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Abstract Introduction Recent data have shown elevated infection rates in several subpopulations at risk of SARS-CoV-2 infection and COVID-19, including immunocompromised (IC) individuals. Previous research suggests that IC persons have reduced risks of hospitalization and medically attended COVID-19 with two doses of mRNA-1273 (SpikeVax; Moderna) compared to two doses of BNT162b2 (Comirnaty; Pfizer/BioNTech). The main objective of this retrospective cohort study was to compare real-world effectiveness of third doses of mRNA-1273 versus BNT162b2 at multiple time points on occurrence of COVID-19 hospitalization and medically attended COVID-19 among IC adults in the United States (US). Methods This retrospective, observational comparative effectiveness study identified patients from the US HealthVerity database from December 11, 2020, through August 31, 2022. Medically attended SARS-CoV-2 infections and hospitalizations were assessed following a three-dose mRNA-1273 versus BNT162b2 regimen. Inverse probability weighting was applied to balance baseline confounders between vaccine groups. Relative risk (RR) and risk difference were calculated for subgroup and sensitivity analyses using a non-parametric method. Results In propensity score-adjusted analyses, receiving mRNA-1273 vs. BNT162b2 as third dose was associated with 32.4% (relative risk 0.676; 95% confidence interval 0.506–0.887), 29.3% (0.707; 0.573–0.858), and 23.4% (0.766; 0.626–0.927) lower risk of COVID-19 hospitalization after 90, 180, and 270 days, respectively. Corresponding reductions in medically attended COVID-19 were 8.4% (0.916; 0.860–0.976), 6.4% (0.936; 0.895–0.978), and 2.4% (0.976; 0.935–1.017), respectively. Conclusions Our findings suggest a third dose of mRNA-1273 is more effective than a third dose of BNT162b2 in preventing COVID-19 hospitalization and breakthrough medically attended COVID-19 among IC adults in the US.

ABSTRACTEmerging SARS-CoV-2 sublineages continue to cause serious COVID-19 disease, but most individuals have not received any COVID-19 vaccine for >1 year. Assessment of long-term effectiveness of bivalent COVID-19 vaccines against circulating sublineages is important to inform the potential need for vaccination with updated vaccines. In this test-negative study at Kaiser Permanente Southern California, sequencing-confirmed BA.4/BA.5- or XBB-related SARS-CoV-2-positive cases (September 1, 2022 to June 30, 2023), were matched 1:3 to SARS-CoV-2-negative controls. We assessed mRNA-1273 bivalent relative (rVE) and absolute vaccine effectiveness (VE) compared to ≥2 or 0 doses of original monovalent vaccine, respectively. The rVE analysis included 20,966 cases and 62,898 controls. rVE (95%CI) against BA.4/BA.5 at 14–60 days and 121–180 days was 52.7% (46.9–57.8%) and 35.5% (−2.8–59.5%) for infection, and 59.3% (49.7–67.0%) and 33.2% (−28.2–68.0%) for Emergency Department/Urgent Care (ED/UC) encounters. For BA.4/BA.5-related hospitalizations, rVE was 71.3% (44.9–85.1%) and 52.0% (−1.2–77.3%) at 14–60 days and 61–120 days, respectively. rVE against XBB at 14–60 days and 121–180 days was 48.8% (33.4–60.7%) and −3.9% (−18.1–11.3%) for infection, 70.7% (52.4–82.0%) and 15.7% (−6.0–33.2%) for ED/UC encounters, and 87.9% (43.8–97.4%) and 57.1% (17.0–77.8%) for hospitalization. VE and subgroup analyses (age, immunocompromised status, previous SARS-CoV-2 infection) results were similar to rVE analyses. rVE of mRNA-1273 bivalent vaccine against BA.4/BA.5 and XBB infections, ED/UC encounters, and hospitalizations waned over time. Periodic revaccination with vaccines targeting emerging variants may be important in reducing COVID-19 morbidity and mortality.

ABSTRACT Bacteriophages, viruses that specifically target plant pathogenic bacteria, have emerged as a promising alternative to traditional agrochemicals. However, it remains unclear how phages should be applied to achieve efficient pathogen biocontrol and to what extent their efficacy is shaped by indirect interactions with the resident microbiota. Here, we tested if the phage biocontrol efficacy of Ralstonia solanacearum phytopathogenic bacterium can be improved by increasing the phage cocktail application frequency and if the phage efficacy is affected by pathogen-suppressing bacteria already present in the rhizosphere. We find that increasing phage application frequency improves R. solanacearum density control, leading to a clear reduction in bacterial wilt disease in both greenhouse and field experiments with tomato. The high phage application frequency also increased the diversity of resident rhizosphere microbiota and enriched several bacterial taxa that were associated with the reduction in pathogen densities. Interestingly, these taxa often belonged to Actinobacteria known for antibiotics production and soil suppressiveness. To test if they could have had secondary effects on R. solanacearum biocontrol, we isolated Actinobacteria from Nocardia and Streptomyces genera and tested their suppressiveness to the pathogen in vitro and in planta. We found that these taxa could clearly inhibit R. solanacearum growth and constrain bacterial wilt disease, especially when combined with the phage cocktail. Together, our findings unravel an undiscovered benefit of phage therapy, where phages trigger a second line of defense by the pathogen-suppressing bacteria that already exist in resident microbial communities.IMPORTANCERalstonia solanacearum is a highly destructive plant-pathogenic bacterium with the ability to cause bacterial wilt in several crucial crop plants. Given the limitations of conventional chemical control methods, the use of bacterial viruses (phages) has been explored as an alternative biological control strategy. In this study, we show that increasing the phage application frequency can improve the density control of R. solanacearum, leading to a significant reduction in bacterial wilt disease. Furthermore, we found that repeated phage application increased the diversity of rhizosphere microbiota and specifically enriched Actinobacterial taxa that showed synergistic pathogen suppression when combined with phages due to resource and interference competition. Together, our study unravels an undiscovered benefit of phages, where phages trigger a second line of defense by the pathogen-suppressing bacteria present in resident microbial communities. Phage therapies could, hence, potentially be tailored according to host microbiota composition to unlock the pre-existing benefits provided by resident microbiota.

Abstract Because of uncertain random noise and unknown disturbance, the observer‐based inverter fault diagnosis meets the problems of large deviation of current observation value and high false alarm rate. An inverter open‐circuit fault diagnosis method is proposed via residual performance evaluation. Firstly, the interval sliding mode observer is constructed by combining the interval observer with the sliding mode observer. Three phase current estimates are obtained and current residuals are calculated. Secondly, the residual performance indicators are calculated using the evaluation function. The fault detection is derived by comparing residual performance with the threshold. Thirdly, a residual information table is established based on the fault information contained in the residual for fault isolation. Finally, the proposed algorithm is validated on simulation and physical platforms. Compared with traditional observer‐based diagnostic methods, the introduction of residual performance evaluation improves the diagnostic speed by more than 50%. The interval sliding mode observer has higher estimation accuracy and anti‐interference ability in the presence of noise and external disturbances.

Programmed cell death (PCD) is common in plant growth and development, such as xylem development, organ senescence, and abscission. Calyx abscission in Korla fragrant pear contributes to fruit quality, while it was not clear whether PCD occurred during calyx abscission and which signals regulated the process. Therefore, it is imperative to clarify the process of PCD in the process of calyx abscission in Korla fragrant pear under natural conditions to enrich the mechanism of calyx abscission. The results showed that the total time of calyx abscission of Korla fragrant pear began from 6 days after pollination (DAP) to 13 DAP, and the peak of calyx abscission occurred 10 DAP. During the whole process of calyx abscission, PCD started 6 DAP. At 9 DAP, the degree of PCD deepened. At 12 DAP, the cells in the abscission zone showed asymmetry on both sides, the organelles in the distal cells of the abscission zone degraded into apoptotic fragments, and the protective layer of the normal development of cells located at the proximal end of the abscission zone region ended the PCD process. ETH concentrations in the abscission zone of the decalyx fruit were significantly higher than those of the persistent calyx fruits in each period during calyx abscission, and high levels of ethylene and hydrogen peroxide and low contents of the GA3, ZT, and hydroxyl radicals promoted calyx abscission before the formation of the abscission zone. At 3 DAP, the ethylene concentration (43.97 ppm) and H2O2 content (8.49 μmol/g) of decalyx fruit in the abscission zone were significantly higher than those of persistent calyx fruit by 67.69% and 27.86%, respectively; however, the GA3, ZT, and hydroxyl radicals showed the opposite. Overall, PCD in the abscission zone of decalyx fruits did occur during the calyx abscission of Korla fragrant pear, and ethylene and H2O2 might play major roles in initiating the PCD process during Korla fragrant pear calyx abscission.

Abstract Background Epithelium-mesenchymal interactions are involved in odontogenic processes. Previous studies have focused on the intracellular signalling regulatory network in tooth development, but the functions of extracellular regulatory molecules have remained unclear. This study aims to explore the gene profile of extracellular proteoglycans and their glycosaminoglycan chains potentially involved in dental epithelium-mesenchymal interactions using high-throughput sequencing to provide new understanding of early odontogenesis. Results Whole transcriptome profiles of the mouse dental epithelium and mesenchyme were investigated by RNA sequencing (RNA-seq). A total of 1,281 and 1,582 differentially expressed genes were identified between the dental epithelium and mesenchyme at E11.5 and E13.5, respectively. Enrichment analysis showed that extracellular regions and ECM-receptor interactions were significantly enriched at both E11.5 and E13.5. Polymerase chain reaction analysis confirmed that the extracellular proteoglycan family exhibited distinct changes during epithelium-mesenchymal interactions. Most proteoglycans showed higher transcript levels in the dental mesenchyme, whereas only a few were upregulated in the epithelium at both stages. In addition, 9 proteoglycans showed dynamic expression changes between these two tissue compartments. Gpc4, Sdc2, Spock2, Dcn and Lum were expressed at higher levels in the dental epithelium at E11.5, whereas their expression was significantly higher in the dental mesenchyme at E13.5, which coincides with the odontogenic potential shift. Moreover, the glycosaminoglycan biosynthetic enzymes Ext1, Hs3st1/5, Hs6st2/3, Ndst3 and Sulf1 also exhibited early upregulation in the epithelium but showed markedly higher expression in the mesenchyme after the odontogenic potential shift. Conclusion This study reveals the dynamic expression profile of extracellular proteoglycans and their biosynthetic enzymes during the dental epithelium–mesenchymal interaction. This study offers new insight into the roles of extracellular proteoglycans and their distinct sulfation underlying early odontogenesis.

Field-effect transistor (FET) biosensors can be used to measure the charge information carried by biomolecules. However, insurmountable hysteresis in the long-term and large-range transfer characteristic curve exists and affects the measurements. Noise signal, caused by the interference coefficient of external factors, may destroy the quantitative analysis of trace targets in complex biological systems. In this report, a “rectified signal” in the output characteristic curve, instead of the “absolute value signal” in the transfer characteristic curve, is obtained and analyzed to solve these problems. The proposed asymmetric Schottky barrier-generated MoS2/WTe2 FET biosensor achieved a 105 rectified signal, sufficient reliability and stability (maintained for 60 days), ultra-sensitive detection (10 aM) of the Down syndrome-related DYRK1A gene, and excellent specificity in base recognition. This biosensor with a response range of 10 aM–100 pM has significant application potential in the screening and rapid diagnosis of Down syndrome.

Abstract Pulmonary microbial diversity may be influenced by biotic or abiotic conditions (e.g., disease, smoking, invasive mechanical ventilation (MV), etc.). Specially, invasive MV may trigger structural and physiological changes in both tissue and microbiota of lung, due to gastric and oral microaspiration, altered body posture, high O2 inhalation-induced O2 toxicity in hypoxemic patients, impaired airway clearance and ventilator-induced lung injury (VILI), which in turn reduce the diversity of the pulmonary microbiota and may ultimately lead to poor prognosis. Furthermore, changes in (local) O2 concentration can reduce the diversity of the pulmonary microbiota by affecting the local immune microenvironment of lung. In conclusion, systematic literature studies have found that invasive MV reduces pulmonary microbiota diversity, and future rational regulation of pulmonary microbiota diversity by existing or novel clinical tools (e.g., lung probiotics, drugs) may improve the prognosis of invasive MV treatment and lead to more effective treatment of lung diseases with precision.

In recent years, with the advancement of natural language processing techniques and the release of models like ChatGPT, how language models understand questions has become a hot topic. In handling complex logical reasoning with pre-trained models, its performance still has room for improvement. Inspired by DAGN, we propose an improved DaGATN (Discourse-apperceptive Graph Attention Networks) model. By constructing a discourse information graph to learn logical clues in the text, we decompose the context, question, and answer into elementary discourse units (EDUs) and connect them with discourse relations to construct a relation graph. The text features are learned through a discourse graph attention network and applied to downstream multiple-choice tasks. Our method was evaluated on the ReClor dataset and achieved an accuracy of 74.3%, surpassing the best-known performance methods utilizing deberta-xlarge-level pre-trained models, and also performed better than ChatGPT (Zero-Shot).

Glioblastoma (GBM) is the most common aggressive malignant tumor in brain neuroepithelial tumors and remains incurable. A variety of treatment options are currently being explored to improve patient survival, including small molecule inhibitors, viral therapies, cancer vaccines, and monoclonal antibodies. Among them, the unique advantages of small molecule inhibitors have made them a focus of attention in the drug discovery of glioblastoma. Currently, the most used chemotherapeutic agents are small molecule inhibitors that target key dysregulated signaling pathways in glioblastoma, including receptor tyrosine kinase, PI3K/AKT/mTOR pathway, DNA damage response, TP53 and cell cycle inhibitors. This review analyzes the therapeutic benefit and clinical development of novel small molecule inhibitors discovered as promising anti-glioblastoma agents by the related targets of these major pathways. Meanwhile, the recent advances in temozolomide resistance and drug combination are also reviewed. In the last part, due to the constant clinical failure of targeted therapies, this paper reviewed the research progress of other therapeutic methods for glioblastoma, to provide patients and readers with a more comprehensive understanding of the treatment landscape of glioblastoma.

In recent years, the incidence of critical-size bone defects has significantly increased. Critical-size bone defects seriously affect patients’ motor functions and quality of life and increase the need for additional clinical treatments. Bone tissue engineering (BTE) has made great progress in repairing critical-size bone defects. As one of the main components of bone tissue engineering, stem cell-based therapy is considered a potential effective strategy to regenerate bone tissues. However, there are some disadvantages including phenotypic changes, immune rejection, potential tumorigenicity, low homing efficiency and cell survival rate that restrict its wider clinical applications. Evidence has shown that the positive biological effects of stem cells on tissue repair are largely mediated through paracrine action by nanostructured extracellular vesicles (EVs), which may overcome the limitations of traditional stem cell-based treatments. In addition to stem cell-derived extracellular vesicles, the potential therapeutic roles of nonstem cell-derived extracellular vesicles in critical-size bone defect repair have also attracted attention from scholars in recent years. Currently, the development of extracellular vesicles-mediated cell-free regenerative medicine is still in the preliminary stage, and the specific mechanisms remain elusive. Herein, the authors first review the research progress and possible mechanisms of extracellular vesicles combined with bone tissue engineering scaffolds to promote bone regeneration via bioactive molecules. Engineering modified extracellular vesicles is an emerging component of bone tissue engineering and its main progression and clinical applications will be discussed. Finally, future perspectives and challenges of developing extracellular vesicle-based regenerative medicine will be given. This review may provide a theoretical basis for the future development of extracellular vesicle-based biomedicine and provide clinical references for promoting the repair of critical-size bone defects.

Abstract The BCL2-inhibitor, Venetoclax (VEN), has shown significant anti-leukemic efficacy in combination with the DNMT-inhibitor, Azacytidine (AZA). To explore the mechanisms underlying the selective sensitivity of mutant leukemia cells to VEN and AZA, we used cell-based isogenic models containing a common leukemia-associated mutation in the epigenetic regulator ASXL1. KBM5 cells with CRISPR/Cas9-mediated correction of the ASXL1 G710X mutation showed reduced leukemic growth, increased myeloid differentiation, and decreased HOXA and BCL2 gene expression in vitro compared to uncorrected KBM5 cells. Increased expression of the anti-apoptotic gene, BCL2, was also observed in bone marrow CD34+ cells from ASXL1 mutant MDS patients compared to CD34+ cells from wild-type MDS cases. ATAC-sequencing demonstrated open chromatin at the BCL2 promoter in the ASXL1 mutant KBM5 cells. BH3 profiling demonstrated increased dependence of mutant cells on BCL2. Upon treatment with VEN, mutant cells demonstrated increased growth inhibition. In addition, genome-wide methylome analysis of primary MDS samples and isogenic cell lines demonstrated increased gene-body methylation in ASXL1 mutant cells, with consequently increased sensitivity to AZA. These data mechanistically link the common leukemia-associated mutation ASXL1 to enhanced sensitivity to VEN and AZA via epigenetic upregulation of BCL2 expression and widespread alterations in DNA methylation.

Abstract In patients with localized scleroderma (LoS), facial deformity induced by subcutaneous atrophy greatly reduces life quality. Autologous fat grafting (AFG) is used for volume restoration but with low‐fat retention due to various reasons. Adipose‐derived stem cells (ADSCs) have shown potential effects in improving fat retention. We aimed to compare the feasibility and efficacy of improving fat retention in LoS patients among the ADSCs‐assisted, the stromal vascular fraction (SVF)‐assisted and conventional AFG methods. A pilot study with a 6‐month follow‐up among 18 LoS patients was conducted. Participants were randomly assigned into three AFG groups: conventional group, SVF‐assisted group, and ADSCs‐assisted group. The SVF‐assisted group received SVF‐assisted AFG at the SVF:fat ratio of 1:1. The ADSCs‐assisted group received the mixture of ADSCs‐enriched fat graft supplemented with 5 × 105 ADSCs/mL fat. Volume retention was measured by magnetic resonance imaging, and clinical photographs were taken for outcome evaluation. At sixth‐month follow‐up, the fat retention of ADSCs‐assisted group was 49.83 ± 3.61%, significantly higher than 31.75 ± 1.73% of SVF‐assisted group (P = .0004), and 21.86 ± 1.68% of the conventional group (P

Background The AHA Registry (American Heart Association COVID‐19 Cardiovascular Disease Registry) captures detailed information on hospitalized patients with COVID‐19. The registry, however, does not capture information on social determinants of health or long‐term outcomes. Here we describe the linkage of the AHA Registry with external data sources, including fee‐for‐service (FFS) Medicare claims, to fill these gaps and assess the representativeness of linked registry patients to the broader Medicare FFS population hospitalized with COVID‐19. Methods and Results We linked AHA Registry records of adults ≥65 years from March 2020 to September 2021 with Medicare FFS claims using a deterministic linkage algorithm and with the American Hospital Association Annual Survey, Rural Urban Commuting Area codes, and the Social Vulnerability Index using hospital and geographic identifiers. We compared linked individuals with unlinked FFS beneficiaries hospitalized with COVID‐19 to assess the representativeness of the AHA Registry. A total of 10 010 (47.0%) records in the AHA Registry were successfully linked to FFS Medicare claims. Linked and unlinked FFS beneficiaries were similar with respect to mean age (78.1 versus 77.9, absolute standardized difference [ASD] 0.03); female sex (48.3% versus 50.2%, ASD 0.04); Black race (15.1% versus 12.0%, ASD 0.09); dual‐eligibility status (26.1% versus 23.2%, ASD 0.07); and comorbidity burden. Linked patients were more likely to live in the northeastern United States (35.7% versus 18.2%, ASD 0.40) and urban/metropolitan areas (83.9% versus 76.8%, ASD 0.18). There were also differences in hospital‐level characteristics between cohorts. However, in‐hospital outcomes were similar (mortality, 23.3% versus 20.1%, ASD 0.08; home discharge, 45.5% versus 50.7%, ASD 0.10; skilled nursing facility discharge, 24.4% versus 22.2%, ASD 0.05). Conclusions Linkage of the AHA Registry with external data sources such as Medicare FFS claims creates a unique and generalizable resource to evaluate long‐term health outcomes after COVID‐19 hospitalization.

To aid physicians in the precision diagnosis of ailments in the cranial region, we propose an overhead collapsible origami-based mount (Over-COM) with the advantages of being mountable, compact, lightweight, portable, and easy-to-use. The Over-COM can hold small diagnosis apparatuses, attach to regions of interest (ROIs) on the head, and adjust the posture and penetration angle of the sensor to detect the optimal medical signal. The prototype of the Over-COM consists of a setup (housing, eight linear actuators, and an IMU) that can be attached to the head with adhesive or straps, and a small box (containing the microcontroller and battery pack) that can be placed away from the patient. In order to verify the performance of the system, experiments investigating the device’s DOFs and scan protocols were carried out. The experimental results demonstrated that the Over-COM could hold the diagnosis device, locate the ROIs, and determine the best sensor posture and penetration angles.

A constellation configuration performance evaluation method is proposed for the performance evaluation of the low-orbit large-scale communication satellite constellations. The practicality and feasibility analysis of the constellation configuration is mainly studied from the constellation coverage performance. Based on the consideration of the coverage performance of the LEO satellite constellation, four simulation models are established for the single coverage rate, observation elevation angle, number of visible satellites under different observation elevation angles, and coverage efficiency of the constellation. A population distribution density function is established according to the characteristics of population distribution to find the average minimum observation elevation angle and the average number of visible satellites under the population distribution. The evaluation method is applied to three typical low-orbit large-scale communication satellite constellations, Telesat, OneWeb, and Starlink, to derive the coverage performance index values of each constellation and to compare and analyze the characteristics of the three constellations. The results show that the evaluation method can evaluate the configuration performance of different types of LEO large-scale constellations and provide a basis and reference for the optimal design and evaluation of future LEO large-scale constellation configurations.

Abstract Background The formation of supernumerary teeth is an excellent model for studying the molecular mechanisms that control stem/progenitor cell homeostasis needed to generate a renewable source of replacement cells and tissues. Although multiple growth factors and transcriptional factors have been associated with supernumerary tooth formation, the regulatory inputs of extracellular matrix in this regenerative process remains poorly understood. Results In this study, we present evidence that disrupting glycosaminoglycans (GAGs) in the dental epithelium of mice by inactivating FAM20B, a xylose kinase essential for GAG assembly, leads to supernumerary tooth formation in a pattern reminiscent of replacement teeth. The dental epithelial GAGs confine murine tooth number by restricting the homeostasis of Sox2(+) dental epithelial stem/progenitor cells in a non-autonomous manner. FAM20B-catalyzed GAGs regulate the cell fate of dental lamina by restricting FGFR2b signaling at the initial stage of tooth development to maintain a subtle balance between the renewal and differentiation of Sox2(+) cells. At the later cap stage, WNT signaling functions as a relay cue to facilitate the supernumerary tooth formation. Conclusions The novel mechanism we have characterized through which GAGs control the tooth number in mice may also be more broadly relevant for potentiating signaling interactions in other tissues during development and tissue homeostasis.

Abstract Background Most nanoparticles (NPs) reportedly block autophagic flux, thereby upregulating p62/SQSTM1 through degradation inhibition. p62 also acts as a multifunctional scaffold protein with multiple domains, and is involved in various cellular processes. However, the autophagy substrate-independent role of p62 and its regulation at the transcriptional level upon NPs exposure remain unclear. Results In this work, we exposed BEAS-2b cells and mice to silica nanoparticles (SiNPs), and found that SiNPs increased p62 protein levels in vivo and vitro. Then, we further explored the role and mechanism of SiNPs-stimulated p62 in vitro, and found that p62 degradation was inhibited due to autophagic flux blockade. Mechanistically, SiNPs blocked autophagic flux through impairment of lysosomal capacity rather than defective autophagosome fusion with lysosomes. Moreover, SiNPs stimulated translocation of NF-E2-related factor 2 (Nrf2) to the nucleus from the cytoplasm, which upregulated p62 transcriptional activation through direct binding of Nrf2 to the p62 promoter. Nrf2 siRNA dramatically reduced both the mRNA and protein levels of p62. These two mechanisms led to p62 protein accumulation, thus increasing interleukin (IL)-1 and IL-6 expression. SiNPs activated nuclear factor kappa B (NF-κB), and this effect could be alleviated by p62 knockdown. Conclusion SiNPs caused accumulation of p62 through both pre- and post-translational mechanisms, resulting in airway inflammation. These findings improve our understanding of SiNP-induced pulmonary damage and the molecular targets available to mitigate it.

Formal verification technology has been widely applied in the fields of mathematics and computer science. The formalization of fundamental mathematical theories is particularly essential. Axiomatic set theory is a foundational system of mathematics and has important applications in computer science. Most of the basic concepts and theories in computer science are described and demonstrated in terms of set theory. In this paper, we present a formal system of axiomatic set theory based on the Coq proof assistant. The axiomatic system used in the formal system refers to Morse-Kelley set theory which is a relatively complete and concise axiomatic set theory. In this formal system, we complete the formalization of the basic definitions of sets, functions, ordinal numbers, and cardinal numbers and prove the most commonly used theorems in Coq. Moreover, the non-negative integers are defined, and Peano's postulates are proved as theorems. According to the axiom of choice, we also present formal proofs of the Hausdorff maximal principle and Schröeder-Bernstein theorem. The whole formalization of the system includes eight axioms, one axiom schema, 62 definitions, and 148 corollaries or theorems. The “axiomatic set theory” formal system is free from the more apparent paradoxes, and a complete axiomatic system is constructed through it. It is designed to give a foundation for mathematics quickly and naturally. On the basis of the system, we can prove many famous mathematical theorems and quickly formalize the theories of topology, modern algebra, data structure, database, artificial intelligence, and so on. It will become an essential theoretical basis for mathematics, computer science, philosophy, and other disciplines.

Femoral head necrosis (FHN) is a clinically progressive disease that leads to overwhelming complications without an effective therapeutic approach. In recent decades, transplantation of mesenchymal stem cells (MSCs) has played a promising role in the treatment of FHN in the initial stage; however, the success rate is still low because of unsuitable cell carriers and abridged osteogenic differentiation of the transplanted MSCs. Biopolymeric-derived hydrogels have been extensively applied as effective cell carriers and drug vesicles; they provide the most promising contributions in the fields of tissue engineering and regenerative medicine. However, the clinical potential of hydrogels may be limited because of inappropriate gelation, swelling, mechanical characteristics, toxicity in the cross-linking process, and self-healing ability. Naturally, gelated commercial hydrogels are not suitable for cell injection and infiltration because of their static network structure. In this study, we designed a novel thermogelling injectable hydrogel using natural silk fibroin-blended chitosan (CS) incorporated with magnesium (Mg) substitutes to improve physical cross-linking, stability, and cell osteogenic compatibility. The presented observations demonstrate that the developed injectable hydrogels can facilitate the controlled delivery of immobilized recombinant human bone morphogenic protein-2 (rhBMP-2) and rat bone marrow-derived MSCs (rBMSCs) with greater cell encapsulation efficiency, compatibility, and osteogenic differentiation. In addition, outcomes of in vivo animal studies established promising osteoinductive, bone mineral density, and bone formation rate after implantation of the injectable hydrogel scaffolds. Therefore, the developed hydrogels have great potential for clinical applications of FHN therapy.

Stem cells maintain a subtle balance between self-renewal and differentiation under the regulatory network supported by both intracellular and extracellular components. Proteoglycans are large glycoproteins present abundantly on the cell surface and in the extracellular matrix where they play pivotal roles in facilitating signaling transduction and maintaining stem cell homeostasis. In this review, we outline distinct proteoglycans profiles and their functions in the regulation of stem cell homeostasis, as well as recent progress and prospects of utilizing proteoglycans/glycosaminoglycans as a novel glycomics carrier or bio-active molecules in bone regeneration.

As important indicators of leaf traits, leaf anatomical traits are sensitive and adaptable to environmental changes. However, how leaf anatomical traits at species and community levels vary along the altitudinal gradients is still unclear. In this study, a total of 60 woody plants from four typical vegetation zones along the 2000 m-elevation gradients in the northern slope of Taibai Mountain were selected to measure the leaf thickness (LT), epidermal thickness (ET), palisade tissue thickness (PT), spongy tissue thickness (ST), and palisade-spongy tissue thickness ratio (PST). Based on the data of the relative dominance of each species within a community, we calculated the community weighted means (CWM) of leaf traits. We aimed to investigate the variation of leaf anatomical traits at both species and community levels along the altitudinal gradients, and to explore their influencing factors. Our results showed that different elevational patterns of leaf anatomical traits occurred between the species and community levels. At the species level, LT, ET, PT, and ST increased with the altitudinal gradient, which were controlled by both of phylogenetic and environmental factors. Differently, the community-level leaf anatomical traits increased first and then decreased with elevation, and were mainly influenced by climatic factors. These results indicated that, different from species-level traits, community-level traits, which included community structure and species information, could better reflect the real plant community and their variation along the elevation. Furthermore, both of environmental factors and phylogenetic differences should be taken into account when exploring the variation in leaf anatomical traits.

Objectives: The goal of this study was to prepare lyophilized platelet-rich fibrin (L-PRF) and analyze the combined use of L-PRF and osteogenic bone marrow mesenchymal stem cell (BMSC) sheet fragments for bone tissue engineering via in vivo injection. Methods: First, fresh PRF (F-PRF) was lyophilized to prepare L-PRF, the characteristics of which were examined through gross morphological, and histological and microstructural observations. In addition, the kinetics of growth factor release from L-PRF and F-PRF were also determined by enzyme-linked immunosorbent assay (ELISA). Subsequently, after assessing the proliferation and osteogenic differentiation of BMSCs exposed to L-PRF or F-PRF in vitro, we subcutaneously injected BMSC sheet fragments with L-PRF or F-PRF into nude mice and assessed bone formation through microcomputed tomography and histological analyses. Results: We observed that L-PRF released growth factors that favored BMSC proliferation and osteogenic differentiation in vitro. The combined use of L-PRF and osteogenic BMSC sheet fragments enabled bone tissue regeneration in vivo, and no significant difference between the F-PRF and L-PRF groups was observed (P = 0.24). Conclusions: The results of this study demonstrate that the combined use of L-PRF and osteogenic BMSC sheets may have potential in the fabrication of engineered bone.

Soils developed from the parent materials of highly weathered granite are particularly susceptible to soil erosion. Therefore, it is of great significance to conduct in-depth research on runoff characteristics and soil loss mechanisms in weathered granite areas. Using the weathered granite area in the hilly region of southeastern China as the research object, we conducted indoor artificial rainfall simulation experiments involving three slope steepnesses (SSs), 8°, 15°, and 25°, and five rainfall intensities (RIs), 0.5, 1.0, 1.5, 2.0, and 2.5 mm/min. The results showed that sediment load (SL) has positively linear relationships with mean runoff velocity (V), Reynolds number (Re), Froude number (Fr), shear stress (τ), and stream power (w). The eroded sediment was principally composed of silt and clay that accounted for 65.41–73.41% of the total SL. There was a boundary point at 0.02 mm for the particle size distribution (PSD) of the eroded sediment. The enrichment ratio (Er) of sand-grained particles (0.02–2 mm) ranged from approximately 0.45 to 0.65, while the Er of fine-grained particles (

As the application requirements of semiconductor lasers continue to increase, severe challenges are brought to the reliability of semiconductor lasers. In order to promote the study of laser failure, this paper proposes an effective failure analysis method for packaged semiconductor lasers with a simple sample preparation and home-made photon emission microscopy (PEM) system. The new simple sample preparation process for failure analysis is presented and the necessary polishing fixture is designed so that sample can be obtained without expensive and complex micro-/nano-processing. Two types of home-made PEM experimental systems were established for observing the failure from the front facet and active region of semiconductor lasers. Experimental results showed that, with the proposed sample preparation flow, the home-made PEM experimental system effectively observed the leakage defects from the front facet and dark spot defects (DSDs) in the active region of semiconductor lasers. The method can help researchers and laser manufactures to perform effective failure analysis of packaged semiconductor lasers.

Four interesting sequoiatones stereoisomers (1–4) were isolated from a wetland soil-derived fungus Talaromyces flavus by chiral HPLC. On the basis of comprehensive NMR and mass analyses, their planar structures were elucidated as the same as that of sequoiatone B. Among them, 1 and 3 (or 2 and 4) were a pair of enantiomers, and 1 and 2 (or 3 and 4) were a pair of stereoisomers with epimerization at C-12, which indicated that sequoiatione-type metabolites exist as enantiomers rather than as optically pure compounds in some strains. With the quantum chemical ECD calculations, the absolute configurations of C-8 in 1–4 were determined, which is the first report to establish the absolute configuration of C-8 in sequoiatones. However, the absolute configurations of C-12 in sequoiatones are still unsolved.

The GRAS (generally recognized as safe) status of Enterococcus has not yet been authenticated, but enterococci, as probiotics, have been increasingly applied in human healthcare and animal husbandry, for instance as a dietary supplement, feed additive, or growth promotor. The food chain is the important route for introducing enterococci into the human gut. The pathogenicity of Enterococcus from probiotic products requires investigation. In the study, 110 commercial probiotic products used for human, animal, aquaculture, and plants were examined, among which 36 enterococci were identified, including 31 from Enterococcus faecium, 2 from E. faecalis, 2 from E. casseliflavus, and 1 from E. gallinarum. Strikingly, 28 of the 36 enterococci isolated from probiotics here did not mention the presence of Enterococcus in the labeled ingredients, and no Enterococcus isolates were found from 5 animal probiotics that were labeled with the genus. In total, 35 of the 110 products exhibited hemolysis, including 5 (10.6%) human probiotics, 14 (41.2%) animal probiotics, 8 (57.1%) aquaculture probiotics, and 8 (53.3%) plant probiotics. The detection rates of virulence factors associated with adhesion, antiphagocytosis, exoenzyme, biofilm, and other putative virulence markers (PVM) in 36 enterococci were 94.4%, 91.7%, 5.6%, 94.4% and 8.3%. Twenty-six of the 36 isolated strains exhibited biofilm formation ability, where 25 strains (69.4%) and one (2.8%) were strong and weak biofilm producers, respectively. We analyzed the resistance rates against erythromycin (97%), vancomycin and ciprofloxacin (8%), tetracycline (3%), and high-level aminoglycosides (0%), respectively. High detection rates of msrC/lsaA (86%) and aac(6′)-Ii (86%) were observed, followed by vanC (8%), tetM (3%). The Tn5801-tetM-like integrative conjugative element (ICE) was identified in E. gallinarum, exhibiting resistance to tetracycline (64 μg/mL). Seven probiotic E. faecalis and E. faecium, as active ingredients in human probiotics, shared the same STs (sequence types) and were distinct from the STs of other contaminated or mislabeled enterococci, indicating that two particular STs belonged to native probiotic isolates. These findings advocate appropriate assessments of enterococci when used in probiotics.

Black phosphorus (BP) as a promising candidate for mid-wave infrared (MWIR) detection has attracted much attention. However, the high-speed photoresponse at the MWIR is yet to be a challenge. In this paper, we report a BP-graphene heterostructure photodetector with fast photoresponse at MWIR range using molybdenum electrode as a contact to realizing a low Schottky barrier. The device exhibits a fast photoresponse in a broad-spectrum range from visible to MWIR (0.67–4.2 μ m). A high photovoltaic responsivity up to 183 mA W ^−1 and EQE up to 35.6% were realized at the visible range of 0.637 μ m light and respectively 7.9 mA W ^−1 and 0.31% at MWIR 3098 nm. The specific detectivity D * = 6.69 × 10 ^8 Jones is obtained at 1 mV bias under the illumination of the MWIR 4.25 μ m in the ambient condition. Our work may open a new way to realizing fast MWIR photoresponse at the low light level.

We demonstrate a silicon-based wavelength-division multiplexing (WDM) tree splitter for optofluidic switching of nanoparticles in a lab-on-a-chip or nanofluidic system. The gradient force and scattering force induced by the evanescent field can, respectively, lead to trapping and transportation of colloidal polystyrene (PS) spheres directly above the waveguide. Guiding of PS into any designated branch within a cascaded tree splitter is achieved by switching of the excitation wavelength. As compared to that based on microrings, an optimized design of the reported tree splitter approach offers a number of advantages in terms of device compactness, wavelength tolerance, response speed, and trap stability, while maintaining the inherent low-loss and low-power performance features of WDM splitters. A network of such splitters can readily lead to a platform for high-throughput and large-scale particle manipulation in nanofluidic systems.

Cancer is a serious threat to human health. With the increasing resistance to known drugs, it is still urgent to find new drugs or pro-drugs with anti-tumor effects. Natural products produced by microorganisms have played an important role in the history of drug discovery, particularly in the anticancer and anti-infective areas. The plant rhizosphere ecosystem is a rich resource for the discovery of actinomycetes with potential applications in pharmaceutical science, especially Streptomyces. We screened Streptomyces-like strains from the rhizosphere soil of wheat (Triticum aestivum L.) in Hebei province, China, and thirty-nine strains were obtained. Among them, the extracts of 14 isolates inhibited the growth of colon tumor cell line HCT-116. Strain NEAU-wh-3-1 exhibited better inhibitory activity, and its active ingredients were further studied. Then, 16S rRNA gene sequence similarity studies showed that strain NEAU-wh3-1 with high sequence similarities to Embleya scabrispora DSM 41855T (99.65%), Embleya hyalina MB891-A1T (99.45%), and Streptomyces lasii 5H-CA11T (98.62%). Moreover, multilocus sequence analysis based on the five other house-keeping genes (atpD, gyrB, rpoB, recA, and trpB) and polyphasic taxonomic approach comprising chemotaxonomic, phylogenetic, morphological, and physiological characterization indicated that the isolate should be assigned to the genus Embleya and was different from its closely related strains, therefore, it is proposed that strain NEAU-wh3-1 may be classified as representatives of a novel species of the genus Embleya. Furthermore, active substances in the fermentation broth of strain NEAU-wh-3-1 were isolated by bioassay-guided analysis and identified by nuclear magnetic resonance (NMR) and mass spectrometry (MS) analyses. Consequently, one new Zincophorin analogue together with seven known compounds was detected. The new compound showed highest antitumor activity against three human cell lines with the 50% inhibition (IC50) values of 8.8−11.6 μg/mL and good antibacterial activity against four pathogenic bacteria, the other known compounds also exhibit certain biological activity.

Epitaxial graphene (EG) on semi-insulating SiC prepared by a thermal decomposition method is the most promising strategy for graphene application in large-scale integrated circuits due to compatibility with current semiconductor processes. In this study, high-quality few-layer graphene (FLG) was epitaxially grown on the semi-insulating on-axis 4H-SiC by microwave plasma chemical vapor deposition (MPCVD). Both sides of the SiC substrate were etched with H _2 plasma at ∼1000 °C to promote the nucleation and the growth of graphite before epitaxial growth. The surface morphology and properties of EG on SiC (0001) were measured by energy-dispersive x-ray (EDX), x-ray photoelectron spectrogram (XPS), and atomic force microscope (AFM). The qualities of EG grown on the two surfaces of SiC at various temperatures were checked by Raman spectroscopy. Furthermore, the EG growth was controlled by the effect of Ar plasma in the MPCVD and the few-layer (1–3 layers) high-quality EG films were formed on SiC (000 $\overline{1}$ ). The room temperature Hall mobility of EGs up to 2790 cm ^2 V ^−1 s ^−1 on SiC(000 $\overline{1}$ ) was realized.

In this work, four vacuolar H+-PPase (VHP) genes were identified in the grape genome. Among them, VvVHP1; 2 was strongly expressed in berry skin and its expression exhibited high correlations to anthocyanin content of berry skin during berry ripening and under ABA and UVB treatments. VvVHP1; 2 was transcriptionally activated directly by VvMYBA1, and VvVHP1; 2 overexpression promoted anthocyanin accumulation in berry skins and Arabidopsis leaves; therefore, VvVHP1; 2 mediated VvMYBA1-regulated berry pigmentation. On the other hand, RNA-Seq analysis of WT and transgenic berry skins revealed that carbohydrate metabolism, flavonoid metabolism and regulation and solute carrier family expression were the most clearly altered biological processes. Further experiments elucidated that VvVHP1; 2 overexpression up-regulated the expression of the genes related to anthocyanin biosynthesis and transport via hexokinase-mediated glucose signal and thereby promoted anthocyanin accumulation in berry skins and Arabidopsis leaves. Additionally, modifications of sugar status caused by enhanced hexokinase activities likely play a key role in VvVHP1; 2-induced sugar signaling.