Unidirectional hyperbolic whispering-gallery phonon-polariton excitation in boron nitride nanotubes.

In two-dimensional (2D) hyperbolic materials, energy is directed into their deep subwavelength polaritonic modes through four narrow beams. Hyperbolic whispering-gallery mode nanocavity-confined phonon polaritons (PhPs) display a strongly enhanced light-matter interaction in the infrared regime. Particularly, the unidirectional phonon-polarization excitation in nanocavities has a potential application value in an on-chip integrated optical circuit design, efficient optical sensors, and enhanced spectral technology. Here, we explore the hyperbolic whispering-gallery mode PhPs on the cross section of a hexagonal BN nanotube (BNNT) and demonstrate that efficient unidirectional excitation can be achieved using a circularly polarized electric dipole, combining with optical spin-orbit coupling. Our results demonstrated that the undirectionality of the hyperbolic polariton propagation in a nanocavity can be conveniently achieved, independent of the structure symmetry of the nanocavity, providing potential applications in nanoscale light propagation, on-chip optical devices, and communication.

Tröger's Base-Embedded Pillararenes─Macrocycles with Both Fixed and Conformational Chirality.

Tröger's base-embedded pillararenes (P[1]TB[3]A), which combine Tröger's base (TB) with dialkoxybenzene units, were prepared via a fragment-coupling macrocyclization strategy. The TB unit in macrocycle P[1]TB[3]A provides a fixed chiral source, while 1,4-alkoxybenzene segments flip quickly to change their arrangement, which could provide reversible conformational chirality for those macrocycles. This rare example of macrocycles holding both fixed and conformational chirality lays a good foundation for expanding pillararenes using the fixed chiral source.

A Comprehensive Accounting of Construction Materials in Belt and Road Initiative Projects.

The Belt and Road Initiative (BRI) stands as the most ambitious infrastructure project in history, marked by its scale of investment, extensive geographical reach across continents and countries, and a diverse array of projects from roads to digital networks. While the BRI's environmental sustainability has raised concerns, the impacts of construction materials used in these projects have been overlooked, especially in developing countries. Here, we map and account for the materials embodied in the BRI by integrating, for the first time, official governmental project reports, geographical information, and material flow analysis. We pinpoint and analyze the BRI material stocks in each individual project by material types, countries, regions, and sectors. Between 2008 and 2023, 328 million tons of construction materials have accumulated in 540 BRI projects around the world, mostly in Asia and Africa. Aggregates (sand and gravel) constitute the largest share (82%), followed by cement, steel, and other materials. Most of the materials are used in transportation infrastructure. Our work further highlights some limitations in terms of data quality for such sustainability assessments. By shedding light on the significant impact of BRI projects on raw material usage across the globe, this study sets the stage for further investigations into environmental impacts of BRI and material stock-flow-nexus from perspective of an initiative.

The role of polymyxin B-immobilized hemoperfusion in reducing mortality and enhancing hemodynamics in patients with sepsis and septic shock: A systematic review and meta-analysis.

Purpose: Polymyxin B-immobilized hemoperfusion (PMX-HP) is a therapeutic strategy for removing circulating endotoxins from patients with sepsis or septic shock. However, the survival advantage of PMX-HP treatment remains controversial for patients with sepsis/septic shock. Therefore, this study collected all the clinical trials to assess the effect and the safety of PMX-HP treatment. Methods: PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for eligible trials fromtheir inception through June 30, 2023. All clinical trials that investigated the effect of polymyxin B hemoperfusion in patients who died with sepsis or septic shock within 28-day mortality were eligible. The Cochrane Risk of Bias Assessment instrument and the ROBINS-I tool were used to assess the risk of bias. Results: A total of 30 trials, including 25680 adult patients, were included. PMX-HP decreased 28-day mortality (OR 0.75, 95 % CI 0.65-0.88; p＜0.00001). Subgroup analysis revealed that 28-day mortality was significantly reduced after PMX-HP treatment in the mixed infection site group and in the age under 70 years old group. PMX-HP might also lower endotoxin levels (MD -1.22, 95 % CI -1.62 - 0.81, p < 0.00001) and improve SOFA scores (MD -2.11, 95 % CI -3.80- 0.43, p = 0.01). PMX-HP was not linked to the development of significant adverse events (p = 0. 05). Conclusion: Our findings suggest that PMX-HP therapy can reduce 28-day mortality in individuals with sepsis or septic shock. The therapeutic effect may be due to the ability of PMX-HP to lower endotoxin levels and enhance hemodynamics. However, further assessment of the clinical effects of PMX-HP on sepsis or septic shock is required.

A novel approach to managing facility airborne diseases: suppressing air pathogens with smoke aerosols generated from fungicide phase transition.

BACKGROUND: Environmental microorganisms are major contributors to the development and spread of disease. Chemical disinfection can inhibit pathogens and play a preventive role against diseases. In agriculture, prolonging the floating time of chemical pesticides in the air has a positive effect on the control of airborne diseases. However, the interaction of chemical pesticides with airborne pathogens is not yet known. RESULTS: Here, triazole fungicide was transformed into stable smoke aerosols in order to assess the feasibility of employing phase transition release pesticides for air disinfection. The phase transition had a minimal impact on hexaconazole (Hexa) and myclobutanil (Mycl), with their smoke formation rates remaining consistently >90%. In microscopic morphology, triadimenol (Tria) and epoxiconazole (Epox) are solid, and tebuconazole (Tebu), Hexa, Mycl and difenoconazole (Dife) are liquid. Liquid smoke has advantages over solid smoke in the inhibition of environmental pathogens. The floatability and spatial distribution of fungicide aerosol were optimized by the combination of smoke particles with different properties, so that the fungicide aerosol could meet the conditions of practical application. In practical applications, smoke exhibits a gentler deposition process at the target interface compared to spray, along with a more homogeneous distribution of fungicides. Moreover, fungicide smoke demonstrates superior control efficacy and leaves behind lower residual amounts on fruit. CONCLUSION: In conclusion, the implementation of fungicide phase transition as a smoke aerosol offers a viable approach to effectively suppress pathogen aerosols and enhance the control of airborne diseases. © 2024 Society of Chemical Industry.

Batch Fabrication of Flexible Strain Sensors with High Linearity and Low Hysteresis for Health Monitoring and Motion Detection.

In recent years, flexible strain sensors have gradually come into our lives due to their superiority in the field of biomonitoring. However, these sensors still suffer from poor durability, high hysteresis, and difficulty in calibration, resulting in great hindrance of practical application. Herein, starting with interfacial interaction regulation and structure-induced cracking, flexible strain sensors with high performance are successfully fabricated. In this strategy, dopamine treatment is used to enhance the bonding between flexible substrates and carbon nanotubes (CNT). The combination within the conductive networks is then controlled by substituting the CNT type. Braid-like fibers are employed to achieve controllable expansion of the conductive layer cracks. Finally, we obtain strain sensors that possess high linearity (R2 = 0.997) with low hysteresis (5%), high sensitivity (GF = 60) and wide sensing range (0-50%), short response time (62 ms), outstanding stability, and repeatability (>10,000 cycles). Flexible strain sensors with all performances good are rarely reported. Static and dynamic respiration and pulse signal monitoring by the fiber sensor are demonstrated. Moreover, a knee joint monitoring system is constructed for the monitoring of various walking stances, which is of great value to the diagnosis and rehabilitation of many diseases.

A soft, fatigue-free, and self-healable ionic elastomer via the synergy of skin-like assembly and Bouligand structure.

Soft ionic elastomers that are self-healable, fatigue-free, and environment-tolerant are ideal structural and sensing materials for artificial prosthetics, soft electronics, and robotics to survive unpredictable service conditions. However, most synthetic strategies failed to unite rapid healing, fatigue resistance, and environmental robustness, limited by their singular compositional/structural designs. Here, we present a soft, tough, fatigue-resistant, and self-healable ionic elastomer (STFSI elastomer), which fuses skin-like binary assembly and Bouligand helicoidal structure into a composite of thermoplastic polyurethane (TPU) fibers and a supramolecular ionic biopolymer. The interlocked binary assembly enables skin-like softness, high stretchability, and strain-adaptive stiffening through a matrix-to-scaffold stress transfer. The Bouligand structure contributes to superhigh fracture toughness (101.6 kJ m-2) and fatigue resistance (4937 J m-2) via mechanical toughening by interlayer slipping and twisted crack propagation path. Besides, the STFSI elastomer is self-healable through a "bridging" method and environment-tolerant (-20 ˚C ~ 60 ˚C, strong acid/alkali, saltwater). To demonstrate the versatile structural and sensing applications, we showcase a safety cushion with efficient damping and suppressed rebounding, and a robotic sensor with excellent fatigue crack tolerance and instant sensation recovery upon cutting-off damage. Our presented synthetic strategy is generalizable to other fiber-reinforced tough polymers for applications involving demanding mechanical/environmental conditions.

Individualized medication of venetoclax based on therapeutic drug monitoring in Chinese acute myeloid leukemia patients using an HPLC method.

OBJECTIVE: The aim of this study was to establish a simple and sensitive high-performance liquid chromatography method for therapeutic drug monitoring of venetoclax (VEN) and optimize regimens. METHODS: The analysis required the extraction of a 50 µl plasma sample and the precipitation of proteins using acetonitrile extraction. The chromatographic method employed a mobile phase of acetonitrile: 0.5% KH2PO4 (pH 3.5) (60/40, v/v) on a Diamond C18 (4.6 mm × 250 mm, 5 µm) column at a flow rate of 1.0 ml/min. The quantitative method was validated based on standards described in 'Bioanalytical Method Validation: Guidance for Industry' published by the US Food and Drug Administration (FDA). RESULTS: The calibration curve was linear (R2 = 0.9998) over the range of 75-4800 ng/ml, with limits of quantification of 25 ng/ml. The coefficients of intraday and interday validation, specificity, recovery, and stability all met the criteria of FDA guidance. The method was successfully applied to analyze VEN concentrations in 30 cases of acute myeloid leukemia patients. The peak concentration (Cmax) was 1881.19 ±â€…756.61 ng/ml, while the trough concentration (Cmin) was 1212.69 ±â€…767.92 ng/ml in acute myeloid leukemia patients. CONCLUSION: Our study establishes a simple, precise, and sensitive high-performance liquid chromatography method for monitoring VEN and confirms its applicability for therapeutic drug monitoring of VEN in hematological cancers.

Merkel cell polyomavirus protein ALTO modulates TBK1 activity to support persistent infection.

While Merkel cell polyomavirus (MCPyV or MCV) is an abundant virus frequently shed from healthy skin, it is one of the most lethal tumor viruses in immunocompromised individuals, highlighting the crucial role of host immunity in controlling MCPyV oncogenic potential. Despite its prevalence, very little is known about how MCPyV interfaces with the host immune response to maintain asymptomatic persistent infection and how inadequate control of MCPyV infection triggers MCC tumorigenesis. In this study, we discovered that the MCPyV protein, known as the Alternative Large Tumor Open Reading Frame (ALTO), also referred to as middle T, effectively primes and activates the STING signaling pathway. It recruits Src kinase into the complex of STING downstream kinase TBK1 to trigger its autophosphorylation, which ultimately activates the subsequent antiviral immune response. Combining single-cell analysis with both loss- and gain-of-function studies of MCPyV infection, we demonstrated that the activity of ALTO leads to a decrease in MCPyV replication. Thus, we have identified ALTO as a crucial viral factor that modulates the STING-TBK1 pathway, creating a negative feedback loop that limits viral infection and maintains a delicate balance with the host immune system. Our study reveals a novel mechanism by which a tumorigenic virus-encoded protein can link Src function in cell proliferation to the activation of innate immune signaling, thereby controlling viral spread, and sustaining persistent infection. Our previous findings suggest that STING also functions as a tumor suppressor in MCPyV-driven oncogenesis. This research provides a foundation for investigating how disruptions in the finely tuned virus-host balance, maintained by STING, could alter the fate of MCPyV infection, potentially encouraging malignancy.

Secure attachment priming inhibits the generalization of conditioned fear.

BACKGROUND: Fear overgeneralization constitutes a susceptibility factor contributing to the development and maintenance of anxiety spectrum disorders. Extant research has demonstrated that exposure to positive and supportive social relationships attenuates fear acquisition and promotes the extinction of conditioned fear responses. However, the literature lacks investigation into the effect of secure attachment priming on inhibiting the generalization of conditioned fear. METHODS: In this study, college students were recruited via online platforms to voluntarily engage in the experimental procedures, resulting in 57 subjects whose data were deemed suitable for analysis. The experimental protocol consisted of four consecutive phases: pre-acquisition, acquisition, priming, and generalization. The priming phase consisted of two experimental conditions: secure attachment priming (experimental group) and positive emotion priming (control group). This study adopted the perceptual discrimination fear conditioning paradigm, employing subjective expectancy of shock ratings and skin conductance responses as primary assessment indices. Individual difference variables were measured using corresponding psychological measurement scales. RESULTS: In terms of generalization degree, a notable divergence surfaced in the skin conductance responses across various generalization materials between the secure attachment priming group and the control group. Similarly, during generalization extinction, a significant disparity emerged in the skin conductance responses across different generalization phases between the secure attachment priming group and the control group. In addition, individual differences analyses revealed that the inhibitory effect of secure attachment priming on fear generalization was not affected by intolerance of uncertainty and attachment orientations. Conversely, slope analyses confirmed that as intolerance of uncertainty increased, the inhibitory effect of positive emotion priming on fear generalization was attenuated. CONCLUSION: The findings suggest that activating participants' representations of secure attachment via imagination effectively attenuates the generalization of perceptual fear at the physiological level. The inhibitory effect of secure attachment priming appears to be distinct from positive emotional modulation and remains unaffected by individual trait attachment styles. These results offer novel insights and avenues for the prevention and clinical intervention of anxiety spectrum disorders.

The effect of ohmic heating conditions and heating modes on gel properties of unwashed pre-rigor common carp (Cyprinus carpio) surimi.

Ohmic heating (OH) at different conditions (voltage: 15, 20, 25 V; frequency: 1, 5, 10 kHz) and one-step water bath (WB) were used to heat wash and unwash surimi prepared from fresh pre-rigor common carp. The optimal heating conditions were established through assessments of gel strength, Texture Profile Analysis (TPA), water-holding capacity (WHC), whiteness, and sensory evaluation. Then, the impact of heating modes on gelation properties of unwashed surimi based on the optimal heating conditions was investigated. The study findings indicated a significant enhancement in gel properties compared to WB. Unwashed surimi gel properties showed improvement when derived from freshly caught raw fish and subjected to OH treatment. Moreover, variations in frequencies and voltages were observed to influence the heating rate. Optimal gel quality was achieved at 10 kHz 20 V (10 V/cm), facilitating swift progression through the gel deterioration stage, inhibition of protein hydrolyzing enzymes activity, and establishment of a stable gel network. Continuing to increase the heating rate would disrupt its network structure, resulting in diminished gel strength and WHC. The best quality of unwashed surimi gel was achieved by heating to 40°C for 30 min, followed by heating to 90°C for another 30 min (40°C 30 min + 90°C 30 min) under 10 kHz 20 V. The gel strength increased when held for 1 h at 40°C. For optimal heating efficiency, the heating mode of 40°C 30 min + 90°C 30 min is recommended to prepare unwashed surimi gel. PRACTICAL APPLICATION: Ohmic heating, as a rapid food heat treatment method, can both increase the heating rate and improve the gelation properties of freshwater surimi. There is a wide range of potential applications for the heat treatment of the surimi.

Pillarurilarenes: Glycoluril-Expanded Pillararenes.

Glycoluril-expanded pillararenes composed of glycoluril and dialkoxybenzene units, namely, pillarurilarenes (PURA), were synthesized through a fragment coupling macrocyclization strategy. Partial replacement of dialkoxybenzene with glycoluril endows PURA with polarized equatorial methine protons for derivatization or CH-anion binding. Crystal structures of pillar[2]uril[4]arene and pillar[1]uril[4]arene containing two glycoluril units and one glycoluril unit, respectively, indicated the inward orientation of the glycoluril unit, as also suggested by 1H nuclear magnetic resonance and density functional theory calculation. This work lays a good foundation for expanding pillararenes using non-aromatic rings.

Assessing the Progress toward a Water-Efficient Economy in the United States from 1985 to 2015.

United Nations Sustainable Development Goal 6 tackles the long-neglected economic dimension of water utilization by monitoring nations' water use efficiency (WUE). However, it is imperative to emphasize the need for consistent spatial-temporal subnational WUE estimates, rather than relying solely on recent national trends, which can obscure crucial water use concerns and improvement opportunities. Here, a time series analysis of national, state, and sectoral (e.g., industrial, service, and agriculture) WUE from 1980 to 2015 was developed by compiling the most comprehensive and disaggregated water and economic data from 3243 US counties and 50 US states. The US total WUE increased by 181% from 16.2 (1985) to 45.6 USD/m3 (2015), driven by service sector WUE enhancements. The increased industry and service WUEs in most states were more strongly correlated with decreased per capita water withdrawal than with economic growth. Simultaneously, reductions in agriculture WUE were observed in 18 states potentially because of the complicated interaction of diverse factors specific to local communities. Expanding WUE gaps between affluent and less affluent states, and persisting WUE gaps between water-abundant andwater-scarce states highlight the need to advance policies to support under-resourced communities in effective water planning and water pricing for advancing equitable development.

Renewable Electroconductive Hydrogels for Accelerated Diabetic Wound Healing and Motion Monitoring.

Diabetic foot ulcers (DFUs), a prevalent complication of diabetes mellitus, may result in an amputation. Natural and renewable hydrogels are desirable materials for DFU dressings due to their outstanding biosafety and degradability. However, most hydrogels are usually only used for wound repair and cannot be employed to monitor motion because of their inherent poor mechanical properties and electrical conductivity. Given that proper wound stretching is beneficial for wound healing, the development of natural hydrogel patches integrated with wound repair properties and motion monitoring was expected to achieve efficient and accurate wound healing. Here, we designed a dual-network (chitosan and sodium alginate) hydrogel embedded with lignin-Ag and quercetin-melanin nanoparticles to achieve efficient wound healing and motion monitoring. The double network formed by the covalent bond and electrostatic interaction confers the hydrogel with superior mechanical properties. Instead of the usual chemical reagents, genipin extracted from Gardenia was used as a cross-linking agent for the hydrogel and consequently improved its biosafety. Furthermore, the incorporation of lignin-Ag nanoparticles greatly enhanced the mechanical strength, antibacterial efficacy, and conductivity of the hydrogel. The electrical conductivity of hydrogels gives them the capability of motion monitoring. The motion sensing mechanism is that stretching of the hydrogel induced by motion changes the conductivity of the hydrogel, thus converting the motion into an electrical signal. Meanwhile, quercetin-melanin nanoparticles confer exceptional adhesion, antioxidant, and anti-inflammatory properties to the hydrogels. The system ultimately achieved excellent wound repair and motion monitoring performance and was expected to be used for stretch-assisted safe and accurate wound repair in the future.

Detection of intracellular microRNA-21 for cancer diagnosis by a nanosystem containing a ZnO@polydopamine and DNAzyme probe.

MicroRNAs (miRNAs) are a series of single-stranded non-coding ribonucleic acid (RNA) molecules which associated closely with various human diseases. Efficient strategies for detecting miRNAs are of great significance to cancer diagnosis and prognosis. Here we provide a novel nanosystem that can be applied for the detection of miRNAs. The nanosystem consists of a single-stranded deoxyribonucleic acid (DNA) probe and a probe carrier. The DNA probe was designed based on a deoxyribozyme (DNAzyme) with several necessary functional sequences and two fluorescent dyes labeled at proper sites. The ZnO@polydopamine (ZnO@PDA) nanomaterial serves not only as a probe carrier, but also as a supplier of Zn2+ that can activate the DNAzyme. The DNA probe will undergo a conformation alteration induced by miRNA-21, which then trigger the DNAzyme catalyzed self-cleavage reaction with the assist of Zn2+ provided by ZnO decomposition under weak acid environment. A change of fluorescent color will occur due to the interruption of fluorescence resonance energy transfer between the two fluorescent dyes, and the dissociated miRNA-21 can repeatedly induce the above responses to amplify the fluorescence signal. The feasibility of the whole procedure was demonstrated by various experiments. This nanosystem showed a good selectivity towards miRNA-21, and under the optimal incubation time of 2 hours, a good linear relationship was obtained in a concentration range of 0.01-2.0 nM with a detection limit of 3.8 pM. In in vivo detection, an obvious fluorescence color change from red to green can be observed in the presence of miRNA-21. The results proved that this miRNA detection strategy has a broad application prospect in tumor diagnosis and miRNA related biological studies.

Constructing amidoxime adsorption sites on the core-shell structured natural silk protein for uranium capture.

Amidoxime-based fiber adsorbents hold significant promise for uranium extraction. However, a notable issue is that these adsorbents primarily originate from synthetic polymer materials, which, aside from providing good mechanical support, have no other functions. In recent study, we shifted our focus to silk fiber (SF), a natural protein fiber known for its unique core-shell structure and rich amino acids. The shell layer, due to its abundant functional groups, makes it easily modifiable, while the core layer provides excellent mechanical strength. Leveraging these inherent properties, an amidoxime-based fiber adsorbent was developed. This adsorbent utilizes amino and carboxyl groups for enhanced performance synergistically. This method involves establishing uranium affinity sites on the outer sericin layer of SF via chemical initiation of graft polymerization (CIGP) and amidoximation (SF-g-PAO). The water absorption ratio of SF-g-PAO is as high as 601.16 % (DG = 97.17 %). Besides, SF-g-PAO demonstrates an exceptional adsorption capacity of 15.69 mg/g in simulated seawater, achieving a remarkable removal rate of uranyl ions at 95.06 %. It can withstand a minimum of five adsorption-elution cycles. Over a 4-week period in natural seawater, SF-g-PAO displayed an adsorption capacity of 4.95 mg/g. Furthermore, SF-g-PAO also exhibits impressive uranium removal efficiency in real nuclear wastewater, with a removal rate of 63 % in just 15 min and a final removal rate of 90 %. It is hoped that this SF-g-PAO, prepared through this straightforward method and characterized by the synergistic action of amino and carboxyl groups, can offer innovative insights into the development of uranium extraction adsorbents.

Cholesterol trafficking to the ER leads to the activation of CaMKII/JNK/NLRP3 and promotes atherosclerosis.

The deposition of cholesterol-rich lipoproteins in the arterial wall triggers macrophage inflammatory responses, which promote atherosclerosis. The NLRP3 inflammasome aggravates atherosclerosis; however, cellular mechanisms connecting macrophage cholesterol accumulation to inflammasome activation are poorly understood. We investigated the mechanisms of NLRP3 inflammasome activation in cholesterol-loaded macrophages and in atherosclerosis-prone Ldlr-/- mice with defects in macrophage cholesterol efflux. We found that accumulation of cholesterol in macrophages treated with modified LDL or cholesterol crystals, or in macrophages defective in the cholesterol efflux promoting transporters ABCA1 and ABCG1, leads to activation of NLRP3 inflammasomes as a result of increased cholesterol trafficking from the plasma membrane to the ER, via Aster-B. In turn, the accumulation of cholesterol in the ER activates the inositol triphosphate-3 receptor, CaMKII/JNK, and induces NLRP3 deubiquitylation by BRCC3. An NLRP3 deubiquitylation inhibitor or deficiency of Abro1, an essential scaffolding protein in the BRCC3-containing cytosolic complex, suppressed inflammasome activation, neutrophil extracellular trap formation (NETosis), and atherosclerosis in vivo. These results identify a link between the trafficking of cholesterol to the ER, NLRP3 deubiquitylation, inflammasome activation, and atherosclerosis.

IL-12-Overexpressed Nanoparticles Suppress the Proliferation of Melanoma Through Inducing ICD and Activating DC, CD8+ T, and CD4+ T Cells.

Purpose: The drug resistance and low response rates of immunotherapy limit its application. This study aimed to construct a new nanoparticle (CaCO3-polydopamine-polyethylenimine, CPP) to effectively deliver interleukin-12 (IL-12) and suppress cancer progress through immunotherapy. Methods: The size distribution of CPP and its zeta potential were measured using a Malvern Zetasizer Nano-ZS90. The morphology and electrophoresis tentative delay of CPP were analyzed using a JEM-1400 transmission electron microscope and an ultraviolet spectrophotometer, respectively. Cell proliferation was analyzed by MTT assay. Proteins were analyzed by Western blot. IL-12 and HMGB1 levels were estimated by ELISA kits. Live/dead staining assay was performed using a Calcein-AM/PI kit. ATP production was detected using an ATP assay kit. The xenografts in vivo were estimated in C57BL/6 mice. The levels of CD80+/CD86+, CD3+/CD4+ and CD3+/CD8+ were analyzed by flow cytometry. Results: CPP could effectively express EGFP or IL-12 and increase ROS levels. Laser treatment promoted CPP-IL-12 induced the number of dead or apoptotic cell. CPP-IL-12 and laser could further enhance CALR levels and extracellular HMGB1 levels and decrease intracellular HMGB1 and ATP levels, indicating that it may induce immunogenic cell death (ICD). The tumors and weights of xenografts in CPP-IL-12 or laser-treated mice were significantly reduced than in controls. The IL-12 expression, the CD80+/CD86+ expression of DC from lymph glands, and the number of CD3+/CD8+T or CD3+/CD4+T cells from the spleen increased in CPP-IL-12-treated or laser-treated xenografts compared with controls. The levels of granzyme B, IFN-γ, and TNF-α in the serum of CPP-IL-12-treated mice increased. Interestingly, CPP-IL-12 treatment in local xenografts in the back of mice could effectively inhibit the growth of the distant untreated tumor. Conclusion: The novel CPP-IL-12 could overexpress IL-12 in melanoma cells and achieve immunotherapy to melanoma through inducing ICD, activating CD4+ T cell, and enhancing the function of tumor-reactive CD8+ T cells.

Inhibition of Anaplastic Lymphoma Kinase Protects From Ischemic Stroke.

BACKGROUND: Ischemic stroke is often accompanied by oxidative stress and inflammatory response, both of which work synergistically to exacerbate the disruption of the blood-brain barrier and ischemic brain injury. ALK (anaplastic lymphoma kinase), a cancer-associated receptor tyrosine kinase, was found to play a role in oxidative stress and inflammation. In this study, we investigated the role of ALK inhibition in a murine model of ischemic stroke. METHODS: Focal cerebral ischemia was induced by temporary occlusion of the right middle cerebral artery in mice with a filament. The ALK inhibitor alectinib was administered following the stroke. ALOX15 (arachidonic acid 15-lipoxygenase) was overexpressed by adenovirus injection. The immunohistochemistry, Western blot, oxidative stress, inflammation, blood-brain barrier leakage, infarct volume, and functional outcomes were determined. RESULTS: We found that the expression of ALK was markedly increased in the neurovascular unit after cerebral ischemia. Treatment with the ALK inhibitor alectinib reduced the accumulation of reactive oxygen species, lipid peroxidation, and oxidative DNA, increased the vascular levels of antioxidant enzymes, inactivated the vascular NLRP3 (nucleotide-binding oligomerization domain-like receptor protein 3) inflammasome pathway, and reduced vascular inflammation (ICAM-1 [intercellular adhesion molecule-1] and MCP-1 [monocyte chemoattractant protein-1]) after ischemia. Moreover, alectinib reduced the loss of cerebrovascular integrity and blood-brain barrier damage, consequently decreasing brain infarction and neurological deficits. Furthermore, alectinib reduced stroke-evoked ALOX15 expression, whereas virus-mediated overexpression of ALOX15 abolished alectinib-dependent inhibition of oxidative stress and vascular inflammation, blood-brain barrier protection, and neuroprotection, suggesting the protective effects of alectinib for stroke may involve ALOX15. CONCLUSIONS: Our findings demonstrated that alectinib protects from stroke by regulating ischemic signaling cascades and suggest that ALK may be a novel therapeutic target for ischemic stroke.

L-arginine alleviates heat stress-induced mammary gland injury through modulating CASTOR1-mTORC1 axis mediated mitochondrial homeostasis.

As global warming intensifies, extreme heat is becoming increasingly frequent. These extreme heatwaves have decreased the milk production of dairy animals such as cows and goats and have caused significant damage to the entire dairy industry. It is known that heat stress (HS) can induce the apoptosis and autophagy of mammary epithelial cells (MECs), leading to a decrease in lactating MECs. L-arginine can effectively attenuate HS-induced decreases in milk yield, but the exact mechanisms are not fully understood. In this study, we found that HS upregulated the arginine sensor CASTOR1 in mouse MECs. Arginine activated mTORC1 activity through CASTOR1 and promoted mitochondrial biogenesis through the mTORC1/PGC-1α/NRF1 pathway. Moreover, arginine inhibited mitophagy through the CASTOR1/PINK1/Parkin pathway. Mitochondrial homeostasis ensures ATP synthesis and a stable cellular redox state for MECs under HS, further alleviating HS-induced damage and improving the lactation performance of MECs. In conclusion, these findings reveal the molecular mechanisms by which L-arginine relieves HS-induced mammary gland injury, and suggest that the intake of arginine-based feeds or feed additives is a promising method to increase the milk yield of dairy animals in extreme heat conditions.