Novel Germline KIT Variants in Families With Severe Piebaldism: Case Series and Literature Review.

INTRODUCTION: Piebaldism is a rare autosomal dominant disorder characterized by congenital white forelock and depigmented patches, which is most commonly caused by deleterious variants in the KIT gene. METHODS: Four KIT variants were identified in a piebaldism case series by whole-exome sequencing. Functional experiments, including in vitro minigene reporter assay and enzyme-linked immunosorbent assay, were carried out to elucidate the pathogenicity of the variants. The genotype-phenotype correlation was summarized through extensive literature reviewing. RESULTS: All the four cases had severe piebaldism presented with typical white forelock and diffuse depigmentation on the ventral trunk and limbs. Four germline variants at the tyrosine kinase (TK) domains of the KIT gene were identified: two novel variants c.1990+1G>A (p.Pro627_Gly664delinsArg) and c.2716T>C (p.Cys906Arg), and two known variants c.1879+1G>A (p.Gly592_Pro627delinsAla) and c.1747G>A (p.Glu583Lys). Both splicing variants caused exon skipping and inframe deletions in the TK1 domain. The missense variants resided at the TK1 and TK2 domains respectively impairing PI3K/AKT and MAPK/ERK signaling pathways, the downstream of KIT. All severe cases were associated with variants in the TK domains, eliciting a major dominant-negative mechanism of the disease. CONCLUSION: Our data expand the mutation spectrum of KIT, emphasized by a dominant-negative effect of variants in the critical TK domains in severe cases. We also share the experience of prenatal diagnosis and informed reproductive choices for the affected families.

MicroRNA-519d-3p antagonizes osteosarcoma resistance against cisplatin by targeting PD-L1.

Accumulating evidence indicates that a ligand of programmed cell death receptor-1 (PD-L1) participates in the progression and recurrence of multiple malignancies, including osteosarcoma. Nevertheless, the role of PD-L1 in chemoresistance development is not fully understood. In the current study, we aim to clarify the interaction of miR-519d-3p and PD-L1 in the development of cisplatin resistance. Immunohistochemistry, quantitative reverse-transcription polymerase reaction, and Western blot were used to evaluate PD-L1 expression. MTT and transwell migration assays were used to measure cell growth and motility, respectively. ENCORI, miRCode, and miRDB databases were recruited to predict candidate miRNAs targeting PD-L1. The binding sequences of miR-519d-3p and PD-L1 3' untranslated region were identified by dual-luciferase reporter and RNA immunoprecipitation assays. Flow cytometric analysis was conducted to measure the cycle distribution and cell apoptosis. Metastatic mouse models were generated with cisplatin-resistant sublines by intravenous injection. We found that PD-L1 expression was positively correlated to cisplatin resistance and metastasis, whereas miR-519d-3p expression was reduced in cisplatin-resistant specimens and was negatively correlated to cisplatin resistance and metastasis of osteosarcoma. We demonstrated that miR-519d-3p overexpression reversed cisplatin resistance, induced G1/S phase arrest and apoptosis. In addition, we proved that miR-519d-3p inhibited lung metastasis by establishing cisplatin-resistant MG63 metastatic xenograft models. The present findings suggest that miR-519d-3p/PD-L1 axis is a novel signaling pathway contributing to cisplatin resistance. Our study provides new clues for curing refractory osteosarcoma beyond immune checkpoint inhibitors.

Encapsulating Cobalt into N-Doping Hollow Frameworks for Efficient Cascade Catalysis.

The development of nonprecious catalysts for hydrogenation of organic molecules is of great importance in heterogeneous catalysis. Herein, we report a series of N-doped hollow carbon frameworks encompassing cobalt nanoparticles (denoted as Co@NHF-900) constructed as a new kind of reusable catalyst for this purpose by pyrolysis of ZIF-8@Co-dopamine under Ar atmospheres. Notably, the framework of ZIF-8 is essential for efficient catalyst by providing a carbon framework to support Co-dopamine. The experimental results reveal that the ZIF-8 renders a large hollow place within the catalysts, allowing the enrichment of the substrate and windows of the hollow structure and the ease of mass transfer of products during the reaction. All of the virtues made Co@NHF-900 a good candidate for hydrogenation of quinolines with high activity (TOF value of 119 h-1, which is several times than that of akin catalysts) and chemoselectivity.

Prenatal risk assessment of Xp21.1 duplication involving the DMD gene by optical genome mapping.

Structural variants (SVs) of unknown significance are great challenges for prenatal risk assessment, especially when involving dose-sensitive genes such as DMD The pathogenicities of 5'-terminal DMD duplications in the database remain controversial. Four prenatal cases with Xp21.1 duplications were identified by routine prenatal genomic testing, encompassing the 5'-UTR to exons 1-2 in family 1 and family 2, and to exons 1-9 in family 3. The duplication in family 4 was non-contiguous covering the 5'-UTR to exon 1 and exons 3-7. All were traced to unaffected males in the family pedigrees. A new genome-wide approach of optical genome mapping was performed in families 1, 2, and 3 to delineate the breakpoints and orientation of the duplicated fragments. The extra copies were tandemly inserted into the upstream of DMD, preserving the integrity of ORF from the second copy. The pathogenicities were thus reclassified as likely benign. Our data highlight the importance of structural delineation by optical genome mapping in prenatal risk assessment of incidentally identified SVs involving DMD and other similar large dose-sensitive genes.

Self-adhesive, conductive, and multifunctional hybrid hydrogel for flexible/wearable electronics based on triboelectric and piezoresistive sensor.

Flexible electronics are highly developed nowadays in human-machine interfaces (HMI). However, challenges such as lack of flexibility, conductivity, and versatility always greatly hindered flexible electronics applications. In this work, a multifunctional hybrid hydrogel (H-hydrogel) was prepared by combining two kinds of 1D polymer chains (polyacrylamide and polydopamine) and two kinds of 2D nanosheets (Ti3C2Tx MXene and graphene oxide nanosheets) as quadruple crosslinkers. The introduced Ti3C2Tx MXene and graphene oxide nanosheets are bonded with the PAM and PDA polymer chains by hydrogen bonds. This unique crosslinking and stable structure endow the H-hydrogel with advantages such as good flexibility, electrical conductivity, self-adhesion, and mechanical robustness. The two kinds of nanosheets not only improved the mechanical strength and conductivity of the H-hydrogel, but also helped to form the double electric layers (DELs) between the nanosheets and the bulk-free water phase inside the H-hydrogel. When utilized as the electrode of a triboelectric nanogenerator (TENG), high electrical output performances were realized due to the dynamic balance of the DELs between the nanosheets and the H-hydrogel's inside water molecules. Moreover, flexible sensors, including triboelectric, and strain/pressure sensors, were achieved for human motion detection at low frequencies. This hydrogel is promising for HMI and e-skin.

Boosting Molecular Cross-Linking in a Phenolic Resin for Spherical Hard Carbon with Enriched Closed Pores toward Enhanced Sodium Storage Ability.

Phenolic resin (PF) is considered a promising precursor of hard carbon (HC) for advanced-performance anodes in sodium-ion batteries (SIBs) because of its facile designability and high residual carbon yield. However, understanding how the structure of PF precursors influences sodium storage in their derived HC remains a significant challenge. Herein, the microstructure of HC is controlled by the degree of cross-linking of resorcinol-benzaldehyde (RB) resin. We reveal that robust molecular cross-linking in RB resin induced by hydrothermal treatment promotes closed-pore formation in the derived HC. The mechanism is devised for the decomposition of a highly cross-linked RB three-dimensional network into randomly stacked short-range graphitic microcrystals during high-temperature carbonization, contributing to the abundant closed pores in the derived HC. In addition, the high cross-linking degree of RB resin endows its derived HC with a small-sized spherical morphology and large interlayer spacing, which improves the rate performance of HC. Consequently, the optimized hydrothermal treatment HC anode shows a higher specific capacity of 372.7 mAh g-1 and better rate performance than the HC anode without hydrothermal treatment (276.0 mAh g-1). This strategy can provide feasible molecular cross-linking engineering for the development of closed pores in PF-based HC toward enhanced sodium storage.

One-Step Construction of Closed Pores Enabling High Plateau Capacity Hard Carbon Anodes for Sodium-Ion Batteries: Closed-Pore Formation and Energy Storage Mechanisms.

Closed pores play a crucial role in improving the low-voltage (<0.1 V) plateau capacity of hard carbon anodes for sodium-ion batteries (SIBs). However, the lack of simple and effective closed-pore construction strategies, as well as the unclear closed-pore formation mechanism, has severely hindered the development of high plateau capacity hard carbon anodes. Herein, we present an effective closed-pore construction strategy by one-step pyrolysis of zinc gluconate (ZG) and elucidate the corresponding mechanism of closed-pore formation. The closed-pore formation mechanism during the pyrolysis of ZG mainly involves (i) the precipitation of ZnO nanoparticles and the ZnO etching on carbon under 1100 °C to generate open pores of 0.45-4 nm and (ii) the development of graphitic domains and the shrinkage of the partial open pores at 1100-1500 °C to convert the open pores to closed pores. Benefiting from the considerable closed-pore content and suitable microstructure, the optimized hard carbon achieves an ultrahigh reversible specific capacity of 481.5 mA h g-1 and an extraordinary plateau capacity of 389 mA h g-1 for use as the anode of SIBs. Additionally, some in situ and ex situ characterizations demonstrate that the high-voltage slope capacity and the low-voltage plateau capacity stem from the adsorption of Na+ at the defect sites and Na-cluster formation in closed pores, respectively.

Novel biaryloxazolidinone derivatives with broad-spectrum antibacterial activity, favorable drug-like profiles and in vivo efficacy against linezolid-resistant Staphylococcusaureus.

The emergence of multidrug-resistant bacteria along with a declining pipeline of clinically useful antibiotics has led to the urgent need for the development of more effective antibacterial agents to treat drug-resistant bacteria. We previously discovered compound OB-158 with potent antibacterial activity but exhibited poor oral bioavailability. Herein, a systematic structural optimization of OB-158 to improve pharmacokinetic profiles yielded 26 novel biaryloxazolidinone analogues, and their activities against Gram-positive S. aureus, multidrug resistant S. aureus and Enterococcus faecalis were evaluated. Remarkably, compound 8b was identified with potent antibacterial activity against S. aureus (MIC = 0.06 µg/mL), MSSA (MIC = 0.125 µg/mL), MRSA (MIC = 0.06 µg/mL), LRSA (MIC = 0.125 µg/mL) and LREFa (MIC = 0.5 µg/mL). Compound 8b was demonstrated as a promising candidate through druglikeness evaluation including metabolism in microsomes and plasma, Caco-2 cell permeability, plasma protein binding, cytotoxicity, and inhibition of CYP450 and human monoamine oxidase. Notably, compound 8b displayed excellent PK profile with appropriate T1/2 of 1.49 h, high peak plasma concentration (Cmax = 2320 ng/mL), high plasma exposure (AUC0-t = 8310 h ng/mL), and superior oral bioavailability (F = 68.1 %) in Sprague-Dawley rats. Ultimately, in vivo efficacy of compound 8b in a mouse model of LRSA systemic infection was also demonstrated. Taken together, compound 8b represents a promising drug candidate for the treatment of linezolid-resistant Gram-positive bacterial strains infection.

[Retracted] miR­486 suppresses the development of osteosarcoma by regulating PKC­Î´ pathway.

Following the publication of the above article, a concerned reader drew to the Editor's attention that, for the Transwell invasion and migration assay experiments shown in Figs. 5 and 6, there were multiple instances of apparently overlapping data panels, such that the data would have been derived from the same original sources where they were intended to show the results from differently performed experiments; moreover, certain of the data shown in Fig. 5B were strikingly similar to data that had appeared in Fig. 2 in a previously published paper written by different authors at different research institutes [Tian F, Ding D and Li D: Fangchinoline targets PI3K and suppresses PI3K/AKT signaling pathway in SGC7901 cells. Int J Oncol 46: 2355­2363, 2015]. In view of the fact that certain of the data in the above article had already appeared in a previously published paper, and given the large number of apparently overlapping data panels identified in the two referenced figures, the Editor of International Journal of Oncology has decided that this paper should be retracted from the publication. After having been in contact with the authors, they accepted the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Oncology 50: 1590­1600, 2017; DOI: 10.3892/ijo.2017.3928].

Ultra-High Sulfur-Doped Hierarchical Porous Hollow Carbon Sphere Anodes Enabling Unprecedented Durable Potassium-Ion Hybrid Capacitors.

Sulfur doping is a promising path to ameliorate the kinetics of carbon-based anodes. However, the similar electronegativity of sulfur and carbon and the poor thermal stability of sulfur severely restrict the development of high-sulfur-content carbon-based anodes. In this work, ultra-high sulfur-doped hierarchical porous hollow carbon spheres (SHCS) with a sulfur content of 6.8 at % are synthesized via a direct high-temperature sulfur-doping strategy. An SHCS has sulfur bonded to the carbon framework including C-S-C and C-SOx-C, which enlarges its interlayer distance (0.411 nm). In the K half-cell, benefiting from the considerable content and the reasonable architecture of sulfur, the SHCS exhibits significantly improved reversible specific capacity, initial Coulombic efficiency, and cyclability than hierarchical porous hollow carbon spheres without sulfur. Remarkably, the potassium ion hybrid capacitor device fabricated with the SHCS anode achieves excellent energy/power density (135.6 W h kg-1/17.7 kW kg-1) and unprecedented durability over 26,000 cycles at 2 A g-1. This research provides a superior strategy to design high-sulfur-content carbon-based anodes with excellent potassium storage performance.

Nonsense suppression induced readthrough of a novel PAX6 mutation in patient-derived cells of congenital aniridia.

BACKGROUND: Congenital aniridia is a severe ocular abnormality characterized by incomplete formation of the iris and many other ocular complications. Most cases are caused by the paired box 6 (PAX6) gene mutations generating premature termination codons (PTCs). METHODS: Ophthalmic examination was performed on a Chinese pedigree with congenital aniridia. The mutation was identified by targeted next-generation sequencing. Nonsense suppression therapy was applied on patient-derived lymphocytes. The PAX6 expression was assayed by real-time polymerase chain reaction and Western blot. RESULTS: Complete aniridia was complicated with horizontal nystagmus, contract, foveal hypoplasia, and microphthalmia. A novel heterozygous c.702_703delinsAT (p.Tyr234*) mutation was found in exon 9 of PAX6, generating a PTC at the homeodomain. There were about 50% reductions of both full-length PAX6 protein and PAX6 mRNA in patient-derived lymphocytes, indicating haploinsufficiency due to nonsense-mediated mRNA decay. Ataluren (PTC124) and geneticin (G418) could induce about 30%-40% translational readthrough. Nonsense suppression therapy restored PAX6 protein to about 65%-70% of unaffected family controls. CONCLUSION: Our data expanded the genetic and phenotypic variations of congenital aniridia, and showed the therapeutic effect of nonsense suppression on this disease using patient-derived cells.

[Epidemiological investigation of welder's pneumoconiosis in two container manufacturing industries in Guangdong province].

OBJECTIVE: To investigate the incidence of welder's pneumoconiosis in container manufacturing industries in Guangdong province and present some preventive and curative strategy. METHODS: Occupational epidemiology study methods were used to study the incidence of welder's pneumoconiosis in two container manufacturing enterprises (enterprise A and enterprise B). RESULTS: Before 2004, the rate of up-to-standard of weld fume concentration in the workplaces was relatively low (< or = 40%), and the maximum value of time weighted average (TWA) was 26.7 mg/m(3). After 2004, with the system of dust control, the rate of up-to-standard was 85% in the enterprise A. Of the 813 weld workers examined, 19 were diagnosed as welder's pneumoconiosis (stage I was 15, while I (+) was 4 ) and the incidence was 2.34% (19/813). The age of electric welders suffering from welder's pneumoconiosis and the duration of dust exposure were (33.45 + 4.64) and (8.04 + 1.97) years respectively. Chest radiographic examination showed mainly small round opacities "p". The value of MVV, FEF25%, FEF50% and FEF75% in lung function tests were significantly lower than those of the control group (P < 0.05 or P < 0.01). CONCLUSION: The main features of welder's pneumoconiosis in container manufacturing industries are the short duration of dust exposure, and small round opacities "p" in the chest radiographs. Therefore, it should be the key point of the prevention and treatment of occupational diseases in this industry to control the harmful weld fume.

miR-627-3p inhibits osteosarcoma cell proliferation and metastasis by targeting PTN.

Dysregulation of microRNA (miRNA) has been observed in several types of tumors, including osteosarcoma. Biochip analysis was used to identify miRNAs differentially expressed in osteosarcoma tissues. The targeting sites of miR-627-3p were analyzed using miRDB software and fluorescein reporter gene. MTT and Transwell assays were used to analyze the effects of miR-627-3p on the growth and migration of osteosarcoma cells. Western blotting and real-time PCR were used to detect the effects of miR-627-3p on related proteins. In vivo experiments were conducted to verify the effect of miR-627-3p on osteosarcoma. We focused on miR-627-3p because it was the most significantly downregulated miRNA in our screening study. Through luciferase reporter assays, western blotting and real-time PCR we found that miR-627-3p directly targets PTN, and that expression levels of miR-627-3p and PTN are negatively correlated in osteosarcoma cells. Downregulation of miR-627-3p promoted osteosarcoma cell proliferation and metastasis, while its overexpression had the opposite effect. By targeting PTN, miR-627-3p also suppressed expression of Cyclin D1 and MMP2. MiR-627-3p inhibited osteosarcoma metastasis in vivo. Thus, miR-627-3p may be a useful therapeutic target for the treatment osteosarcoma or prevention of metastasis.

Keratin 9 L164P mutation in a Chinese pedigree with epidermolytic palmoplantar keratoderma, cytokeratin analysis, and literature review.

BACKGROUND: Epidermolytic palmoplantar keratoderma (EPPK) is characterized by hyperkeratotic lesions on palms and soles. The disorder is caused by mutations of keratin 9 (KRT9) or KRT1 gene. METHODS: Epidermolytic palmoplantar keratoderma was diagnosed by physical examination and histopathological analysis in a five-generation Chinese family. Mutation was screened by Sanger sequencing. The palmar expression of multiple cytokeratins were analyzed by tape-stripping and Real-time PCR. Literatures of EPPK with additional symptoms were reviewed. RESULTS: Affected family members showed diffuse palmoplantar keratosis, with knuckle pads, friction-related lesions and a novel additional symptom of palmar constriction. A heterozygous mutation of c.T491C (p.L164P) of KRT9 was found within the helix initiation motif. The hydrophobic effect was decreased and the initiation of coiled-coil conformation was delayed. The KRT16/KRT6 expression were significantly increased in the patients, especially on the right, indicating activation of stress-response and wound-healing cytokeratins. There were also increased KRT9/KRT2, unchanged KRT10/KRT1, and undetectable KRT14/KRT5 expression. The genetic and phenotypic heterogeneity of EPPK with additional symptoms were summarized by literature review. CONCLUSION: The p.L164P mutation of KRT9 caused EPPK with a novel symptom of palmar constriction. The expression of multiple cytokeratins was altered in EPPK patients.

miR-141-3p is a key negative regulator of the EGFR pathway in osteosarcoma.

BACKGROUND: Many studies have used miRNA to modulate osteosarcoma development by regulating protein expression, and these studies showed that the expression of EGFR is increased in osteosarcoma. METHODS: Western blot, real-time PCR and immunohistochemical were used to detect the expression of EGFR and miR-141 in osteosarcoma tissues and cells. The correlation between miR-141 and the grading of osteosarcoma and the correlation with the survival time of the patients were analyzed. After predicting the target effect of miR-141 on EGFR by miRDB, correlation analysis was used to analyze the correlation between miR-141 and EGFR. Luciferase reporter gene, western blot and real-time PCR were used to detect the targeting effect of miR-141 on EGFR. Then we detected the effect of miR-141 on proliferation by MTT and PI staining. The effect of miR-141 on cell apoptosis was detected by Hochest33258 and AV-PI staining, and the effect of miR-141 on cell migration was detected by Transwell. The regulatory effects of miR-141 on related proteins were detected by western blot and real-time PCR. Finally, we transfected EGFR and EGFR DEL (mutation with miR-141 binding site) in osteosarcoma cells, and detected the effects of miR-141 on cell proliferation, apoptosis, migration and related proteins. RESULTS: The expression of miR-141-3p was negatively correlated with the expression of EGFR in osteosarcoma. The overexpression of miR-141-3p was not only closely related to the classification and size of the osteosarcoma but also had a negative effect on the growth and migration of the osteosarcoma through negative regulation of the expression of EGFR. MiR-141 can inhibit the growth and metastasis of osteosarcoma cells by targeting EGFR and affecting its downstream pathway proteins. CONCLUSION: Our study provides miR-141-3p may be a new theoretical basis for the treatment of osteosarcoma.

miR-486 suppresses the development of osteosarcoma by regulating PKC-δ pathway.

Osteosarcoma is one of the most highly malignant types of cancer in adolescents and young adults with a high mortality rate. Despite advances in surgery, radiation therapy and chemotherapy, the prognosis for patients with osteosarcoma has not significantly improved over the past several decades. It is necessary to find new indicators of prognosis and therapeutic targets of osteosarcoma. Through the analysis of 40 osteosarcoma tissues, we found that the expression of miR­486 was low and the expression of PKC­Î´ was high in osteosarcoma. Median survival of patients with low expression of miR-486 (30 months) was shorter than the patients with higher expression of miR­486 (40 months). We further found that miR-486 can inhibit the targeting of PKC­Î´ signaling pathways, and this inhibition can inhibit the growth and invasion of osteosarcoma cells. After transfection of miR­486 for 24 h, the proliferation of osteosarcoma cells was inhibited by ~20%, and the migration was inhibited by ~15%. In the present investigation, we demonstrated that miR­486 is negatively associated with the expression of PKC-δ and could regulate the development of osteosarcoma. miR-486 may be a potential target for the treatment of osteosarcoma.