Engineering a precise adenine base editor with minimal bystander editing.

Adenine base editors (ABEs) catalyze A-to-G transitions showing broad applications, but their bystander mutations and off-target editing effects raise safety concerns. Through structure-guided engineering, we found ABE8e with an N108Q mutation reduced both adenine and cytosine bystander editing, and introduction of an additional L145T mutation (ABE9), further refined the editing window to 1-2 nucleotides with eliminated cytosine editing. Importantly, ABE9 induced very minimal RNA and undetectable Cas9-independent DNA off-target effects, which mainly installed desired single A-to-G conversion in mouse and rat embryos to efficiently generate disease models. Moreover, ABE9 accurately edited the A5 position of the protospacer sequence in pathogenic homopolymeric adenosine sites (up to 342.5-fold precision over ABE8e) and was further confirmed through a library of guide RNA-target sequence pairs. Owing to the minimized editing window, ABE9 could further broaden the targeting scope for precise correction of pathogenic single-nucleotide variants when fused to Cas9 variants with expanded protospacer adjacent motif compatibility. bpNLS, bipartite nuclear localization signals.

Infantile fibrosarcoma of the perineum with dorsal metastasis in a neonate: a case report original.

BACKGROUND: Infantile fibrosarcoma is a rare pediatric soft tissue tumor and usually appears in children before one year of age. Distal extremities constitute the most frequently affected locations, and other tissues such as the trunk, head and neck, gut, sacrococcygeal region, and viscera are uncommon sites. CASE PRESENTATION: We describe a rare case of infantile fibrosarcoma arising from the perineum. First, a cystic mass was detected using prenatal ultrasonography, and then an echo was changed in serial ultrasound examinations. A solid cystic lesion was found at term; a hypoechoic lesion occurred in the back. The tumor became so large that massive bleeding occurred, which then underwent surgical resection. Pathological examination confirmed infantile fibrosarcoma. CONCLUSION: Our report demonstrates not all ultrasonographic findings in cases of infantile fibrosarcoma exhibit a solid mass during the initial examination - an early-stage lesion may reveal a cystic echo. Infantile fibrosarcoma has a good prognosis and surgery constitute the main treatment, with adjuvant chemotherapy being received if necessary.

Metalloporphyrin-Decorated Titanium Dioxide Nanosheets for Efficient Photocatalytic Carbon Dioxide Reduction.

In photocatalysis, the most efficient way to separate photogenerated electron-hole pairs has been extensively studied. However, the methods to increase the quantities of free electrons are neglected. Herein, we used a self-assembly method to fabricate MTCPP/TiO2 composite materials with a series of metalloporphyrins (MTCPPs, M = Fe, Co, Zn) as sensitizers to modify TiO2 nanosheets. First, abundant carboxyl and hydroxyl on porphyrin were adsorbed by metal ions. Then, the remaining carboxyl and hydroxyl on porphyrin were anchored on the surface of TiO2 nanosheets. Finally, MTCPP/TiO2 was obtained by a layer-by-layer self-assembly process. MTCPP broadens the light response of TiO2 from ultraviolet light to visible light and enhances the CO2 adsorption ability. Moreover, metal ions coordinating with porphyrin regulate the electron density of the porphyrin ring and provide a stronger π feedback bond, which promote charge separation. Consequently, by optimizing the type of metal ion, the yield of ZnTCPP/TiO2 composites reached 109.33 µmol/(g h) of CO and 9.94 µmol/(g h) of CH4, which was more than 50 times that of pure TiO2. This study proposes a possible visible-light-induced CO2 reduction mechanism of metal-ion-based photocatalysis, which provides great insights into optimizing the designation of efficient photocatalysis.

Cu@Cu3 P Core-Shell Nanowires Attached to Nickel Foam as High-Performance Electrocatalysts for the Hydrogen Evolution Reaction.

The development of highly efficient and inexpensive electrocatalysts is of great importance for generating renewable energy. In this work, Cu@Cu3 P core-shell nanowires grown on nickel foam (Cu@Cu3 P/NF) are prepared by a novel in situ reduction of CuSO4 ⋅5 H2 O, which forms Cu, followed by surface oxidation and low-temperature phosphorization. The unique hierarchical architecture of Cu@Cu3 P/NF integrates the advantages of enlarged surface area, fast electron transport, numerous channels for gas rapid diffusion, non-polymer binder, and enhanced catalytic performance. Remarkably, Cu@Cu3 P/NF-50, with a molar ratio of Cu/Cu3 P of around 2.63, reveals a highly efficient catalytic performance for the hydrogen evolution reaction in alkaline solution with a Tafel slope of 59 mV dec-1 and a long durability of 48 h. Overpotentials as low as 218 and 302 mV are required to reach current densities of 10 and 100 mA cm-2 , respectively. Furthermore, the scientific understanding and design principle of Cu@Cu3 P/NF with controlled performance will encourage more research into other high-performance, low-cost electrocatalysts for renewable energy.

3D Self-Supported Porous NiO@NiMoO4 Core-Shell Nanosheets for Highly Efficient Oxygen Evolution Reaction.

Novel 3D self-supported porous NiO@NiMoO4 core-shell nanosheets are grown on nickel foam through a facile stepwise hydrothermal method. Ultrathin NiO nanosheets on the nickel foam cross-linked to each other are used as the core, and tiny NiMoO4 nanosheets are further engineered to be immobilized uniformly on the NiO nanosheets to form the shell. This step-by-step construction of the architecture composed of ultrathin primary and secondary nanosheets efficiently avoids the agglomeration problems of individual ultrathin nanosheets. The ingenious architecture possesses the advantages of numerous diffusion channels for electrolyte ions, ideal pathways for electrons, and a large interfacial area for electrochemical reaction. The introduction of the NiMoO4 secondary nanosheets on the NiO primary nanosheets not only endows the heterostructure with high electrical conductivity and a large active area but also promotes an increase in oxygen vacancy content, which favors the improvement of electrocatalytic properties for the oxygen evolution reaction. The Tafel plot for the NiO@NiMoO4 core-shell architecture is as low as 32 mV dec-1, and the overpotential needed to reach 10 mA·cm-2 for NiO@NiMoO4 nanosheets is only 0.28 V.

Identification of DJ-1 as a contributor to multidrug resistance in human small-cell lung cancer using proteomic analysis.

Proteomic approaches have been proven to provide an important tool in identifying drug resistance-associated proteins. The aim of this study was to investigate the protein profiling of drug resistance-related proteins in small-cell lung cancer (SCLC) by proteomic analysis. The proteomic profiling was performed by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with MALDI-TOF-TOF of SCLC in the multidrug-resistant cell line H69AR and its parental cell line H69. A total of 11 proteins were identified to be >2-fold up-or downregulated between the two cell lines. DJ-1, one of the differently expressed proteins identified by proteomics, was further examined by immunohistochemistry staining in 116 cases of SCLC tissues. Immunohistochemical results demonstrated that DJ-1 was expressed in 51.7% (60/116) of SCLC. DJ-1 expression was correlated significantly with survival time of SCLC patients (P < 0.05), but not with other clinical parameters such as gender, age and clinical stage (P > 0.05). Downregulation of DJ-1 using DJ-1-siRNA in H69AR cells sensitized cancer cells to chemotherapeutic drugs through increasing drug-induced cell apoptosis accompanied with G0-G1 phase arrest. These findings suggest DJ-1 may serve as a potential biomarker for chemoresistance and prognostic factor for patients with SCLC.

Targeted radionuclide therapy for lung cancer with iodine-131-labeled peptide in a nude-mouse model.

Integrin α3ß1 has been shown to be a novel candidate target for the imaging and specific therapy of non-small-cell lung cancer. We have previously reported on a peptide containing a novel motif of NGXG that specifically binds to the integrin α3 receptor on lung cancer cells using a one-bead one-peptide combinatorial library. In this study, we developed the peptide cNGEGQQc-based therapeutic agent labeling with radionuclide iodine-131 (I) and evaluated its characteristics including stability, biodistribution, antitumor activity, and safety. The results showed that I-cNGEGQQc was stable in serum. Furthermore, the biodistribution of I-cNGEGQQc was determined in normal mice and rabbits. In-vivo biodistribution studies showed that radiolabeled peptide in the kidney was significantly higher than that in other organs. Nude mice bearing lung cancer cell xenografts (H1975 and L78) were used as an in-vivo model for tumor-inhibition efficacy studies with I-cNGEGQQc. The tumor growth decreased significantly in mice receiving I-labeled peptide compared with the controls and the effect of I-labeled peptide can be blocked by unlabeled cNGEGQQc. Safety studies showed that I-cNGEGQQc was relatively safe for animals without significant toxicity. Our data suggest that I-cNGEGQQc has potential as a targeted radiotherapeutic agent for non-small-cell lung cancer.

Elevated Expression of Kin17 in Cervical Cancer and Its Association With Cancer Cell Proliferation and Invasion.

BACKGROUND: Cervical cancer is one of the most common cancers in women worldwide. Emerging evidence suggests that kin17 is a tumor-promoting protein in some types of solid tumors. However, whether kin17 contributes to cervical cancer carcinogenesis remains unknown. METHODS: Kin17 expression in clinical samples from Guangdong Women and Children's Hospital and Health Institute was detected by immunohistochemical staining. A series of functional experiments including 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide assay, 5-bromo-2'-deoxyuridine assay, colony formation, transwell assay, flow cytometry of apoptosis, and cell cycle were performed to explore the roles of kin17 in cervical cancer cells HeLa. RESULTS: In this study, we showed for the first time that the expression of kin17 was significantly increased in clinical cervical cancer samples, and associated with tumor differentiation, lymph node metastasis, and ki-67 expression in a clinicopathologic characteristics review. Furthermore, silence of kin17 in HeLa cells inhibited cell proliferation, clone formation, cell cycle progression, migration, and invasion, and also promoted cell apoptosis. CONCLUSION: Our findings demonstrate that kin17 is closely related to the cell proliferation and invasion of cervical cancer and could be a novel diagnostic and therapeutic target for cervical cancer management. The underlying mechanisms should be elucidated in future research.

Long noncoding RNA-HOTAIR affects chemoresistance by regulating HOXA1 methylation in small cell lung cancer cells.

Homeobox (HOX) transcript antisense RNA (HOTAIR), a long intergenic noncoding RNA (lincRNA), has been reported to play an oncogenic role in various cancers including small cell lung cancer (SCLC). However, it is not known whether HOTAIR can modulate chemoresistance in SCLC. The aim of this study is to investigate the roles of HOTAIR in chemoresistance of SCLC and its possible molecular mechanism. Knockdown of HOTAIR was carried out in SCLC multidrug-resistant cell lines (H69AR and H446AR) and the parental cell lines (H69 and H446) to assess its influence on chemoresistance. The results showed that downregulation of HOTAIR increased cell sensitivity to anticancer drugs through increasing cell apoptosis and cell cycle arrest, and suppressed tumor growth in vivo. Moreover, HOXA1 methylation increased in the resistant cells using bisulfite sequencing PCR. Depletion of HOTAIR reduced HOXA1 methylation by decreasing DNMT1 and DNMT3b expression. The interaction between HOTAIR and HOXA1 was validated by RNA immunoprecipitation. Taken together, our study suggested that HOTAIR mediates chemoresistance of SCLC by regulating HOXA1 methylation and could be utilized as a potential target for new adjuvant therapies against chemoresistance.

One-Pot Fabrication of Hierarchical Nanosheet-Based TiO2 -Carbon Hollow Microspheres for Anode Materials of High-Rate Lithium-Ion Batteries.

Hierarchical and hollow nanostructures have recently attracted considerable attention because of their fantastic architectures and tunable property for facile lithium ion insertion and good cycling stability. In this study, a one-pot and unusual carving protocol is demonstrated for engineering hollow structures with a porous shell. Hierarchical TiO2 hollow spheres with nanosheet-assembled shells (TiO2 NHS) were synthesized by the sequestration between the titanium source and 2,2'-bipyridine-5,5'-dicarboxylic acid, and kinetically controlled etching in trifluoroacetic acid medium. In addition, annealing such porous nanostructures presents the advantage of imparting carbon-doped functional performance to its counterpart under different atmospheres. Such highly porous structures endow very large specifics surface area of 404 m(2) g(-1) and 336 m(2) g(-1) for the as-prepared and calcination under nitrogen gas. C/TiO2 NHS has high capacity of 204 mA h g(-1) at 1 C and a reversible capacity of 105 mA h g(-1) at a high rate of 20 C, and exhibits good cycling stability and superior rate capability as an anode material for lithium-ion batteries.

Brønsted Acid/Lewis Acid Cooperatively Catalyzed Addition of Diazoester to 2H-chromene Acetals.

A novel Brønsted acid/Lewis acid dual catalyst system has been developed to promote an efficient C-C bond formation between a range of oxocarbenium precursors derived from chromene acetals and ethyl diazoacetate. The reaction proceeds under mild conditions and is tolerant of common functionalized 2H-chromene and isochromene acetals. In addition, an asymmetric variant of diazoacetate addition towards 2H-chromene acetal is described. Continued investigations include the further optimization of asymmetric induction towards the formation of diazo ester substituted 2H-chromene.

Our experience diagnosing 225 patients with cervical glandular lesions: current technologies, lessons learned, and areas for improvement.

OBJECTIVE: To explore the relative sensitivity of different methods for detecting cervical glandular lesions. METHODS: A total of 225 patients with cervical glandular lesions diagnosed from January 2018 to February 2023 were retrieved from the pathology database of Guangdong Maternal and Child Health Hospital, and their clinicopathological features were reviewed. RESULTS: Four human papillomavirus (HPV) genotypes: HPV18, 16, 45, and 52, dominated all glandular lesions, and accounting for 74.10% of HPV-positive tumors. Furthermore, 36.89% of abnormal squamous cells were diagnosed as abnormal based on cytological examinations leading to the detection of cervical glandular lesions; only 16.89% were diagnosed based on the initial detection of abnormal glandular cytology. The most common abnormal cervical screening result was ASC-US on cytology (14.22%), followed by HSIL (11.56%). Only few number of patients were diagnosed with or suspected of having cervical adenopathy via a Pap test (18.22%). Nearly one-third of cervical glandular lesions cases were not detected on the Pap test; but were diagnosed upon cervical biopsy or based on the histological examination of ECC, LEEP, or CKC specimens. The LEEP or CKC biopsy specimens had negative margins in 49 cases (40.83%), while the margins were positive in the other 71 cases (59.17%). Five cases (10.20%) with negative margins still had residual lesions following total hysterectomy, and 19 (26.76%) with positive margins had no residual lesions after total hysterectomy. CONCLUSION: The ability to detect cervical glandular lesions varies for routine HPV genotyping, Pap test, or biopsy/ECC, with different sensitivities and advantages and disadvantages for each method.

Defect Engineering in Ce-Based Metal-Organic Frameworks toward Enhanced Catalytic Performance for Hydrogenation of Dicyclopentadiene.

Defective metal-organic frameworks (MOFs) have shown great potential for catalysis due to abundant active sites and adjustable physical and chemical properties. A series of Ce-based MOFs with different defect contents were synthesized via a modulator-induced defect engineering strategy with the aid of the cell pulverization technique. The effects of modulators on the pore structure, morphology, valence distribution of Ce, and Lewis acidity of Ce-MOF-801 were systematically investigated. Among the different samples studied, the optimal Ce-MOF-801-50eq sample exhibited remarkable catalytic activity for DCPD hydrogenation, achieving a conversion rate of 100%, which is significantly higher compared to other Ce-MOF-801-neq samples as well as the Zr-MOF-801-50eq and Hf-MOF-801-50eq samples. The enhanced catalytic performance of Ce-MOF-801-50eq can be attributed to advantages provided by defect engineering, such as the high specific surface area, proper pore size distribution, abundant unsaturated metal sites, and Ce3+/Ce4+ atom ratio, which have been supported by various characterizations. This study provides important insights into the rational design of Ce-MOFs in the field of catalytic DCPD hydrogenation.

Artificial Intelligence and High-Throughput Computational Workflows Empowering the Fast Screening of Metal-Organic Frameworks for Hydrogen Storage.

Metal-organic frameworks (MOFs) are one of the most promising hydrogen-storing materials due to their rich specific surface area, adjustable topological and pore structures, and modified functional groups. In this work, we developed automatically parallel computational workflows for high-throughput screening of ∼11,600 MOFs from the CoRE database and discovered 69 top-performing MOF candidates with work capacity greater than 1.00 wt % at 298.5 K and a pressure swing between 100 and 0.1 bar, which is at least twice that of MOF-5. In particular, ZITRUP, OQFAJ01, WANHOL, and VATYIZ showed excellent hydrogen storage performance of 4.48, 3.16, 2.19, and 2.16 wt %. We specifically analyzed the relationship between pore-limiting diameter, largest cavity diameter, void fraction, open metal sites, metal elements or nonmetallic atomic elements, and deliverable capacity and found that not only geometrical and physical features of crystalline but also chemical properties of adsorbate sites determined the H2 storage capacity of MOFs at room temperature. It is highlighted that we first proposed the modified crystal graph convolutional neural networks by incorporating the obtained geometrical and physical features into the convolutional high-dimensional feature vectors of period crystal structures for predicting H2 storage performance, which can improve the prediction accuracy of the neural network from the former mean absolute error (MAE) of 0.064 wt % to the current MAE of 0.047 wt % and shorten the consuming time to about 10-4 times of high-throughput computational screening. This work opens a new avenue toward high-throughput screening of MOFs for H2 adsorption capacity, which can be extended for the screening and discovery of other functional materials.

Adenine transversion editors enable precise, efficient A•T-to-C•G base editing in mammalian cells and embryos.

Base editors have substantial promise in basic research and as therapeutic agents for the correction of pathogenic mutations. The development of adenine transversion editors has posed a particular challenge. Here we report a class of base editors that enable efficient adenine transversion, including precise A•T-to-C•G editing. We found that a fusion of mouse alkyladenine DNA glycosylase (mAAG) with nickase Cas9 and deaminase TadA-8e catalyzed adenosine transversion in specific sequence contexts. Laboratory evolution of mAAG significantly increased A-to-C/T conversion efficiency up to 73% and expanded the targeting scope. Further engineering yielded adenine-to-cytosine base editors (ACBEs), including a high-accuracy ACBE-Q variant, that precisely install A-to-C transversions with minimal Cas9-independent off-targeting effects. ACBEs mediated high-efficiency installation or correction of five pathogenic mutations in mouse embryos and human cell lines. Founder mice showed 44-56% average A-to-C edits and allelic frequencies of up to 100%. Adenosine transversion editors substantially expand the capabilities and possible applications of base editing technology.

Malignant Peripheral Nerve Sheath Tumor in the Nasal Cavity of a Neonate: A Case Report.

Malignant peripheral nerve sheath tumor (MPNST) is a rare tumor that can develop on the lining of nerves and within the network of nerve fibers in different organs, and it is commonly found in the head and neck, limbs, and trunk. These tumors can occur in patients of any age. They most commonly occur in adults aged 20 to 50 years; however, fewer cases of this tumor in children have been reported. To date, no neonatal case of MPNST in the nasal cavity has been reported. Here, we report the case of a 4-day-old female newborn who presented with a nasal mass that re-enlarged after surgery and was diagnosed as MPNST of the nasal cavity on the basis of pathological results. This is the first report of MPNST in the nasal cavity of a neonate. Differential diagnosis and treatment of nasal masses have been proposed in the related literature.

A novel MOFs-induced strategy for preparing anatase-free hierarchical TS-1 zeolite:synthesis routes, growth mechanisms and enhanced catalytic performance.

Titanosilicate-1 zeolites (TS-1) as one of the most commonly used catalysts for alkene epoxidation, construction of hierarchical pores as well as elimination of anatase to promote mass transportation and avoid invalid decomposition of hydrogen peroxide are always desirable yet challenging goals. Here, a novel and unique Ti-based metal organic frameworks (MOFs)-induced synthetic strategy for fabricating anatase-free hierarchical TS-1 was first proposed. All the components of MOFs perform different functions: the uniformly distributed Ti nodes replace conventional tetrabutyl titanate (TBOT) to serve as sole Ti source for constructing zeolite crystal; the separated ligands can be embedded in the zeolite framework and act as template to in situ build hierarchical pore structure; the coordination interaction between Ti nodes and ligands can efficiently avoid the anatase generation by balancing the forming rates of Ti-OH and Si-OH. This synthetic strategy is of general applicability, and two different synthetic routes including traditional hydrothermal process and steam assisted crystallization (SAC) procedure are successfully adopted. The obtained hydrothermal TS-1 and SAC anatase-free samples all possess abundant intercrystalline mesopores of 20-50 nm and even macropores between 50 and 150 nm, improving the conversion over 25 % for 1­hexene epoxidation than TS-1 sample prepared by conventional route. The influences of the amount of Ti MOFs precursor and the crystallization process are studied in detail, and possible synthesis mechanisms are proposed. This MOFs-induced strategy might open up an avenue for the rational design of ideal and hierarchical zeolite to boost the catalytic efficiency.

Phosphorus-Doped directly interconnected networks of amorphous Metal-Organic framework nanowires for efficient methanol oxidation.

Developing high-performance and low-cost electrocatalysts toward methanol oxidation reaction (MOR) is essential for fuel cell applications. Herein, we report a defect engineering strategy integrating amorphization and phosphorization to construct directly interconnected networks of amorphous NiCo-based metal-organic framework nanowires (a-NiCo-MOFNWs) with phosphorus (P) doping. The resulting P-doped a-NiCo-MOFNWs (a-NiCo-MOFNWs-P) network displays superior MOR efficiency and long-term durability over 1000 cyclic voltammetry (CV) measurements. The special structure of directly interconnected networks and the synergistic effect between the amorphous MOFs and dispersed phosphorus species give rise to abundant exposed active sites, accelerated electron transport, and increased porosity for mass transfer, thus boosting the reaction kinetics of MOR. This work provides additional insights into the network assembly and structural evolution of one-dimensional (1D) MOFs, and also opens up new avenues for the design of highly reactive and robust non-precious metal-based electrocatalysts.

Prognostic factor analysis and clinical significance of HER­2­positive breast cancers with negative lymph nodes and a tumor diameter ≤1 cm.

The 2021 National Comprehensive Cancer Network guidelines recommend that adjuvant chemotherapy combined with trastuzumab be considered for human epidermal growth factor receptor 2 (HER-2)-positive breast cancer patients with small tumors (tumor diameter ≤1 cm) and negative lymph nodes. Additionally, the prognostic factors and clinical significance of HER-2-positive breast cancer with negative lymph nodes and a tumor diameter ≤1 cm remain unclear. In the present study, the clinical data and prognostic factors of 87 patients with HER-2-positive breast cancer with negative lymph nodes and a tumor diameter ≤1 cm admitted to Guangdong Women and Children Hospital from January 2013 to December 2019 were retrospectively analyzed. The median follow-up time was 70 months, the disease-free survival (DFS) of all patients was 94.3% and the overall survival (OS) was 100%. Univariate analysis of prognosis demonstrated that patients aged ≤40 years had significantly lower DFS than those aged >40 (80.8 vs. 100.0%, P<0.001). DFS was significantly improved in patients who were hormone-receptor-positive and patients who received endocrine therapy compared with patients who were estrogen receptor negative and patients who did not receive endocrine therapy (100.0 vs. 89.6%, P=0.039; 100.0 vs. 90.0%, P=0.049). Prognostic univariate analysis demonstrated that patient age, hormone receptor status and use of endocrine therapy were significantly related to the DFS (P<0.05), while none of these were independent factors related to the DFS in the prognostic multivariate analysis (P=0.240, P=0.976 and P=0.925). The proportion of patients with a tumor diameter 0.5-1 cm receiving adjuvant anti-HER-2 treatment was significantly greater compared with patients with tumors with a diameter ≤0.5 cm (46.4 vs. 18.6%, P<0.05). There was no significance difference in the DFS of patients treated with adjuvant chemotherapy with or without anti-HER-2 therapy with tumor diameters ≤0.5 cm (P>0.05), but there was a significant difference in the DFS of patients with a tumor diameter 0.5-1 cm (P<0.05). These results suggested that adjuvant chemotherapy, with or without anti-HER-2 therapy, may affect the prognosis of HER-2-positive breast cancer patients with negative lymph nodes and a tumor diameter of 0.5-1 cm. Therefore, it could be recommended that such patients receive adjuvant chemotherapy and anti-HER-2 therapy in the future.