Plasma proteome mediate the impact of PM2.5 on stroke: A 2-step Mendelian randomization study.

The objectives of this study were to measure the mediation effect of plasma proteins and to clarify their mediating role in the relationship between stroke risk and particulate matter 2.5 (PM2.5) exposure. The possible mediating role of plasma proteins on the causative link between PM2.5 exposure and stroke incidence were examined using a two-step Mendelian randomization (MR) approach based on two-sample Mendelian randomization (TSMR). The findings revealed a significant positive causal relationship between PM2.5 exposure and stroke, with an inverse variance weighted odds ratio of 1.219 (95 % CI: 1.002 - 1.482, P < 0.05). Additionally, a positive causal association was identified between PM2.5 exposure and several plasma proteins, including FAM134B, SAP, ITGB7, Elafin, and DCLK3. Among these, FAM134B, ITGB7, Elafin, and DCLK3 also demonstrated a positive causal association with stroke, whereas only SAP was found to be negatively causally associated with stroke. Remarkably, four plasma proteins, namely DCLK3, FAM134B, Elafin, and ITGB7, were identified as mediators, accounting for substantial proportions (14.5 %, 13.6 %, 11.1 %, and 9.9 %) of the causal association between PM2.5 and stroke. These results remained robust across various sensitivity analyses. Consequently, the study highlights the significant and independent impact of PM2.5 on stroke risk and identifies specific plasma proteins as potential targets for preventive interventions against PM2.5-induced stroke.

Tumor necrosis factor mediates the impact of PM2.5 on bone mineral density: Inflammatory proteome Mendelian randomization and colocalization analyses.

To assess the causal effect of particulate matter 2.5 (PM2.5) on human bone mineral density (BMD) and to explore the possible mechanism and proportion mediated by inflammation-related protein. The genetic correlation between PM2.5 and BMD was assessed using the Linkage Disequilibrium Score (LDSC), and the causal effect between PM2.5 and BMD was assessed by two-sample Mendelian randomization (TSMR). A 2-step Mendelian randomization (MR) approach was employed to evaluate the potential role of inflammation-associated protein as the mediator in the causal association between PM2.5 and BMD. The multivariate Mendelian randomization (MVMR) study was designed to perform mediation analyses, exclude possible confounders and calculate the proportion of mediation. Subsequently, we used Bayesian colocalization analysis to consolidate the MR results. Finally, using drug-target MR design, we evaluated the potential repurposing of tumor necrosis factor (TNF) inhibitors for the treatment of osteoporosis (OP). The results of the analyses show that BMD is negatively influenced by PM2.5 (Inverse variance weighted [IVW] beta [ß] = -0.288, 95% confidence interval [CI]: -0.534 - -0.042, P < 0.05). PM2.5 has a positive causal association with TNF (IVW ß = 1.564, 95% CI: 0.155 - 2.973, P < 0.05) and a negative causal association with protachykinin-1 (TAC-1) (IVW ß = -1.654, 95% CI: -3.063 - -0.244, P < 0.05). TNF has a negative causal association with BMD (Wald ratio ß = -0.082, 95% CI: -0.165 - 0.000, P < 0.05) and TAC-1 has a positive causal association with BMD (IVW ß = 0.042, 95% CI: 0.007 - 0.077, P < 0.05). After adjusting TNF and TAC-1, PM2.5 has no causal association with BMD (IVW ß = -0.200, 95% CI: -0.579 - 0.179, P > 0.05). After adjusting PM2.5 and TAC-1, there was still a negative causal association between TNF and BMD (IVW ß = -0.089, 95% CI: -0.166 - -0.012, P < 0.05). In the final drug-target MR study, the protective effect of TNF/TNF receptor 1 (TNFR1) inhibition on BMD was observed. For every 10% decrease of circulating C-reactive protein (CRP) achieved by TNF/TNF receptor 1 (TNFR1) blockade, ß was 0.540 (95% CI: 0.040-1.040) for BMD. We found a negative causal association between PM2.5 and BMD and that causal association was mediated by TNF. The results of drug-target MR do support TNFR1 as a promising target for OP prevention among the general population.

Molecular phylogenetic analysis of the East Asian hemicultrine fishes (Teleostei: Cyprinidae: Xenocypridinae), with suggestions to their generic classification and redescription of the recently described species Hemiculter yungaoi Vasil'eva et al. 2022.

The hemicultrine fishes are a group of small-sized cyprinids, widely distributed but endemic to East Asian rivers and lakes. Till now, the taxonomic boundaries and relationships within this group remain poorly explored. In the present study, we study the phylogeny of this group, providing suggestions for classification of the hemicultrine group. Using two mitochondrial and three nuclear genes, and samples representing all genera, our results showed that the group consists of seven major lineages, of which four (Hemiculterella, Hainania, Pseudolaubuca, and Anabarilius) were monophyletic and three (Hemiculter, Toxabramis, and Pseudohemiculter) were not. Based on the phylogenetic tree, we redefined the genera. We revive the genus Siniichthys, which has three species, Siniichthys bleekeri, Siniichthys lucidus, and S. varpachovskii, that were previously treated as members of the genus Hemiculter but showed distant relationships to the genus Hemiculter in our phylogenetic tree. With the new results, a diagnostic key for clades of the hemicultrine group is provided. Furthermore, we provide more detailed information on diagnostic features of the recently described species Hemiculter yungaoi (Vasil'eva et al., 2022). This work will facilitate future systematic studies, pave the way for evolutionary studies, and provide valuable information for the urgent conservation of hemicultrine fishes.

Biocompatible Material-Based Flexible Biosensors: From Materials Design to Wearable/Implantable Devices and Integrated Sensing Systems.

Human beings have a greater need to pursue life and manage personal or family health in the context of the rapid growth of artificial intelligence, big data, the Internet of Things, and 5G/6G technologies. The application of micro biosensing devices is crucial in connecting technology and personalized medicine. Here, the progress and current status from biocompatible inorganic materials to organic materials and composites are reviewed and the material-to-device processing is described. Next, the operating principles of pressure, chemical, optical, and temperature sensors are dissected and the application of these flexible biosensors in wearable/implantable devices is discussed. Different biosensing systems acting in vivo and in vitro, including signal communication and energy supply are then illustrated. The potential of in-sensor computing for applications in sensing systems is also discussed. Finally, some essential needs for commercial translation are highlighted and future opportunities for flexible biosensors are considered.

Mendelian-randomization study reveals causal relationships between nitrogen dioxide and gut microbiota.

Exposure to nitrogen dioxide might potentially change the makeup and operation of gut microbes. Nitrogen dioxide data was procured from the IEU Open GWAS (N = 456 380). Subsequently, a two-sample Mendelian randomization study was executed, utilizing summary statistics of gut microbiota sourced from the most expansive available genome-wide association study meta-analysis, conducted by the MiBioGen consortium (N = 13 266). The causal relationship between nitrogen dioxide and gut microbiota was determined using inverse variance weighted, maximum likelihood, MR-Egger, Weighted Median, Weighted Model, Mendelian randomization pleiotropy residual sum and outlier, and constrained maximum likelihood and model averaging and Bayesian information criterion. The level of heterogeneity of instrumental variables was quantified by utilizing Cochran's Q statistic. The colocalization analysis was used to examine whether nitrogen dioxide and the identified gut microbiota shared casual variants. Inverse variance weighted estimate suggested that nitrogen dioxide was causally associated with Akkermansia (ß = -1.088, 95% CI: -1.909 to -0.267, P = 0.009). In addition, nitrogen dioxide presented a potential association with Bacteroides (ß = -0.938, 95% CI: -1.592 to -0.284, P = 0.005), Barnesiella (ß = -0.797, 95% CI: -1.538 to -0.055, P = 0.035), Coprococcus 3 (ß = 1.108, 95% CI: 0.048-2.167, P = 0.040), Eubacterium hallii group (E. hallii) (ß = 0.776, 95% CI: 0.090-1.463, P = 0.027), Holdemania (ß = -1.354, 95% CI: -2.336 to -0.372, P = 0.007), Howardella (ß = 1.698, 95% CI: 0.257-3.139, P = 0.021), Olsenella (ß = 1.599, 95% CI: 0.151-3.048, P = 0.030) and Sellimonas (ß = -1.647, 95% CI: -3.209 to -0.086, P = 0.039). No significant heterogeneity of instrumental variables or horizontal pleiotropy was found. The associations of nitrogen dioxide with Akkermansia (PH4 = 0.836) and E. hallii (PH4 = 0.816) were supported by colocalization analysis. This two-sample Mendelian randomization study found that increased exposure to nitrogen dioxide had the potential to impact the human gut microbiota.

Effects of water temperature and discharge on natural reproduction time of the Chinese sturgeon, Acipenser sinensis, in the Yangtze River, China and impacts of the impoundment of the Three Gorges Reservoir.

Chinese sturgeon, Acipenser sinensis, is a critically endangered anadromous fish species spawning in the Yangtze River of China during October and November. In this study, we analyzed the effects of hydrological factors, such as water temperature and discharge, on the natural reproduction time of the Chinese sturgeon and evaluated the impact of the impoundment of the Three Gorges Reservoir (TGR) based on our survey data from 1998 to 2011. The results showed that the first spawning dates were significantly (P < 0.05) correlated with the date of water temperature reaching 20°C (20°C WT dates), October mean discharge (Oct. discharge), and the discharge change from October to November (Oct-Nov Δdischarge). Regression analysis suggested that one day delay of 20°C WT dates could postpone the first spawning date by 0.673 days. A discharge increase of 1000 m(3)s(-1) in October could bring forward the first spawning date by two days. Our results also indicated that the impoundment of the TGR had delayed the first spawning time due to water temperature lag and flow regulation. We suggest the following ecological regulations in order to facilitate conservation of the Chinese sturgeon: to eliminate water temperature lag by regulating water temperature downstream of the Three Gorges Dam (TGD), to enhance water discharge downstream in October, and to complete impoundment before October.

Pheochromocytoma-induced diffuse alveolar hemorrhage after cholecystectomy: A case report and literature review.

Diffuse alveolar hemorrhage (DAH) can be caused by various conditions, categorized as autoimmune and non-autoimmune. Immunofactor-mediated vasculitis, such as Wegener granulomatosis, microscopic polyangiitis, Goodpasture syndrome, connective tissue disorders, and antiphospholipid antibody syndrome, are common autoimmune causes. Non-autoimmune factors include infectious or toxic exposures and neoplastic conditions. The diagnosis of DAH, resulting from excessive catecholamine release from an adrenal pheochromocytoma or extra-adrenal paraganglioma, can present diagnostic challenges and necessitate prompt treatment. In this report, we present a case of pheochromocytoma that manifested as an adrenal incidentaloma (diagnosed during the management of sudden-onset DAH after cholecystectomy). Case report: A 39-year-old female patient with adrenal incidentaloma developed DAH following a cholecystectomy procedure, presenting with sudden-onset hemoptysis and dyspnea. Administration of glucocorticoids, known to precipitate pheochromocytoma crisis (PCC), was required before the cause was determined. Intubation and mechanical ventilation were necessary due to persistent hypoxemic respiratory failure and acute respiratory distress syndrome (ARDS). The patient in this case experienced two epidoses of PCC while she was on mechanical ventilation. Subsequent work-up revealed a 26 × 25 mm left adrenal adenoma with hormonal confirmation of catecholamine hypersecretion. A laparoscopic adrenalectomy was done eight months later to excise the left adrenal gland. Subsequent examination of the tissue revealed pheochromocytoma, thereby validating the initial diagnosis. Conclusion: Adrenal incidentalomas may be pheochromocytomas (adrenal incidentalomas can manifest as pheochromocytomas), even without adrenergic symptoms. It is recommended that adrenal incidentalomas undergo evaluation for pheochromocytoma before undergoing invasive surgery or receiving corticosteroid treatment. When considering potential causes of DAH without further elucidation, including a pheochromocytoma or paraganglioma (PPGLs) in the differential diagnosis is important.

The immune cells have complex causal regulation effects on cancers.

BACKGROUND: There was a large body of evidence linking immune cells to cancer risk. However, the causal relationship between immune cells, cancer, and what genes play an important role is unclear. METHODS: In this study, we performed comprehensive two-sample Mendelian randomization analysis (TSMR) to determine the causal relationship between immune cells and common cancers. We also performed Multimarker Analysis of Genomic Annotation (MAGMA) on immune cells causally associated with cancer to identify their relevant genes and used data summary-based MR (SMR) analysis to investigate the causal relationship between their gene expression, methylation, and cancer, and further used drug prediction and molecular docking to validate the medicinal value of the targets. Finally, reverse TSMR analysis was performed on cancer and immune cells to rule out reverse causality. RESULTS: After FDR correction (PFDR < 0.05), the results showed that 2 immune cells were associated with lung cancer risk, and 1 immune cell was significantly associated with pancreatic cancer risk. The expression of OSBPL10, CHD4, SMDT1, PHETA2, and NAGA was positively and causally related to the risk of lung cancer by SMR analysis and HEIDI test. We also found that increased expression of ANP32E decreased the risk of pancreatic cancer and that the methylation level of OSBPL10, CHD4, SULF2, CENPM, and CYP2D6 had a causal association with lung cancer. The methylation level of FCGR3A was causally associated with pancreatic cancer. The results of molecular docking indicated a strong affinity between the drugs and proteins that possessed existing structural information. CONCLUSION: This data-driven Mendelian randomization (MR) study demonstrates the causal role of immune cells in cancers. In addition, this study identifies candidate genes that may be potential anti-cancer drug targets.

Effects of environmental factors on natural reproduction of the four major Chinese carps in the Yangtze River, China.

The four major Chinese carps are commercially important fish species with high production in China. However, their recruitment decreased sharply in the Yangtze River since the late 20(th) century. In the present study, to reveal the relationships between spawning activities of the four species and environmental factors, drifting eggs were collected at Yidu City, in the middle reaches of the Yangtze River, from May to July each year between 2005 and 2010. Classification and regression trees (CART) analysis was applied to identify the key factors associated with spawning activities of the four carp species. Twelve predictor variables (hydrological and meteorological variables) and one response variable (egg presence or number of egg) were included in the CART. Our CART analysis showed that water temperature and the diurnal increase of water level were the two most significant factors for the spawning activities. When water temperature was between 18°C and 24°C, especially in association with the diurnal increase of water level greater than 0.55 m·d(-1), spawning activities was always favored. Unlike the hydrological factors, meteorological factors seemed to have no influence on initiating the spawning activities. The density of drifting eggs of the four species was mainly influenced by the diurnal variation of water level, the diurnal variation of water discharge, water temperature, humidity, and air pressure. We then related our results to the ecological regulation of the Three Gorge Reservoir in the middle reaches of the Yangtze River. We suggested that, when water temperature was between 18-24°C from May to July, to ensure the successful spawning of the four carp species, the ecological regulation should be managed to create flood peaks and make the diurnal increase of water level greater than 0.55 m·d(-1).

The nano-windmill exerts superior anti-inflammatory effects via reducing choline uptake to inhibit macrophage activation.

Macrophages' activation plays a central role during the development and progression of inflammation, while the regulation of metabolic reprogramming of macrophages has been recently identified as a novel strategy for anti-inflammatory therapies. Our previous studies have found that tetrahedral framework nucleic acid (tFNA) plays a mild anti-inflammatory effect by inhibiting macrophage activation, but the specific mechanism remains unclear. Here, by metabolomics and RNA sequencing, choline uptake is identified to be significantly repressed by decreased slc44a1 expression in tFNA-treated activated macrophages. Inspired by this result, combined with the excellent delivery capacities of tFNA, siR-slc44a1 is loaded into the tFNA to develop a new tFNA-based small interfering RNA (siRNA) delivery system named 'nano-windmill,' which exhibits a synergetic role by targeting slc44a1, finally blowing up the anti-inflammatory effects of tFNA to inhibit macrophages activation via reducing choline uptake. By confirming its anti-inflammatory effects in chronic (periodontitis) and acute (sepsis) inflammatory disease, the tFNA-based nanomedicine developed for inflammatory diseases may provide broad prospects for tFNA upgrading and various biological applications such as anti-inflammatory.

Mitochondrial Calcium Ion Nanogluttons Alleviate Periodontitis via Controlling mPTPs.

The mitochondrial permeability transition (mPT) directly affects mitochondrial function in macrophages. Under inflammatory conditions, mitochondrial calcium ion (mitoCa2+ ) overload triggers the persistent opening of mPT pores (mPTPs), further aggravating Ca2+ overload and increasing reactive oxygen species (ROS) to form an adverse cycle. However, there are currently no effective drugs targeting mPTPs to confine or unload excess Ca2+ . It is novelly demonstrated that the initiation of periodontitis and the activation of proinflammatory macrophages depend on the persistent overopening of mPTPs, which is mainly triggered by mitoCa2+ overload and facilitates further mitochondrial ROS leakage into the cytoplasm. To solve the above problems, mitochondrial-targeted "nanogluttons" with PEG-TPP conjugated to the surface of PAMAM and BAPTA-AM encapsulated in the core are designed. These nanogluttons can efficiently "glut" Ca2+ around and inside mitochondria to effectively control the sustained opening of mPTPs. As a result, the nanogluttons significantly inhibit the inflammatory activation of macrophages. Further studies also unexpectedly reveal that the alleviation of local periodontal inflammation in mice is accompanied by diminished osteoclast activity and reduced bone loss. This provides a promising strategy for mitochondria-targeted intervention in inflammatory bone loss in periodontitis and can be extended to treat other chronic inflammatory diseases associated with mitoCa2+ overload.

Hypoxia Drives Material-Induced Heterotopic Bone Formation by Enhancing Osteoclastogenesis via M2/Lipid-Loaded Macrophage Axis.

Heterotopic ossification (HO) is a double-edged sword. Pathological HO presents as an undesired clinical complication, whereas controlled heterotopic bone formation by synthetic osteoinductive materials shows promising therapeutic potentials for bone regeneration. However, the mechanism of material-induced heterotopic bone formation remains largely unknown. Early acquired HO being usually accompanied by severe tissue hypoxia prompts the hypothesis that hypoxia caused by the implantation coordinates serial cellular events and ultimately induces heterotopic bone formation in osteoinductive materials. The data presented herein shows a link between hypoxia, macrophage polarization to M2, osteoclastogenesis, and material-induced bone formation. Hypoxia inducible factor-1α (HIF-1α), a crucial mediator of cellular responses to hypoxia, is highly expressed in an osteoinductive calcium phosphate ceramic (CaP) during the early phase of implantation, while pharmacological inhibition of HIF-1α significantly inhibits M2 macrophage, subsequent osteoclast, and material-induced bone formation. Similarly, in vitro, hypoxia enhances M2 macrophage and osteoclast formation. Osteoclast-conditioned medium enhances osteogenic differentiation of mesenchymal stem cells, such enhancement disappears with the presence of HIF-1α inhibitor. Furthermore, metabolomics analysis reveals that hypoxia enhances osteoclastogenesis via the axis of M2/lipid-loaded macrophages. The current findings shed new light on the mechanism of HO and favor the design of more potent osteoinductive materials for bone regeneration.

The genetic background determines material-induced bone formation through the macrophage-osteoclast axis.

Osteoinductive materials are characterized by their ability to induce bone formation in ectopic sites. Thus, osteoinductive materials hold promising potential for repairing bone defects. However, the mechanism of material-induced bone formation remains unknown, which limits the design of highly potent osteoinductive materials. Here, we demonstrated a genetic background link among macrophage polarization, osteoclastogenesis and material-induced bone formation. The intramuscular implantation of an osteoinductive material in FVB/NCrl (FVB) mice resulted in more M2 macrophages at week 1, more osteoclasts at week 2 and increased bone formation after week 4 compared with the results obtained in C57BL/6JOlaHsd (C57) mice. Similarly, in vitro, with a greater potential to form M2 macrophages, monocytes derived from FVB mice formed more osteoclasts than those derived from C57 mice. A transcriptomic analysis identified Csf1, Cxcr4 and Tgfbr2 as the main genes controlling macrophage-osteoclast coupling, which were further confirmed by related inhibitors. With such coupling, macrophage polarization and osteoclast formation of monocytes in vitro successfully predicted in vivo bone formation in four other mouse strains. Considering material-induced bone formation as an example of acquired heterotopic bone formation, the current findings shed a light on precision medicine for both bone regeneration and the treatment of pathological heterotopic bone formation.

TCM Constitution Analysis Method Based on Parallel FP-Growth Algorithm in Hadoop Framework.

This work is devoted to establishing a comparatively accurate classification model between symptoms, constitutions, and regimens for traditional Chinese medicine (TCM) constitution analysis to provide preliminary screening and decision support for clinical diagnosis. However, for the analysis of massive distributed medical data in a cloud platform, the traditional data mining methods have the problems of low mining efficiency and large memory consumption, and long tuning time, an association rules method for TCM constitution analysis (ARA-TCM) is proposed that based on FP-growth algorithm and the open-source distributed file system in Hadoop framework (HDFS) to make full use of its powerful parallel processing capability. Firstly, the proposed method was used to explore the association rules between the 9 kinds of TCM constitutions and symptoms, as well as the regimen treatment plans, so as to discover the rules of typical clinical symptoms and treatment rules of different constitutions and to conduct an evidence-based medical evaluation of TCM effects in constitution-related chronic disease health management. Secondly, experiments were applied on a self-built TCM clinical records database with a total of 30,071 entries and it is found that the top three constitutions are mid constitution (42.3%), hot and humid constitution (31.3%), and inherited special constitution (26.2%), respectively. What is more, there are obvious promotions in the precision and recall rate compared with the Apriori algorithm, which indicates that the proposed method is suitable for the classification of TCM constitutions. This work is mainly focused on uncovering the rules of "disease symptoms constitution regimen" in TCM medical records, but tongue image and pulse signal are also very important to TCM constitution analysis. Therefore, this additional information should be considered into further studies to be more in line with the actual clinical needs.

Development of an innovative nomogram of risk factors to predict postoperative recurrence of gastrointestinal stromal tumors.

BACKGROUND: There are many staging systems for gastrointestinal stromal tumors (GISTs), and the risk indicators selected are also different; thus, it is not possible to quantify the risk of recurrence among individual patients. AIM: To develop and internally validate a model to identify the risk factors for GIST recurrence after surgery. METHODS: The least absolute shrinkage and selection operator (LASSO) regression model was performed to identify the optimum clinical features for the GIST recurrence risk model. Multivariable logistic regression analysis was used to develop a prediction model that incorporated the possible factors selected by the LASSO regression model. The index of concordance (C-index), calibration curve, receiver operating characteristic curve (ROC), and decision curve analysis were used to assess the discrimination, calibration, and clinical usefulness of the predictive model. Internal validation of the clinical predictive capability was also evaluated by bootstrapping validation. RESULTS: The nomogram included tumor site, lesion size, mitotic rate/50 high power fields, Ki-67 index, intracranial necrosis, and age as predictors. The model presented perfect discrimination with a reliable C-index of 0.836 (95%CI: 0.712-0.960), and a high C-index value of 0.714 was also confirmed by interval validation. The area under the curve value of this prediction nomogram was 0.704, and the ROC result indicated good predictive value. Decision curve analysis showed that the predicting recurrence nomogram was clinically feasible when the recurrence rate exceeded 5% after surgery. CONCLUSION: This recurrence nomogram combines tumor site, lesion size, mitotic rate, Ki-67 index, intracranial necrosis, and age and can easily predict patient prognosis.

A concise access to bridged [2,2,1] bicyclic lactones with a quaternary stereocenter via stereospecific hydroformylation.

Chiral bridged [2,2,1] bicyclic lactones are privileged structural units in pharmaceutics and bioactive nature products. However, the synthetic methods for these compounds are rare. Here we report an efficient method for enantioselective construction of bridged [2,2,1] bicyclic lactones bearing a quaternary stereocenter via Rh-catalyzed asymmetric hydroformylation/intramolecular cyclization/pyridium chlorochromate (PCC) oxidation. By employing a hybrid phosphine-phosphite chiral ligand, a series of cyclopent-3-en-1-ols are transformed into corresponding γ-hydroxyl aldehydes with specific syn-selectivity. Then, hemiacetals form in situ and oxidation with PCC in one-pot affords bridged [2,2,1] bicyclic lactones in high yields and excellent enantiomeric excess. Replacing the hydroxyl group by an ester group, cyclopentanecarbaldehydes with a chiral all-carbon quaternary stereocenter in the γ-position can be generated efficiently.

Serial cellular events in bone formation initiated by calcium phosphate ceramics.

To better understand the biological mechanisms triggered by osteoinductive materials in vivo, we evaluated the timeline of cellular responses to osteoinductive materials subcutaneously implanted in FVB mice. More F4/80-positive macrophages were present in osteoinductive tri-CaP ceramic (TCP) with submicron surface topography (TCPs) than non-osteoinductive TCP with micron surface topography (TCPb) at week 1. Moreover, TCPs (but not TCPb) significantly enhanced osteoclastogenesis, and induced macrophages to polarize from M1 to M2 in the first week. The time sequence and relevance of macrophages and osteoclasts responses involved in bone formation was then evaluated through peri-implant injection of specific chemicals in mice implanted with osteoinductive TCPs. Day-1 injection of clodronate liposomes (LipClod) depleted macrophages, inhibited macrophage polarization to M2, blocked osteoclastogenesis and bone formation, while the day-6 injection was less effective. Anti-RANKL antibody (aRANKL) did not affect macrophage colonization but inhibited osteoclastogenesis. Injection of aRANKL before week 2 aborted bone formation in TCPs, while injection at week 4 partially inhibited bone formation. The overall data show that following ectopic implantation, osteoinductive materials allow macrophage colonization in hours to days, macrophage polarization to M2 in days (within 7 days), osteoclastogenesis in weeks (e.g. in 2 weeks) and bone formation thereafter (after 4 weeks). The serial cellular events verified herein bring a new insight on material-induced bone formation and pave the way to further explore the mechanisms triggered by osteoinductive materials. STATEMENT OF SIGNIFICANCE: A series of key cellular events triggered by osteoinductive calcium phosphate ceramic was revealed: macrophages colonized within hours to days, polarization of M2 macrophages occurred within 7 days, osteoclastogenesis mainly occurred in weeks (e.g. in 2 weeks) and bone formation finally arose thereafter (after 4 weeks). Moreover, such time sequence of cellular events was confirmed with specific chemicals (clodronate liposomes and anti-RANKL antibody). The findings verified herein bring a new insight on material-induced bone formation and pave the way to further explore the mechanisms triggered by osteoinductive materials.

Inorganic Perovskite Quantum Dot-Based Strain Sensors for Data Storage and In-Sensor Computing.

Although remarkable improvement has been achieved in stretchable strain sensors, challenges still exist in aspects including intelligent sensing, simultaneous data processing, and scalable fabrication techniques. In this work, a strain-sensitive device is presented by fabricating a CsPbBr3 quantum dots (QDs) floating-gate field-effect transistor (FET) sensing array on thin polyimide (PI) films. The FET exhibits an excellent on/off ratio (>103) and a large memory window (>2 V). With the introduction of CsPbBr3 QDs as the trapping layer, an additional UV response is obtained because of the photogenerated charge carriers that significantly enhance the source-drain current (IDS) of the device. At each electrical state, the IDS varies with the strains and the sensing range is from compressive +12.5% to tensile -10.8%. Excellent data retainability and mechanical durability demonstrate the high quality and reliability of the fabricated sensors. Furthermore, synapse functions including long-term potentiation (LTP), long-term depression (LTD), etc., are emulated at the device level. Linearity factor changes of LTP/LTD in different sensing scenarios demonstrate the reliability of the device and further confirm the different sensing mechanisms with/without UV illumination. Our results exhibit the potential of transistor-based devices for multifunctional intelligent sensing.

Stacked Two-Dimensional MXene Composites for an Energy-Efficient Memory and Digital Comparator.

Two-dimensional MXene has enormous potential for application in industry and academia owing to its surface hydrophilicity and excellent electrochemical properties. However, the application of MXene in optoelectronic memory and logical computing is still facing challenges. In this study, an optoelectronic resistive random access memory (RRAM) based on silver nanoparticles (Ag NPs)@MXene-TiO2 nanosheets (AMT) was prepared through a low-cost and facile hydrothermal oxidation process. The fabricated device exhibited a typical bipolar switching behavior and controllable SET voltage. Furthermore, we successfully demonstrated a 4-bit in-memory digital comparator with AMT RRAMs, which can replace five logic gates in a traditional approach. The AMT-based digital comparator may open the door for future integrated functions and applications in optoelectronic data storage and simplify the complex logic operations.

Macrophage polarization plays roles in bone formation instructed by calcium phosphate ceramics.

To investigate the roles of macrophages in material-instructed bone formation, two calcium phosphate (TCP) ceramics with the same chemistry but various scales of surface topography were employed in this study. After being implanted subcutaneously in FVB mice for 8 weeks, TCPs (TCP ceramics with submicron surface topography) gave rise to bone formation, while TCPb (TCP ceramics with micron surface topography) did not, showing the crucial role of surface topography scale in material-instructed bone formation. Depletion of macrophages with liposomal clodronate (LipClod) blocked such bone formation instructed by TCPs, confirming the role of macrophages in material-instructed bone formation. Macrophage cells (i.e. RAW 264.7 cells) cultured on TCPs in vitro polarized to tissue repair macrophages as evidenced by gene expression and cytokine production, while polarizing to pro-inflammatory macrophages on TCPb. Submicron surface topography of TCP ceramics directed macrophage polarization via PI3K/AKT pathways with the synergistic regulation of integrin ß1. Finally, the tissue repair macrophage polarization on TCPs resulted in osteogenic differentiation of mesenchymal stem cells in vitro. At early implantation in FVB mice, TCPs recruited more macrophages which polarized towards tissue repair macrophages with time. The present data demonstrate the important roles of macrophage polarization in bone formation instructed by calcium phosphate ceramics.