High-efficiency photocatalytic H2-evolution in water/seawater over a novel noble metal free Ni3C/Mn0.5Cd0.5S Schottky junction.

Solar-powered seawater production of clean hydrogen fuel is highly prospective. In this work, Ni3C/Mn0.5Cd0.5S (NCMCS) Schottky junctions with excellent visible-light correspondence and photogenerated carrier separation properties are constructed using electrostatic attraction. The material achieves a hydrogen evolution rate of 6472.9 µmol h-1 g-1 in simulated seawater, which is 11 times higher than that of a single Mn0.5Cd0.5S (MCS). More attractively, the composite exhibits excellent hydrogen evolution rates in natural river water, groundwater and tap water, with significantly enhanced practical applicability. The underlying hydrogen evolution mechanism was extrapolated from a combination of experimental and theoretical calculations. The present work provides a low-cost and efficient hydrogen evolution photocatalyst for practical application, which can help promote the efficient conversion of solar-hydrogen energy.

How to predict postoperative delirium in geriatric patients with hip fracture as soon as possible? A retrospective study.

PURPOSE: Inflammation may play a role in the mechanism of postoperative delirium (POD), a severe complication among older postoperative patients. The purpose of this study was to investigate the risk factors of POD in postoperative patients with hip fracture, especially the inflammation marker- neutrophil-lymphocyte ratio (NLR). METHODS: This retrospective investigation utilized data from the Seventh Medical Center of People's Liberation Army. 1,242 Eligible patients with hip fracture (829 females), median age 81 years, mean neutrophil-lymphocyte ratio (NLR) 5.28, were enrolled. Receiver operating characteristic (ROC) curve was performed to identify the optimal cut point of NLR for POD. The relationship between NLR and POD occurrence, NLR and POD duration were analyzed by multivariable analysis. RESULTS: ROC curve showed that the optimal cut point of NLR for POD was NLR ≥ 7.6. Multivariate logistic regression analysis showed that NLR ≥ 7.6 (odds ratio [OR] 2.75, [95% confidence interval [CI] 1.51 to 5.02], p = 0.001), stroke (OR 1.05, [95% CI 1.02 to 1.09], p = 0.005), complications, general anesthesia, long length of stay were risk factors of POD, with the largest effect for NLR ≥ 7.6. NLR ≥ 7.6 (ß 0.59, [95% CI 0.209 to 0.886], p = 0.038), older age (ß 0.054, [95% CI 0.009 to 0.099], p = 0.019), previous stroke (ß 0.908, [95% CI 0.085 to 1.731], p = 0.031), and previous heart failure (ß 1.679, [95% CI 0.448 to 2.910], p = 0.008) suggested long POD duration. CONCLUSIONS: This study demonstrates an association between NLR and postoperative delirium in geriatric hip fracture patients, and contribute new evidence to support NLR as a potential marker for prediction of POD and POD duration.

Effects of rumen metabolite butyric acid on bovine skeletal muscle satellite cells proliferation, apoptosis and transcriptional states during myogenic differentiation.

Butyric acid, a pivotal short-chain fatty acid in rumen digestion, profoundly influences animal digestive and locomotor systems. Extensive research indicates its direct or indirect involvement in the growth and development of muscle and fat cells. However, the impact of butyric acid on the proliferation and differentiation of bovine skeletal muscle satellite cells (SMSCs) remains unclear. This study aimed to elucidate the effects of butyrate on SMSCs proliferation and differentiation. After isolating, SMSCs were subjected to varying concentrations of sodium butyrate (NaB) during the proliferation and differentiation stages. Optimal treatment conditions (1 mM NaB for 2 days) were determined based on proliferative force, cell viability, and mRNA expression of proliferation and differentiation marker genes. Transcriptome sequencing was employed to screen for differential gene expression between 1 mM NaB-treated and untreated groups during SMSCs differentiation. Results indicated that lower NaB concentrations (≤1.0 mM) inhibited proliferation while promoting differentiation and apoptosis after a 2-day treatment. Conversely, higher NaB concentrations (≥2.0 mM) suppressed proliferation and differentiation and induced apoptosis. Transcriptome sequencing revealed differential expression of genes(ND1, ND3, CYTB, COX2, ATP6, MYOZ2, MYOZ3, MYBPC1 and ATP6V0A4,etc.) were associated with SMSCs differentiation and energy metabolism, enriching pathways such as Oxidative phosphorylation, MAPK, and Wnt signaling. These findings offer valuable insights into the molecular mechanisms underlying butyrate regulation of bovine SMSCs proliferation and differentiation, as well as muscle fiber type conversion in the future study.

Multi-particle quantum walks on 3D integrated photonic chip.

Quantum walks provide a speed-up in computational power for various quantum algorithms and serve as inspiration for the construction of complex graph representations. Many pioneering works have been dedicated to expanding the experimental state space and the complexity of graphs. However, these experiments are mostly limited to small experimental scale, which do not reach a many-body level and fail to reflect the multi-particle quantum interference effects among non-adjacent modes. Here, we present a quantum walk with three photons on a two-dimensional triangular lattice, which is mapped to a 19 × 19 × 19 high-dimensional state space and constructs a complex graph with 6859 nodes and 45,486 edges. By utilizing the statistical signatures of the output combinations and incorporating machine learning techniques, we successfully validate the nonclassical properties of the experiment. Our implementation provides a paradigm for exponentially expanding the state space and graph complexity of quantum walks, paving the way for surmounting the classical regime in large-scale quantum simulations.

LncRNA MACC1-AS1 facilitates the cell growth of small cell lung cancer by sequestering miR-579-3p and mediating NOTCH1-pathway.

As reported, long non-coding RNAs (lncRNAs) have been confirmed to be of great importance in regulating the progression of diseases, especially of cancers. LncRNA MACC1 antisense RNA 1 (MACC1-AS1) has been studied in some cancers, whereas its biological role and underlying mechanism is still unclear in small cell lung cancer (SCLC). In the current research, we found high level of MACC1-AS1 in SCLC cells. Subsequently, it was discovered that MACC1-AS1 knockdown considerably restrained the proliferative and migratory ability of SCLC cells by inducing the apoptosis. Importantly, the knockdown of MACC1-AS1 inhibited protein levels of genes of NOTCH pathway, and NOTCH pathway activator (Jagged1) countervailed the inhibition of MACC1-AS1 depletion on SCLC cell growth. Further, the deficiency of NOTCH1 hampered SCLC cell growth. More importantly, miR-579-3p was identified as a downstream gene of MACC1-AS1 and thereby targeted to NOTCH1. In addition, miR-579-3p repression recovered the suppressive role of MACC1-AS1 knockdown in NOTCH1 expression. Rescue assays indicated that repressed SCLC cell growth caused by MACC1-AS1 knockdown could be reserved by miR-579-3p repression or NOTCH1 overexpression. In brief, lncRNA MACC1-AS1 boosted SCLC cell growth via sequestering miR-579-3p and mediating NOTCH1-pathway.

Strong, Spontaneous, and Self-Healing Poly(Ionic Liquid) Elastomer Underwater Adhesive with Borate Ester Dynamic Crosslinking.

Adhesion in aqueous environments is often hindered by the water layer on the surface of the substrate due to the water sensitivity of the adhesive, greatly limiting the application environment. Here, a borate ester dynamically crosslinked poly(ionic liquid) elastomer adhesive (PIEA) with high strength, toughness, self-healing abilities, and ionic conductivity is synthesized by copolymerizing hydrophobic ionic liquid monomer ([HPVIm][TFSI]) and 2-methoxyethyl acrylate (MEA). The adhesion strength of PIEA can increase spontaneously from almost no adhesion to 314 kPa after 12 h without any external preloading due to the dissociation of the borate ester in water, leading to noncovalent interactions between the hydroxyl groups of PIEA and the substrate. Additionally, PIEA can be developed for soft sensors or ion electrodes to enable underwater detection and communication. This strategy offers broad application potential for the development of novel underwater smart adhesives.

Ambient air pollution and risk of allergic respiratory diseases in European and East Asian populations: A Mendelian randomization study.

BACKGROUND: Ambient air pollution has become a challenging global health issue since industrialization, especially affecting respiratory diseases. However, the causal link between air pollution and allergic respiratory diseases (ARDs) remains unclear due to confounding factors in conventional epidemiological studies across different populations. Thus, we aimed to clarify the causal associations between air pollution and ARDs in European and East Asian populations using Mendelian randomization (MR). METHODS: MR utilizes genetic variants and provides a satisfactory level of causal evidence. Genetic data for exposures (PM2.5, PM2.5 absorbance, PM10, PMcoarse, NO2 and NOx) and outcomes (allergic rhinitis, chronic rhinosinusitis, asthma, and obesity related asthma) were obtained from genome-wide association studies. Instrumental variables were strictly filtered based on core assumptions. Two-sample MR and sensitivity analyses were conducted separately for European and East Asian populations. RESULTS: PMcoarse was causally associated with an increased risk of chronic rhinosinusitis (OR = 1.588 [1.002-2.518]; p = 0.049) and obesity related asthma (OR = 1.956 [1.012-3.780]; p = 0.046) in European population, and PM10 was associated with a decreased risk of allergic rhinitis in East Asian population (OR = 0.882 [0.798-0.974]; p = 0.013). No heterogeneity or pleiotropy was detected in any significant causal association. CONCLUSION: Our findings indicate that ambient air pollution has opposite impacts on the etiology of ARDs in European and East Asian populations, which provides evidence for decisions on public policies and suggests that different responses to environmental factors such as air pollution may contribute to racial heterogeneity of ARDs.

Engineering Hyperechogenic Colloids with Clot-Targeting Capabilities from Platelet-Derived Membranes.

Thrombosis-related cardiovascular diseases remain the leading global cause of mortality and morbidity. In this study, we present a pioneering approach in the field of nanobiotechnology, with a focus on clinical translation, aimed at advancing early diagnosis and enhancing treatment options for thrombotic disorders. We introduce the fabrication of Platelet Membrane-Derived Bubbles (PMBs), which exhibit distinctive characteristics compared to conventional nanoparticles. These PMBs possess an average diameter of 700 nm and a negative ζ-potential, mirroring the attributes of parent platelet membranes. Utilizing diagnostic ultrasound imaging, we demonstrated the ability to visualize PMBs as hyperechogenic entities in agarose phantoms in vitro and in live mice in vivo. Furthermore, through confocal laser microscopy, we verified the retention of crucial transmembrane proteins, such as CD41 (GPIIb) and CD42 (GPIb), pivotal in conferring platelet-specific targeting functions. Importantly, our platelet aggregation studies confirmed that PMBs do not induce platelet aggregation but instead adhere to preformed platelet-rich in vitro thrombi. Overall, our work showcases the safe and precise utilization of PMBs to directly target acute thrombosis induced by laser injury in murine mesenteric veins in vivo, as visualized through intravital microscopy. In conclusion, we have successfully developed a rapid method for generating PMBs with unique ultrasound-directed and thrombus-targeting properties. These exceptional attributes of PMBs hold significant promise for advancing the field of ultrasound diagnostic thrombus imaging and clot-targeted therapy in the clinical context.

Node-sparing modified short-course Radiotherapy Combined with CAPOX and Tislelizumab for locally Advanced MSS of Middle and low rectal Cancer (mRCAT): an open-label, single-arm, prospective, multicentre clinical trial.

BACKGROUND: Neoadjuvant chemoradiotherapy followed by total mesorectal excision is a standard treatment for locally advanced rectal cancer. Mismatch repair-deficient locally advanced rectal cancer (LARC) was highly sensitive to PD-1 blockade. However, most rectal cancers are microsatellite stable (MSS) or mismatch repair-proficient (pMMR) subtypes for which PD-1 blockade is ineffective. Radiation can trigger the activation of CD8 + T cells, further enhancing the responses of MSS/pMMR rectal cancer to PD-1 blockade. Radioimmunotherapy offers a promising therapeutic modality for rectal cancer. Progenitor T exhausted cells are abundant in tumour-draining lymph nodes and play an important role in immunotherapy. Conventional irradiation fields include the mesorectum and regional lymph nodes, which might cause considerable damage to T lymphocytes and radiation-induced fibrosis, ultimately leading to a poor response to immunotherapy and rectal fibrosis. This study investigated whether node-sparing modified short-course irradiation combined with chemotherapy and PD-1 blockade could be effective in patients with MSS/ pMMR LARC. METHODS: This was a open-label, single-arm, multicentre, prospective phase II trial. 32 LARC patients with MSS/pMMR will receive node-sparing modified short-course radiotherapy (the irradiated planned target volume only included the primary tumour bed but not the tumour-draining lymph nodes, 25 Gy/5f, 5 Gy/f) followed by CAPOX and tislelizumab. CAPOX and tislelizumab will be started two days after the completion of radiotherapy: oxaliplatin 130 mg/m2 intravenous infusion, day 1; capecitabine 1000 mg/m2 oral administration, days 1-14; and tislelizumab 200 mg, intravenous infusion, day 1. There will be four 21-day cycles. TME will be performed at weeks 14-15. We will collect blood, tumour, and lymphoid specimens; perform flow cytometry and in situ multiplexed immunofluorescence detection; and analyse the changes in various lymphocyte subsets. The primary endpoint is the rate of pathological complete response. The organ preservation rate, tumour regression grade, local recurrence rate, disease-free survival, overall survival, adverse effects, and quality of life will also be analysed. DISCUSSION: In our research, node-sparing modified radiotherapy combined with immunotherapy probably increased the responsiveness of immunotherapy for MSS/pMMR rectal cancer patients, reduced the occurrence of postoperative rectal fibrosis, and improved survival and quality of life. This is the first clinical trial to utilize a node-sparing radiation strategy combined with chemotherapy and PD-1 blockade in the neoadjuvant treatment of rectal cancer, which may result in a breakthrough in the treatment of MSS/pMMR rectal cancer. TRIAL REGISTRATION: This study was registered at www. CLINICALTRIALS: gov . TRIAL REGISTRATION NUMBER: NCT05972655. Date of registration: 31 July 2023.

Polarized spectral bidirectional reflectance distribution function in visible band based on Cauchy's empirical dispersion equation.

The polarized bidirectional reflectance distribution function (pBRDF) can describe the changes between the Stokes vectors of incident and reflected light. The existing model can only describe the spatial distribution of the target's polarization characteristics at a single wavelength, so further research is needed for the description of the target's polarized spectral characteristics. In this paper, a modified three-component polarized spectral bidirectional reflectance distribution function (pSBRDF) is proposed, which combines Fresnel equation in the specular reflection component with Cauchy's empirical dispersion equation, by introducing the wavelength variable and dispersion constants that do not change with wavelength. The degree of the linear polarization (DoLP) of two types of coated fabric samples was measured at three incident angles and 400 to 760 nm wavelength. The error of the model in describing the spectral and the spatial distribution of DoLP are controlled within 0.00743 and 0.0757 respectively, which proves the accuracy of the model. This research provides the model basis for analysis of the target's polarization characteristics and the theoretical basis for the application of polarization detection.

Enhancing short-chain fatty acids production from waste activated sludge anaerobic fermentation with addition of red mud: Performance and mechanisms.

Red mud (RM) as hazardous waste produced from aluminum refining industry has threatened the environment and human health. In this study, RM was added into the fermenter to promote short chain fatty acids (SCFAs) production from waste activated sludge (WAS) anaerobic fermentation. Results showed that the addition of RM could effectively improve the SCFAs production, especially, acetic acid. In particular, the production of total SCFAs and acetic acid in 20 g/L RM added fermenter were 1108.1 mg COD/L and 415.5 mg COD/L, which were 116.0% and 1308.0% higher than that in control fermenter. Batch experiment revealed that RM could enhance the hydrolysis and acidification process. Further study indicated that the activity of enzyme related to hydrolysis-acidification, abundance of fermentative bacteria for SCFAs production and functional metabolism genome were all improved with the addition of RM. The potential mechanism maybe that the RM promoted the hydrolysis-acidification process with the contained varies Fe(Ⅲ) oxides as electron acceptor, and the produced Fe2+ could serve as necessary trace elements to synthesize enzyme and then stimulate the expression of enzyme genes.

Single-cell analysis reveals that TCF7L2 facilitates the progression of ccRCC via tumor-associated macrophages.

BACKGROUND: Tumor-associated macrophages (TAMs) play an important role in the recurrence and progression of clear cell renal cell carcinoma (ccRCC). However, the specified mechanism has not been elucidated. METHODS: Single-cell and transcriptome analysis were applied to characterize the heterogeneity of TAMs. SCENIC would infer regulators of different subsets of TAMs. The CellChat algorithm was used to infer macrophage-tumor interaction networks, whereas pseudo-time traces were used to parse cell evolution and dynamics. RESULTS: In this study, single-cell transcriptomic data of ccRCC were analyzed. Notably, the macrophages were clustered to select the cluster with a tendency toward M2-type TAM, which has an impact on the occurrence and metastasis of ccRCC. This macrophage cluster was defined as "TAM2". And this study revealed that TCF7L2 as a potential transcription factor regulating TAM2 transcriptional heterogeneity and differentiation. Pseudotime traces showed TCF7L2 trajectories during TAM2 cell cluster development. In addition, the results of cell interaction showed that TAM2 had the highest number and strength of interactions with cancer cells and endothelial cells. In vitro experiments, this study found that TCF7L2 was highly expressed in TAMs and promoted the polarization of macrophages to M2-type macrophages. And then overexpression of TCF7L2 in macrophages markedly promoted ccRCC invasion and proliferation. CONCLUSION: TCF7L2 could play a key role in the progression of ccRCC via enhancing TAMs recruitment and M2-type polarization.

Probing multi-mobility edges in quasiperiodic mosaic lattices.

The mobility edge (ME) is a crucial concept in understanding localization physics, marking the critical transition between extended and localized states in the energy spectrum. Anderson localization scaling theory predicts the absence of ME in lower dimensional systems. Hence, the search for exact MEs, particularly for single particles in lower dimensions, has recently garnered significant interest in both theoretical and experimental studies, resulting in notable progress. However, several open questions remain, including the possibility of a single system exhibiting multiple MEs and the continual existence of extended states, even within the strong disorder domain. Here, we provide experimental evidence to address these questions by utilizing a quasiperiodic mosaic lattice with meticulously designed nanophotonic circuits. Our observations demonstrate the coexistence of both extended and localized states in lattices with broken duality symmetry and varying modulation periods. By single site injection and scanning the disorder level, we could approximately probe the ME of the modulated lattice. These results corroborate recent theoretical predictions, introduce a new avenue for investigating ME physics, and offer inspiration for further exploration of ME physics in the quantum regime using hybrid integrated photonic devices.

Impact of an enhanced recovery after surgery program integrating cardiopulmonary rehabilitation on post-operative prognosis of patients treated with CABG: protocol of the ERAS-CaRe randomized controlled trial.

BACKGROUND: Coronary artery bypass grafting is associated with a high occurrence of postoperative cardiopulmonary complications. Preliminary evidence suggested that enhanced recovery after surgery can effectively reduce the occurrence of postoperative cardiopulmonary complications. However, enhanced recovery after surgery with systematic integration of cardiopulmonary rehabilitation (ERAS-CaRe) into for Coronary artery bypass grafting has not been evaluated so far. We thus design the ERAS-CaRe randomized-controlled trial to evaluate possible superiority of embedding cardiopulmonary rehabilitation in ERAS over ERAS alone as well as to investigate effects of differential timing of cardiopulmonary rehabilitation within enhanced recovery after surgery (pre-, post-, perio-operative) on post-operative cardiopulmonary complications following Coronary artery bypass grafting surgery. METHODS: ERAS-CaRe is a pragmatic, randomized-controlled, parallel four-arm, clinical trial. Three hundred sixty patients scheduled for Coronary artery bypass grafting in two Chinese hospitals will be grouped randomly into (i) Standard enhanced recovery after surgery or (ii) pre-operative ERAS-CaRe or (iii) post-operative ERAS-CaRe or (iv) perio-operative ERAS-CaRe. Primary outcome is the occurrence of cardiopulmonary complications at 10 days after Coronary artery bypass grafting. Secondary outcomes include the occurrence of other individual complications including cardiac, pulmonary, stroke, acute kidney injury, gastrointestinal event, ICU delirium rate, reintubation rate, early drainage tube removal rate, unplanned revascularization rate, all-cause mortality, ICU readmission rate, plasma concentration of myocardial infarction-related key biomarkers etc. DISCUSSION: The trial is designed to evaluate the hypothesis that a cardiopulmonary rehabilitation based enhanced recovery after surgery program reduces the occurrence of cardiopulmonary complications following Coronary artery bypass grafting and to determine optimal timing of cardiopulmonary rehabilitation within enhanced recovery after surgery. The project will contribute to increasing the currently limited knowledge base in the field as well as devising clinical recommendations. TRIAL REGISTRATION: The trial was registered at the Chinese Clinical Trials Registry on 25 August 2023 (ChiCTR2300075125; date recorded: 25/8/2023, https://www.chictr.org.cn/ ).

Multi-Bioinspired Fog Harvesting Structure with Asymmetric Surface for Hydrogen Revolution.

The urgent need for sustainable energy storage drives the fast development of diverse hydrogen production based on clean water resources. Herein, a unique type of multi-bioinspired functional device (MFD) is reported with asymmetric wettability that combines the curvature gradient of cactus spines, the wetting gradient of lotus, and the slippery surface of Nepenthes alata for efficient fog harvesting. The precisely printed MFDs with microscale features, spanning dimensions, and a thin wall are endowed with asymmetric wettability to enable the Janus effects on their surfaces. Fog condenses on the superhydrophobic surface of the MFDs in the form of microdroplets and unidirectionally penetrates its interior due to the Janus effects, and drops onto the designated area with a better fog harvesting rate of 10.64 g cm-2 h-1. Most significantly, the collected clean water can be used for hydrogen production with excellent stability and durability. The findings demonstrate that safe, large-scale, high-performance water splitting and gas separation and collection with fog collection based on MFDs are possible.

Using salicylic acid-responsive promoters to drive the expression of jasmonic acid-regulated genes enhances plant resistance to whiteflies.

BACKGROUND: Jasmonic acid (JA) is an important phytohormone used to defend against herbivores, but it does not respond to whitefly feeding. Conversely, another phytohormone, salicylic acid (SA), is induced when plants are fed upon by whiteflies. JA has a better anti-whitefly effect than SA; however, there is limited research on how to effectively improve plant resistance by utilizing the different responses of these phytohormones to whitefly feeding. RESULTS: We discovered that protease inhibitors 8 (PI8) and terpene synthase 10 (TPS10) located downstream of the JA-regulated pathway in plants have anti-whitefly effects, but these two genes were not induced by whitefly feeding. To identify whitefly-inducible promoters, we compared the transcriptome data of tobacco fed upon by Bemisia tabaci with the control. We focused on pathogenesis-related (PR) genes because they are known to be induced by SA. Among these PR genes, we found that expression levels of pathogenes-related protein 1C-like (PR1) and glucose endo-1,3-beta-glucosidase (BGL) can be significantly induced by whitefly feeding and regulated by SA. We then engineered the whitefly-inducible promoters of BGL and PR1 to drive the expression of PI8 and TPS10. We found that compared with control plants that did not induce the expression of PI8 or TPS10, transformed plants expressing PI8 or TPS10 under the PR1 or BGL promoter showed a significant increase in the expression levels of PI8 and TPS10 after whitefly infection, significantly improving their resistance to whiteflies. CONCLUSION: Our findings suggest that using SA-inducible promoters as tools to drive the expression of JA-regulated defense genes can enhance plant resistance to whiteflies. Our study provides a novel pathway for the enhancement of plant resistance against insects. © 2024 Society of Chemical Industry.

SpatialDeX is a Reference-Free Method for Cell Type Deconvolution of Spatial Transcriptomics Data in Solid Tumors.

The rapid development of spatial transcriptomics (ST) technologies has enabled transcriptome-wide profiling of gene expression in tissue sections. Despite the emergence of single-cell resolution platforms, most ST sequencing studies still operate at a multi-cell resolution. Consequently, deconvolution of cell identities within the spatial spots has become imperative for characterizing cell type-specific spatial organization. To this end, we developed SpatialDeX, a regression model-based method for estimating cell type proportions in tumor ST spots. SpatialDeX exhibited comparable performance to reference-based methods and outperformed other reference-free methods with simulated ST data. Using experimental ST data, SpatialDeX demonstrated superior performance compared with both reference-based and reference-free approaches. Additionally, a pan-cancer clustering analysis on tumor spots identified by SpatialDeX unveiled distinct tumor progression mechanisms both within and across diverse cancer types. Overall, SpatialDeX is a valuable tool for unraveling the spatial cellular organization of tissues from ST data without requiring scRNA-seq references.

Shear-Sensing by C-Reactive Protein: Linking Aortic Stenosis and Inflammation.

BACKGROUND: CRP (C-reactive protein) is a prototypical acute phase reactant. Upon dissociation of the pentameric isoform (pCRP [pentameric CRP]) into its monomeric subunits (mCRP [monomeric CRP]), it exhibits prothrombotic and proinflammatory activity. Pathophysiological shear rates as observed in aortic valve stenosis (AS) can influence protein conformation and function as observed with vWF (von Willebrand factor). Given the proinflammatory function of dissociated CRP and the important role of inflammation in the pathogenesis of AS, we investigated whether shear stress can modify CRP conformation and induce inflammatory effects relevant to AS. METHODS: To determine the effects of pathological shear rates on the function of human CRP, pCRP was subjected to pathophysiologically relevant shear rates and analyzed using biophysical and biochemical methods. To investigate the effect of shear on CRP conformation in vivo, we used a mouse model of arterial stenosis. Levels of mCRP and pCRP were measured in patients with severe AS pre- and post-transcatheter aortic valve implantation, and the presence of CRP was investigated on excised valves from patients undergoing aortic valve replacement surgery for severe AS. Microfluidic models of AS were then used to recapitulate the shear rates of patients with AS and to investigate this shear-dependent dissociation of pCRP and its inflammatory function. RESULTS: Exposed to high shear rates, pCRP dissociates into its proinflammatory monomers (mCRP) and aggregates into large particles. Our in vitro findings were further confirmed in a mouse carotid artery stenosis model, where the administration of human pCRP led to the deposition of mCRP poststenosis. Patients undergoing transcatheter aortic valve implantation demonstrated significantly higher mCRP bound to circulating microvesicles pre-transcatheter aortic valve implantation compared with post-transcatheter aortic valve implantation. Excised human stenotic aortic valves display mCRP deposition. pCRP dissociated in a microfluidic model of AS and induces endothelial cell activation as measured by increased ICAM-1 and P-selectin expression. mCRP also induces platelet activation and TGF-ß (transforming growth factor beta) expression on platelets. CONCLUSIONS: We identify a novel mechanism of shear-induced pCRP dissociation, which results in the activation of cells central to the development of AS. This novel mechanosensing mechanism of pCRP dissociation to mCRP is likely also relevant to other pathologies involving increased shear rates, such as in atherosclerotic and injured arteries.

A Dual-Function LipoAraN-E5 Coloaded with N4-Myristyloxycarbonyl-1-ß-d-arabinofuranosylcytosine (AraN) and a CXCR4 Antagonistic Peptide (E5) for Blocking the Dissemination of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a hematological malignancy with a high recurrence rate. The interaction of chemokine receptor 4/chemokine ligand 12 (CXCR4/CXCL12) mediates homing and adhesion of AML cells in bone marrow, leading to minimal residual disease in patients, which brings a hidden danger for future AML recurrence. Ara-C is a nonselective chemotherapeutic agent against AML. Due to its short half-life and severe side effects, a lipid-like Ara-C derivative (AraN) was synthesized and a dual-function LipoAraN-E5 (135 nm, encapsulation efficiency 99%) was developed, which coloaded AraN and E5, a peptide of the CXCR4 antagonist. LipoAraN-E5 effectively improved the uptake, enhanced the inhibition of leukemia cell proliferation, migration, and adhesion to stromal cells in bone marrow, and mobilized the leukemia cells from bone marrow to peripheral blood via interfering with the CXCR4/CXCL12 axis. LipoAraN-E5 prolonged the plasma half-life of AraN (8.31 vs 0.56 h) and was highly enriched in peripheral blood (3.67 vs 0.05 µmol/g at 8 h) and bone marrow (379 vs 148 µmol/g at 24 h). LipoAraN-E5 effectively prevented the infiltration of leukemia cells in peripheral blood, bone marrow, spleen, and liver, prolonged the mice survival, and showed outstanding antineoplastic efficacy with negligible toxicity, which were attributed to the ingenious design of AraN, the use of a liposomal delivery carrier, and the introduction of E5. Our work revealed that LipoAraN-E5 may be a promising nanocandidate against AML.

Enrichment and characterization of thermophilic anaerobic ammonium oxidizing bacteria from hot spring.

Anaerobic ammonium oxidization (Anammox) process plays a crucial role in the global nitrogen cycle and sustainable biological nitrogen removal from wastewater. Although Anammox bacteria have been detected across mesophilic and thermophilic conditions, the direct cultivation of Anammox bacteria from thermal environments has remained elusive. This impedes limiting our understanding of their physiology and ecology in high-temperature habitats. Here, we successfully enriched Anammox bacteria from hot spring sediments at 45 °C, achieving an ammonium oxidation rate of 158.0 mg NH4+-N l-1d-1, with the genus 'Candidatus Brocadia' presenting 22.9 % of the total microbial community after about 500 days of operation. Metagenomic analysis recovered two high-quality genomes of novel Anammox bacteria, which we designed as 'Candidatus Brocadia thermophilus' and 'Candidatus Brocadia thermoanammoxidans'. Both of them encoded and actively expressed key metabolic genes involved in Anammox process and several genes associated with thermotolerance, demonstrating their remarkable ability to perform Anammox reaction in thermophilic environments. Notably, phylotypes related to 'Candidatus Brocadia thermoanammoxidans' have frequently been retrieved from geographically distinct natural habitats. These findings expand our understanding of thermophilic Anammox bacteria and underscore their potential in the nitrogen cycle of thermal natural and engineering ecosystems.