A Purposefully Designed pH/GSH-Responsive MnFe-Based Metal-Organic Frameworks as Cascade Nanoreactor for Enhanced Chemo-Chemodynamic-Starvation Synergistic Therapy.

Metal-organic frameworks (MOFs) have emerged as promising novel therapeutics for treating malignancies due to their tunable porosity, biocompatibility, and modularity to functionalize with various chemotherapeutics drugs. However, the design and synthesis of dual-stimuli responsive MOFs for controlled drug release in tumor microenvironments are vitally essential but still challenging. Meanwhile, the catalytic effect of metal ions selection and ratio optimization in MOFs for enhanced chemodynamic therapy (CDT) is relatively unexplored. Herein, a series of MnFe-based MOFs with pH/glutathione (GSH)-sensitivity are synthesized and then combined with gold nanoparticles (Au NPs) and cisplatin prodrugs (DSCP) as a cascade nanoreactor (SMnFeCGH) for chemo-chemodynamic-starvation synergistic therapy. H+ and GSH can specifically activate the optimal SMnFeCGH nanoparticles in cancer cells to release Mn2+/4+ /Fe2+/3+ , Au NPs, and DSCP rapidly. The optimal ratio of Mn/Fe shows excellent H2 O2 decomposition efficiency for accelerating CDT. Au NPs can cut off the energy supply to cancer cells for starvation therapy and strengthen CDT by providing large amounts of H2 O2 . Then H2 O2 is catalyzed by Mn2+ /Fe2+ to generate highly toxic •OH with the depletion of GSH. Meanwhile, the reduced DSCP accelerates cancer cell regression for chemotherapy. The ultrasensitivity cascade nanoreactor can enhance the anticancer therapeutic effect by combining chemotherapy, CDT, and starvation therapy.

dSTORM-Based Single-Cell Protein Quantitative Analysis Can Effectively Evaluate the Degradation Ability of PROTACs.

As an emerging therapeutic strategy, proteolysis-targeting chimeras (PROTACs) have been proven to be superior to traditional drugs in many aspects. However, due to their unique mechanism of action, existing methods for evaluating the degradation still have many limitations, which seriously restricts the development of PROTACs. In this methodological study, using direct stochastic optical reconstruction microscopy (dSTORM)-based single-cell protein quantitative analysis, we systematically investigated the dynamic degradation characteristics of FLT3 protein during PROTACs treatment. We found that the distribution of FLT3 varies between FLT3-ITD mutation and FLT3-WT cells. PROTACs had an obvious time-course effect on protein degradation and present two distinct phases; this provided a basis for deciding when to evaluate protein degradation. High concentrations of PROTACs were more effective than long-time administration because a higher Dmax was achieved. Two-color dSTORM-based colocalization analysis efficiently detected the proportion of ternary complexes, making it very useful in screening PROTACs. Taken together, our findings show that the dSTORM method is an ideal tool for evaluating PROTACs and will accelerate the development of new PROTACs.

Upregulation of acetylcholinesterase caused by downregulation of microRNA-132 is responsible for the development of dementia after ischemic stroke.

MicroRNA-132 (miR-132) has been shown to participate in many diseases. This study aimed to understand the correlation between the level of miR-132 and the severity of dementia post-ischemic stroke. An online tool (www.mirdb.org) was used to find the miR-132 binding site in acetylcholinesterase (ACHE) 3'-untranslated region (UTR), followed by a luciferase reporter assay to validate ACHE as a miR-132 target. A similar relationship between miR-132 and ACHE was also established in cerebrospinal fluid samples collected from human subjects. A negative correlation was established between ACHE and miR-132 by measuring the relative luciferase activity. Meanwhile, Western blot analysis and real-time polymerase chain reaction were also conducted to compare the levels of ACHE messenger RNA and protein between two groups (dementia positive, n = 26 and dementia negative, n = 26) or among cells treated with miR-132 mimics, ACHE small interfering RNA, and miR-132 inhibitors. As shown in the results, miR-132 can reduce the expression of ACHE. Further experiments were also carried out to study the effect of miR-132 and ACHE on cell viability and apoptosis, and the results demonstrated that miR-132 enhanced cell viability while suppressing apoptosis. In addition, ACHE reduced cell viability while promoting apoptosis. miR-132 targeted ACHE and suppressed its expression. Additionally, miR-132 and ACHE have been shown to affect the cell viability and apoptosis in the central nervous system.

Metabolic syndrome and liver-related events: a systematic review and meta-analysis.

BACKGROUND: Previous studies have suggested that metabolic syndrome (MetS) and its component conditions are linked to the development of many benign or malignant diseases. Some studies have described relationships among metabolic syndrome or diabetes and liver cancer, but not many articles described the relationships between MetS and cirrhosis, acute hepatic failure, end-stage liver disease, and even death. However, liver cancers, cirrhosis, acute hepatic failure, end-stage liver disease, and liver-related mortality-collectively described as liver-related events (LREs)-may have different relationships with MetS. We undertook this meta-analysis to examine the association between MetS and LREs, and to determine whether geographic region or hepatitis B virus (HBV) positivity might influence the association. METHODS: Relevant studies were identified from PubMed, EMBASE, and the Cochrane database. Two reviewers independently searched records from January 1980 to December 2017. The search terms included 'metabolic syndrome', 'diabetes mellitus', 'insulin resistance syndrome', and 'metabolic abnormalities', combined with 'cirrhosis', 'hepatic fibrosis ', 'hepatocellular carcinoma', 'complication', 'LRE', 'HCC', 'liver-related events', and 'liver cancer'. No language restriction was applied to the search. We chose the studies reporting an association between MetS and LREs. We used Begg's and Egger's tests and visually examined a funnel plot to assess publication bias. All analyses were conducted in Stata 14.0 software. RESULTS: There were 19 studies (18 cohort and 1 case-control) included in the analysis, with a total of 1,561,457 participants. The subjects' ages ranged from 18 to 84 years. The combined analysis showed an overall 86% increase risk of LREs in cases with MetS (RR: 1.86,95% CI: 1.56-2.23). The funnel plot was asymmetrical, and the Egger's test p values showed a publication bias in this meta analysis. However, through the trim and fill method, we obtained a new RR value for LREs with MetS of 1.49 (95% CI: 1.40-1.58, p = 0.000). There was no obvious difference with the two answers, so we concluded that the results were robust. For hepatitis B positive patients, the RR for MetS and LREs was 2.15 (95% CI:1.02-4.53, p = 0.038), but for the hepatitis B negative patients, the RR was 1.85 (95% CI:1.53-2.24, p = 0.000). And for non-Asians, the RR for MetS and LREs was 2.21 (95% CI: 1.66-2.69, p = 0.000), while for Asians, the RR was 1.73 (95% CI: 1.35-2.22, p = 0.000). CONCLUSIONS: This meta-analysis showed that MetS is associated with a moderately increased risk of LREs prevalence. Patients with MetS together with hepatitis B are more likely to develop hepatic events. For non-Asians, MetS is more likely to increase the incidence of LREs.

[Clinical classification and genetic mutation study of two pedigrees with type II Waardenburg syndrome].

OBJECTIVE: To explore the molecular etiology of two pedigrees affected with type II Waardenburg syndrome (WS2) and to provide genetic diagnosis and counseling. METHODS: Blood samples were collected from the proband and his family members. Following extraction of genomic DNA, the coding sequences of PAX3, MITF, SOX10 and SNAI2 genes were amplified with PCR and subjected to DNA sequencing to detect potential mutations. RESULTS: A heterozygous deletional mutation c.649_651delAGA in exon 7 of the MITF gene has been identified in all patients from the first family, while no mutation was found in the other WS2 related genes including PAX3, MITF, SOX10 and SNAI2. CONCLUSION: The heterozygous deletion mutation c.649_651delAGA in exon 7 of the MITF gene probably underlies the disease in the first family. It is expected that other genes may also underlie WS2.

The journey of p38 MAP kinase inhibitors: From bench to bedside in treating inflammatory diseases.

The p38 mitogen-activated protein kinase (MAPK) pathway is pivotal in regulating inflammatory responses and has emerged as a key target for the development of small-molecule inhibitors aimed at treating inflammatory diseases. In arthritis, especially rheumatoid arthritis (RA), the p38 MAPK pathway contributes to chronic inflammation and joint destruction by promoting the production of pro-inflammatory cytokines. Preclinical studies have shown that small-molecule inhibitors targeting the p38 MAPK pathway hold significant promise, exhibiting the potential to reduce inflammation and preserve joint integrity. Targeting this pathway presents a novel therapeutic approach to mitigating inflammation. This review traces the evolution of p38 MAP kinase inhibitors from initial laboratory studies to clinical candidates, underscoring their potential to significantly alter the treatment approach for inflammatory diseases.

The evolution of small-molecule Akt inhibitors from hit to clinical candidate.

Akt, a key regulator of cell survival, proliferation, and metabolism, has become a prominent target for treatment of cancer and inflammatory diseases. The journey of small-molecule Akt inhibitors from discovery to the clinic has faced numerous challenges, with a significant emphasis on optimization throughout the development process. Early discovery efforts identified various classes of inhibitors, including ATP-competitive and allosteric modulators. However, during preclinical and clinical development, several issues arose, including poor specificity, limited bioavailability, and toxicity. Optimization efforts have been central to overcoming these hurdles. Researchers focused on enhancing the selectivity of inhibitors to target Akt isoforms more precisely, reducing off-target effects, and improving pharmacokinetic properties to ensure better bioavailability and distribution. Structural modifications and the design of prodrugs have played a crucial role in refining the efficacy and safety profile of these inhibitors. Additionally, efforts have been made to optimize the therapeutic window, balancing effective dosing with minimal adverse effects. The review highlights how these optimization strategies have been key in advancing small-molecule Akt inhibitors toward clinical success and underscores the importance of continued refinement in their development.

Development and validation of a nomogram for predicting poor operative visibility during FESS in Chinese adult patients with CRS.

Objective: The purpose of this study is to develop and evaluate a nomogram that is capable of predicting poor operative visibility during functional endoscopic sinus surgery. Method: To identify potential risk factors, patients with chronic rhinosinusitis who underwent functional endoscopic sinus surgery (FESS) between January 2019 and December 2022 were selected from our hospital's electronic medical record system. Data on general patient information, clinical manifestations, clotting-related test indices, Lund-Machay score of sinuses CT scanning, Lund-kennedy score of nasal endoscopies, anesthesia methods, intraoperative blood pressure and heart rate, and Boezaart bleeding score were collected. Minimum absolute convergence and selection operator (LASSO) regression, as well as multivariate logistic regression, were used to determine the risk factors. A nomogram was developed in order to predict poor operating visibility during FESS, and its performance was evaluated utilizing both the training and verification datasets via various measures including receiver operating characteristic (ROC) curve analysis, area under the curve (AUC), Hosmer-Lemeshow goodness-of-fit test, calibration curve, and decision curve analysis. Results: Of the 369 patients who met the inclusion criteria, 88 of them exhibited POV during FESS. By deploying LASSO and multivariate logistic regression analyses, six risk factors were identified and used to construct a nomogram for predicting POV during FESS. These factors include prothrombin time (PT), prothrombin activity (PTA), Lund-Mackay score (LMS), Lund-Kennedy score (LKS), anesthetic method, and intraoperative hypertension. The AUC of the training set was found to be 0.820 while that of the verification set was 0.852. The Hosmer-Lemeshow goodness-of-fit test and calibration curve analysis revealed good consistency between predicted and actual probabilities. Also, the decision curve demonstrated that the nomogram had a high degree of clinical usefulness and net benefit. Conclusion: The constructed nomogram has a strong ability to predict the poor intraoperative field in patients with chronic rhinosinusitis, which can help preoperative judgment of high-risk patients and provide evidence for perioperative management and preoperative plan formulation.

FLT3-selective PROTAC: Enhanced safety and increased synergy with Venetoclax in FLT3-ITD mutated acute myeloid leukemia.

Acute myeloid leukemia (AML) patients carrying Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations often face a poor prognosis. While some FLT3 inhibitors have been used clinically, challenges such as short efficacy and poor specificity persist. Proteolytic targeting chimera (PROTAC), with its lower ligand affinity requirement for target proteins, offers higher and rapid targeting capability. Gilteritinib, used as the ligand for the target protein, was connected with different E3 ligase ligands to synthesize several series of PROTAC targeting FLT3-ITD. Through screening and structural optimization, the optimal lead compound PROTAC Z29 showed better specificity than Gilteritinib. Z29 induced FLT3 degradation through the proteasome pathway and inhibited tumor growth in subcutaneous xenograft mice. We verified Z29's minimal impact on platelets in a patient-derived xenografts (PDX) model compared to Gilteritinib. The combination of Z29 and Venetoclax showed better anti-tumor effects, lower platelet toxicity, and lower hepatic toxicity in FLT3-ITD+ models. The FLT3-selective PROTAC can mitigate the platelet toxicity of small molecule inhibitors, ensuring safety and efficacy in monotherapy and combination therapy with Venetoclax. It is a promising strategy for FLT3-ITD+ patients, especially those with platelet deficiency or liver damage.

Head-to-head comparison of 68Ga-PSMA-11 PET/CT and 68Ga-PSMA-11 PET/MRI in the detection of biochemical recurrence of prostate cancer: summary of head-to-head comparison studies.

PURPOSE: Our meta-analysis aimed to evaluate the diagnostic performance of 68Ga-PSMA-11 PET/CT vs. 68Ga-PSMA-11 PET/MRI for biochemical recurrence of prostate cancer. METHODS: We searched for relevant articles in PubMed and Embase until February 2022. Studies evaluating head-to-head comparison of 68Ga-PSMA-11 PET/CT and 68Ga-PSMA-11 PET/MRI in men with prostate cancer biochemical recurrence were included. The quality of each study was assessed using the Quality Assessment of Diagnostic Performance Studies-2 (QUADAS-2) tool. RESULTS: A total of 5 studies with 219 patients were included in the analysis. The pooled overall detection rates of 68Ga-PSMA-11 PET/CT and 68Ga-PSMA-11 PET/MRI in detecting recurrent PCa after definitive treatment were 0.89 (95% CI: 0.65-1.00), 0.92 (95% CI: 0.77-1.00), while the detection rates were 0.20 (95% CI: 0.05-0.41) and 0.29 (95% CI: 0.10-0.53) in local recurrence, 0.51 (95% CI: 0.33-0.69) and 0.52 (95% CI: 0.44-0.61) in lymph node metastasis, 0.18 (95% CI: 0.07-0.33) and 0.20 (95% CI: 0.09-0.35) in bone metastasis. There was no significant difference between the two imaging modalities in the overall detection rate (P = 0.82). In addition, detection rates were also not significantly different in local recurrence, lymph node metastasis, or bone metastasis (P = 0.54, 1.00, 0.82). CONCLUSIONS: 68Ga-PSMA-11 PET/CT and 68Ga-PSMA-11 PET/MRI seem to have equivalent performance in detecting biochemical recurrence in prostate cancer. However, the results of the meta-analysis were drawn from studies with small samples. Further larger studies in this setting are warranted.

Engineered bacteria combined with doxorubicin nanoparticles suppress angiogenesis and metastasis in murine melanoma models.

Methods capable of distributing antitumour therapeutics uniformly throughout an entire tumour and that can suppress metastasis at the same time, would be of great significance in improving cancer treatment. Bacteria-mediated synergistic therapies have been explored for better specificity, temporal and spatial controllability, as well for providing regulation of the immune microenvironment, in order to provide improved cancer treatment. To achieve this goal, here we developed an engineered bacteria delivery system (GDOX@HSEc) using synthetic biology and interfacial chemistry technologies. The engineered bacteria were concurrently modified to express heparin sulfatase 1 (HSulf-1) inside (HSEc), to attach doxorubicin-loaded glycogen nanoparticles (GDOX NPs) on their surface. Here we demonstrate that HSEc can actively target and colonise tumour sites resulting in HSulf-1 overexpression, thereby suppressing angiogenesis and metastasis. Simultaneously, the GDOX NPs were able to penetrate into tumour cells, leading to intracellular DNA damage. Our results confirmed that a combination of biotherapy and chemotherapy using GDOX@HSEc resulted in significant melanoma suppression in murine models, with reduced side effects. This study provides a powerful platform for the simultaneous delivery of biomacromolecules and chemotherapeutic drugs to tumours, representing an innovative strategy potentially more effective in treating solid tumours. STATEMENT OF SIGNIFICANCE: An original engineered bacteria-based system (GDOX@HSEc) was developed using synthetic biology and interfacial chemistry technologies to concurrently produce naturally occurring heparin sulfatase 1 (HSulf-1) inside and anchor doxorubicin-loaded glycogen nanoparticles on the surface. GDOX@HSEc allowed for combined local delivery of chemotherapeutic agents along with the enzymes and immunostimulatory bacterial adjuvants, which resulted in a synergistic action in the inhibition of tumour growth and metastasis. The study provides a potential therapeutic approach that allows therapeutic agents to be distributed in a spatiotemporally controllable manner in tumours for combinatorial enhanced therapy.

The asymmetric effect of technology shocks on CO2 emissions: a panel analysis of BRICS economies.

Technological innovation positively contributes to economic development in BRICS countries; their environmental consequences cannot be ignored. Thus, it is imperious to explore the impact of technological shocks on environmental quality. We used ARDL and NARDL models to draw empirical consensus on the data set from 1990 to 2019 for BRICS economies. The results of ARDL model reveal that technological shocks positively affect carbon emissions in the long-run and short-run. The findings of NARDL model reveal that positive shocks in technology positively affect carbon emissions in the long-run and short-run, implying that an increase in technological development triggers an increase in carbon emissions. However, the negative shocks in technology have a negative impact on carbon emissions in the long-run, inferring that a reduction in technological development leads to a decrease in carbon emissions. The negative shock in technology has no significant impact on carbon emissions in the short-run. The findings emphasize the importance of environmental friendly technology to achieving sustainable development goals.

Role of STAT3 Expression in Thyroid Cancer: A Meta-Analysis and Systematic Review Based on the Chinese Population.

Background: Signal transduction and activator of transcription 3 (STAT3) is an oncogene with transcriptional activity. In recent years, there have been several studies concerning the clinicopathological significance of the expression of the STAT3 protein in thyroid cancer. However, the results are still inconsistent. In this study, we conducted a meta-analysis to evaluate the relationship between the expression of STAT3 protein and thyroid cancer susceptibility and its clinicopathological characteristics. Methods: We searched the China National Knowledge Infrastructure (CNKI) database, Chinese Biomedical Literature Database (CBM), Chinese Scientific and Journal Database (VIP), Wanfang, PubMed, and EMBASE. The time frame of the publication search was from the establishment of each of the databases until December 2021. We performed a meta-analysis to quantitatively evaluate the relationship between the expression of the STAT3 protein in thyroid cancer and its clinicopathological characteristics. Results: A total of eight articles were included in the meta-analysis, covering 448 thyroid cancer patients and 227 controls. Results indicated that the expression of STAT3 protein in thyroid cancer tissue is highly expressed (OR = 14.41, 95% CI (6.94, 29.91), p < 0.001). Besides, we also discovered that STAT3 protein is negatively correlated with thyroid cancer tumor diameter and TNM stage (OR = 0.13, 95% CI (0.05, 0.33), p < 0.001; OR = 0.40, 95% CI (0.24, 0.67), p < 0.001) and positively correlated with lymph node metastasis (OR = 2.83, 95% CI (1.08, 7.46), p = 0.035). However, STAT3 expression is not related to gender (OR = 0.88, 95% CI (0.54, 1.44), p = 0.609), age (OR = 0.54, 95% CI (0.21, 1.36), p = 0.191), capsular invasion (OR = 2.98, 95% CI (0.23, 38.29), p = 0.403), or tumor multiplicity (OR = 0.25, 95% CI (0.003, 19.28), p = 0.533). Conclusions: This study reveals that STAT3 protein expression is significantly related to the susceptibility and clinicopathological characteristics of thyroid cancer. It also suggests that STAT3 may be a potential predictor of the clinical progression of thyroid cancer.

Dexamethasone microspheres and celecoxib microcrystals loaded into injectable gels for enhanced knee osteoarthritis therapy.

The combination of corticosteroids and nonsteroidal anti-inflammatory drugs (NSAIDs) has been commonly used for inflammation and chronic articular pain in the clinic. Nonetheless, the long-term administration of both medications might result in osteonecrosis of the knee due to repeated injections of steroids and side effects in the gastrointestinal and cardiovascular systems. To overcome these unmet medical needs, we designed a microsphere-microcrystal-gel delivery system for intra-articular injection. Dexamethasone (DEX)-loaded microspheres (DMs) were optimized by Plackett-Burman and Taguchi orthogonal designs to extend their retention time in the knee joint. Celecoxib (CLX) microcrystals (CMs) were manufactured using an ultrasonic method to improve solubility and bioavailability. Moreover, a green solvent-free method was employed to crosslink and synthesize a novel poloxamer 407/Gantrez® S97-based gel system (GZF), which can undergo the sol-gel transition at lower concentrations. Then, DM and CM were loaded by GZF to form intra-articular injectable gels (DM/CM/Gel). The in vitro release of DEX and CLX showed a fast phase in 24 h followed by a controlled release of ∼8 d. Both blank microspheres and GZF gels displayed great biocompatibility against RAW264.7 macrophages. The most suitable dosages of 5 nM DEX and 125 nM CLX in the formulation were chosen because of their significant effects against macrophage inflammation with a lower administrative amount. An In vivo animal evaluation showed that DM/CM/Gel suppressed the release of inflammatory cytokines (TNF-α and IL-6) after 21 d of treatment. In addition, a histological evaluation revealed that DM/CM/Gel interrupted the progression of cartilage surface denudation and matrix loss. Therefore, DM/CM/Gel provides a prospective strategy for reforming traditional therapy for chronic articular disease.

Enzyme-loaded glycogen nanoparticles with tumor-targeting Activatable host-guest supramolecule for augmented chemodynamic therapy.

Chemodynamic therapy (CDT) has advantages in site-specific killing tumor and avoiding systemically side effect. Although numerous nano-systems have been developed to enhance the intracellular hydrogen peroxide (H2O2) for improving CDT effect, the biocompatibility of the materials limits their further biomedical applications. Herein glycogen, as a natural biological macromolecule, was used to construct a new targeted separable GOx@GF/HC nanoparticle system to deliver glucose oxidase (GOx) for CDT/starvation tumor therapy. Amination glycogen-ferrocene (GF) as a guest core and hyaluronic acid-ß-cyclodextrin (HC) as a host shell were synthesized and self-assembled through host-guest interactions to deliver GOx. After being entered into tumor cells, GOx were released to catalyze glucose to produce gluconic acid and H2O2, which in turn cut off the nutrition of tumor cells for starvation therapy and enhanced the generation of OH with ferrous ion through Fenton reaction. Furthermore, GOx@GF/HC also exhibited remarkable tumor-targeting and tumor-suppression in vivo. Therefore, the GOx@GF/HC system can exert excellent synergistic effect of CDT and starvation therapy on cancer treatment through a cascade reaction, which have some potential application for the development of CDT tumor-treatment.

Cardiac-Related Lesions in Newly Diagnosed Patients With Acute Leukemia: A Chinese Population-Based Real-World Study.

The relationship between newly diagnosed acute leukemia (AL) and heart-related lesions remains unclear. This study aimed to investigate baseline cardiac function and risk of cardiovascular diseases (CVDs) in patients with new-onset AL, and provide data on cardiac management strategies for patients with AL. We retrospectively collected data on baseline characteristics, echocardiography, and biochemical blood indicators (e.g., myocardial enzymes) from 408 patients, 200 with newly diagnosed AL, 103 with coronary artery disease (CAD), and 105 controls from January 1, 2015 to August 31, 2019. The creatine kinase isoenzyme myocardial band, lactate dehydrogenase, highly sensitive troponin-I, and B-type natriuretic peptide levels and left ventricular internal diameter (LVID) were significantly higher in patients with newly diagnosed AL than in the control group. The degree of cardiac damage was lower in newly diagnosed AL patients than in CAD patients. The best predictor of heart damage was LVID (AUC [area under the curve] = 0.709; 95% CI [confidence interval]: 0.637-0.781; p < 0.001), and independent prognostic risk factors were age and ejection fraction (HR [hazard ratio] = 1.636; 95% CI: 1.039-2.575; p = 0.033). The ratio of leukemia blasts among patients with AL was positively correlated with cardiac damage. Our data indicated that newly diagnosed AL patients had certain myocardial damage before treatment. Clinicians need to pay attention to these manifestations, which may be related to the prognosis.

Study of sticky rice-lime mortar technology for the restoration of historical masonry construction.

Replacing or repairing masonry mortar is usually necessary in the restoration of historical constructions, but the selection of a proper mortar is often problematic. An inappropriate choice can lead to failure of the restoration work, and perhaps even further damage. Thus, a thorough understanding of the original mortar technology and the fabrication of appropriate replacement materials are important research goals. Many kinds of materials have been used over the years in masonry mortars, and the technology has gradually evolved from the single-component mortar of ancient times to hybrid versions containing several ingredients. Beginning in 2450 BCE, lime was used as masonry mortar in Europe. In the Roman era, ground volcanic ash, brick powder, and ceramic chip were added to lime mortar, greatly improving performance. Because of its superior properties, the use of this hydraulic (that is, capable of setting underwater) mortar spread, and it was adopted throughout Europe and western Asia. Perhaps because of the absence of natural materials such as volcanic ash, hydraulic mortar technology was not developed in ancient China. However, a special inorganic-organic composite building material, sticky rice-lime mortar, was developed. This technology was extensively used in important buildings, such as tombs, in urban constructions, and even in water conservancy facilities. It may be the first widespread inorganic-organic composite mortar technology in China, or even in the world. In this Account, we discuss the origins, analysis, performance, and utility in historic preservation of sticky rice-lime mortar. Mortar samples from ancient constructions were analyzed by both chemical methods (including the iodine starch test and the acid attack experiment) and instrumental methods (including thermogravimetric differential scanning calorimetry, X-ray diffraction, Fourier transform infrared, and scanning electron microscopy). These analytical results show that the ancient masonry mortar is a special organic-inorganic composite material. The inorganic component is calcium carbonate, and the organic component is amylopectin, which is presumably derived from the sticky rice soup added to the mortar. A systematic study of sticky rice-lime mortar technology was conducted to help determine the proper courses of action in restoring ancient buildings. Lime mortars with varying sticky rice content were prepared and tested. The physical properties, mechanical strength, and compatibility of lime mortar were found to be significantly improved by the introduction of sticky rice, suggesting that sticky rice-lime mortar is a suitable material for repairing mortar in ancient masonry. Moreover, the amylopectin in the lime mortar was found to act as an inhibitor; the growth of the calcium carbonate crystals is controlled by its presence, and a compact structure results, which may explain the enhanced performance of this organic-inorganic composite compared to single-component lime mortar.

Bacteria-mediated cancer therapies: opportunities and challenges.

In recent years, cancer therapy strategies utilizing live tumor-targeting bacteria have presented unique advantages. Engineered bacteria have the particular ability to distinguish tumors from normal tissues with less toxicity. Live bacteria are naturally capable of homing to tumors, resulting in high levels of local colonization because of insufficient oxygen and low pH in the tumor microenvironment. Bacteria initiate their antitumor effects by directly killing the tumor or by activating innate and adaptive antitumor immune responses. The bacterial vectors can be reprogrammed following advanced DNA synthesis, sophisticated genetic bioengineering, and biosensors to engineer microorganisms with complex functions, and then produce and deliver anticancer agents based on clinical needs. However, because of the lack of knowledge on the mechanisms and side effects of microbial cancer therapy, developing such smart microorganisms to treat or prevent cancer remains a significant challenge. In this review, we summarized the potential, status, opportunities and challenges of this growing field. We illustrated the mechanism of tumor regression induced by engineered bacteria and discussed the recent advances in the application of bacteria-mediated cancer therapy to improve efficacy, safety and drug delivery. Finally, we shared our insights into the future directions of tumor-targeting bacteria in cancer therapy.

Microscale Schottky superlubric generator with high direct-current density and ultralong life.

Miniaturized or microscale generators that can effectively convert weak and random mechanical energy into electricity have significant potential to provide solutions for the power supply problem of distributed devices. However, owing to the common occurrence of friction and wear, all such generators developed so far have failed to simultaneously achieve sufficiently high current density and sufficiently long lifetime, which are crucial for real-world applications. To address this issue, we invent a microscale Schottky superlubric generator (S-SLG), such that the sliding contact between microsized graphite flakes and n-type silicon is in a structural superlubric state (an ultra-low friction and wearless state). The S-SLG not only generates high current (~210 Am-2) and power (~7 Wm-2) densities, but also achieves a long lifetime of at least 5,000 cycles, while maintaining stable high electrical current density (~119 Am-2). No current decay and wear are observed during the experiment, indicating that the actual persistence of the S-SLG is enduring or virtually unlimited. By excluding the mechanism of friction-induced excitation in the S-SLG, we further demonstrate an electronic drift process during relative sliding using a quasi-static semiconductor finite element simulation. Our work may guide and accelerate the future use of S-SLGs in real-world applications.

Fabrication of pH/Reduction Sensitive Polyethylene Glycol-Based Micelles for Enhanced Intracellular Drug Release.

At present, the drug is still difficult to release completely and quickly only with single stimulation. In order to promote the rapid release of polymeric micelles at tumor site, pH/reduction sensitive polymers (PCT) containing disulfide bonds and orthoester groups were synthesized. The PCT polymers can self-assemble in water and entrap doxorubicin to form drug-loaded micelles (DOX/PCT). In an in vitro drug release experiment, the cumulative release of DOX/PCT micelles in the simulated tumor microenvironment (pH 5.0 with GSH) reached (89.7 ± 11.7)% at 72 h, while it was only (16.7 ± 6.1)% in the normal physiological environment (pH 7.4 without GSH). In addition, pH sensitive DOX loaded micellar system (DOX/PAT) was prepared as a control. Furthermore, compared with DOX/PAT micelles, DOX/PCT micelles showed the stronger cytotoxicity against tumor cells to achieve an effective antitumor effect. After being internalized by clathrin/caveolin-mediated endocytosis and macropinocytosis, DOX/PCT micelles were depolymerized in intercellular acidic and a reductive environment to release DOX rapidly to kill tumor cells. Additionally, DOX/PCT micelles had a better inhibitory effect on tumor growth than DOX/PAT micelles in in vivo antitumor activity studies. Therefore, pH/reduction dual sensitive PCT polymers have great potential to be used as repaid release nanocarriers for intercellular delivery of antitumor drugs.