Tight Junction Component Occludin Binds to FIP5 to Regulate Endosome Trafficking and Mitotic Spindle Function.

The genetic basis of vertebrate emergence during metazoan evolution has remained largely unknown. Understanding vertebrate-specific genes, such as the tight junction protein Occludin (Ocln), may help answer this question. Here, it is shown that mammary glands lacking Ocln exhibit retarded epithelial branching, owing to reduced cell proliferation and surface expansion. Interestingly, Ocln regulates mitotic spindle orientation and function, and its loss leads to a range of defects, including prolonged prophase and failed nuclear and/or cytoplasmic division. Mechanistically, Ocln binds to the RabGTPase-11 adaptor FIP5 and recruits recycling endosomes to the centrosome to participate in spindle assembly and function. FIP5 loss recapitulates Ocln null, leading to prolonged prophase, reduced cell proliferation, and retarded epithelial branching. These results identify a novel role in OCLN-mediated endosomal trafficking and potentially highlight its involvement in mediating membranous vesicle trafficking and function, which is evolutionarily conserved and essential.

Targeting Tumor Heterogeneity by Breaking a Stem Cell and Epithelial Niche Interaction Loop.

Tumor heterogeneity, the presence of multiple distinct subpopulations of cancer cells between patients or among the same tumors, poses a major challenge to current targeted therapies. The way these different subpopulations interact among themselves and the stromal niche environment, and how such interactions affect cancer stem cell behavior has remained largely unknown. Here, it is shown that an FGF-BMP7-INHBA signaling positive feedback loop integrates interactions among different cell populations, including mammary gland stem cells, luminal epithelial and stromal fibroblast niche components not only in organ regeneration but also, with certain modifications, in cancer progression. The reciprocal dependence of basal stem cells and luminal epithelium is based on basal-derived BMP7 and luminal-derived INHBA, which promote their respective expansion, and is regulated by stromal-epithelial FGF signaling. Targeting this interaction loop, for example, by reducing the function of one or more of its components, inhibits organ regeneration and breast cancer progression. The results have profound implications for overcoming drug resistance because of tumor heterogeneity in future targeted therapies.

Sprouty genes regulate activated fibroblasts in mammary epithelial development and breast cancer.

Stromal fibroblasts are a major stem cell niche component essential for organ formation and cancer development. Fibroblast heterogeneity, as revealed by recent advances in single-cell techniques, has raised important questions about the origin, differentiation, and function of fibroblast subtypes. In this study, we show in mammary stromal fibroblasts that loss of the receptor tyrosine kinase (RTK) negative feedback regulators encoded by Spry1, Spry2, and Spry4 causes upregulation of signaling in multiple RTK pathways and increased extracellular matrix remodeling, resulting in accelerated epithelial branching. Single-cell transcriptomic analysis demonstrated that increased production of FGF10 due to Sprouty (Spry) loss results from expansion of a functionally distinct subgroup of fibroblasts with the most potent branching-promoting ability. Compared to their three independent lineage precursors, fibroblasts in this subgroup are "activated," as they are located immediately adjacent to the epithelium that is actively undergoing branching and invasion. Spry genes are downregulated, and activated fibroblasts are expanded, in all three of the major human breast cancer subtypes. Together, our data highlight the regulation of a functional subtype of mammary fibroblasts by Spry genes and their essential role in epithelial morphogenesis and cancer development.

Paravertebral Muscular Neurophysiological Function as an Independent Outcome Predictor of Recurring Herniation/Low Back Pain after Radiofrequency Ablation: A Prospective Follow-Up and Case-Control Study Based on Surface Electromyography.

OBJECTIVE: Spinal endoscopy radiofrequency is a minimally invasive technique for lumbar disc herniation (LDH) and low back pain (LBP). However, recurring LDH/LBP following spinal endoscopy radiofrequency is a significant problem. Paravertebral musculature plays a crucial role in spine stability and motor function, and the purpose of the present study was to identify whether patients' baseline lumbar muscular electrophysiological function could be a predictor of recurring LDH/LBP. METHODS: This was a prospective follow-up and case-control study focusing on elderly patients with LDH who were treated in our department between January 1, 2018, and October 31, 2021. The end of follow-up was recurring LBP, recurring LDH, death, missing to follow-up or 2 years postoperation. The surface electromyography test was performed before the endoscopy C-arm radiofrequency (ECRF) operation to detect the flexion-relaxation ratio (FRR) of the lumbar multifidus (FRRLM ) and the longissimus erector spinae (FRRES ), and the other baseline parameters included the general characteristics, the visual analogue scale, the Japanese Orthopaedic Association score, and the Oswestry Disability Index. Intergroup comparisons were performed by independent t-test and χ2 -test, and further binary logistic regression analysis was performed. RESULTS: Fifty-four patients completed the 2-year follow-up and were retrospectively divided into a recurring LDH/LBP group (Group R) (n = 21) and a no recurring group (Group N) (n = 33) according to their clinical outcomes. FRRLM and FRRES in Group N were much higher than those in Group R (p < 0.001, p = 0.009). Logistic regression analysis showed that only the FRRLM (odds ratio [OR] = 0.123, p = 0.011) and FRRES (OR = 0.115, p = 0.036) were independent factors associated with the ECRF outcome. CONCLUSIONS: Lumbar disc herniation patients' baseline FRRLM and FRRES are independent outcome predictors of recurring LDH/LBP after ECRF. For every unit increase in baseline FRRLM , the risk of recurring LDH/LBP is decreased by 87.7%, and for every unit increase in baseline FRRES , the risk of recurring LDH/LBP is decreased by 88.5%.

Safety of Three-Dimensional Conformal Radiotherapy on the Sheep with Pulmonary Cystic Echinococcosis: A Preliminary Study.

PURPOSE: Radiotherapy showed the potential to effectively kill the cysts of pulmonary cystic echinococcosis (CE). However, little is known about its safety. This study was designed to investigate the safety of three-dimensional conformal radiotherapy (3D-CRT) on the normal lung tissue adjacent to the cyst and blood of sheep naturally infected with pulmonary CE. METHODS: Twenty pulmonary CE sheep were randomly divided into control group (n = 5) and radiation groups with a dose of 30 Gray (Gy) (n = 5), 45 Gy (n = 5), and 60 Gy (n = 5), respectively. Animals in control group received no radiation. Heat shock protein 70 (Hsp70), tumor growth factor-ß (TGF-ß), matrix metalloproteinase-2 (MMP-2) and MMP-9 in the lung tissues adjacent to the cysts, which were considered to be closely related to the pathogenesis of CE, were evaluated after 3D-CRT. A routine blood test was conducted. RESULTS: The results showed that there were multiple cysts of various sizes with protoscoleces in the lung tissues of sheep, and necrotic cysts were found after 3D-CRT. 3D-CRT significantly increased the mRNA level of Hsp70, enhanced the protein level of TGF-ß and slightly increased the expression of MMP-2 and MMP-9 in lung tissues adjacent to the cysts. 3D-CRT did not significantly alter the amount of WBC, HB and PLT in sheep blood. CONCLUSIONS: The results suggested that 3D-CRT may suppress the inflammation and induce less damage of the normal lung tissues and blood. We preliminarily showed that 3D-CRT under a safe dose may be used to treat pulmonary CE.

Band structure optimization of superconducting photonic crystals based on transmission spectrum calculation.

The design of photonic crystals using novel materials is of great significance for the construction of high-performance, next-generation photonic crystal devices. We propose a universal Band structure-Transmission optimization-Band structure method based on moving asymptotic (MMA) method, which can be widely applied to photonic crystal structures. In this paper, we use the method to optimize the band structure of high temperature superconducting photonic crystal, and obtain a wider photonic bandgap and better band flatness in a specific frequency band. This method avoids the disadvantages of traditional scanning methods such as low efficiency and high resource consumption, allows multi-parameter optimization, and improves the accuracy and effectiveness of band modulation based on the iterative process of numerical calculation. The study provides some insights for the design of novel wide-bandgap optical devices.

Investigation of Vacancy-Ordered Double Perovskite Halides A2Sn1-xTixY6 (A = K, Rb, Cs; Y = Cl, Br, I): Promising Materials for Photovoltaic Applications.

In the present study, the structural, mechanical, electronic and optical properties of all-inorganic vacancy-ordered double perovskites A2Sn1-xTixY6 (A = K, Rb, Cs; Y = Cl, Br, I) are explored by density functional theory. The structural and thermodynamic stabilities are confirmed by the tolerance factor and negative formation energy. Moreover, by doping Ti ions into vacancy-ordered double perovskite A2SnY6, the effect of Ti doping on the electronic and optical properties was investigated in detail. Then, according to the requirement of practical applications in photovoltaics, the optimal concentration of Ti ions and the most suitable halide element are determined to screen the right compositions. In addition, the mechanical, electronic and optical properties of the selected compositions are discussed, exhibiting the maximum optical absorption both in the visible and ultraviolet energy ranges; thus, the selected compositions can be considered as promising materials for application in solar photovoltaics. The results suggest a great potential of A2Sn1-xTixY6 (A = K, Rb, Cs; Y = Cl, Br, I) for further theoretical research as well as experimental research on the photovoltaic performance of stable and toxic-free perovskite solar cells.

The Tunable Electronic and Optical Properties of Two-Dimensional Bismuth Oxyhalides.

Two-dimensional (2D) bismuth oxyhalides (BiOX) have attracted much attention as potential optoelectronic materials. To explore their application diversity, we herewith systematically investigate the tunable properties of 2D BiOX using first-principles calculations. Their electronic and optical properties can be modulated by changing the number of monolayers, applying strain, and/or varying the halogen composition. The band gap shrinks monotonically and approaches the bulk value, the optical absorption coefficient increases, and the absorption spectrum redshifts as the layer number of 2D BiOX increases. The carrier transport property can be improved by applying tensile strain, and the ability of photocatalytic hydrogen evolution can be obtained by applying compressive strain. General strain engineering will be effective in linearly tuning the band gap of BiOX in a wide strain range. Strain, together with halogen composition variation, can tune the optical absorption spectrum to be on demand in the range from visible to ultraviolet. This suggests that 2D BiOX materials can potentially serve as tunable novel photodetectors, can be used to improve clean energy techniques, and have potential in the field of flexible optoelectronics.

A sandwiched ventricular explant assay to model mouse coronary angiogenesis ex vivo.

Developing an ex vivo system that mimics in vivo developmental coronary angiogenesis provides an improved understanding of its underlying molecular and cellular mechanisms. Here, we present a sandwiched embryonic ventricular explant assay to model mouse coronary angiogenesis ex vivo. We describe steps for breeding mice, labeling endocardial cells, isolating murine hearts, dissecting left ventricles, and making sandwiched explants in Matrigel. We then detail procedures for modeling coronary angiogenesis and taking images. For complete details on the use and execution of this protocol, please refer to Lu et al. (2023)1.

Shade-induced RTFL/DVL peptides negatively regulate the shade response by directly interacting with BSKs in Arabidopsis.

For shade-intolerant species, shade light indicates the close proximity of neighboring plants and triggers the shade avoidance syndrome (SAS), which causes exaggerated growth and reduced crop yield. Here, we report that non-secreted ROT FOUR LIKE (RTFL)/DEVIL (DVL) peptides negatively regulate SAS by interacting with BRASSINOSTEROID SIGNALING KINASEs (BSKs) and reducing the protein level of PHYTOCHROME INTERACTING FACTOR 4 (PIF4) in Arabidopsis. The transcription of at least five RTFLs (RTFL13/16/17/18/21) is induced by low R:FR light. The RTFL18 (DVL1) protein is stabilized under low R:FR conditions and localized to the plasma membrane. A phenotype analysis reveals that RTFL18 negatively regulates low R:FR-promoted petiole elongation. BSK3 and BSK6 are identified as partners of RTFL18 through binding assays and structural modeling. The overexpression of RTFL18 or knockdown of BSK3/6 reduces BRASSINOSTEROID signaling and reduces low R:FR-stabilized PIF4 levels. Genetically, the overexpression of BSK3/6 and PIF4 restores the petiole phenotype acquired by RTFL18-overexpressing lines. Collectively, our work characterizes a signaling cascade (the RTFLs-BSK3/6-PIF4 pathway) that prevents the excessive activation of the shade avoidance response in Arabidopsis.

Exploring the effect of C6H5-x/FxBr (x = 0-3) passivating agent on surface properties at different termination ends: first principles.

To prevent further decomposition of organic-inorganic hybrid perovskite by defects, in this work density functional theory was applied to explore the electronic properties, carrier surface mobility and theoretical photoelectric conversion efficiency (PCE) of passivating molecules with different fluorine atom content at the symmetric site of the benzene ring at different termination ends of MAPbI3, which shed light on the control of perovskite surface passivation by different element atoms in the same molecule. We found that the same molecule acts as a different passivation agent at different termination faces. Passivating molecules on the surface termination end by MAI play a Lewis acid role, with molecules with stronger dipole moments narrowing the band gap from the original 1.77 to 1.73 eV. The exciton binding energy of molecules with stronger dipole moments (0.187-0.292 meV) is significantly lower than that of MAPbI3 (0.332 meV), so the effective separation of interface electrons and holes can be realized. Bromopenta-fluorobenzene has a lower adsorption energy of -0.17 eV, which can stably adsorb on the surface of perovskite and increase visible light absorption. Ultimately, the theoretical PCE increased from 15.8% to 16.16%. In addition, on the surface terminated by PbI2, BrB with a strong dipole moment can provide electrons for Pb2+ and act as a Lewis base. At the surface end, it can form an ionic bond with Pb2+, while the antibonding molecular orbital characteristic is dominant, which increases the band gap from 1.76 to 1.87 eV. After increasing to 4-F-BrB, the fluorine atom has strong electronegativity and can easily bond with Pb2+. The conjugate π cycle intensifies the promotion of electron transfer, reducing the work function from 5.262 to 4.703 eV, reducing the effective electron and hole mass (0.514, 0.204 m0), and improving the photovoltaic performance. Finally, increasing the number of passivation molecules resulted in a decrease in the PCE from 15.93% to 14.75%.

Crk and Crkl Are Required in the Endocardial Lineage for Heart Valve Development.

Background Endocardial cells are a major progenitor population that gives rise to heart valves through endocardial cushion formation by endocardial to mesenchymal transformation and the subsequent endocardial cushion remodeling. Genetic variants that affect these developmental processes can lead to congenital heart valve defects. Crk and Crkl are ubiquitously expressed genes encoding cytoplasmic adaptors essential for cell signaling. This study aims to explore the specific role of Crk and Crkl in the endocardial lineage during heart valve development. Methods and Results We deleted Crk and Crkl specifically in the endocardial lineage. The resultant heart valve morphology was evaluated by histological analysis, and the underlying cellular and molecular mechanisms were investigated by immunostaining and quantitative reverse transcription polymerase chain reaction. We found that the targeted deletion of Crk and Crkl impeded the remodeling of endocardial cushions at the atrioventricular canal into the atrioventricular valves. We showed that apoptosis was temporally increased in the remodeling atrioventricular endocardial cushions, and this developmentally upregulated apoptosis was repressed by deletion of Crk and Crkl. Loss of Crk and Crkl also resulted in altered extracellular matrix production and organization in the remodeling atrioventricular endocardial cushions. These morphogenic defects were associated with altered expression of genes in BMP (bone morphogenetic protein), connective tissue growth factor, and WNT signaling pathways, and reduced extracellular signal-regulated kinase signaling activities. Conclusions Our findings support that Crk and Crkl have shared functions in the endocardial lineage that critically regulate atrioventricular valve development; together, they likely coordinate the morphogenic signals involved in the remodeling of the atrioventricular endocardial cushions.

Correlation of microsatellite status and EBV infection with clinical characteristics of patients with gastric cancer.

This study was designed to investigate the correlation of microsatellite status (MS) and Epstein-Barr virus (EBV) infection with the clinical characteristics of gastric cancer (GC) patients. MS was detected by immunohistochemistry. EBV was detected by in situ hybridization. There were 31.3% cases showed mismatch repair-deficient (dMMR)/ microsatellite instability (MSI) and 68.7% cases showed mismatch repair-proficient (pMMR)/ microsatellite stability (MSS). The dMMR/MSI was more common in the elderly, in patients with cardia GC, smaller tumor diameter or non-poorly differentiated carcinoma. The survival in dMMR/MSI patients tended to be longer than that in pMMR/MSS patients. Total 7.6% cases showed EBV-positive (EBV(+)) among 198 GC patients. EBV(+) was more common in patients with advanced GC or poorly differentiated adenocarcinoma. MSI was more common in EBV-negative (EBV(-)) patients than in EBV(+) patients. The dMMR/MSI patients with stage II GC benefited from chemotherapy. The survival of EBV(+) patients tended to be longer than that of EBV(-) patients.

Expression Pattern and Ligand Binding Characteristics Analysis of Chemosensory Protein SnitCSP2 from Sirex nitobei.

Sirex nitobei is an important wood-boring wasp to conifers native to Asia, causing considerable economic and ecological damage. However, the current control means cannot achieve better efficiency, and it is expected to clarify the molecular mechanism of protein-ligand binding for effective pest control. This study analyzed the expression pattern of CSP2 in S. nitobei (SnitCSP2) and its features of binding to the screened ligands using molecular docking and dynamic simulations. The results showed that SnitCSP2 was significantly expressed in female antennae. Molecular docking and dynamic simulations revealed that SnitCSP2 bound better to the host plant volatile (+)-α-pinene and symbiotic fungal volatiles terpene and (-)-globulol than other target ligands. By the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method, the free binding energies of the three complexes were calculated as -44.813 ± 0.189 kJ/mol, -50.446 ± 0.396 kJ/mol, and -56.418 ± 0.368 kJ/mol, and the van der Waals energy was found to contribute significantly to the stability of the complexes. Some key amino acid residues were also identified: VAL13, GLY14, LYS61, MET65, and LYS68 were important for the stable binding of (+)-α-pinene by SnitCSP2, while for terpenes, ILE16, ALA25, TYR26, CYS29, GLU39, THR37, and GLY40 were vital for a stable binding system. We identified three potential ligands and analyzed the interaction patterns of the proteins with them to provide a favorable molecular basis for regulating insect behavioral interactions and developing new pest control strategies.

Investigating SnocCSP4 expression and key compound interactions with SnocOBP4 in Sirex noctilio Fabricius (Hymenoptera: Siricidae).

Sirex noctilio, a significant pest impacting Pinus sylvestris var. mongolica, presents control difficulties due to its wood-boring behavior, paucity of natural antagonists, and wide-ranging habitats. Our research aims to elucidate the functionality and operational mechanisms of chemosensory proteins 4 (SnocCSP4), providing strategic insights for pest management and fostering further exploration in CSPs. Techniques such as qPCR, fluorescence binding affinity assays, molecular docking, and dynamic simulations were utilized to investigate the tissue-specific distribution, ligand binding capacities, and mechanistic underpinnings of SnocCSP4. The findings revealed a high abundance of SnocCSP4 in male genitalia, significant sexual dimorphism in its expression, and high binding affinities to (-)-Globulol and 10-Oxodecanoic acid. Subsequent analysis identified hydrophobic cavities formed by non-polar amino acids (VAL, LEU, ILE, LYS) and the critical role of polar amino acids (ALA 46, GLU 45, THR 75) in maintaining system stability. These insights suggest the primary role of SnocCSP4 in binding or transporting these volatiles and indicate that modifying key amino acids could inform the design of more effective pest control measures.

ß-Catenin regulates endocardial cushion growth by suppressing p21.

Endocardial cushion formation is essential for heart valve development and heart chamber separation. Abnormal endocardial cushion formation often causes congenital heart defects. ß-Catenin is known to be essential for endocardial cushion formation; however, the underlying cellular and molecular mechanisms remain incompletely understood. Here, we show that endothelial-specific deletion of ß-catenin in mice resulted in formation of hypoplastic endocardial cushions due to reduced cell proliferation and impaired cell migration. By using a ß-catenin DM allele in which the transcriptional function of ß-catenin is selectively disrupted, we further reveal that ß-catenin regulated cell proliferation and migration through its transcriptional and non-transcriptional function, respectively. At the molecular level, loss of ß-catenin resulted in increased expression of cell cycle inhibitor p21 in cushion endocardial and mesenchymal cells in vivo. In vitro rescue experiments with HUVECs and pig aortic valve interstitial cells confirmed that ß-catenin promoted cell proliferation by suppressing p21. In addition, one savvy negative observation is that ß-catenin was dispensable for endocardial-to-mesenchymal fate change. Taken together, our findings demonstrate that ß-catenin is essential for cell proliferation and migration but dispensable for endocardial cells to gain mesenchymal fate during endocardial cushion formation. Mechanistically, ß-catenin promotes cell proliferation by suppressing p21. These findings inform the potential role of ß-catenin in the etiology of congenital heart defects.

First-principles calculation of the optical properties of the YBa2Cu3O7-δ oxygen vacancies model.

We used first-principles methods to investigate how oxygen vacancy defects affect the optical properties of YBa2Cu3O7-δ (0 < δ < 1), a high-temperature superconductor with potential applications in optical detectors. We calculated the electronic structure of YBa2Cu3O7-δ with different amounts of oxygen vacancies at three different sites: Cu-O chains, CuO2 planes, and apical oxygens. The formation energy calculations support the formation of oxygen vacancies in the Cu-O chain at higher concentrations of vacancy defects, with a preference for alignment in the same chain. The presence of oxygen vacancies affects the optical absorption peak of YBa2Cu3O7-δ in different ways depending on their location and concentration. The optical absorption peaks in the visible range (1.6-3.2 eV) decrease in intensity and shift towards the infrared spectrum as oxygen vacancies increase. We demonstrate that oxygen vacancies can be used as a powerful tool to manipulate the optical response of YBa2Cu3O7-δ to different wavelengths in optical detector devices.

Simultaneous determination of abrine, hypaphorine, schaftoside and soyasaponin Bb in rat plasma by UPLC-MS/MS and its application to a pharmacokinetic study after oral administration of Abrus cantoniensis Hance extract.

A simple and sensitive liquid chromatography tandem mass spectrometry method was established and validated for the quantitative determination of abrine, hypaphorine, schaftoside and soyasaponin Bb in rat plasma. After preparation by protein precipitation with acetonitrile, the analytes and internal standard were separated on a Waters CORTECS T3 column using acetonitrile containing 0.1% formic acid and 0.1% formic acid in water as mobile phase by gradient elution in 2 min. The method showed excellent linearity over the range of 5-500 ng/ml with acceptable intra- and inter-day precision, accuracy, matrix effect and recovery. The stability assay indicated that the four analytes were stable during the analysis process. The method was applied to a pharmacokinetic study of Abrus cantoniensis Hance in rats. The result suggested that after oral administration, the four analytes were quickly absorbed into the plasma. The dose-normalized exposure of hypaphorine was the highest with a long elimination half-life (t1/2 9.83 h), followed by abrine and schaftoside with t1/2 values of 1.07 and 1.15 h. The dose normalized exposure of soyasaponin Bb was the lowest, which is possibily due to the high polarity and poor permeability. This study provides a basis for elucidating the material foundation of A. cantoniensis Hance.

Photocatalysis screening for group III-V vdW heterostructures constructed by MX (M = Ga, In and X = P, As) monolayers.

To harvest solar energy for water splitting and produce pollution-free hydrogen and oxygen, high-performance photocatalysts are essential. Here, by combining different two-dimensional (2D) group III-V MX (M = Ga, In and X = P, As) monolayers, we designed 144 van der Waals (vdW) heterostructures to identify efficient photoelectrochemical materials. Using first-principles calculations, we investigated the stabilities, electronic properties, and optical properties of these heterostructures. After a careful screening process, we elected GaP/InP in a BB-II stacking configuration as the most promising candidate. This specific GaP/InP configuration has a type-II band alignment with a gap value of 1.83 eV. The conduction band minimum (CBM) is located at -4.276 eV, and the valence band maximum (VBM) is located at -6.217 eV, fully satisfying the requirements of the catalytic reaction under pH = 0. Additionally, light absorption has been improved through the construction of the vdW heterostructure. These results could help in understanding the properties of the III-V heterostructures and guide the experimental synthesis of these materials for photocatalysis applications.