Genome-wide analysis of the U-box E3 ligases gene family in potato (Solanum tuberosum L.) and overexpress StPUB25 enhance drought tolerance in transgenic Arabidopsis.

BACKGROUND: Plant U-box (PUB) E3 ubiquitin ligases have vital effects on various biological processes. Therefore, a comprehensive and systematic identification of the members of the U-box gene family in potato will help to understand the evolution and function of U-box E3 ubiquitin ligases in plants. RESULTS: This work identified altogether 74 PUBs in the potato (StPUBs) and examined their gene structures, chromosomal distributions, and conserved motifs. There were seventy-four StPUB genes on ten chromosomes with diverse densities. As revealed by phylogenetic analysis on PUBs within potato, Arabidopsis, tomato (Solanum lycopersicum), cabbage (Brassica oleracea), rice (Oryza sativa), and corn (Zea mays), were clustered into eight subclasses (C1-C8). According to synteny analysis, there were 40 orthologous StPUB genes to Arabidopsis, 58 to tomato, 28 to cabbage, 7 to rice, and 8 to corn. In addition, RNA-seq data downloaded from PGSC were utilized to reveal StPUBs' abiotic stress responses and tissue-specific expression in the doubled-monoploid potato (DM). Inaddition, we performed RNA-seq on the 'Atlantic' (drought-sensitive cultivar, DS) and the 'Qingshu NO.9' (drought-tolerant cultivar, DT) in early flowering, full-blooming, along with flower-falling stages to detect genes that might be involved in response to drought stress. Finally, quantitative real-time PCR (qPCR) was carried out to analyze three candidate genes for their expression levels within 100 mM NaCl- and 10% PEG 6000 (w/v)-treated potato plantlets for a 24-h period. Furthermore, we analyzed the drought tolerance of StPUB25 transgenic plants and found that overexpression of StPUB25 significantly increased peroxidase (POD) activity, reduced ROS (reactive oxygen species) and MDA (malondialdehyde) accumulation compared with wild-type (WT) plants, and enhancing drought tolerance of the transgenic plants. CONCLUSION: In this study, three candidate genes related to drought tolerance in potato were excavated, and the function of StPUB25 under drought stress was verified. These results should provide valuable information to understand the potato StPUB gene family and investigate the molecular mechanisms of StPUBs regulating potato drought tolerance.

Density Functional Theory Calculations on Fluorescence-Enhanced Mechanisms of the Optical Sensor for Zinc Ions, ADPA.

N-(9-anthracenylmethyl)-N-(2-pyridinylmethyl)-2-pyridinemethanamine (ADPA) as a specific ion sensor for Zn2+ has been widely applied. Although the photo-induced electron transfer (PET) mechanism was proposed previously, its fluorescence-enhanced effect still remains somewhat ambiguous, according to unknown influences of non-radiative energy decay pathways, such as intersystem crossing and internal conversion. Herein, a thorough study using density functional theory has been performed for low-lying electronic states of the ADPA monomer and hydrated ADPA-Zn2+ complex. Based on interfragment charge transfer analyses, we quantitatively calculated the amount of transferred electrons in the monomer and complex, providing solid evidences for the PET mechanism and in line with the conclusion of frontier molecular orbital analyses. Moreover, the ISC process of S1→T2 was confirmed to play a considerable role in the excitation energy relaxation process of the ADPA monomer, but this influence was significantly suppressed in the hydrated ADPA-Zn2+ complex. These results provide additional clues for the design of new metal ion-specific fluorescence probes.

Safety and efficacy of CT-guided percutaneous microwave ablation for stage I non-small cell lung cancer in patients with comorbid idiopathic pulmonary fibrosis.

OBJECTIVES: To evaluate the safety and efficacy of microwave ablation (MWA) for stage I non-small cell lung cancer (NSCLC) in patients with idiopathic pulmonary fibrosis (IPF). MATERIALS AND METHODS: A retrospective single-center cohort study was conducted in patients with clinical stage I NSCLC who underwent CT-guided MWA from Nov 2016 to Oct 2021. The patients were divided into the IPF group and the non-IPF group. The primary endpoints were 90-day adverse events and hospital length of stay (HLOS). The secondary endpoints included overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 107 patients (27 with IPF and 80 without IPF) were finally included for analysis. No procedure-related acute exacerbation of IPF or death occurred post-MWA. The rates of adverse events were similar between the groups (48.6% vs. 47.7%; p = 0.998). The incidence of grade 3 adverse events in the IPF group was higher than that in the non-IPF group without a significant difference (13.5% vs. 4.6%; p = 0.123). Median HLOS was 5 days in both groups without a significant difference (p = 0.078). The 1-year and 3-year OS were 85.2%/51.6% in the IPF group, and 97.5%/86.4% in the non-IPF group. The survival of patients with IPF was significantly poorer than the survival of patients without IPF (p < 0.001). There was no significant difference for PFS (p = 0.271). CONCLUSION: MWA was feasible in the treatment of stage I NSCLC in patients with IPF. IPF had an adverse effect on the survival of stage I NSCLC treated with MWA. CLINICAL RELEVANCE STATEMENT: CT-guided microwave ablation is a well-tolerated and effective potential alternative treatment for stage I non-small cell lung cancer in patients with idiopathic pulmonary fibrosis. KEY POINTS: • Microwave ablation for stage I non-small cell lung cancer was well-tolerated without procedure-related acute exacerbation of idiopathic pulmonary fibrosis and death in patients with idiopathic pulmonary fibrosis. • No differences were observed in the incidence of adverse events between patients with idiopathic pulmonary fibrosis and those without idiopathic pulmonary fibrosis after microwave ablation (48.6% vs. 47.7%; p = 0.998). • The 1-year and 3-year overall survival rates (85.2%/51.6%) in the idiopathic pulmonary fibrosis group were worse than those in the non- idiopathic pulmonary fibrosis group (97.5%/86.4%) (p < 0.001).

Homer1 ameliorates ischemic stroke by inhibiting necroptosis-induced neuronal damage and neuroinflammation.

OBJECTIVE: Proinflammatory necroptosis is the main pathological mechanism of ischemic stroke. Homer scaffolding protein 1 (Homer1) is a postsynaptic scaffolding protein that exerts anti-inflammatory effects in most central nervous system diseases. However, the relationship between Homer1 and proinflammatory necroptosis in ischemic stroke remains unclear. AIM: This study aimed to investigate the role of Homer1 in ischemia-induced necroptosis. METHODS: C57BL/6 mice were used to establish a model of permanent middle cerebral artery occlusion model (pMCAO). Homer1 knockdown mice were generated using adeno-associated virus (AAV) infection to explore the role of Homer1 and its impact on necroptosis in pMCAO. Finally, Homer1 protein was stereotaxically injected into the ischemic cortex of Homer1flox/flox/Nestin-Cre +/- mice, and the efficacy of Homer1 was investigated using behavioral assays and molecular biological assays to explore potential mechanisms. RESULTS: Homer1 expression peaked at 8 h in the ischemic penumbral cortex after pMCAO and colocalized with neurons. Homer1 knockdown promoted neuronal death by enhancing necroptotic signaling pathways and aggravating ischemic brain damage in mice. Furthermore, the knockdown of Homer1 enhanced the expression of proinflammatory cytokines. Moreover, injection of Homer1 protein reduced necroptosis-induced brain injury inhibited the expression of proinflammatory factors, and ameliorated the outcomes in the Homer1flox/flox/Nestin-Cre+/- mice after pMCAO. CONCLUSIONS: Homer1 ameliorates ischemic stroke by inhibiting necroptosis-induced neuronal damage and neuroinflammation. These data suggested that Homer1 is a novel regulator of neuronal death and neuroinflammation.

Extracellular Matrix Stiffness Regulates Microvascular Stability by Controlling Endothelial Paracrine Signaling to Determine Pericyte Fate.

BACKGROUND: The differentiation of pericytes into myofibroblasts causes microvascular degeneration, ECM (extracellular matrix) accumulation, and tissue stiffening, characteristics of fibrotic diseases. It is unclear how pericyte-myofibroblast differentiation is regulated in the microvascular environment. Our previous study established a novel 2-dimensional platform for coculturing microvascular endothelial cells (ECs) and pericytes derived from the same tissue. This study investigated how ECM stiffness regulated microvascular ECs, pericytes, and their interactions. METHODS: Primary microvessels were cultured in the TGM2D medium (tubular microvascular growth medium on 2-dimensional substrates). Stiff ECM was prepared by incubating ECM solution in regular culture dishes for 1 hour followed by PBS wash. Soft ECM with Young modulus of ≈6 kPa was used unless otherwise noted. Bone grafts were prepared from the rat skull. Immunostaining, RNA sequencing, RT-qPCR (real-time quantitative polymerase chain reaction), Western blotting, and knockdown experiments were performed on the cells. RESULTS: Primary microvascular pericytes differentiated into myofibroblasts (NG2+αSMA+) on stiff ECM, even with the TGFß (transforming growth factor beta) signaling inhibitor A83-01. Soft ECM and A83-01 cooperatively maintained microvascular stability while inhibiting pericyte-myofibroblast differentiation (NG2+αSMA-/low). We thus defined 2 pericyte subpopulations: primary (NG2+αSMA-/low) and activated (NG2+αSMA+) pericytes. Soft ECM promoted microvascular regeneration and inhibited fibrosis in bone graft transplantation in vivo. As integrins are the major mechanosensor, we performed RT-qPCR screening of integrin family members and found Itgb1 (integrin ß1) was the major subunit downregulated by soft ECM and A83-01 treatment. Knocking down Itgb1 suppressed myofibroblast differentiation on stiff ECM. Interestingly, ITGB1 phosphorylation (Y783) was mainly located on microvascular ECs on stiff ECM, which promoted EC secretion of paracrine factors, including CTGF (connective tissue growth factor), to induce pericyte-myofibroblast differentiation. CTGF knockdown or monoclonal antibody treatment partially reduced myofibroblast differentiation, implying the participation of multiple pathways in fibrosis formation. CONCLUSIONS: ECM stiffness and TGFß signaling cooperatively regulate microvascular stability and pericyte-myofibroblast differentiation. Stiff ECM promotes EC ITGB1 phosphorylation (Y783) and CTGF secretion, which induces pericyte-myofibroblast differentiation.

Sharp needle reconstructs peripheral outflow for patients with malfunctional arteriovenous fistula.

OBJECTIVE: To investigate the feasibility and efficacy of combining ultrasound-guided sharp needle technique with percutaneous transluminal angioplasty (PTA) for treating outflow stenosis or dysfunction in arteriovenous fistula (AVF) among hemodialysis patients. METHODS: From October 2021 to March 2023, patients with occluded or malfunctional fistula veins not amenable to regularly angioplasty were retrospectively enrolled in the study. They underwent ultrasound-guided sharp needle intervention followed by PTA. Data on the location and length between the two veins, technical success, clinical outcomes, and complications were collected. Patency rates post-angioplasty were calculated through Kaplan-Meier analysis. RESULTS: A total of 23 patients were included. The mean length of the reconstructed extraluminal segment was 3.18 cm. The sharp needle opening was performed on the basilic vein (60.9%), brachial vein (26.1%), or upper arm cephalic vein (13%) to create outflow channels. Postoperatively, all cases presented with mild subcutaneous hematomas around the tunneling site and minor diffuse bleeding. The immediate patency rate for the internal fistulas was 100%, with 3-month, 6-month, and 12-month patency rates at 91.3%, 78.3%, and 43.5%, respectively. CONCLUSION: Sharp needle technology merged with PTA presents an effective and secure minimally invasive method for reconstructing the outflow tract, offering a new solution for recanalizing high-pressure or occluded fistulas.

Genome-Wide Identification of LOX Gene Family and Its Expression Analysis under Abiotic Stress in Potato (Solanum tuberosum L.).

The lipoxygenases (LOXs) are non-heme iron-containing dioxygenases that play an important role in plant growth and defense responses. There is scarce knowledge regarding the LOX gene family members and their involvement in biotic and abiotic stresses in potato. In this study, a total of 17 gene family members (StLOXs) in potato were identified and clustered into three subfamilies: 9-LOX type I, 13-LOX type I, and 13-LOX type II, with eleven, one, and five members in each subfamily based on phylogenetic analysis. By exploiting the RNA-seq data in the Potato Genome Sequencing Consortium (PGSC) database, the tissue-specific expressed and stress-responsive StLOX genes in double-monoploid (DM) potato were obtained. Furthermore, six candidate StLOX genes that might participate in drought and salt response were determined via qPCR analysis in tetraploid potato cultivars under NaCl and PEG treatment. Finally, the involvement in salt stress response of two StLOX genes, which were significantly up-regulated in both DM and tetraploid potato under NaCl and PEG treatment, was confirmed via heterologous expression in yeast under salt treatment. Our comprehensive analysis of the StLOX family provides a theoretical basis for the potential biological functions of StLOXs in the adaptation mechanisms of potato to stress conditions.

Comprehensive Characterization of the C3HC4 RING Finger Gene Family in Potato (Solanum tuberosum L.): Insights into Their Involvement in Anthocyanin Biosynthesis.

The C3HC4 RING finger gene (RING-HC) family is a zinc finger protein crucial to plant growth. However, there have been no studies on the RING-HC gene family in potato. In this study, 77 putative StRING-HCs were identified in the potato genome and grouped into three clusters based on phylogenetic relationships, the chromosome distribution, gene structure, conserved motif, gene duplication events, and synteny relationships, and cis-acting elements were systematically analyzed. By analyzing RNA-seq data of potato cultivars, the candidate StRING-HC genes that might participate in tissue development, abiotic stress, especially drought stress, and anthocyanin biosynthesis were further determined. Finally, a StRING-HC gene (Soltu.DM.09G017280 annotated as StRNF4-like), which was highly expressed in pigmented potato tubers was focused on. StRNF4-like localized in the nucleus, and Y2H assays showed that it could interact with the anthocyanin-regulating transcription factors (TFs) StbHLH1 of potato tubers, which is localized in the nucleus and membrane. Transient assays showed that StRNF4-like repressed anthocyanin accumulation in the leaves of Nicotiana tabacum and Nicotiana benthamiana by directly suppressing the activity of the dihydroflavonol reductase (DFR) promoter activated by StAN1 and StbHLH1. The results suggest that StRNF4-like might repress anthocyanin accumulation in potato tubers by interacting with StbHLH1. Our comprehensive analysis of the potato StRING-HCs family contributes valuable knowledge to the understanding of their functions in potato development, abiotic stress, hormone signaling, and anthocyanin biosynthesis.

The Development of Visible-Light Organic Photocatalysts for Atom Transfer Radical Polymerization via Conjugation Extension.

This work aimed to develop organic photocatalysts (PCs) that could mediate organocatalytic atom transfer radical polymerization (O-ATRP) under visible light. Through the core-modification of known chromophoric structures and ring-locking to reach a conjugation extension, annulated N-aryl benzo[kl]acridines were identified as effective visible light-responsive photocatalysts. The corresponding selenium-doped structure showed excellent performance in the O-ATRP of methacrylates, which could afford polymer products with controlled molecular weights and low dispersities under the irradiation of visible light at a 100 ppm catalyst loading.

Methylene-Bridged [6]-, [8]-, and [10]Cycloparaphenylenes: Size-Dependent Properties and Paratropic Belt Currents.

Cycloparaphenylenes (CPPs) and carbon nanobelts (CNBs) represent some of the most iconic cyclic molecular nanocarbons in recent chemistry owing to their unique properties derived from rigid, strained, and cyclic π-conjugated systems. In the last decade, the synthesis of various sizes of CPPs and CNBs has been achieved that allowed not only for investigating their size-dependent properties and strategically using such properties in various applications but also understanding the fundamental features of cyclic π-conjugated systems and molecular nanocarbons in general. Herein, we report on the synthesis, size-dependent properties, and paratropic belt currents of methylene-bridged [n]cycloparaphenylenes ([n]MCPP, n = 6, 8, 10). [8]MCPP and [10]MCPP were synthesized by the same strategy we developed for [6]MCPP synthesis. With readily available ethoxy-substituted pillar[8]arene and pillar[10]arene as precursors, [8]MCPP and [10]MCPP were successfully synthesized in three steps consisting of de-ethylation, triflation, and nickel-mediated aryl-aryl coupling. The structural and electronic properties of MCPPs were investigated by nuclear magnetic resonance analyses, absorption/fluorescence measurements, X-ray crystallographic analyses, and computational studies, revealing their interesting size-dependent properties. The differences in the size dependency between MCPPs and CPPs reflect the belt-form features of MCPPs, namely, methylene-bridging effects on MCPPs. Moreover, an interesting paratropic belt current along the MCPP backbone has been uncovered both experimentally and theoretically. The 1H NMR chemical shifts of MCPPs confirmed the presence of a paratropic belt current, whose strength rapidly decreases with increasing nanobelt size.

Microwave Ablation for Inoperable Stage I Non-Small Cell Lung Cancer in Patients Aged ≥70 Years: A Prospective, Single-Center Study.

PURPOSE: To evaluate the safety and survival outcomes of computed tomography-guided microwave ablation (MWA) for medically inoperable Stage I non-small cell lung cancer (NSCLC) in patients aged ≥70 years. MATERIALS AND METHODS: This study was a prospective, single-arm, single-center clinical trial. The MWA clinical trial enrolled patients aged ≥70 years with medically inoperable Stage I NSCLC from January 2021 to October 2021. All patients received biopsy and MWA synchronously with the coaxial technique. The primary endpoints were 1-year overall survival (OS) and progression-free survival (PFS). The secondary endpoint was adverse events. RESULTS: A total of 103 patients were enrolled. Ninety-seven patients were eligible and analyzed. The median age was 75 years (range, 70-91 years). The median diameter of tumors was 16 mm (range, 6-33 mm). Adenocarcinoma (87.6%) was the most common histologic finding. With a median follow-up of 16.0 months, the 1-year OS and PFS rates were 99.0% and 93.7%, respectively. There were no procedure-related deaths in any patient within 30 days after MWA. Most of the adverse events were minor. CONCLUSION: MWA is an effective and safe treatment for patients aged ≥70 years with medically inoperable Stage I NSCLC.

Mechanism of lncRNA FOXD3-AS1/miR-338-3p in the malignant progression of nasopharyngeal carcinoma through ceRNA.

This work aimed to analyze the impact of lncRNA FOXD3-AS1 (F-A) on the regulation of miR-338-3p (M) on the proliferation (Pro), migration (Mig), and invasion (Inv) of nasopharyngeal carcinoma (NPC) cells. F-A and M levels in human normal nasopharyngeal (NNP) NP69 cells and NPC CNE1 and CNE2 cells were detected by real-time quantitative PCR. After transfection or cotransfection with F-A shRNA, miR-338-3p mimic (MM), and miR-338-3p inhibitor (MI), cell Pro, Mig, and Inv (PMI) were detected using CCK-8, scratch healing, and Transwell chamber experiments, respectively. As a result, relative to NP69 cells, F-A was upregulated in CNE1 and CNE2 cells, while M was downregulated (P<0.01). F-A in CNE1 and CNE2 cells was downregulated and M was upregulated relative to shF-A (P<0.01). Furthermore, shF-A and MM groups demonstrated drastically reduced cell proliferative activity, Mig, and Inv versus CNE1/CNE2 groups. The cell proliferative activity, Mig, and Inv number of the MI group increased substantially (P<0.01). The shF-A+MM group exhibited markedly reduced cell proliferative activity, Mig, and cell number of Inv relative to those of CNE1/CNE2 (P<0.01). Moreover, the shF-A+MI group exhibited greatly increased cell proliferative activity, Mig, and cell number of Inv versus the shF-A+MM group (P<0.01). In short, lncRNA F-A level was abnormally upregulated, and that of M was downregulated in NPC. Interfering with lncRNA F-A level can upregulate M expression. Silencing of lncRNA F-A can inhibit PMI of NPC cells.

Synchronous percutaneous core-needle biopsy and microwave ablation for stage I non-small cell lung cancer in patients with Idiopathic pulmonary fibrosis: initial experience.

PURPOSE: This study aimed to retrospectively evaluate the safety and feasibility of computed tomography (CT)-guided synchronous percutaneous core-needle biopsy (CNB) and microwave ablation (MWA) for stage I non-small cell lung cancer (NSCLC) in patients with idiopathic pulmonary fibrosis (IPF). METHODS: From January 2019 to January 2023, nineteen stage I NSCLC patients with IPF underwent CT-guided synchronous percutaneous CNB and MWA in this study. The technical success rate, complications, local tumor progression (LTP) and overall survival (OS) were observed, and the effect of synchronous percutaneous CNB and MWA were evaluated. RESULTS: The technical success rate of synchronous percutaneous CNB and MWA was 100%. With a median follow-up time of 20.36 months, the median OS was 25 months (95% CI: 21.79, 28.20). The six-, twelve- and eighteen-month OS rates were 94.73%, 89.47% and 57.89%, respectively. The six-, twelve- and eighteen-month LTP rates were 0%, 10.52% and 31.57%, respectively. Major complications including pneumothorax, bronchopleural fistula and pneumonia occurred in 26.32% (5/19) patients. None of the patients died during the procedure. CONCLUSIONS: According to the results of the current study, CT-guided synchronous percutaneous CNB and MWA appears to be a safe and effective for stage I NSCLC in patients with IPF and providing an alternative therapeutic option for local control of pulmonary malignancy in high-risk patients.

TSG-SLAM: SLAM Employing Tight Coupling of Instance Segmentation and Geometric Constraints in Complex Dynamic Environments.

Although numerous effective Simultaneous Localization and Mapping (SLAM) systems have been developed, complex dynamic environments continue to present challenges, such as managing moving objects and enabling robots to comprehend environments. This paper focuses on a visual SLAM method specifically designed for complex dynamic environments. Our approach proposes a dynamic feature removal module based on the tight coupling of instance segmentation and multi-view geometric constraints (TSG). This method seamlessly integrates semantic information with geometric constraint data, using the fundamental matrix as a connecting element. In particular, instance segmentation is performed on frames to eliminate all dynamic and potentially dynamic features, retaining only reliable static features for sequential feature matching and acquiring a dependable fundamental matrix. Subsequently, based on this matrix, true dynamic features are identified and removed by capitalizing on multi-view geometry constraints while preserving reliable static features for further tracking and mapping. An instance-level semantic map of the global scenario is constructed to enhance the perception and understanding of complex dynamic environments. The proposed method is assessed on TUM datasets and in real-world scenarios, demonstrating that TSG-SLAM exhibits superior performance in detecting and eliminating dynamic feature points and obtains good localization accuracy in dynamic environments.

Panchromatic Light-Absorbing [70]Fullerene-Perylene-BODIPY Triad with Cascade of Energy Transfer as an Efficient Singlet Oxygen Sensitizer.

A panchromatic light-absorbing [70]fullerene-perylene-BODIPY triad (C70-P-B) was synthesized and applied as a heavy atom-free organic triplet photosensitizer for photooxidation. The photophysical processes were comprehensively investigated by the methods of steady-state spectroscopy, time-resolved spectroscopy, as well as theoretical calculations. C70-P-B shows a strong absorption ability from 300-620 nm. Efficient cascading intramolecular singlet-singlet energy transfer in C70-P-B was confirmed by the luminescence study. The backward triplet excited state energy transfer from C70 moiety to perylene then occurs to populate 3perylene*. Thus, the triplet excited states of C70-P-B are distributed on both C70 and perylene moiety with lifetimes of 23 ± 1 µs and 175 ± 17 µs, respectively. C70-P-B exhibits excellent photooxidation capacity, and its yield of singlet oxygen reaches 0.82. The photooxidation rate constant of C70-P-B is 3.70 times that of C70-Boc and 1.58 times that of MB, respectively. The results in this paper are useful for designing efficient heavy atom-free organic triplet photosensitizers for practical application in photovoltaics, photodynamic therapy, etc.

Boryl Radicals Enabled a Three-Step Sequence to Assemble All-Carbon Quaternary Centers from Activated Trichloromethyl Groups.

The construction of diversely substituted all-carbon quaternary centers has been a longstanding challenge in organic synthesis. Methods that add three alkyl substituents to a simple C(sp3) atom rely heavily on lengthy multiple processes, which usually involve several preactivation steps. Here, we describe a straightforward three-step sequence that uses a range of readily accessible activated trichloromethyl groups as the carbon source, the three C-Cl bonds of which are selectively functionalized to introduce three alkyl chains. In each step, only a single C-Cl bond was cleaved with the choice of an appropriate Lewis base-boryl radical as the promoter. A vast range of diversely substituted all-carbon quaternary centers could be accessed directly from these activated CCl3 trichloromethyl groups or by simple derivatizations. The use of different alkene traps in each of the three steps enabled facile collections of a large library of products. The utility of this strategy was demonstrated by the synthesis of variants of two drug molecules, whose structures could be easily modulated by varying the alkene partner in each step. The results of kinetic and computational studies enabled the design of the three-step reaction and provided insights into the reaction mechanisms.

Pinpointing novel risk loci for Lewy body dementia and the shared genetic etiology with Alzheimer's disease and Parkinson's disease: a large-scale multi-trait association analysis.

BACKGROUND: The current genome-wide association study (GWAS) of Lewy body dementia (LBD) suffers from low power due to a limited sample size. In addition, the genetic determinants underlying LBD and the shared genetic etiology with Alzheimer's disease (AD) and Parkinson's disease (PD) remain poorly understood. METHODS: Using the largest GWAS summary statistics of LBD to date (2591 cases and 4027 controls), late-onset AD (86,531 cases and 676,386 controls), and PD (33,674 cases and 449,056 controls), we comprehensively investigated the genetic basis of LBD and shared genetic etiology among LBD, AD, and PD. We first conducted genetic correlation analysis using linkage disequilibrium score regression (LDSC), followed by multi-trait analysis of GWAS (MTAG) and association analysis based on SubSETs (ASSET) to identify the trait-specific SNPs. We then performed SNP-level functional annotation to identify significant genomic risk loci paired with Bayesian fine-mapping and colocalization analysis to identify potential causal variants. Parallel gene-level analysis including GCTA-fastBAT and transcriptome-wide association analysis (TWAS) was implemented to explore novel LBD-associated genes, followed by pathway enrichment analysis to understand underlying biological mechanisms. RESULTS: Pairwise LDSC analysis found positive genome-wide genetic correlations between LBD and AD (rg = 0.6603, se = 0.2001; P = 0.0010), between LBD and PD (rg = 0.6352, se = 0.1880; P = 0.0007), and between AD and PD (rg = 0.2136, se = 0.0860; P = 0.0130). We identified 13 significant loci for LBD, including 5 previously reported loci (1q22, 2q14.3, 4p16.3, 4q22.1, and 19q13.32) and 8 novel biologically plausible genetic associations (5q12.1, 5q33.3, 6p21.1, 8p23.1, 8p21.1, 16p11.2, 17p12, and 17q21.31), among which APOC1 (19q13.32), SNCA (4q22.1), TMEM175 (4p16.3), CLU (8p21.1), MAPT (17q21.31), and FBXL19 (16p11.2) were also validated by gene-level analysis. Pathway enrichment analysis of 40 common genes identified by GCTA-fastBAT and TWAS implicated significant role of neurofibrillary tangle assembly (GO:1902988, adjusted P = 1.55 × 10-2). CONCLUSIONS: Our findings provide novel insights into the genetic determinants of LBD and the shared genetic etiology and biological mechanisms of LBD, AD, and PD, which could benefit the understanding of the co-pathology as well as the potential treatment of these diseases simultaneously.

Correlations of RENAL, PADUA and NePhRO Scores With Complications and Outcomes in Patients After CT-Guided Microwave Ablation of Renal Tumors.

OBJECTIVE: This retrospective study aimed to access the correlations of RENAL, PADUA and NePhRO scores with operative complications, chronic kidney disease (CKD) upstaging, and oncologic outcomes after CT-guided percutaneous Microwave Ablation (MWA) of renal tumors in order to determine their status as independent predictors of outcomes after MWA. This study also aimed to generally evaluate the efficacy of MWA in treating renal tumors. METHODS: From January 2017 to December 2019, 18 patients with 27 renal tumors who had undergone simultaneous biopsy and MWA were recruited in this single-center retrospective study. Data collection included tumor characteristics, procedural protocols, complications, CKD upstaging data, local tumor control data and overall survival. All lesions were evaluated using RENAL, PADUA and NePhRO scores, and further analysis was performed to determine whether the scores were correlated with operative complications, CKD upstaging, local tumor control and overall survival. RESULTS: The minor and major complication rates were 16.7% and 0%, respectively. Two patients with solitary kidney experienced CKD upstaging. Local tumor recurrence was identified in one type of tumor (3.7%) in the first year of follow-up. L. parameter (P = .031), longitudinal (polar) location score (P = .011), Ne. parameter (P = .036), number of kidneys (P = .005), and number of lesions (P = .008), were predictive factors significantly associated with the occurrence of complications. Besides, CKD upstaging was associated with A. parameter (P = .032) and urinary collecting system score (P = .028). RENAL, PADUA, and NePhRO scores were significantly correlated with complications, overall survival, and CKD upstaging, respectively (P < .05). CONCLUSION: CT-guided percutaneous MWA was found to be a valuable alternative in the treatment of renal tumors for selected patients. Furthermore, RENAL, PADUA and NePhRO scores were not independent predictors of outcomes of MWA.

Synthesis and Evaluation of a Paclitaxel-Binding Tripeptide Micelle for Lung Cancer Therapy.

A C10CO-NalLeuVal (C10NLV) tripeptide was synthesized and explored as a carrier for paclitaxel (TAX) delivery. Five types of TAX-loaded micelles were produced by loading TAX with different doses of C10NLV. 3-(4,5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay showed that TAX-loaded micelles dramatically reduced TAX IC50 values of TAX-resistant A549 (A549/TAX) and Lewis lung carcinoma (LLC) cells in a C10NLV-dose-dependent manner, with micelles 4 and 5 exhibited comparable inhibitory effects on A549/TAX proliferation. Flow cytometry analysis showed that TAX-loaded micelles 4 promoted lung cancer cell apoptosis in a TAX-dose-dependent manner. Immunofluorescent staining and Western blotting revealed that TAX-loaded micelles 4 dramatically reduced the protein levels of F-actin, p53, Bcl-2, and LC3A/B in A549/TAX cells. Wound healing, cell adhesion, migration, and invasion assays demonstrated that TAX-loaded micelles 4 suppressed the metastatic abilities of lung cancer cells. Furthermore, compared with the same dose of free TAX, TAX-loaded micelles 4 significantly reduced the volumes and weights of A549/TAX-generated tumors as well as the numbers of LLC-generated pulmonary metastatic foci in mice, without affecting the organ/body weight ratios, body weights, and blood cell counts. Histological analysis demonstrated that TAX-loaded micelles 4 administration resulted in tubulin and CD206 downregulation as well as cytoplasm disappearance and nuclear shrinkage in xenograft tumors. These data suggest that TAX-loaded micelles 4 inhibits the proliferative and metastatic capacity of lung cancer cells, despite TAX resistance. TAX-loaded micelles 4 suppresses lung tumor growth and metastasis in vivo without inducing systemic toxicity. Thus, the C10NLV-based TAX delivery is effective and safe to combat TAX resistance and metastasis in lung cancer.

Sintilimab plus Bronchial Arterial Infusion Chemotherapy/Drug-Eluting Embolic Chemoembolization for Advanced Non-Small Cell Lung Cancer: A Preliminary Study of 10 Patients.

PURPOSE: To evaluate the short-term efficacy and safety of immunotherapy with sintilimab combined with bronchial arterial infusion (BAI) chemotherapy/drug-eluting embolic (DEE) bronchial arterial chemoembolization (BACE) for advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Ten patients with advanced NSCLC were treated with sintilimab plus BAI/DEE-BACE between December 2019 and November 2020 and retrospectively evaluated. The Response Evaluation Criteria in Solid Tumors version 1.1 was applied to evaluate the treatment response. The local tumor control duration, progression-free survival (PFS), and overall survival (OS) were estimated using the Kaplan-Meier analysis. RESULTS: At 30 days after the last multimodal treatment, complete response, partial response, and stable disease were recorded in 1 (10%), 7 (70%), and 2 (20%) patients, respectively, for an objective response rate of 80% and a disease control rate of 100%. No patient experienced progressive disease. The median duration of local tumor control was 8.0 months (95% CI, 6.2-9.7 months). The median PFS and OS were 11.0 months (95% CI, 6.9-15.1 months) and 8.0 months (95% CI, 5.5-10.5 months), respectively. Two cases of Grade III adverse events related to medications were reported. CONCLUSIONS: Sintilimab combined with BAI/DEE-BACE for patients with advanced NSCLC appears to be safe and feasible. Compared with previous studies on BAI/DEE-BACE, the addition of immunotherapy may improve survival.