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Alteration of tissue inhibitors of matrix metalloproteinases (TIMP)/matrix metalloproteinases (MMP) associated with collagen upregulation has an important role in sustained atrial fibrillation (AF). The expression of miR‐146b‐5p, whose the targeted gene is TIMPs, is upregulated in atrial cardiomyocytes during AF. This study was to determine whether miR‐146b‐5p could regulate the gene expression of TIMP4 and the contribution of miRNA to atrial fibrosis in AF. Collagen synthesis was observed after miR‐146b‐5p transfection in human induced pluripotent stem cell‐derived atrial cardiomyocytes (hiPSC‐aCMs)‐fibroblast co‐culture cellular model in vitro. Furthermore, a myocardial infarction (MI) mouse model was used to confirm the protective effect of miR‐146b‐5p downregulation on atrial fibrosis. The expression level of miR‐146b‐5p was upregulated, while the expression level of TIMP4 was downregulated in the fibrotic atrium of canine with AF. miR‐146b‐5p transfection in hiPSC‐aCMs‐fibroblast co‐culture cellular model increased collagen synthesis by regulating TIMP4/MMP9 mediated extracellular matrix proteins synthesis. The inhibition of miR‐146b‐5p expression reduced the phenotypes of cardiac fibrosis in the MI mouse model. Fibrotic marker MMP9, TGFB1 and COL1A1 were significantly downregulated, while TIMP4 was significantly upregulated (at both mRNA and protein levels) by miR‐146b‐5p inhibition in cardiomyocytes of MI heart. We concluded that collagen fibres were accumulated in extracellular space on miR‐146b‐5p overexpressed co‐culture cellular model. Moreover, the cardiac fibrosis induced by MI was attenuated in antagomiR‐146 treated mice by increasing the expression of TIMP4, which indicated that the inhibition of miR‐146b‐5p might become an effective therapeutic approach for preventing atrial fibrosis.

Whether large conductance Ca(2+)-activated potassium (BK) channels are present in the substantia nigra pars reticulata (SNr) is a matter of debate. Using the patch-clamp technique, we examined the functional expression of BK channels in neurons of the SNr and showed that the channels were activated or inhibited by internal high-energy phosphates (IHEPs) at positive and negative membrane potentials, respectively. SNr neurons showed membrane potential hyperpolarization under glucose-deprivation conditions which was attenuated by paxilline, a specific BK channel blocker. In addition, Fluo-3 fluorescence recording detected an increase in the level of internal free calcium ([Ca(2+)](i)) during ischemic hyperpolarization. These results confirm that BK channels are present in SNr neurons and indicate that their unique IHEP sensitivity is requisite in neuronal ischemic responses. Bearing in mind that the K(ATP) channel blocker tolbutamide also attenuated the hyperpolarization, we suggest that BK channels may play a protective role in the basal ganglia by modulating the excitability of SNr neurons along with K(ATP) channels under ischemic stresses.

Several metasurface diffraction-free beam generators are designed by using a set of resonant V-shaped nanoholes. Cosine beams, Bessel beams and cosine Bessel beams are generated through the corresponding metasurface structures with V-shaped nanoholes arranged in different ways. Theoretical analysis provides the design mechanism for these diffraction-free beam generators, numerical simulations and experiment measurement give the powerful verification for the generation of diffraction-free beams. The proposed diffraction-free beam generators have advantages of ultra-thin thickness, compact structure, ease to manufacture and flexibility to operate. The generated diffraction-free beams show high efficiency, polarization independence and validity for any visible wavelength. The compact design is benefit to the applications of diffraction-free beams in nanometer fabrication, optical integrated imaging and optical micromanipulation.

To describe the long-term health outcomes of patients with COVID-19 and investigate the potential risk factors. Clinical data during hospitalization and at a mean (SD) day of 249 (15) days after discharge from 40 survivors with confirmed COVID-19 (including 25 severe cases) were collected and analyzed retrospectively. At follow-up, severe cases had higher incidences of persistent symptoms, DLCO impairment, and higher abnormal CT score as compared with mild cases. CT score at follow-up was positively correlated with age, LDH level, cumulative days of oxygen treatment, total dosage of glucocorticoids used, and CT peak score during hospitalization. DLCO% at follow-up was negatively correlated with cumulative days of oxygen treatment during hospitalization. DLCO/VA% at follow-up was positively correlated with BMI, and TNF-α level. Among the three groups categorized as survivors with normal DLCO, abnormal DLCO but normal DLCO/VA, and abnormal DLCO and DLCO/VA, survivors with abnormal DLCO and DLCO/VA had the lowest serum IL-2R, IL-8, and TNF-α level, while the survivors with abnormal DLCO but normal DLCO/VA had the highest levels of inflammatory cytokines during hospitalization. Altogether, COVID-19 had a greater long-term impact on the lung physiology of severe cases. The long-term radiological abnormality maybe relate to old age and the severity of COVID-19. Either absent or excess of inflammation during COVID-19 course would lead to the impairment of pulmonary diffusion function.

HER2 belongs to the human epidermal growth factor receptor tyrosine kinase family. Its overexpression or hyperactivation is a leading cause for multiple types of cancers. HER2 functions mainly through dimerization with other family members, such as EGFR. However, the molecular details for heterodimer assembly have not been completely understood. Here, we report cryo-EM structures of the EGF- and epiregulin-bound EGFR/HER2 ectodomain complexes at resolutions of 3.3 Å and 4.5 Å, respectively. Together with the functional analyses, we demonstrate that only the dimerization arm of HER2, but not that of EGFR, is essential for their heterodimer formation and signal transduction. Moreover, we analyze the differential membrane dynamics and transient interactions of endogenous EGFR and HER2 molecules in genome-edited cells using single-molecule live-cell imaging. Furthermore, we show that the interaction with HER2 could allow EGFR to resist endocytosis. Together, this work deepens our understanding of the unique structural properties and dynamics of the EGFR/HER2 complex.

Background Critical-sized bone defects remain challenging to repair because successful regeneration requires both mechanical stability and the coordinated promotion of osteogenesis and vascularization. To address these needs, we developed a composite scaffold (GV@PHL) that integrates structural support with sustained pro-angiogenic signaling. Methods A 3D-printed framework composed of polycaprolactone (PCL), nano-hydroxyapatite (nano-HA), and Laponite (PHL) was fabricated to form an interconnected porous architecture with intrinsic osteogenic potential and printability. A GelMA hydrogel was photo-crosslinked within the scaffold pores and covalently tethered to vascular endothelial growth factor (VEGF) to create a photo-embedded GelMA–VEGF phase, enabling sustained VEGF release. The composite scaffold (GV@PHL) was evaluated through in vitro and in vivo experiments to assess architecture stability, osteogenic differentiation, VEGF release behavior, endothelial cell responses, and vascularization. Results The GV@PHL scaffold maintained a stable porous architecture and exhibited synergistic performance combining structural integrity with biological activity. The PHL framework supported osteogenic differentiation, while the photo-crosslinked GelMA–VEGF hydrogel enabled controlled, sustained release of VEGF. Released VEGF promoted endothelial cell survival and enhanced vascularization in vitro and in vivo, demonstrating coordinated support for osteogenesis and angiogenesis. Conclusions GV@PHL represents a practical strategy for integrating structural design and biological function in bone tissue engineering. By combining a mechanically stable, osteoinductive 3D-printed framework with sustained VEGF delivery to promote vascularization, this platform shows promise for treating critical-sized craniofacial and orthopedic bone defects.

Mineral carbonation of mafic–ultramafic rocks has been highlighted as a promising way for permanent carbon capture and storage. Carbonatization involves the release of Ca, Mg and Fe from silicate minerals by dissolution and reaction in the aqueous phase to form stable carbonate minerals. Diopside is one of the most abundant mafic minerals in the lithosphere and contributes a portion of Mg and Ca to surface weathering. Here, we present detailed processes of the carbonation-coupled serpentinization of diopsidite from the Yushishan Nb–Ta deposit in the Altun Mountain, northwest China. Diopsidite is the prograde metamorphic product of siliceous dolomitic marble by full decarbonation process. Retrograde serpentinization and carbonation of diopsidite lead to the addition of CO 2 , H 2 O, light rare earth elements and fluid-mobile elements but the loss of SiO 2 . The diopsides are replaced by calcite and chrysotile by mineral alteration to form pseudomorphic textures. Dissolution–precipitation processes significantly affect diopside serpentinization and carbonation. The carbonation of diopside-rich rocks may be suitable for permanent CO 2 storage.

PurposeComprehensive project portfolio risk (PPR) analysis is essential for the success and sustainable development of project portfolios (PPs). However, project interdependency creates complexity for PPR analysis. In this study, considering the interdependency effect among projects, the authors develop a quantitative evaluation model to analyze PPR based on a fuzzy Bayesian network.Design/methodology/approachIn this paper, the primary purpose is to comprehensively evaluate project portfolio risk considering the interdependency effect using a systematical model. Accordingly, a fuzzy Bayesian network (FBN) is developed based on the existing studies. Specifically, first, the risks in project portfolios are identified from the project interdependencies perspective. Second, a fuzzy Bayesian network is adopted to model and quantify the interaction relationships among risks. Finally, the model is implemented to analyze the occurrence situation and characteristics of risks.FindingsThe interdependency effect can lead to high-stake risks, including weak financial liquidity, a lack of cross-project members and project priority imbalance. Furthermore, project schedule risks and inconsistency between product supply and market demand are relatively sensitive and should also be prioritized. Also, the validity of this risk evaluation model has been proved.Originality/valueThe findings identify the most sensitive risks for guaranteeing portfolio implementation and reveal interdependency effect can trigger some specific risks more often. This study proposes for the first time to measure and analyze project portfolio risk by a systematical model. It can help systematically assess and manage the complicated and interdependent risks associated with project portfolios.

Background and Objectives: Uric acid to high-density lipoprotein cholesterol ratio (UHR) plays a significant role in metabolic and inflammatory responses. However, the association between UHR and osteoporosis (OP) remains unclear in type 2 diabetes mellitus (T2DM) with metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to investigate this association and identify potential biomarkers for early OP screening. Methods and Study Design: A total of 420 T2DM patients with MASLD aged >=50 years were enrolled in this retrospective study. All subjects underwent dual energy X-ray absorptiometry (DXA) examination to measure bone mineral density (BMD) and were divided into three groups according to UHR tertiles, and the differences in BMD levels and OP prevalence among the three groups were compared. Logistic regression was used to analyze the relationship between UHR and OP. Results: Patients in the highest tertile of UHR group (UHR >363.46) had lower BMD and a higher incidence of OP than those in the lower tertiles. In the UHR >363.46 group, UHR was negatively correlated with lumbar spine, whole body, and femoral neck BMD (p <0.05). After adjusting for confounding factors, UHR >363.46 was associated with a significantly increased risk of OP compared to UHR <=312.35 (OR equivalent 3.341, 95%CI: 1.129-9.887, p equivalent 0.029). ROC curve indicated that UHR combined with Age, HOMA-IR and 25(OH)D had a high predictive value for OP, with an area under the curve of 0.837 (p <0.001). Conclusions: Increased UHR is significantly associated with higher risk of OP, suggesting that clinical monitoring of UHR is valuable for early detection of OP in T2DM with MASLD.