High-Entropy Design for 2D Halide Perovskite.

Hybrid halide perovskites are good candidates for a range of functional materials such as optical electronic and photovoltaic devices due to their tunable band gaps, long carrier diffusion lengths, and solution processability. However, the instability in moisture/air, the toxicity of lead, and rigorous reaction setup or complex postprocessing have long been the bottlenecks for practical application. Herein, we present a simultaneous configurational entropy design at A-sites, B-sites, and X-sites in the typical (CHA)2PbBr4 two-dimensional (2D) hybrid perovskite. Our results demonstrate that the high-entropy effect favors the stabilization of the hybrid perovskite phase and facilitates a simple crystallization process without precise control of the cooling rate to prepare regular crystals. Moreover, high-entropy 2D perovskite crystals exhibit tunable energy band gaps, broadband emission, and a long carrier lifetime. Meanwhile, the high-entropy composition almost maintains the initial crystal structure in deionized water for 18 h while the original (CHA)2PbBr4 crystal mostly decomposes, suggesting obviously improved humidity stability. This work offers a facile approach to synthesize humidity-stable hybrid perovskites under mild conditions, accelerating relevant preparation of optoelectronics and light-emitting devices and facilitating the ultimate commercialization of halide perovskite.

Quantitative response of the spatial distribution of diesel oil to freezing and thawing temperatures in groundwater.

The mobilization and redistribution of organic contaminants in groundwater is the basis and key to explore its dynamic evolution and appropriate remediation. The naturally occurring diametrical temperature gradient during freezing and thawing cycle leads to distinct behaviors of organic contaminants in groundwater. In this study, the pore-scale distribution of diesel oil in the porous media was quantitatively divided into capillary fluid state (CFS) and free fluid state (FFS) based on multiphase flow dynamics, employing low-field nuclear magnetic resonance (LF-NMR) technology. The pore-scale distribution of diesel oil depends not only on the freezing and thawing cycle but also on the temperature gradient according to LF-NMR results. The content of diesel oil in the CFS generally increases with a positive temperature gradient (e.g. freezing) compared to a negative temperature gradient (e.g. thawing), while the content of diesel oil in the FFS generally decreases. This dependence of the temperature gradient on pore-scale distribution of the diesel oil is positively correlated with the particle size of the porous medium. Furthermore, the pore-scale distribution of the diesel oil during the freezing and thawing cycle is influenced by the kinematic viscosity of the diesel oil. There is an exponential relationship between the diesel oil content and the kinematic viscosity, independent of the freezing or thawing process. During the freezing process, the diesel oil migrates from FFS to CFS, while this migration is reversed during the thawing process. The reverse migration of the diesel oil between the freezing and thawing processes leads to a spatial redistribution of the diesel oil, which is controlled by both the fluid energy and the capillary force. The present work provide meaningful guidance for the remediation of groundwater contamination in cold regions.

Expression pattern of the bone morphogenetic protein-4 and its relationship with inflammation, vascular injury in patients suffered the arterial occlusive diseases. / åŠ¨è„‰é˜»å¡žæ€§ç–¾ç— æ‚£è€ è¡€æµ†éª¨å½¢æ€å‘ç”Ÿè›‹ç™½-4çš„è¡¨è¾¾å˜åŒ–åŠå ¶ä¸Žç‚Žç—‡å’Œè¡€ç®¡æŸä¼¤çš„ç›¸å ³æ€§.

OBJECTIVES: Bone morphogenetic protein-4 (BMP4) has been proved to be an important regulatory factor for the pathological process of atherosclerosis (AS). However, there are few related clinical studies. This study aims to investigate the levels of plasma BMP4 in patients suffering from the arterial occlusive diseases (ACD) characterized by AS, and further to test the relationship between BMP4 and inflammation and vascular injury. METHODS: A total of 38 ACD patients (the ACD group) and 38 healthy people for the physical examination (the control group) were enrolled. The plasma in each subject from both groups was obtained to test the levels of BMP4, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-10, and vascular endothelial cadherin (VE-cadherin), and the relationship between BMP4 and the detected indicators above were further analyzed. RESULTS: Compared with the control group, the patients in the ACD group displayed significant elevations in the neutrophil to lymphocyte ratio [NLR, 1.63 (1.26, 1.91) vs 3.43 (2.16, 6.61)] and platelet to lymphocyte ratio [PLR, 6.37 (5.26, 7.74) vs 15.79 (7.97, 20.53)], while decrease in the lymphocyte to monocyte ratio [LMR, 5.67 (4.41, 7.14) vs 3.43 (2.07, 3.74)] (all P<0.05). Besides, the ACD patients displayed significant elevations in plasma BMP4 [581.26 (389.85, 735.64) pg/mL vs 653.97(510.95, 890.43) pg/mL], TNF-α [254.16 (182.96, 340.70) pg/mL vs 293.29(238.90, 383.44) pg/mL], and VE-cadherin [1.54 (1.08, 2.13) ng/mL vs 1.85 (1.30, 2.54) ng/mL], and decrease in IL-10 [175.89 (118.39, 219.25) pg/mL vs 135.92 (95.80, 178.04) pg/mL] (all P<0.05). While the levels of IL-1ß remained statistically comparable between the 2 groups (P=0.09). Furthermore, the plasma BMP4 levels were further revealed to be positively correlated with the levels of IL-1ß (r=0.35), TNF-α (r=0.31) and VE-cadherin (r=0.47), while they were negatively correlated with the levels of IL-10 (r=-0.37; all P<0.01). CONCLUSIONS: After ACD occurrence, the patients' plasma concentrations of BMP4 would be upregulated, which may serve as a candidate to indicate the levels of inflammation and vascular injury.

Boosting Thermoelectric Performance via Weakening Carrier-Phonon Coupling in BiCuSeO-Graphene Composites.

BiCuSeO is a promising oxygen-containing thermoelectric material due to its intrinsically low lattice thermal conductivity and excellent service stability. However, the low electrical conductivity limits its thermoelectric performance. Aliovalent element doping can significantly improve their carrier concentration, but it may also impact carrier mobility and thermal transport properties. Considering the influence of graphene on carrier-phonon decoupling, Bi0.88 Pb0.06 Ca0.06 CuSeO (BPCCSO)-graphene composites are designed. For further practical application, a rapid preparation method is employed, taking less than 1 h, which combines self-propagating high-temperature synthesis with spark plasma sintering. The incorporation of graphene simultaneously optimizes the electrical properties and thermal conductivity, yielding a high ratio of weighted mobility to lattice thermal conductivity (144 at 300 K and 95 at 923 K). Ultimately, BPCCSO-graphene composites achieve exceptional thermoelectric performance with a ZT value of 1.6 at 923 K, bringing a ≈40% improvement over BPCCSO without graphene. This work further promotes the practical application of BiCuSeO-based materials and this facile and effective strategy can also be extended to other thermoelectric systems.

Fractional derivative method for anomalous aquitard flow in a leaky aquifer system with depth-decaying aquitard hydraulic conductivity.

Aquitards significantly affect groundwater flow in multi-aquifer systems through adjacent aquifer leakage. Despite this, studies focusing on their heterogeneity and the non-conventional diffusion patterns of their flow are still limited. In this study, a factional derivative approach was first extended to explore the time-dependent behavior of flow transport in the aquitard. Two analytical solutions were derived for specific discharges in independent aquitards under different boundary conditions. The findings revealed that aquitard flow exhibits obvious anomalous diffusion behaviors, characterized by slower decay and heavy-tailed specific discharge data. The fractional derivative model provided a more accurate representation of this behavior than traditional models, as evidenced by its superior agreement with experimental data. Moreover, a transient model for pumping tests in a leaky aquifer system was developed, incorporating the memory effect of anomalous flow and vertical heterogeneity in aquitards. Relevant semi-analytical solutions were derived to explore the impacts of memory factor ß and decay exponent of aquitard hydraulic conductivity (K) on the leakage aquifer system. Theoretical results demonstrated that stronger memory effect reduces drawdowns in the aquitard and confined aquifer during mid-to-late times. A larger dimensionless decay exponent (Ad) decreases aquitard drawdown and increases aquifer drawdown at late times. Sensitivity analysis showed aquitard drawdown experiences two peaks in sensitivity to ß and Ad at early- or mid-times, affected by memory effect and decay exponent of aquitard K, signifying maximal impact at these specific intervals. This study provides a practical model to effectively manage groundwater resources by accurately reflecting aquitard memory and heterogeneity effects.

Effects of CEO water shortage experience and power intensity on corporate water performance - Evidence from China.

Corporate water performance and sustainable development are currently vital focus areas for scholars. Therefore, this paper investigates the experience of Chief Executive Officers (CEOs) with water shortage influences corporate water performance by focusing on listed companies in water-intensive and high-water-risk industries in China between 2014 and 2019. This paper manually collected information relative to the cities and provinces where CEOs grew up to evaluate their early exposure to water shortages. Furthermore, this paper develops an evaluation scale, based on the Enterprise Water Conservation Evaluation Guide (GB/T 7119-2006), to compute the enterprise water management practices scores. These results will constitute the enterprise water performance evaluation score. Moreover, this paper focuses on CEOs who have experienced water resource shortages through a positive impact on the water resource performance of their companies. As for the findings, they demonstrate that CEOs who grew up in regions with higher water scarcity have a more pronounced positive effect on their water shortage experience through corporate water performance. Furthermore, CEO power intensity positively moderates the relationship between the CEO's water shortage experience and corporate water resource performance. Further investigation reveals generational differences in the impact of CEO water shortage experience on company water performance. CEOs, who grew up during periods with a higher incidence of droughts, demonstrate a more significant promoting effect on corporate water performance. To sum up, this study expands the understanding of factors influencing corporate water resource performance and deepens the knowledge of the early life experiences of CEOs.

Research on the Thermal Insulation Properties of Three-Dimensional Spacer Jacquard Fabric Treated with Silica Aerogel.

Three-dimensional (3D) spacer fabric has the characteristics of a light weight and high strength, and its unique three-dimensional structure gives it great potential for development in terms of insulation. For the purpose of further improving the thermal insulation performance of 3D spacer fabric, the fabric was treated with silica aerogel while solving the problem of powdering during use. Firstly, the electronic Jacquard machine was modified for weaving spacer fabrics. The ground warp yarns were controlled by two groups of heald frames with various positions of heald eye, forming a double-shuttle. The longitudinal warp yarns were controlled by the Jacquard healdwine to prepare a spacer Jacquard fabric with a spacing of 5 mm. Secondly, polyurethane foam was applied as a carrier to compound with silica aerogel. The experimental results demonstrate that the strength of the composite fabrics is significantly increased, while the toughness is decreased. With the increase in silica aerogel content, the pore size of foam becomes smaller, and the degree of foam fragmentation increases, showing a trend of increasing thermal insulation performance followed by a decreasing insulation performance. When the aerogel content is 3.3%, the composite fabric has the optimal thermal insulation performance.

Gb3-Coated Bovine Milk Exosomes as a Practical Neutralizer for Shiga Toxin.

Shiga toxin (Stx) is associated with foodborne infections of some Shigella spp. and Shiga toxin-producing Escherichia coli (STEC), leading to life-threatening hemolytic uremic syndrome (HUS). Target-specific therapeutics against HUS are currently unavailable in clinical practice. Herein, we reported the construction and in vitro characterization of Gb3-coated bovine milk exosomes (Gb3-mExo) as a multivalent Shiga toxin neutralizer, utilizing the natural advantages of milk exosomes (mExo) in drug delivery and multivalent interactions between Stx and its receptor Gb3. Gb3-mExo constructs were achieved by conjugating mExo with the Gb3 derivatives containing stearic acid-derived lipid tail, which was prepared through an efficient chemoenzymatic approach. The constructs were able to potently neutralize the binding of the B subunit of Stx2 (Stx2B) to receptor Gb3 immobilized on the plate or expressed on model cells. General safety of the constructs was evidenced by the cytotoxicity analysis and hemolysis assay. In addition to the excellent stability under conventional storage and handling conditions, the construct can also retain most of its neutralization potency under gastrointestinal pH extremes, showing the potential for oral administration. Considering the natural availability and excellent biocompatibility of mExo, Gb3-mExo conjugates should prove to be a practical prophylactic and therapeutic for the Shiga toxin-related infections.

Serum Sema7A is increased in patients with acute aortic dissection.

BACKGROUND: To observe the level of serum Sema7A in acute aortic dissection (AAD) and its diagnostic value for AAD. RESEARCH DESIGN AND METHODS: Patients with sudden chest pain including AAD, acute myocardial infarction (AMI) or pulmonary embolism (PE) were enrolled. Patients without chest pain or cardiovascular diseases were included as the controls. Serum Sema7A and plasma D-dimer were detected and compared in each group. RESULTS: 85 AAD patients, 55 AMI patients, 15 PE patients, and 30 controls were enrolled. The concentration of Serum Sema7A in the AAD group was significantly higher than that in the control, AMI and PE group. Serum Sema7A was positively correlated with D-dimer. In AAD patients who underwent invasive intervention therapy, serum Sema7A levels were significantly decreased after the intervention. Serum Sema7A was an independent risk factor for the presence of AAD. The areas under the ROC curve of Sema7A and D-dimer for differential diagnosis of AAD from other chest pain disorders were 0.842 (0.776, 0.909) and 0.788 (0.714, 0.862), respectively. CONCLUSIONS: Sema7A is highly expressed in patients with AAD. Sema7A might be a valuable biomarker for the early diagnosis of AAD and has the potential to differentiate AAD from AMI and PE.

Volatilization behavior of diesel oil-water-glass bead system exposed to freeze-thaw cycles.

Volatilization plays an important role in the attenuation and redistribution of petroleum products in contaminated porous media. However, the volatilization behavior of petroleum products exposed to freeze-thaw cycles is not well understood. In this study, we investigated the volatilization behavior of diesel oil-water-glass bead systems under different freeze-thaw cycles. Low-field nuclear magnetic resonance (LF-NMR) was used to quantitatively and spatially monitor the mass loss of the diesel oil-water-glass bead system during volatilization. The mechanism of the influence of freeze-thaw cycles on volatilization in the diesel oil-water-glass bead system was analyzed. The results show that the freeze-thaw cycles have a significant effect on the volatilization rate of diesel oil and water. As the number of freeze-thaw cycles increases, the volatilization rate of diesel oil shows an overall downward trend while the volatilization rate of water shows an overall upward trend. The volatilization loss of the liquids (both diesel oil and water) is mainly due to the volatilization loss of water, indicating that water is more volatile than diesel oil in the diesel oil-water system. The spatial distribution of the diesel oil signal monitored by LF-NMR showed that diesel oil volatilizes mainly in the upper layer of the sample, associating with the preferential volatilization loss in the large pores. The lumped parameter λ related to the characteristic volatilization length LV was introduced to characterize the volatilization rate of diesel oil and water with the increase of volatilization time. For a diesel oil-water-glass bead system exposed to freeze-thaw cycles, the 1/ LV of diesel oil decreases exponentially and rapidly with increasing volatilization time, while the 1/ LV of water decreases almost linearly and slowly with increasing volatilization time. This different dependence of 1/ LV on volatilization time leads to the individual volatilization behavior of diesel oil and water.

Synthesis of structure-defined ß-1,4-GlcNAc-modified wall teichoic acids as potential vaccine against methicillin-resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is a high priority pathogen due to its life-threating infections to human health. Development of prophylactic or therapeutic anti-MRSA vaccine is a potential approach to treat S. aureus infections and overcome the resistance crisis. ß-1,4-GlcNAc glycosylated wall teichoic acids (WTAs) derived from S. aureus are a new type of antigen that is closely associated with ß-lactam resistance. In this study, structure-defined ß-1,4-GlcNAc-modified WTAs varied in chain length and numbers of GlcNAc modification were synthesized by an ionic liquid-supported oligosaccharide synthesis (ILSOS) strategy in high efficiency and chromatography-free approach. Then the obtained WTAs were conjugated with tetanus toxin (TT) as vaccine candidates and were further evaluated in a mouse model to determine the structure-immunogenicity relationship. In vivo immunological studies revealed that the WTAs-TT conjugates provoked robust T cell-dependent responses and elicited high levels of specific anti-WTAs IgG antibodies production associated with the WTAs structure including chain length as well as the ß-1,4-GlcNAc modification pattern. Heptamer WTAs conjugate T6, carrying three copy of ß-1,4-GlcNAc modified RboP, was identified to elicit the highest titers of specific antibody production. The T6 antisera exhibited the highest recognition and binding affinity and the most potent OP-killing activities to MSSA and MRSA cells. This study demonstrated that ß-1,4-GlcNAc glycosylated WTAs are promising antigens for further development against MRSA.

A liposomal carbohydrate vaccine, adjuvanted with an NKT cell agonist, induces rapid and enhanced immune responses and antibody class switching.

BACKGROUND: Congenital disorders of glycosylation (CDGs) are genetic diseases caused by gene defects in glycan biosynthesis pathways, and there is an increasing number of patients diagnosed with CDGs. Because CDGs show many different clinical symptoms, their accurate clinical diagnosis is challenging. Recently, we have shown that liposome nanoparticles bearing the ALG1-CDG and PMM2-CDG biomarkers (a tetrasaccharide: Neu5Ac-α2,6-Gal-ß1,4-GlcNAc-ß1,4-GlcNAc) stimulate a moderate immune response, while the generated antibodies show relatively weak affinity maturation. Thus, mature antibodies with class switching to IgG are desired to develop high-affinity antibodies that may be applied in medical applications. RESULTS: In the present study, a liposome-based vaccine platform carrying a chemoenzymatic synthesized phytanyl-linked tetrasaccharide biomarker was optimized. The liposome nanoparticles were constructed by dioleoylphosphatidylcholine (DOPC) to improve the stability and immunogenicity of the vaccine, and adjuvanted with the NKT cell agonist PBS57 to generate high level of IgG antibodies. The results indicated that the reformulated liposomal vaccine stimulated a stronger immune response, and PBS57 successfully induce an antibody class switch to IgG. Further analyses of IgG antibodies elicited by liposome vaccines suggested their specific binding to tetrasaccharide biomarkers, which were mainly IgG2b isotypes. CONCLUSIONS: Immunization with a liposome vaccine carrying a carbohydrate antigen and PBS57 stimulates high titers of CDG biomarker-specific IgG antibodies, thereby showing great potential as a platform to develop rapid diagnostic methods for ALG1-CDG and PMM2-CDG.

Compositing effects for high thermoelectric performance of Cu2Se-based materials.

Thermoelectric materials can realize direct conversion between heat and electricity, showing excellent potential for waste heat recovery. Cu2Se is a typical superionic conductor thermoelectric material having extraordinary ZT values, but its superionic feature causes poor service stability and low mobility. Here, we reported a fast preparation method of self-propagating high-temperature synthesis to realize in situ compositing of BiCuSeO and Cu2Se to optimize the service stability. Additionally, using the interface design by introducing graphene in these composites, the carrier mobility could be obviously enhanced, and the strong phonon scatterings could lead to lower lattice thermal conductivity. Ultimately, the Cu2Se-BiCuSeO-graphene composites presented excellent thermoelectric properties with a ZTmax value of ~2.82 at 1000 K and a ZTave value of ~1.73 from 473 K to 1000 K. This work provides a facile and effective strategy to largely improve the performance of Cu2Se-based thermoelectric materials, which could be further adopted in other thermoelectric systems.

New emission inventory reveals termination of global dioxin declining trend.

Accurate estimates of spatiotemporally resolved Polychlorinated dibenzo-p-dioxins (PCDD/Fs, or dioxins) emissions are critical for understanding their environmental fate and associated health risks. In this study, by utilizing an empirical regression model for PCDD/Fs emissions, we developed a global emission inventory for 17 toxic PCDD/Fs congeners from 8 source sectors with a spatial resolution of 1° × 1° from 2002 to 2018. The results show that PCDD/Fs emissions decreased by 25.7 % (12.5 kg TEQ) between 2002 and 2018, mostly occurring in upper- and lower-middle income countries. Globally, open-burning processes, waste incineration, ferrous and nonferrous metal production sectors and heat and power generation were the major source sectors of PCDD/Fs. Spatially, high PCDD/Fs emissions were mainly identified in East and South Asia, Southeast Asia, and part of Sub-Saharan Africa. We find that the declining trend of dioxin emissions over the past decades terminated from the early 2010s due to increasing significance of wildfire induced emissions in the total emission. The PCDD/Fs emission inventory developed in the present study was verified by inputting the inventory as initial conditions into an atmospheric transport model, the Canadian Model for Environmental Transport of Organochlorine Pesticides (CanMETOP), to simulate PCDD/Fs concentrations in air and soil. The predicted concentrations were compared to field sampling data. The good agreement between the modeled and measured concentrations demonstrates the reliability of the inventory.

Does the belt and road initiative reduce the carbon emission intensity of African participating countries?

The ambition of the Belt and Road Initiative (BRI) became an integral part of carbon emission abatement. The BRI impact on African participating countries' battle against carbon emissions intensity is a contentious subject. Urbanization and industrialization are the main sources of CO2 emissions in Africa and the driving force in the BRI. Using data on variables from 2010 to 2019 in 54 African countries, applying Difference-in-differences model (DID) and Propensity Score Matching-Difference-in-differences regression (PSM-DID), and robustness tests to investigate if the BRI's participation tends to reduce the carbon emissions intensity of African participating countries. This study finds that African countries' participation in the BRI minimizes the intensity of carbon emissions in those countries. Further analysis shows that low carbon development of BRI countries is more significant in countries that joined the BRI than those that did not join it. In addition, our results show that improving economic transformation such as the innovation in technology and industries' structures can boost the CO2 emission reduction technologies. These findings suggest that developing BRI collaboration with China will benefit the environment and African BRI participating countries' ability to achieve sustainable development. Our results further support the BRI's effect and recommend policy implications and methods for those countries' CO2 emission prevention and control actions.

Synthesis of CuO/GO-DE Catalyst and Its Catalytic Properties and Mechanism on Ciprofloxacin Degradation.

A new catalyst, copper oxide/graphene oxide-diatomaceous earth (CuO/GO-DE), was prepared by the ultrasonic impregnation method. The optimal conditions for catalyst preparation were explored, and its structure and morphology were characterized by BET, XRD, SEM, TEM, FTIR, Raman and XPS. By taking ciprofloxacin as the target pollutant, the performance and reusability of CuO/GO-DE to degrade antibiotic wastewater was evaluated, and the optimal operating conditions were obtained. The main oxidizing substances in the catalytic system under different pH conditions were analyzed, as well as the synergistic catalytic oxidation mechanism. The intermediate products of ciprofloxacin degradation were identified by LC-MS, and the possible degradation process of ciprofloxacin was proposed.

Hyaluronic Acid-Coated Bovine Milk Exosomes for Achieving Tumor-Specific Intracellular Delivery of miRNA-204.

Cell type-specific drug delivery is a straightforward strategy to achieve targeted cancer therapy and reduce side effects. Hyaluronic acid (HA), an U.S. Food and Drug Administration (FDA)-approved biocompatible carbohydrate polymer, has been extensively employed as a targeting ligand for a drug delivery system due to its natural ability to bind to tumor cells overexpressing cluster of differentiation 44 (CD44) receptors. Here, we report the preparation and antitumor efficacy of HA-coated bovine milk exosomes (HA-mExo) for tumor-specific delivery of microRNA-204-5p mimics (miR-204). The exosome-based delivery formulation was prepared with miR-204 encapsulated inside the lumen and HA displayed outside the membrane. The resultant formulation of HA-mExo-miR204 was able to specifically target CD44-positive cancer cells, with a concomitant increase in the intracellular uptake of miR-204. Compared to the uncoated mExo-miR204 formulation, HA-mExo-miR204 showed significantly increased antitumor efficacy both in vitro and in vivo. Importantly, HA-mExo-miR204 showed excellent biocompatibility and did not cause significant systemic toxicity. Given that both HA and bovine milk exosomes are low-cost and highly accessible biogenic materials with broad biomedical applications, HA-decorated bovine milk exosomes can be proven to be a practical drug delivery system of RNA drugs for targeted cancer therapy.

Progress of advanced nanomaterials in diagnosis of neurodegenerative diseases.

Neurodegenerative diseases (NDDs) encompass a wide range of clinically and pathologically diverse diseases characterized by progressive long-term cognitive decline, memory and function loss in daily life. Due to the lack of effective drugs and therapeutic strategies for preventing or delaying neurodegenerative progression, it is urgent to diagnose NDDs as early and accurately as possible. Nanomaterials, emerged as one of the most promising materials in the 21st century, have been widely applied and play a significant role in diagnosis and treatment of NDDs because of their remarkable properties including stability, prominent biocompatibility, unique structure, novel physical and chemical characteristics. In this review, we outlined general strategies for the application of different types of advanced materials in early and staged diagnosis of NDDs in vivo and in vitro. According to applied technology, in vivo research mainly involves magnetic resonance, fluorescence, and surface enhanced Raman imaging on structures of brain tissues, cerebral vessels and related distributions of biomarkers. In vitro research is focused on the detection of fluid biomarkers in cerebrospinal fluid and peripheral blood based on fluorescence, electrochemical, Raman and surface plasmon resonance techniques. Finally, we discussed the current challenges and future perspectives of biomarker-based NDDs diagnosis as well as potential applications regarding advanced nanomaterials.

Chemoenzymatic Synthesis of a Rhamnose-Functionalized Bispecific Nanobody as a Bispecific Antibody Mimic for Cancer Immunotherapy.

Bispecific antibodies (BsAbs) are next-generation therapeutics for complex cancer treatment. Herein, we developed a dual-targeting non-IgG format of bsAbs by using a bispecific nanobody (bsNb) that can simultaneously target EGFR and HER2 on tumor cells. Site-specific modification of the anti-EGFR-HER2 bsNb was conducted using the rhamnose (Rha) hapten via sortase A-mediated ligation to reconstitute the missing crystallizable fragment (Fc) effector biological functions. Functionally similar to bsAbs, bsNb-Rha conjugates retained dual-targeting activity and exerted potent anticancer effects via the Fc-domain-mediated engagement of endogenous anti-Rha antibodies. Further, an optimized bsNb-Rha conjugate exhibited markedly improved pharmacokinetics and efficient inhibitory effects against xenograft tumor growth in vivo. Our strategy provides a general and cost-effective platform to generate a new bsAb format for cancer immunotherapy.

Repurposing the Pentameric B-Subunit of Shiga Toxin for Gb3-Targeted Immunotherapy of Colorectal Cancer by Rhamnose Conjugation.

Globotriaosylceramide (Gb3 or CD77) is a tumor-associated carbohydrate antigen implicated in several types of cancer that serves as a potential cancer marker for developing target-specific diagnosis and therapy. However, the development of Gb3-targeted therapeutics has been challenging due to its carbohydrate nature. In the present work, taking advantage of its natural pentamer architecture and Gb3-specific targeting of shiga toxin B subunit (StxB), we constructed a pentameric antibody recruiting chimera by site-specifically conjugating StxB with the rhamnose hapten for immunotherapy of colorectal cancer. The Sortase A-catalyzed enzymatic tethering of rhamnose moieties to the C terminus of Stx1B and Stx2B had very moderate effect on their pentamer architectures and thus the resultant conjugates maintained the potent ability to bind to Gb3 antigen both immobilized on an assay plate and expressed on colorectal cancer cells. All StxB-rhamnose constructs were capable of efficiently mediating the binding of rhamnose antibodies onto HT29 colorectal cancer cells, which was further shown to be able to induce cancer cell lysis by eliciting potent antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) in vitro. Finally, the best StxB-rhamnose conjugate, i.e. 1B-3R, was confirmed to be able to inhibit the colorectal tumor growth using a HT29-derived xenograft murine model. Taken together, our data demonstrated the potential of repurposing StxB as an excellent multivalent scaffold for developing Gb3-targeted biotherapeutics and StxB-rhamnose conjugates might be promising candidates for targeted immunotherapy of Gb3-related colorectal cancer.