Interstitial Fluid Shear Stress Induces the Synthetic Phenotype Switching of VSMCs to Release Pro-calcified Extracellular Vesicles via EGFR-MAPK-KLF5 Pathway.

Phenotypic switching (from contractile to synthetic) of vascular smooth muscle cells (VSMCs) is essential in the progression of atherosclerosis. The damaged endothelium in the atherosclerotic artery exposes VSMCs to increased interstitial fluid shear stress (IFSS). However, the precise mechanisms by which increased IFSS influences VSMCs phenotypic switching are unrevealed. Here, we employed advanced numerical simulations to calculate IFSS values accurately based on parameters acquired from patient samples. We then carefully investigated the phenotypic switching and extracellular vesicles (EVs) secretion of VSMCs under various IFSS conditions. By employing a comprehensive set of approaches, we found that VSMCs exhibited synthetic phenotype upon atherosclerotic IFSS. This synthetic phenotype is the upstream regulator for the enhanced secretion of pro-calcified EVs. Mechanistically, as a mechanotransducer, the epidermal growth factor receptor (EGFR) initiates the flow-based mechanical cues to MAPK signaling pathway, facilitating the nuclear accumulation of the transcription factor krüppel-like factor 5 (KLF5). Furthermore, pharmacological inhibiting either EGFR or MAPK signaling pathway blocks the nuclear accumulation of KLF5 and finally results in the maintenance of contractile VSMCs even under increased IFSS stimulation. Collectively, targeting this signaling pathway holds potential as a novel therapeutic strategy to inhibit VSMCs phenotypic switching and mitigate the progression of atherosclerosis.

Behavior of Lithium Amide Under Argon Plasma.

Alkali and alkaline earth metal amides are a type of functional materials for hydrogen storage, thermal energy storage, ion conduction, and chemical transformations such as ammonia synthesis and decomposition. The thermal chemistry of lithium amide (LiNH2), as a simple but representative alkali or alkaline earth metal amide, has been well studied previously encouraged by its potentials in hydrogen storage. In comparison, little is known about the interaction of plasma and LiNH2. Herein, we report that the plasma treatment of LiNH2 in an Ar flow under ambient temperature and pressure gives rise to distinctly different reaction products and reaction pathway from that of the thermal process. We found that plasma treatment of LiNH2 leads to the formation of Li colloids, N2, and H2 as observed by UV-vis absorption, EPR, and gas products analysis. Inspired by this very unique interaction between plasma and LiNH2, a chemical loop for ammonia decomposition to N2 and H2 mediated by LiNH2 was proposed and demonstrated.

Deep Learning Based Underwater Acoustic Target Recognition: Introduce a Recent Temporal 2D Modeling Method.

In recent years, the application of deep learning models for underwater target recognition has become a popular trend. Most of these are pure 1D models used for processing time-domain signals or pure 2D models used for processing time-frequency spectra. In this paper, a recent temporal 2D modeling method is introduced into the construction of ship radiation noise classification models, combining 1D and 2D. This method is based on the periodic characteristics of time-domain signals, shaping them into 2D signals and discovering long-term correlations between sampling points through 2D convolution to compensate for the limitations of 1D convolution. Integrating this method with the current state-of-the-art model structure and using samples from the Deepship database for network training and testing, it was found that this method could further improve the accuracy (0.9%) and reduce the parameter count (30%), providing a new option for model construction and optimization. Meanwhile, the effectiveness of training models using time-domain signals or time-frequency representations has been compared, finding that the model based on time-domain signals is more sensitive and has a smaller storage footprint (reduced to 30%), whereas the model based on time-frequency representation can achieve higher accuracy (1-2%).

Repeated misdiagnosis of small intestine bronchogenic cyst: a case report.

Bronchogenic cysts are uncommon congenital malformations of the respiratory system. These cysts can be categorized as intrapulmonary, mediastinal, or ectopic. Ectopic bronchogenic cysts, which lack distinctive clinical and imaging features, are particularly challenging to diagnose. This study presents a 48-year-old woman having a small intestinal bronchogenic cyst. She was repeatedly misdiagnosed as having an ovarian chocolate cyst or a cystic mass of bladder origin three years ago. However, no cyst was found during the operation. Half a year prior to presenting at our hospital, the patient developed frequent urination, prompting her to seek further treatment. We eventually discovered a cyst in the small intestine. The histological evaluation of the specimen showed a bronchogenic cyst. Small intestine bronchogenic cysts are extremely rare and easily misdiagnosed. It should be considered as one of the differential diagnoses of pelvic cysts. Particularly, when intraoperative exploration of the pelvic cavity fails to detect any cysts, consideration should be given to the possibility of small intestine bronchogenic cysts.

Light-driven ammonia synthesis under mild conditions using lithium hydride.

Photon-driven chemical processes are usually mediated by oxides, nitrides and sulfides whose photo-conversion efficiency is limited by charge carrier recombination. Here we show that lithium hydride undergoes photolysis upon ultraviolet illumination to yield long-lived photon-generated electrons residing in hydrogen vacancies, known as F centres. We demonstrate that photon-driven dehydrogenation and dark rehydrogenation over lithium hydride can be fulfilled reversibly at room temperature, which is about 600 K lower than the corresponding thermal process. As light-driven F centre generation could provide an alternative approach to charge carrier separation to favour chemical transformations that are kinetically or thermodynamically challenging, we show that light-activated lithium hydride cleaves the N≡N triple bond to form a N-H bond under mild conditions. Co-feeding a N2/H2 mixture with low H2 partial pressure leads to photocatalytic ammonia formation at near ambient conditions. This work provides insights into the development of advanced materials and processes for light harvesting and conversion.

Replication and Expression of the Consensus Genome of Hepatitis B Virus Genotype C from the Chinese Population.

Hepatitis B virus (HBV) genotype C is a prevalent HBV genotype in the Chinese population. Although genotype C shows higher sequence heterogeneity and more severe liver disease than other genotypes, its pathogenesis and immunological traits are not yet fully elucidated. In this study, we first established and chemically synthesized the consensus sequence based on representative 138 full-length HBV genotype C genomes from the Chinese population. The pHBV1.3C plasmid system, containing a 1.3-fold full-length HBV genotype C consensus sequence, was constructed for subsequent validation. Next, we performed functional assays to investigate the replicative competence of pHBV1.3C in vitro through the transient transfection of HepG2 and Huh7 cells and validated the in vivo function via a hydrodynamic injection to BALB/c recipient mice. The in vitro investigation revealed that the extracellular HBV DNA and intracellular replicative intermediate (i.e., pregenomic RNA, pgRNA) were apparently measurable at 48 h, and the HBsAg and HBcAg were still positive in hepatoma cells at 96 h. We also found that HBsAg and HBeAg accumulated at the extracellular and intracellular levels in a time-dependent manner. The in vivo validation demonstrated that pHBV1.3C plasmids induced HBV viremia, triggered morphological changes and HBsAg- or HBcAg- positivity of hepatocytes, and ultimately caused inflammatory infiltration and focal or piecemeal necrosis in the livers of the murine recipients. HBV protein (HBsAg) colocalized with CD8+ T cells or CD4+ T cells in the liver. F4/80+ Kupffer cells were abundantly recruited around the altered murine hepatocytes. Taken together, our results indicate that the synthetic consensus sequence of HBV genotype C is replication-competent in vitro and in vivo. This genotype C consensus genome supports the full HBV life cycle, which is conducive to studying its pathogenesis and immune response, screening novel antiviral agents, and further optimizing testing and therapeutics.

Zn Promotes Chemical Looping Ammonia Synthesis Mediated by LiH-Li2 NH Couple.

Chemical looping ammonia synthesis (CLAS) is a promising alternative route to ammonia production because of its advantages of avoiding competitive adsorption of N2 and hydrogen source (H2 O or H2 ) and intervening the scaling relations in the catalytic process. Our previous studies showed that NH3 can be synthesized at low temperatures via a CLAS mediated by an alkali or alkaline earth metal hydride-imide couple with the aid of transition metal catalysts. Herein, we demonstrate that a group-IIB metal Zn, which has rarely been studied in the thermal-catalytic process, can significantly promote the performance of the lithium hydride-lithium imide (LiH-Li2 NH)-mediated CLAS process (denoted as Zn-LiH-Li2 NH). The addition of Zn dramatically changes the reaction pathway of the LiH-Li2 NH mediated loop by forming a series of intermediates including Li2 NH, lithium zinc intermetallic compounds (LiZnx ), and a ternary metal nitride (LiZnN). LiZnN together with Li2 NH functions as nitrogen carrier in the Zn-LiH-Li2 NH-mediated CLAS. Because of these properties, the kinetics of N2 fixation is significantly enhanced with a reduction in apparent activation energy from 102 kJ mol-1 to 50 kJ mol-1 . The ammonia production rate reaches 956 µmol g-1 h-1 at 350 °C, which is 19 times higher than that of the neat LiH-Li2 NH-mediated CLAS.

[Latest Findings on the Pathogenic Mechanisms of Thoracic Aortic Dissection].

Thoracic aortic dissection (TAD) is a cardiovascular disease entailing a high lethality between 65% and 85%. Surgery-assissed implant/interventional stenting is the prevailing treatment of TAD. However, surgical treatment can cause severe postoperative complications and patients incur a relatively higher risk of postoperative mortality. Since the pathogenic mechanism underlying TAD is not clear, effective medication therapies are still not available. In recent years, along with advances in single-cell sequencing and other molecular biological technologies, there have been prelimiary findings suggesting the special role of dysfunctional vascular smooth muscle cells (VSMCs) in the pathogenesis and development of TAD. Furthermore, the molecular mechanisms regulating the dysfunction of VSMCs have been initially explored. It is expected that these new findings will contribute to the development of new strategies to prevent TAD and lead to new ideas for the identifiction of potential drug therapeutic targets. Herein, we summarized the critical role of dysfunctional VSMCs in the pathogenesis and development of TAD and presented in detail the biological factors and the related molecular mechanisms that regulate the dysfunction of VSMCs. We hope this review will provide a reference for further investigation into the central role of dysfunctional VSMCs in the pathogenesis and development of TAD and exploration for effective molecular drug targets for TAD.

The formation of a lithium-iridium complex hydride toward ammonia synthesis.

Noble metal elements are focal catalytic candidates for many chemical processes, but have received little attention in the field of nitrogen fixation except ruthenium and osmium. Iridium (Ir), as a representative, has been shown to be catalytically inactive for ammonia synthesis because of its weak nitrogen adsorption and severe competitive adsorption of H over N that strongly inhibits the activation of N2 molecules. Here we show that, upon compositing with lithium hydride (LiH), iridium can catalyze ammonia formation at much enhanced reaction rates. The catalytic performance of the LiH-Ir composite can be further improved by dispersion on a MgO support with a high specific surface area. At 400 °C and 10 bar, the MgO-supported LiH-Ir (LiH-Ir/MgO) catalyst shows a ca. 100-fold increase in activity compared to the bulk LiH-Ir composite and the MgO-supported Ir metal catalyst (Ir/MgO). The formation of a lithium-iridium complex hydride phase was identified and characterized, and this phase may be responsible for the activation and hydrogenation of N2 to NH3.

Barium hydride activates Ni for ammonia synthesis catalysis.

Nickel (Ni) metal has long been considered to be far less active for catalytic ammonia synthesis as compared to iron, cobalt, and ruthenium. Herein, we show that Ni metal synergized with barium hydride (BaH2) can catalyse ammonia synthesis with an activity comparable to that of an active Cs-Ru/MgO catalyst typically below 300 °C. Kinetic analyses show that the addition of BaH2 makes the apparent activation energy for the Ni catalyst decrease dramatically from 150 kJ mol-1 to 87 kJ mol-1. This result together with N2-TPR experiments suggests a strong synergistic effect between Ni and BaH2 for promoting N2 activation and hydrogenation to NH3. It is suggested that an intermediate [N-H] species is generated upon N2 fixation and then is hydrogenated to NH3 with the regeneration of hydride species, forming a catalytic cycle.

Trail Formation Alleviates Excessive Adhesion and Maintains Efficient Neutrophil Migration.

Migrating neutrophils are found to leave behind subcellular trails in vivo, but the underlying mechanisms remain unclear. Here, an in vitro cell migration test plus an in vivo observation was applied to monitor neutrophil migration on intercellular cell adhesion molecule-1 (ICAM-1) presenting surfaces. Results indicated that migrating neutrophils left behind long-lasting, chemokine-containing trails. Trail formation tended to alleviate excessive cell adhesion enhanced by the trans-binding antibody and maintain efficient cell migration, which was associated with differential instantaneous edge velocity between the cell front and rear. CD11a and CD11b worked differently in inducing trail formation with polarized distributions on the cell body and uropod. Trail release at the cell rear was attributed to membrane ripping, in which ß2-integrin was disrupted from the cell membrane through myosin-mediated rear contraction and integrin-cytoskeleton dissociation, potentiating a specialized strategy of integrin loss and cell deadhesion to maintain efficient migration. Moreover, neutrophil trails left on the substrate served as immune forerunners to recruit dendritic cells. These results provided an insight in elucidating the mechanisms of neutrophil trail formation and deciphering the roles of trail formation in efficient neutrophil migration.

Multi-layer reconstruction of skull base after endoscopic transnasal surgery for invasive pituitary adenomas.

OBJECTIVE: To explore the efficacy of multi-layer skull base reconstruction after endoscopic transnasal surgery for invasive pituitary adenomas (IPAs). CLINICAL RATIONALE FOR THE STUDY: Skull base reconstruction for IPAs. MATERIAL AND METHODS: This retrospective analysis involved 160 patients with IPAs who underwent operations from October 2018 to October 2020. All patients were diagnosed with IPAs by pituitary enhanced magnetic resonance imaging, and all tumours were confirmed to be Knosp grades 3a, 3b, or 4. The experimental group and the control group comprised 80 patients in each, and we used different methods to reconstruct the skull base in each group. The comparison indicators included cerebrospinal fluid leakage, sellar floor bone flap (or middle turbinate) shifting, delayed healing of the skull base reconstructed tissue, nasal discomfort, and epistaxis. We used the chi-square test, and p < 0.05 was considered statistically significant. RESULTS: In the experimental group, cerebrospinal fluid leakage occurred intraoperatively in 73 patients, two of whom had cerebrospinal fluid leakage postoperatively. Brain CT 12 months postoperatively showed no sellar floor bone flap (or middle turbinate) shifting. Endoscopic transnasal checks performed seven days after surgery showed that the skull base reconstructed tissue had healed in 74 patients and had failed to heal in six. However, endoscopic transnasal checks showed that all six of these patients' pedicled nasoseptal flaps had healed well by 14 days after surgery. Other sequelae comprised nasal discomfort in four patients, and epistaxis in four. In the control group, cerebrospinal fluid leakage occurred intraoperatively in 71 patients, 14 of whom had cerebrospinal fluid leakage postoperatively. Brain CT 12 months postoperatively showed floor bone flap (or middle turbinate) shifting in 12 patients. Endoscopic transnasal checks performed seven days after surgery showed that the skull base reconstructed tissue had healed in 65 patients. In 12 patients, pedicled nasoseptal flaps had healed well by 14 days after surgery, while the remaining three patients required reoperation. Other sequelae comprised nasal discomfort in five patients, and epistaxis in six. CONCLUSIONS: This new method of multi-layer skull base reconstruction could play an important role in endoscopic transnasal IPA surgery.

Fluid Shear Stress Regulates Osteogenic Differentiation via AnnexinA6-Mediated Autophagy in MC3T3-E1 Cells.

Fluid shear stress (FSS) facilitates bone remodeling by regulating osteogenic differentiation, and extracellular matrix maturation and mineralization. However, the underlying molecular mechanisms of how mechanical stimuli from FSS are converted into osteogenesis remain largely unexplored. Here, we exposed MC3T3-E1 cells to FSS with different intensities (1 h FSS with 0, 5, 10, and 20 dyn/cm2 intensities) and treatment durations (10 dyn/cm2 FSS with 0, 0.5, 1, 2 and 4 h treatment). The results demonstrate that the 1 h of 10 dyn/cm2 FSS treatment greatly upregulated the expression of osteogenic markers (Runx2, ALP, Col I), accompanied by AnxA6 activation. The genetic ablation of AnxA6 suppressed the autophagic process, demonstrating lowered autophagy markers (Beclin1, ATG5, ATG7, LC3) and decreased autophagosome formation, and strongly reduced osteogenic differentiation induced by FSS. Furthermore, the addition of autophagic activator rapamycin to AnxA6 knockdown cells stimulated autophagy process, and coincided with more expressions of osteogenic proteins ALP and Col I under both static and FSS conditions. In conclusion, the findings in this study reveal a hitherto unidentified relationship between FSS-induced osteogenic differentiation and autophagy, and point to AnxA6 as a key mediator of autophagy in response to FSS, which may provide a new target for the treatment of osteoporosis and other diseases.

Transition-Metal-Free Barium Hydride Mediates Dinitrogen Fixation and Ammonia Synthesis.

Transition-metal-mediated dinitrogen fixation has been intensively investigated. The employment of main group elements for this vital reaction has recently sparked interest because of new dinitrogen reaction chemistry. We report ammonia synthesis via a chemical looping process mediated by a transition-metal-free barium hydride (BaH2 ). Experimental and computational studies reveal that the introduction of hydrogen vacancies is essential for creating multiple coordinatively unsaturated Ba sites for N2 activation. The adjacent lattice hydridic hydrogen (H- ) then undergoes both reductive elimination and reductive protonation to convert N2 to NHx . The ammonia production rate supports this hydride-vacancy mechanism via a chemical looping route that far exceeds that of a catalytic process. The BaH2 -mediated chemical looping process has prospects in future technologies for ammonia synthesis using transition-metal-free materials.

Cholesterol inhibits TCR signaling by directly restricting TCR-CD3 core tunnel motility.

Cholesterol molecules specifically bind to the resting αßTCR to inhibit cytoplasmic CD3ζ ITAM phosphorylation through sequestering the TCR-CD3 complex in an inactive conformation. The mechanisms of cholesterol-mediated inhibition of TCR-CD3 and its activation remain unclear. Here, we present cryoelectron microscopy structures of cholesterol- and cholesterol sulfate (CS)-inhibited TCR-CD3 complexes and an auto-active TCR-CD3 variant. The structures reveal that cholesterol molecules act like a latch to lock CD3ζ into an inactive conformation in the membrane. Mutations impairing binding of cholesterol molecules to the tunnel result in the movement of the proximal C terminus of the CD3ζ transmembrane helix, thereby activating the TCR-CD3 complex in human cells. Together, our data reveal the structural basis of TCR inhibition by cholesterol, illustrate how the cholesterol-binding tunnel is allosterically coupled to TCR triggering, and lay a foundation for the development of immunotherapies through directly targeting the TCR-CD3 complex.

Synthesis of pyrimidines from dinitrogen and carbon.

The element nitrogen and nitrogenous compounds are vital to life. The synthesis of nitrogen-containing compounds using dinitrogen as the nitrogen source, not through ammonia, is of great interest and great value but remains a grand challenge. Herein, we describe a strategy to realize this transformation by combining the heterogeneous approach with the homogeneous methodology. The N2 molecule was first fixed with carbon and LiH through a one-pot heterogeneous process, forming Li2CN2 as an 'activated' nitrogen source with high efficiency. Then subsequent homogeneous treatments of Li2CN2 to construct the organic synthon carbodiimide and the RNA/DNA building block pyrimidines were fulfilled. By using 15N2 as the feedstock, their corresponding 15N-labeled carbodiimide and pyrimidines were readily obtained. This homogeneous-heterogeneous synergy strategy will open a new chapter for N2 transformation.

Enabling Semihydrogenation of Alkynes to Alkenes by Using a Calcium Palladium Complex Hydride.

Selective hydrogenation of alkynes to alkenes requires a catalytic site with suitable electronic properties for modulating the adsorption and conversion of alkyne, alkene as well as dihydrogen. Here, we report a complex palladium hydride, CaPdH2, featured by electron-rich [PdH2]δ- sites that are surrounded by Ca cations that interacts with C2H2 and C2H4 via σ-bonding to Pd and unusual cation-π interaction with Ca, resulting in a much weaker chemisorption than those of Pd metal catalysts. Concomitantly, the dissociation of H2 and hydrogenation of C2Hx (x = 2-4) species experience significant energy barriers over CaPdH2, which is fundamentally different from those reported Pd-based catalysts. Such a unique catalytic environment enables CaPdH2, the very first complex transition-metal hydride catalyst, to afford a high alkene selectivity for the semihydrogenation of alkynes.