Advancement of anti-LAG-3 in cancer therapy.

Immune checkpoint inhibitors have effectively transformed the treatment of many cancers, particularly those highly devastating malignancies. With their widespread popularity, the drawbacks of immune checkpoint inhibitors are also recognized, such as drug resistance and immune-related systematic side effects. Thus, it never stops investigating novel immune checkpoint inhibitors. Lymphocyte Activation Gene-3 (LAG-3) is a well-established co-inhibitory receptor that performs negative regulation on immune responses. Recently, a novel FDA-approved LAG-3 blocking agent, together with nivolumab as a new combinational immunotherapy for metastatic melanoma, brought LAG-3 back into focus. Clinical data suggests that anti-LAG-3 agents can amplify the therapeutic response of other immune checkpoint inhibitors with manageable side effects. In this review, we elucidate the intercellular and intracellular mechanisms of LAG-3, clarify the current understanding of LAG-3 in the tumor microenvironment, identify present LAG-3-associated therapeutic agents, discuss current LAG-3-involving clinical trials, and eventually address future prospects for LAG-3 inhibitors.

The "supercompensation" effect of children's lockdown during COVID-19: based on the analysis of changes in physical activity, sleep, and psychology.

OBJECTIVE: To investigate the "supercompensation" effect of preschoolers during the coronavirus disease 2019 lockdown by comparing the changes in physical activity (PA), psychological, and sleep indicators before and after the lockdown. METHODS: A total of 127 children (aged 3-6 years) were recruited. Before and after the lockdown, the children's PA levels were measured using the ActiGraph GT3X+, and their psychological and sleep indicators were measured using the Strengths and Difficulties Questionnaire (SDQ) and Child Sleep Habit Questionnaire (CSHQ), respectively. RESULTS: Regarding PA, the children's total physical activity, low-intensity physical activity, and medium-intensity physical activity (MVPA) were higher after the lockdown than before the lockdown, with significant differences in MVPA (p < 0.05). Regarding psychology, the children's SDQ and multidimensional scores were better after the lockdown than before the lockdown, with a significant difference in SDQ scores (p < 0.05). Regarding sleep, the children's CSHQ scores were better after the lockdown than before the lockdown, with a highly significant difference in CSHQ scores (p < 0.01). CONCLUSION: After lockdown, children's PA, psychological, and sleep effects were "supercompensated." In particular, the PA of preschoolers before, during, and after the lockdown may show a "baseline-inhibition-supercompensation" process.

Moderate anthropogenic disturbance stimulates versatile microbial taxa contributing to denitrification and aromatic compound degradation.

Wastewater treatment plants (WWTPs) effluent often contains a significant amount of residual organic pollutants and nutrients, causing disturbance to the coastal effluent receiving areas (ERA). Microbial communities in coastal ERA sediments may benefit from the coexistence of organic pollutants and nutrients, promoting the emergence of versatile taxa that are capable of eliminating these substances simultaneously. However, the identification and exploration of versatile taxa in natural environments under anthropogenic disturbances remain largely uncharted territory. In this study, we specifically focused on the versatile taxa coupled by the degradation of aromatic compounds (ACs) and denitrification, using Hangzhou Bay in China as our study area. We explored how WWTPs effluent disturbance would affect the versatile taxa, and particularly examined the role of disturbance intensity in shaping their composition. Intriguingly, we found that versatile taxa were mainly derived from denitrifiers like Pseudomonas, suggesting the fulfilled potential of denitrifiers regarding ACs degradation. We also discovered that moderate disturbance stimulated the diversity of versatile taxa, resulting in strengthened functional redundancy. Through correlation network analysis, we further demonstrated that moderate disturbance enhanced the community-level cooperation. Thus, moderate disturbance serves as a catalyst for versatile taxa to maintain community function, making them more resilient to effluent disturbances. Additionally, we identified COD and NO3--N concentrations as significant environmental factors influencing the versatile taxa. Overall, our findings reveal the role of effluent disturbances in the promotion of versatile taxa, and highlight moderate disturbance can foster more robust versatile taxa that are better equipped to handle effluent disturbances.

Efficacy of agomelatine with cognitive behavioral therapy for delayed sleep-wake phase disorder in young adults: A randomized controlled study.

BACKGROUND: Delayed sleep-wake phase disorder (DSWPD) is common and easily misdiagnosed in young people, and to date, there is no evidence-based treatment. PURPOSE: A nonblinded randomized controlled study evaluated the effect of agomelatine therapy (AT) and cognitive behavior therapy (CBT) on DSWPD in young adults. METHODS: Sixty adolescents and young adults (range = 19-24 years, mean = 22 years, 52% female) diagnosed with DSWPD were randomized to receive 4 weeks of agomelatine therapy with or without cognitive behavior therapy. Sleep diaries, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Insomnia Severity Index (ISI), and World Health Organization wellbeing questionnaire (WHO-5) were measured pre-treatment and post-treatment. RESULTS: Agomelatine therapy for 4 weeks shifted the sleep-wake rhythm (p < .001) forward in both groups at the week 4 assessment. There were no significant differences in sleep onset (p = .099) and sleep offset (p = .959) between the CBT group and the no treatment (NT) group at the follow-up visits. However, significant differences were found in sleep duration (p = .002), sleep quality (p=0.005), sleep difficulties (p < .001), daytime sleepiness (p = .001), and wellbeing (p = .007) between groups. CONCLUSIONS: The improvements were received largely through the sleep-promoting effects of agomelatine therapy, and combining with cognitive behavior therapy on maintenance of altered sleep rhythms might be feasible.

The hypoxia-driven crosstalk between tumor and tumor-associated macrophages: mechanisms and clinical treatment strategies.

Given that hypoxia is a persistent physiological feature of many different solid tumors and a key driver for cancer malignancy, it is thought to be a major target in cancer treatment recently. Tumor-associated macrophages (TAMs) are the most abundant immune cells in the tumor microenvironment (TME), which have a large impact on tumor development and immunotherapy. TAMs massively accumulate within hypoxic tumor regions. TAMs and hypoxia represent a deadly combination because hypoxia has been suggested to induce a pro-tumorigenic macrophage phenotype. Hypoxia not only directly affects macrophage polarization, but it also has an indirect effect by altering the communication between tumor cells and macrophages. For example, hypoxia can influence the expression of chemokines and exosomes, both of which have profound impacts on the recipient cells. Recently, it has been demonstrated that the intricate interaction between cancer cells and TAMs in the hypoxic TME is relevant to poor prognosis and increased tumor malignancy. However, there are no comprehensive literature reviews on the molecular mechanisms underlying the hypoxia-mediated communication between tumor cells and TAMs. Therefore, this review has the aim to collect all recently available data on this topic and provide insights for developing novel therapeutic strategies for reducing the effects of hypoxia.

Metal-Organic Framework-Encapsulated CoCu Nanoparticles for the Selective Transfer Hydrogenation of Nitrobenzaldehydes: Engineering Active Armor by the Half-Way Injection Method.

A novel armor-type composite of metal-organic framework (MOF)-encapsulated CoCu nanoparticles with a Fe3 O4 core (Fe3 O4 @SiO2 -NH2 -CoCu@UiO-66) has been designed and synthesized by the half-way injection method, which successfully serves as an efficient and recyclable catalyst for the selective transfer hydrogenation. In this half-way injection approach, the pre-synthetic Fe3 O4 @SiO2 -NH2 -CoCu was injected into the UiO-66 precursor solution halfway through the MOF budding period. The formed MOF armor could play a role of providing significant additional catalytic sites besides CoCu nanoparticles, protecting CoCu nanoparticles, and improving the catalyst stability, thus facilitating the selective transfer hydrogenation of nitrobenzaldehydes into corresponding nitrobenzyl alcohols in high selectivity (99 %) and conversion (99 %) rather than nitro group reduction products. Notably, this method achieves the precise assembly of a MOF-encapsulated composite, and the ingenious combination of MOF and nanoparticles exhibits excellent catalytic performance in the selective hydrogen transfer reaction, implementing a "1+1>2" strategy in catalysis.

Fetal malnutrition is associated with impairment of endogenous melatonin synthesis in pineal via hypermethylation of promoters of protein kinase C alpha and cAMP response element-binding.

This study investigated whether and how fetal malnutrition would influence endogenous melatonin synthesis, and whether such effect of fetal malnutrition would transmit to the next generation. We enrolled 2466 participants and 1313 of their offspring. The urine 6-hydroxymelatonin sulfate and serum melatonin rhythm were measured. Methylation microarray detection and bioinformatics analysis were performed to identify hub methylated sites. Additionally, rat experiment was performed to elucidate mechanisms. The participants with fetal malnutrition had lower 6-hydroxymelatonin sulfate (16.59 ± 10.12 µg/24 hours vs 24.29 ± 11.99 µg/24 hours, P < .001) and arear under curve of melatonin rhythm (67.11 ± 8.16 pg/mL vs 77.11 ± 8.04 pg/mL, P < .001). We identified 961 differentially methylated sites, in which the hub methylated sites were locating on protein kinase C alpha (PRKCA) and cAMP response element-binding protein (CREB1) promoters, mediating the association of fetal malnutrition with impaired melatonin secretion. However, such effects were not observed in the offspring (all P > .05). Impaired histomorphology of pineal, decreased melatonin in serum, pineal, and pinealocyte were also found in the in vivo and in vitro experiments (P < .05 for the differences of the indicators). Hypermethylation of 10 CpG sites on the PRKCA promoter and 8 CpG sites on the CREB1 promoter were identified (all P < .05), which down-regulated PRKCA and CREB1 expressions, leading to decreased expression of AANAT, and then resulting in the impaired melatonin synthesis. Collectively, fetal malnutrition can impair melatonin synthesis through hypermethylation of PRKCA and CREB1 promoters, and such effects cannot be transmitted to the next generation.

Lab-on-fiber sensing system based on responsive Fabry-Perot optical resonance cavities prepared throughin situconstruction strategy.

For decades, lab-on-fiber (LOF) sensing systems have become an emerging optical sensing platform due to the features of small size and light weight. Herein, a simple and efficientin situconstruction strategy was reported for the preparation of LOF sensing platform based on the integration of responsive Fabry-Perot optical resonance cavity on optical fibers. The responsive Fabry-Perot optical resonance cavity with thermal poly(N-isopropylacrylamide) polymer brush layer sandwiched by two silver layers was constructed on the end surface of the optical fiber through combiningin situsurface-initiated polymerization and metal film deposition techniques. Owing to the thermo-responsiveness of the intermediate layer, the as-prepared LOF sensing system shows a sensitive response towards the environmental temperature. Importantly, the as-prepared LOF sensing system also possesses excellent repeatability and rapid response rate. Together with the features of high sensitivity, excellent repeatability and rapid response rate, we believe such LOF sensing system will provide a foundation for the future applications of medical diagnosis,in vivodetection and public security.

Preparation of MOF Film/Aerogel Composite Catalysts via Substrate-Seeding Secondary-Growth for the Oxygen Evolution Reaction and CO2 Cycloaddition.

Substrate-supported metal-organic frameworks (MOFs) films are desired to realize their potential in practical applications. Herein, a novel substrate-seeding secondary-growth strategy is developed to prepare composites of uniform MOFs films on aerogel walls. Briefly, the organic ligand is "pre-seeded" onto the aerogel walls, and then a small amount of metal-ion solution is sprayed onto the prepared aerogel. The sprayed solution diffuses along the aerogel walls to form a continuous thin layer, which confines the nucleation reaction, promoting the formation of uniform MOFs films on the aerogel walls. The whole process is simple in operation, highly efficient, and eco-friendly. The resulting hierarchical MOFs/aerogel composites have abundant accessible active sites and enable excellent mass transfer, which endows the composite with outstanding catalytic activity and stability in both liquid-phase CO2 cycloaddition and electrochemical oxygen evolution reaction (OER) process.

Structural and Morphological Transformation of Two-Dimensional Metal-Organic Frameworks Accompanied by Controlled Preparation Using the Spray Method.

An interesting reversible shape and structure transformation between two types of two-dimensional (2D) metal-organic frameworks (MOFs) has been successfully achieved by the spray method. The ability to precisely control the morphology and structure of 2D MOFs is also developed by altering the amount of MOF precursors and reversing the spray order. Meanwhile, the mechanism of the transformation between two MOFs is studied and conversion is induced by the change of the acidity in the reaction system. In addition, the prepared non-interpenetrate CuBDC twists exhibit more remarkable catalytic performance in C-S coupling reaction than Cu(BDC)(DMF) nanosheets owing to the more unsaturated coordination copper active sites from the non-interpenetrate structure. The catalytic result reveals the relationship between structure and function.

Retention time shift analysis and correction in chemical isotope labeling liquid chromatography/mass spectrometry for metabolome analysis.

RATIONALE: In chemical isotope labeling (CIL) liquid chromatography/mass spectrometry (LC/MS) metabolome analysis, the peak pairs of the same metabolite detected from different samples are aligned according to their mass and retention time (RT). Any RT shift of a peak pair in one of the sample files that falls outside the tolerance window will result in misalignment of the pair as a different metabolite. Thus, determination and correction of any significant RT shift are important to ensure the generation of high-quality metabolome results. METHODS: In CIL LC/MS, the heavy-isotope-labeled pooled sample is spiked into all light-isotope-labeled individual samples. As a result, in the analysis of labeled samples of the same type, many common metabolites are detectable with high intensity in all LC/MS runs. We have developed a method to select a few of these metabolites as internal RT reference markers to check the occurrence of any RT shift in an LC/MS run. If a significant shift is found, an expanded list of these markers with their RT values covering the entire LC RT window is selected to serve as internal RT calibrants to recalibrate the chromatogram to correct any RT shift. RESULTS: We developed a software program in R to perform RT check (RTC) and recalibration (RT-calib). This program can quickly determine the occurrence of any RT shift falling outside a user-defined threshold in an LC/MS run, thereby triggering a timely intervention to correct the problem (e.g., fixing a small leak or changing a column). In the analysis of 278 dansylation LC/MS runs of human urine samples, we show that the RT values can be corrected to be within a 30-second window. CONCLUSIONS: An RT-check method and program tailored to CIL LC/MS metabolome analysis have been developed for quick detection and correction of RT shifts during the course of running many metabolome samples.

Sea urchin-like CuO particles prepared using Cu3(PO4)2 flowers as precursor for high-performance ethanol sensing.

Cu3(PO4)2 flowers are reported for the first time as a solid precursor for the preparation of hierarchical CuO particles with sea urchin-like morphology in the absence of self-assembled templates or matrixes. In the alkaline condition, Cu3(PO4)2 transforms into Cu(OH)2 firstly, and then into CuO through dehydration at room temperature. Different from soluble Cu salt as precursor, the basic building blocks for CuO are continuously supplied in a controlled manner form Cu3(PO4)2 precursor, which ensures a nearly sustained supersaturated concentration that favors heterogeneous nucleation and progressive growth of sea urchin-like CuO particles. The gas sensing property of as-prepared sea urchin-like CuO particles to ethanol is investigated. The sea urchin-like CuO particles exhibit a good sensing performance in terms of high response, short response/recovery time, good selectivity, good reproducibility, and long-term stability. The facile strategy demonstrated here opens up a new strategy to fabricate hierarchical CuO particles with enormous potential from the perspective of practical application.

Encapsulation of metal oxide nanoparticles inside metal-organic frameworks via surfactant-assisted nanoconfined space.

Encapsulation of metal oxide nanoparticles (MO NPs) inside metal-organic frameworks (MOFs) has been realized successfully via surfactant-assisted nano-confined space strategy, which is a universal method for various MO NPs@MOFs. The size of MO NPs was limited by the confined nano-space and could be adjusted to a certain extent. The synthesis mechanism of MO NPs@MOFs was revealed via detailed structural characterizations and a series of control experiments. Surfactants introduced during MOFs (CuBDC, BDC = 1,4-benzenedicarboxylic acid) formation process plays a very important role in producing uniform voids of nano-confined space. Cu ions in MOF frameworks were directly used as precursors to fabricate CuO NPs in these confined void spaces. The synthesized CuO@CuBDC composites showed excellent catalytic activity in C-S cross-coupling reactions and dye pollutant photo-degradation reactions.

The efficient degradation of sulfisoxazole by singlet oxygen (1O2) derived from activated peroxymonosulfate (PMS) with Co3O4-SnO2/RSBC.

Co3O4-SnO2/rice straw biochar (RSBC) was prepared for the first time via calcining oxalate precipitation precursor dispersed on the surface of RSBC and used as a catalyst for activating PMS to degrade sulfisoxazole (SIZ). The results demonstrated that Co3O4-SnO2/RSBC possessed much better catalytic performance than Co3O4, Co3O4-SnO2, Co3O4/RSBC, and SnO2/RSBC, which is ascribed to the synergy of Co3O4, SnO2 and RSBC. Approximately 98% of SIZ (50 mg/L) was decomposed by PMS (1 mmol/L) activated with Co3O4-SnO2/RSBC (0.1 g/L) within 5 min. The optimal degradation efficiency of SIZ was realized at the initial pH 9. Co3O4-SnO2/RSBC also displayed remarkable stability and reusability, and the degradation rate of SIZ maintained over 90% even after the fifth recycle run. The electron paramagnetic resonance (EPR) technique and quenching experiments proved singlet oxygen (1O2) to be the main reactive oxygen species (ROS) responsible for the SIZ decomposition in the Co3O4-SnO2/RSBC/PMS system. On the basis of the characterization analysis, the identification of the ROS and the SIZ degradation products, the possible mechanism and pathways of the SIZ degradation by a combination of PMS and Co3O4-SnO2/RSBC were further proposed. This study provides not only a new insight into non-radical mechanism for the heterogeneous activating PMS over Co3O4-SnO2/RSBC to degrade organic pollutants but also an eco-friendly synthetic route for exploring novel and efficient catalysts.

New zonal structure and transition of the membrane to mammillae in the eggshell of chicken Gallus domesticus.

Avian eggshell is a typical bio-engineered ceramics characterized by layer structures. These layers are categorized mainly by the form of crystalline calcite. Whether there exist other layer structures, how the membrane layer is transformed to the carbonate one, what form the carbonate takes after the transition. These questions remain to be clarified. Here we examine the eggshell of chicken Gallus domesticus by optical microscope, scanning electron microscope and transmission electron microscope. We find that there exists another layer structure defined by variation of organic matrices. The transition from the membrane to the mammillary cones is implemented through the calcium reserve assemblies or the mammillary cores. The integrity of the transitional structure was weakens as the reserved calcium is displaced, and loses completely in about 10 days of incubation. As the first deposited carbonate layer after the transition, the mammillary cones comprise amorphous calcium carbonate and clusters/assemblies of calcite crystallites the size about a nanometer, plus bubble pores extending preferentially in the lateral direction. Our results provide new insights into the structure and component of the avian eggshell, and may help decipher the constitution of the bio-ceramics in the perspective of material science.

Ultrafine FeCu Alloy Nanoparticles Magnetically Immobilized in Amine-Rich Silica Spheres for Dehalogenation-Proof Hydrogenation of Nitroarenes.

A novel core-shell structured nanocatalyst (Fe3 O4 @SiO2 -NH2 -FeCu nanoparticles) with ultrafine FeCu alloy NPs magnetically immobilized in porous silica has been fabricated. The obtained catalyst revealed excellent activity and chemoselectivity for catalyzing the hydrogenation of nitroarenes to corresponding anilines using hydrazine hydrate as the hydrogen source, and the reaction could be carried out smoothly in water, which is an environmentally friendly solvent. The FeCu alloy effectively prevented the dehalogenation of halonitroarenes, and X-ray photoelectron spectroscopy (XPS) study showed that it resulted from the electron-enrichment of Fe from Cu. A kinetics study indicated that the reaction order was about 1.5 towards 4-CNB and the apparent active energy (Ea ) was 48.1 kJ mol-1 , which is a relatively low value. Furthermore, the FeCu NPs are magnetically immobilized in the silica spheres (Fe3 O4 @SiO2 ), therefore the catalyst can be easily recovered by use of an external magnet and also possesses a long life time.

Highly Transparent, Conductive, and Bendable Ag Nanowire Electrodes with Enhanced Mechanical Stability Based on Polyelectrolyte Adhesive Layer.

In this paper, a highly transparent, conductive, and bendable Ag nanowire (AgNW)-based electrode with excellent mechanical stability was prepared through the introduction of an adhesive polyelectrolyte multilayer between AgNW networks and a polyethylene terephthalate (PET) substrate. The introduction of the adhesive layer was performed based on a peel-assembly-transfer procedure, and the adhesive polyelectrolyte greatly improved the mechanical stability of the AgNW transparent conductive films (TCFs) without obviously attenuating the morphology and optoelectrical properties of the AgNW networks. The as-prepared AgNW TCFs simultaneously possess high optical transparency, good conductivity, excellent flexibility, and remarkable mechanical stability. It is believed that the proposed strategy would pave a new way for preparing flexible transparent electrodes with a long-term stability, which is significant in the development and practical applications of flexible transparent electronic devices operated in severe environments.

Approach to Fabricating a Compact Gold Nanoparticle Film with the Assistance of a Surfactant.

We report a facile method to fabricate a compact Au nanoparticle film with the assistance of surfactants. First, the dodecanethiol-coated Au nanoparticles were floated on the surface of the toluene/acetonitrile solvent mixture and adjusted to an expanded dispersion by changing the mixture ratio. Silicone oil was then added as a surfactant to compress the floating nanoparticles from the original loose status to a closely packed arrangement that produced a compact nanoparticle film. The relationship of the compressed film area to the silicone oil concentration was plotted and compared to the surface tension curve of silicone oil. The results were quite consistent, suggesting that the surface location of the surfactant induced the nanoparticles' compression. The resulting nanoparticle film was uniform and sufficiently robust to be transferred to the solid substrate. Moreover, it could be applied to catalyze the reduction of 4-nitrophenol. Our study indicated that the utilization of surfactants to compress the well-dispersed nanoparticles on the liquid surface is a simple, fast, and adaptable method of fabricateing compact nanoparticle films with great promise for future applications.

Fabrication of Metal-Organic Framework and Infinite Coordination Polymer Nanosheets by the Spray Technique.

We have developed a rapid and convenient method for fabricating metal-organic framework (MOF) and infinite coordination polymer (ICP) nanosheets by spraying the atomized solution of metal ions onto the organic ligand solution. Nanosheet formation could be attributed to the anisotropic diffusion of metal ions in the ligand solution, which may give rise to a lateral interface of metal ions and organic ligands, where the crystals tend to grow laterally in the form of nanosheets. Three kinds of Zn- and Cu-based MOF nanosheets and two kinds of Co-based ICP nanosheets have been successfully obtained by spraying under mild conditions. The two-dimensional structures of nanosheets with a nanometer thickness and a homogeneous size can be evidenced by scanning electron microscopy, atomic force microscopy, X-ray diffraction, Brunauer-Emmett-Teller, and Fourier transform infrared spectroscopy measurements. Furthermore, the fabricated ICP nanosheets have exhibited efficient catalytic performance for the conversion of CO2 to high-value-added chemicals. This spray technique simplifies the nanosheet production process by industrialized means and enhances its controllability by the fast liquid-liquid interfacial fabrication, thus allowing access to the industrialized fabrication of MOF and ICP nanosheets.

Optimally designed gold nanorattles with strong built-in hotspots and weak polarization dependence.

Localized electromagnetic fields generated by interparticle plasmon coupling suffer greatly from nonreproducibility because they are extremely sensitive to the nanoparticle aggregation status and the incident polarization. Here, we synthesize gold nanorattles that exhibit inherent aggregation-insensitive hotspots due to the intraparticle core-shell plasmon coupling, and investigate the structural effect on the intraparticle coupling strength and its polarization dependence. Through optimizing the structural parameters, we successfully synthesize gold nanorattles with strong built-in hotspots and weak polarization dependence. These aggregation-insensitive and weakly polarization-dependent hotspots make the Raman enhancement from nanorattle aggregates show an unusual weak dependence on the particle aggregation status, which therefore affords the opportunity to fabricate uniform and reproducible surface enhanced Raman scattering substrates.