c.138delC and c.833del variants of the MEF2C gene probably underlay the pathogenesis of MEDHSIL in the two children. Above findings have enriched the mutational spectrum of the MEF2C gene and enabled genetic counseling for their families.

Prenatal diagnosis to identify compound heterozygous variants in PKDCC that causes rhizomelic limb shortening with dysmorphic features in a fetus from China.

BACKGROUND: Rhizomelic limb shortening with dysmorphic features (RLSDF) has already been a disorder of the rare autosomal recessive skeletal dysplasia, just having a few reported cases. RLSDF is caused by protein kinase domain containing, cytoplasmic(PKDCC)gene variants. In this study, we describe the clinical features and potential RLSDF molecular etiology in a fetus from China. METHODS: Genomic DNA (gDNA) extracted from the fetal muscle tissue and parents' peripheral blood was subjected to chromosomal microarray analysis (CMA) and trio-based whole exome sequencing (Trio-WES). The candidate pathogenic variants were verified by using Sanger sequencing. RESULTS: Trio-WES identified two compound heterozygous variants in PKDCC, c.346delC (p.Pro117Argfs*113) and c.994G > T (p.Glu332Ter), inherited from the father and mother, respectively. Both variants are classified as pathogenic according to American College of Medical Genetics and Genomics guidelines. CONCLUSIONS: We reported the first prenatal case of RLSDF caused by PKDCC in the Chinese population. Our findings extended the variation spectrum of PKDCC and emphasized the necessity of WES for the early diagnosis of skeletal dysplasia and other ultrasound structural abnormalities in fetuses.

Experimental quantum natural gradient optimization in photonics.

Variational quantum algorithms (VQAs) combining the advantages of parameterized quantum circuits and classical optimizers, promise practical quantum applications in the noisy intermediate-scale quantum era. The performance of VQAs heavily depends on the optimization method. Compared with gradient-free and ordinary gradient descent methods, the quantum natural gradient (QNG), which mirrors the geometric structure of the parameter space, can achieve faster convergence and avoid local minima more easily, thereby reducing the cost of circuit executions. We utilized a fully programmable photonic chip to experimentally estimate the QNG in photonics for the first time, to the best of our knowledge. We obtained the dissociation curve of the He-H+ cation and achieved chemical accuracy, verifying the outperformance of QNG optimization on a photonic device. Our work opens up a vista of utilizing QNG in photonics to implement practical near-term quantum applications.

[Prenatal diagnosis and genetic analysis for two Chinese pedigrees carrying large fragment deletions of 13q21].

OBJECTIVE: To explore the strategies of prenatal diagnosis and genetic counseling for fetuses of two families with large deletions of 13q21. METHODS: Two singleton fetuses who were diagnosed with chromosome 13 microdeletions by non-invasive prenatal testing (NIPT) at Ningbo Women and Children's Hospital in March 2021 and December 2021 respectively were selected as the study subjects. Chromosomal karyotyping and chromosomal microarray analysis (CMA) were carried on amniotic samples. Peripheral blood samples were collected from the two couples for CMA assay to determine the origin of abnormal chromosomes identified in the fetuses. RESULTS: The karyotypes of the two fetuses were both normal. CMA revealed that they have respectively harbored heterozygous deletions spanning 11.935 Mb at 13q21.1q21.33 and 10.995 Mb at 13q14.3q21.32, which were respectively inherited from their mother and father. Both deletions had low gene density and lacked haploinsufficient genes, and were predicted to be likely benign variants based on database and literature search. Both couples had opted to continue with the pregnancy. CONCLUSION: The deletions of the 13q21 region in both families may be of benign variants. As the follow-up time was short, there was no sufficient evidence for the determination of pathogenicity, though our finding may still provide a basis for the prenatal diagnosis and genetic counseling.

Vibration-induced streaming flow near a sharp edge: Flow structure and instabilities in a large span of forcing amplitude.

The steady streaming generated near solid walls by the periodic forcing of a viscous fluid is known to be strongly enhanced near sharp structures, owing to centrifugal effects that lead to the generation of an intense jet from the sharp tip. This flow has been shown to provide efficient active mixing in microchannels, due to strong transverse velocity. The forcing is often prescribed by acoustic transducers, but it can also be generated from low-frequency time-periodic flow ensured by mechanical vibrations. In this paper, we study the flow structure generated by low-frequency forcing (typically 10 Hz) around a sharp tip. Using direct numerical simulations, we extract both the time-periodic and steady responses within a large span of amplitude of vibrations. When the amplitude is smaller than the tip radius of curvature, we recover the flow structure observed at higher frequencies (>1 kHz) in previous studies, namely, an intense symmetric central jet and a quadratic dependence for the characteristic streaming velocity with the oscillating velocity v_{s}∼v_{a}^{2}. At higher amplitudes, such a scaling no longer holds and the streaming flow pattern loses its left-right symmetry. We then analyze the mechanisms of the instability from the careful examination of the instationary flow fields, and we propose possible mechanisms for such a flow transition involving the coupling between the streaming jet and instationary vorticity.

[Genetic analysis of a Chinese pedigree featuring non-simplex blepharocheilodontic syndrome].

OBJECTIVE: To explore the genetic etiology of a Chinese pedigree featuring non-simplex blepharocheilodontic syndrome. METHODS: Whole exome sequencing was carried out to detect genetic variant and copy number variations (CNVs) in the pedigree. Suspected variants were verified by Sanger sequencing and qPCR. RESULTS: The fetus and its elder brother, father and grandfather were found to harbor a heterozygous c.83delG (p.A29Rfs*55) variant of the CTNND1 gene, which was unreported previously. In addition, its elder brother was also found to be a double heterozygote for a c.235delC (p.L79Cfs*3) variant of GJB2 gene and a c.538C>T (p.R180X) variant of GJB3 gene, which were respectively inherited from his mother and father. CNVs analysis revealed a de novo heterozygotic deletion (1.46 Mb) at 17q12 in the mother, which was confirmed by qPCR. Based on American College of Medical Genetics and Genomics guidelines, the c.83delG variant, the c.235delC variant and the 17q12 microdeletion were predicted as pathogenic, while the c.538C>T variant was of uncertain significance. CONCLUSION: The c.83delG (p.A29Rfs*55) variant of the CTNND1 gene probably underlay the pathogenesis of non-simplex blepharocheilodontic syndrome in this pedigree. The double heterozygous variants of c.235delC (p.L79Cfs*3) of GJB2 gene and c.538C>T (p.R180X) of GJB3 gene probably underlay the hearing loss in the elder brother. The bilateral renal cysts in the mother may be attributed to the 17q12 microdeletion. Above results have provided guidance for genetic counseling and prenatal diagnosis for this pedigree.

Variational Entanglement-Assisted Quantum Process Tomography with Arbitrary Ancillary Qubits.

Quantum process tomography is a pivotal technique in fully characterizing quantum dynamics. However, exponential scaling of the Hilbert space with the increasing system size extremely restrains its experimental implementations. Here, we put forward a more efficient, flexible, and error-mitigated method: variational entanglement-assisted quantum process tomography with arbitrary ancillary qubits. Numerically, we simulate up to eight-qubit quantum processes and show that this tomography with m ancillary qubits (0≤m≤n) alleviates the exponential costs on state preparation (from 4^{n} to 2^{n-m}), measurement settings (at least a 1 order of magnitude reduction), and data postprocessing (efficient and robust parameter optimization). Experimentally, we first demonstrate our method on a silicon photonic chip by rebuilding randomly generated one-qubit and two-qubit unitary quantum processes. Further using the error mitigation method, two-qubit quantum processes can be rebuilt with average gate fidelity enhanced from 92.38% to 95.56%. Our Letter provides an efficient and practical approach to process tomography on the noisy quantum computing platforms.

[A large-scale retrospective analysis of copy number variations in single center using ACMG-ClinGen latest guidelines].

OBJECTIVE: Through a retrospective large sample analysis of copy number variants in single center, we explored the technical standards for the interpretation and reporting of constitutional copy-number variants (CNVs) jointly proposed by the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen) in 2019, analyzing its impact on CNVs ratings and the improvement in the consistency of the classification of CNVs in clinical laboratories. METHODS: 236 CNVs that assessed as pathogenic, uncertain significant (including likely pathogenic, uncertain and likely benign) by the 2011 ACMG guidelines between August 2018 and December 2019 in our center were re-analyzed. Four working group members of the center reclassified and evaluated 235 CNVs according to 2019 ACMG guidelines. RESULTS: The consistency of clinical significance classification of CNVs was 91% and the α test coefficient was 0.98 among four working group members. Compared with the 2011 and 2019 ACMG technical standards for the CNVs classification, evaluation of pathogenicity and uncertain significant is basically consistent. 90% (45/50) of likely pathogenic and likely benign CNVs were Re-evaluated as variants of uncertain significance, and the difference is significant. CONCLUSION: The new version ACMG/ClinGen guidelines for the evaluation of CNVs developed semi-quantitative point-based scoring system and help to improve the consistency in clinical classifications. It can also make the interpretation of CNVs more standardized and transparent.

Development and Verification of Prognostic Nomogram for Penile Cancer Based on the SEER Database.

Aim: We aimed to establish a prognostic nomogram for penile cancer (PC) patients based on the Surveillance, Epidemiology, and End Results Program (SEER) database. Methods: Data from 1643 patients between 2010 and 2015 were downloaded and extracted from the SEER database. They were randomly divided into the development group (70%) and the verification group (30%), and then, univariate and multivariate Cox proportional hazards regression, respectively, was used to explore the possible risk factors of PC. The factors significantly related to overall survival (OS) and cancer-specific survival (CSS) were used to establish the nomogram, which was assessed via the concordance index (C-index), receiver operating characteristic (ROC) curve, and calibration curve. An internal validation was conducted to test the accuracy and effectiveness of the nomogram. Kaplan-Meier calculation was used to predict the further OS and CSS status of these patients. Results: On multivariate Cox proportional hazards regression, the independent prognostic risk factors associated with OS were age, race, marital status, N/M stage, surgery, surgery of lymph nodes, and histologic type, with a moderate C-index of 0.737 (95% confidence interval (CI): 0.713-0.760) and 0.766 (95% CI: 0.731-0.801) in the development and verification groups, respectively. The areas under the ROC (AUC) of 3- and 5-year OS were 0.749 and 0.770, respectively. While marital status, N/M stage, surgery, surgery of lymph nodes, and histologic type were significantly linked to PC patients' CSS, which have better C-index of 0.802 (95% confidence interval (CI): 0.771-0.833) and 0.82 (95% CI: 0.775-0.865) in the development and verification groups, and the AUC of 3- and 5-year CSS were 0.766 and 0.787. Both of the survival calibration curves of 3- and 5-year OS and CSS brought out a high consistency. Conclusion: Our study produced a satisfactory nomogram revealing the survival of PC patients, which could be helpful for clinicians to assess the situation of PC patients and to implement further treatment.

Optimization of quantum light sources and four-wave mixing based on a reconfigurable silicon ring resonator.

Being a key component on a photonic chip, the microring usually specializes in a certain nonlinear optical process and can not simultaneously meet different working conditions for different processes. Here, we theoretically and experimentally investigate a reconfigurable silicon microring resonator to act as a optimization strategy for both classical four-wave mixing and quantum light sources. Experimental results show that the four-wave mixing efficiency with continuous wave and pulsed pump can be both optimized to a high value well matching numerical analysis. A variety of quantum light sources - including the heralded single-photon source, two-photon source and multi-photon source - are demonstrated to present a high performance and their key parameters including the pair generation rates (PGR), the heralding efficiency (HE) and the coincidence-to-accidental ratio (CAR) are controllable and optimizable. Such tunable nonlinear converter is immune to fabrication variations and can be popularized to other nonlinear optical materials, providing a simple and compact post-fabrication trimming strategy for on-chip all-optical signal processing and photonic quantum technologies.

[Analysis of TUBB2B gene variant in a fetus with complex cortical dysplasia with other brain malformations-7].

OBJECTIVE: To explore the genetic basis for a fetus with dysgenesis of corpus callosum and other brain malformations. METHODS: Whole exome sequencing was carried out for the fetus and its parents. Suspected pathogenic variants were verified by Sanger sequencing. RESULTS: A novel de novo missense variant c.758T>A (p.L253Q) of the TUBB2B gene was identified, which was unreported previously. Based on the guidelines from the American College of Medical Genetics, the c.758T>A variant was predicted to be likely pathogenic. Bioinformatics analysis predicted that the leucine at position 253 was highly conserved among various species, and the c.758T>A variant may impact the formation of hydrogen bonds between Leu253 and Asp249 and Met257 residues, which in turn may affect the combination of GTP/GDP and function of the TUBB2B protein. CONCLUSION: The c.758T>A variant of the TUBB2B gene probably underlay the fetal malformations in this Chinese family. Above discovery has enriched the spectrum of TUBB2B gene variants and provided a basis for genetic counseling and prenatal diagnosis.

[Variation analysis of EPG5 gene in a Vici syndrome family].

OBJECTIVE: To explore the genetic etiology of Vici syndrome in a Chinese family. METHODS: Whole exome sequencing (WES) technology was used to detect gene variants in a fetus of abnormal ultrasonic structure without abnormalities in routine chromosome karyotype analysis and SNP-array. Sanger sequencing and bioinformatics prediction were performed for the suspected variants of the fetus and parents. RESULTS: The fetus and the elder sister have carried c. 2427delC (p.T809fs) and c.1886A>T (p.E629V) compound heterozygous variants of the EPG5 gene, which were respectively inherited from their mother and father. Neither variant was reported previously. According to ACMG guidelines, the c.2427delC variant was predicted as pathogenic, while the c.1886A>T variant was of uncertain significance. PolyPhen-2 and PROVEAN software indicated that c.1886A>T variant was probably damaging. CONCLUSION: The c.2427delC and c.1886A>T variants of the EPG5 gene probably underlie the pathogenesis of the Vici syndrome in this family. Above finding has enriched the variational spectrum of EPG5 gene and provided a basis for genetic counseling and prenatal diagnosis for the family.

Defect-Free Metal Deposition on 2D Materials via Inkjet Printing Technology.

2D materials have many outstanding properties that make them attractive for the fabrication of electronic devices, such as high conductivity, flexibility, and transparency. However, integrating 2D materials in commercial devices and circuits is challenging because their structure and properties can be damaged during the fabrication process. Recent studies have demonstrated that standard metal deposition techniques (like electron beam evaporation and sputtering) significantly damage the atomic structure of 2D materials. Here it is shown that the deposition of metal via inkjet printing technology does not produce any observable damage in the atomic structure of ultrathin 2D materials, and it can keep a sharp interface. These conclusions are supported by abundant data obtained via atomistic simulations, transmission electron microscopy, nanochemical metrology, and device characterization in a probe station. The results are important for the understanding of inkjet printing technology applied to 2D materials, and they could contribute to the better design and optimization of electronic devices and circuits.

Variability and Yield in h-BN-Based Memristive Circuits: The Role of Each Type of Defect.

In the race of fabricating solid-state nano/microelectronic devices using 2D layered materials (LMs), achieving high yield and low device-to-device variability are the two main challenges. Electronic devices that drive currents in-plane and homogeneously along the 2D-LMs (i.e., transistors, memtransistors) are strongly affected by local defects (i.e., grain boundaries, wrinkles, thickness fluctuations, polymer residues), as they create inhomogeneities and increase the device-to-device variability, resulting in a poor performance at the circuit level. Here, it is shown that memristors are insensitive to most types of defects in 2D-LMs, even when fabricated in academic laboratories that do not meet industrial standards. The reason is that the currents produced in these devices, which flow out-of-plane across the 2D-LM, are always driven locally by the most conductive locations. Consequently, it is concluded that it is much easier to fabricate 2D-LMs-based solid-state nano/microelectronic circuits using memristors than using transistors or memtransistors, not only due to the inherent simpler fabrication process (i.e., less lithography steps) but also because the local defects do not degrade the yield and variability of memristors considerably.