The prognostic and biology of tumour-infiltrating lymphocytes in the immunotherapy of cancer.

Tumour immunotherapy has achieved remarkable clinical success in many different types of cancer in the past two decades. The outcome of immune checkpoint inhibitors in cancer patients has been linked to the quality and magnitude of T cell, NK cell, and more recently, B cell within the tumour microenvironment, suggesting that the immune landscape of a tumour is highly connected to patient response and prognosis. It is critical to understanding tumour immune microenvironments for identifying immune modifiers of cancer progression and developing cancer immunotherapies. The infiltration of solid tumours by immune cells with anti-tumour activity is both a strong prognostic factor and a therapeutic goal. Recent approaches and applications of new technologies, especially single-cell mRNA analysis in dissecting tumour microenvironments have brought important insights into the biology of tumour-infiltrating immune cells, revealed a remarkable degree of cellular heterogeneity and distinct patterns of immune response. In this review, we will discuss recent advances in the understanding of tumour infiltrated lymphocytes, their prognostic benefit, and predictive value for immunotherapy.

Systematic Identification and Functional Analysis of the Hypericum perforatum L. bZIP Gene Family Indicating That Overexpressed HpbZIP69 Enhances Drought Resistance.

Basic leucine zipper (bZIP) transcription factors play significant roles in plants' growth and development processes, as well as in response to biological and abiotic stresses. Hypericum perforatum is one of the world's top three best-selling herbal medicines, mainly used to treat depression. However, there has been no systematic identification or functional analysis of the bZIP gene family in H. perforatum. In this study, 79 HpbZIP genes were identified. Based on phylogenetic analysis, the HpbZIP gene family was divided into ten groups, designated A-I and S. The physicochemical properties, gene structures, protein conserved motifs, and Gene Ontology enrichments of all HpbZIPs were systematically analyzed. The expression patterns of all genes in different tissues of H. perforatum (i.e., root, stem, leaf, and flower) were analyzed by qRT-PCR, revealing the different expression patterns of HpbZIP under abiotic stresses. The HpbZIP69 protein is localized in the nucleus. According to the results of the yeast one-hybrid (Y1H) assays, HpbZIP69 can bind to the HpASMT2 (N-acetylserotonin O-methyltransferase) gene promoter (G-box cis-element) to activate its activity. Overexpressing HpbZIP69 in Arabidopsis wild-type lines enhanced their tolerance to drought. The MDA and H2O2 contents were significantly decreased, and the activity of superoxide dismutase (SOD) was considerably increased under the drought stress. These results may aid in additional functional studies of HpbZIP transcription factors, and in cultivating drought-resistant medicinal plants.

Enantioselective Total Synthesis of Spirotryprostatin A.

In this paper, we disclosed a novel enantioselective total synthesis of spirotryprostatin A (1) in 15 steps with a 7.4% total yield from commercially available 2-iodo-5-methoxyaniline and γ-butyrolactone. The key step features of this synthesis include the copper-catalyzed cascade reaction of o-iodoaniline derivatives with alkynone to introduce the quaternary carbon stereocenter and an aza-Michael tandem reaction to construct the spiro[pyrrolidine-3,3'-oxindole] moiety.

Elevated Temperatures Decrease the Photodegradation Rate of Pyrethroid Insecticides on Spinach Leaves: Implications for the Effect of Climate Warming.

Climate warming is seldom considered in the transformation of pesticides on a plant leaf. This study investigated the effects of photodegradation temperature and spinach growth temperature from 15 to 21 °C on the photodegradation of bifenthrin, cypermethrin, fenvalerate, and deltamethrin on spinach leaves under xenon lamp irradiation in climate incubators. The photodegradation temperature had minor effects on pyrethroid photodegradation. Interestingly, the photodegradation rates decreased with increasing spinach growth temperature. For example, the photodegradation rate constant of bifenthrin on a spinach cultivated at 15 °C (3.73 (±0.59, 95% confidence level) × 10-2 h-1) was 1.9 times higher than that at 21 °C (1.96 (±0.17) × 10-2 h-1). Hydroxyl radicals (·OH) played a dominant role in the photodegradation. We speculate that ·OH originated from the degradation of hydroperoxide that was formed by oxidation of phenolic CH═CH, aliphatic CH3 and aromatic C-O-C, and subsequent hydrogen abstraction. The contents of these functional groups decreased with increasing growth temperature, which resulted in lower photodegradation rates at higher growth temperatures. A possible photodegradation pathway including ester bond cleavage, decyanation, and phenyl group removal was proposed. This work provides new insight into the effects of climate warming on the generation of reactive oxygen species and the transformation of pesticides on a plant leaf.

Influence of application of manganese ore in constructed wetlands on the mechanisms and improvement of nitrogen and phosphorus removal.

Vertical up-flow constructed wetlands (CWs) with manganese ore (Mn ore) as media (M-CWs) were developed to treat simulated polluted river water. The results showed that the average removal efficiencies for NH4-N, NO3-N, TN and TP were 91.74%, 83.29%, 87.47% and 65.12% in M-CWs, respectively, which were only 79.12%, 72.90%, 75.85% and 43.23% in the CWs without Mn ore (C-CWs). Nutrient mass balance showed that nitrogen (N) removal was improved by enhanced microbial processes, media storage and plant uptake in M-CWs. Moreover, almost 50% of phosphorus (P) was retained by media storage because of the adsorption processes on Mn ore. It was found that addition of Mn ore enhanced denitrification as the relative abundance of denitrifying bacteria increased. The produced Mn(II) and more abundant Gammaproteobacteria confirmed alternative N removal pathways including anoxic nitrification coupled to Mn ore reduction and denitrification using Mn(II) as electron donor. Mn(II) concentration in the effluent of M-CWs was below the drinking water limit of 0.1 mg/L, which makes them environmentally-friendly.

Clock protein LHY targets SNAT1 and negatively regulates the biosynthesis of melatonin in Hypericum perforatum.

Hypericum perforatum, also known as "natural fluoxetine," is a commonly used herbal remedy for treating depression. It is unclear whether melatonin in plants regulated by the endogenous circadian clock system is like in vertebrates. In this work, we found that the melatonin signal and melatonin biosynthesis gene, serotonin N-acetyltransferase HpSNAT1, oscillates in a 24-hour cycle in H. perforatum. First, we constructed a yeast complementary DNA library of H. perforatum and found a clock protein HpLHY that can directly bind to the HpSNAT1 promoter. Second, it was confirmed that HpLHY inhibits the expression of HpSNAT1 by targeting the Evening Element. Last, it indicated that HpLHY-overexpressing plants had reduced levels of melatonin in 12-hour light/12-hour dark cycle photoperiod, while loss-of-function mutants exhibited high levels, but this rhythm seems to disappear as well. The results revealed the regulatory role of LHY in melatonin biosynthesis, which may make an important contribution to the field of melatonin synthesis regulation.

Composite Scheme for Deferred Thermal Depolarization of Lead-Free Bi0.5Na0.5TiO3-Based Piezoelectric Ceramics.

The relatively low thermal depolarization temperature (Td) has hindered the development and practical application of lead-free Bi0.5Na0.5TiO3-based systems; therefore, a feasible strategy is urgently needed to defer the depolarization behavior. In this work, a perovskite/metal 0.78 Bi0.5Na0.5TiO3-0.22 Bi0.5K0.5TiO3/xAg (BNT-22BKT/xAg) composite ceramic is designed and successfully prepared. The introduction of metal Ag with a larger thermal expansion coefficient leads to an increased fraction and enhanced lattice distortion of the rhombohedral phase, as well as an enlarged domain size. The thermal stability thus is effectively improved, and the optimal Td value of 166 °C is obtained at x = 0.03, which is about 60 °C higher than that of prototype ceramics. This research provides a perovskite/metal composite scheme to increase the depolarization temperature of BNT-based ceramics and promotes their potential for practical applications.

Highly regioselective synthesis of lactams via cascade reaction of α,ß-unsaturated ketones, ketoamides, and DBU as a catalyst.

Herein, the aldol/Michael cascade reaction on the ß,γ-positions of α,ß-unsaturated ketones with ketoamides to construct bicyclic lactams via DBU catalysis has been developed. The substrates were well-tolerated with high regio- and diastereoselectivities in moderate to good yields (32 examples). The control experiments revealed that the hydrogen of the amide was the key factor.

Compensation Method for the Nonlinear Characteristics with Starting Error of a Piezoelectric Actuator in Open-Loop Controls Based on the DSPI Model.

Nanopositioning stages with piezoelectric actuators have been widely used in fields such as precision mechanical engineering, but the nonlinear start-up accuracy problem under open-loop control has still not been solved, and more errors will accumulate, especially under open-loop control. This paper first analyzes the causes of the starting errors from both the physical properties of materials and voltages: the starting errors are affected by the material properties of piezoelectric ceramics, and the magnitude of the voltage determines the magnitude of the starting errors. Then, this paper adopts an image-only model of the data separated by a Prandtl-Ishlinskii model (DSPI) based on the classical Prandtl-Ishlinskii model (CPI), which can improve the positioning accuracy of the nanopositioning platform after separating the data based on the start-up error characteristics. This model can improve the positioning accuracy of the nanopositioning platform while solving the problem of nonlinear start-up errors under open-loop control. Finally, the DSPI inverse model is used for the feedforward compensation control of the platform, and the experimental results show that the DSPI model can solve the nonlinear start-up error problem existing under open-loop control. The DSPI model not only has higher modeling accuracy than the CPI model but also has better performance in terms of compensation results. The DSPI model improves the localization accuracy by 99.427% compared to the CPI model. When compared with another improved model, the localization accuracy is improved by 92.763%.

Histone deacetylase inhibitors inhibit lung adenocarcinoma metastasis via HDAC2/YY1 mediated downregulation of Cdh1.

Metastasis is a leading cause of mortality in patients with lung adenocarcinoma. Histone deacetylases have emerged as promising targets for anti-tumor drugs, with histone deacetylase inhibitors (HDACi) being an active area of research. However, the precise mechanisms by which HDACi inhibits lung cancer metastasis remain incompletely understood. In this study, we employed a range of techniques, including qPCR, immunoblotting, co-immunoprecipitation, chromatin-immunoprecipitation, and cell migration assays, in conjunction with online database analysis, to investigate the role of HDACi and HDAC2/YY1 in the process of lung adenocarcinoma migration. The present study has demonstrated that both trichostatin A (TSA) and sodium butyrate (NaBu) significantly inhibit the invasion and migration of lung cancer cells via Histone deacetylase 2 (HDAC2). Overexpression of HDAC2 promotes lung cancer cell migration, whereas shHDAC2 effectively inhibits it. Further investigation revealed that HDAC2 interacts with YY1 and deacetylates Lysine 27 and Lysine9 of Histone 3, thereby inhibiting Cdh1 transcriptional activity and promoting cell migration. These findings have shed light on a novel functional mechanism of HDAC2/YY1 in lung adenocarcinoma cell migration.

Switchable multipath cascade cyclization to synthesize bicyclic lactams and succinimides via chemodivergent reaction.

Herein, a novel switchable multipath cascade cyclization via chemodivergent reaction between readily available ketoamides and deconjugated butenolides was developed to efficiently synthesize γ-lactone fused γ-lactams and succinimide fused hemiketals. The Aldol/aza-Michael reaction and Aldol/imidation/hemiketalization reaction were enabled by catalytic amounts of two bases, namely tetramethyl guanidine and NaOAc. A wide range of substrate scope with diverse functional group compatibility was demonstrated to deliver the corresponding products with good yield and excellent diastereoselectivity (>60 examples).

Sintilimab-induced Alopecia Universalis in a Patient With the Anti-tumor Effect of Complete Remission After Hepatectomy.

Immune checkpoint blockades have been widely used to treat various malignancies. Programmed cell death protein 1 (PD-1) inhibitor-induced alopecia areata, one of the immune-related adverse events, is rarely reported. We present a case of alopecia universalis during the treatment of Sintilimab, a monoclonal anti-PD-1 antibody, in a patient with hepatocellular carcinoma. A 65-year-old male was diagnosed with hepatocellular carcinoma in liver segment VI (S6) and chose to receive Sintilimab due to predicted insufficient residual liver volume for hepatectomy. He presented extensive hair loss in all the parts of the body 4 weeks after Sintilimab treatment. And without using any dermatologic drug, the alopecia areata gradually developed to be alopecia universalis after Sintilimab continuous treatment for 21 months. The pathological examination of skin revealed remarkable increased lymphocytes infiltration around the hair follicles, which contained predominantly CD8 positive T cells in the dermis. During single immunotherapy, the tumor marker of serum alpha-fetoprotein level soon decreased from 512.1 mg/L to a normal level within 3 months, accompanied with a remarkable tumor regression in liver S6 by magnetic resonance imaging scans. The patient received hepatectomy and pathological examination demonstrated the nodule was full of extensive necrosis. By combining immunotherapy and hepatectomy, the patient finally achieved a remarkable anti-tumor effect of complete remission. Immune checkpoint blockades-induced alopecia areata is a rare immune-related adverse event and accompanied with a good anti-tumor efficacy in our case. Regardless of alopecia treatment, PD-1 inhibitor treatment is recommended to be continued, especially when the immunotherapy is effective.

Case report: A case of heterogeneity of the antitumor response to immune checkpoint inhibitors in a patient with relapsed hepatocellular carcinoma.

The existence of tumor heterogeneity is widely recognized; however, heterogeneity of the antitumor response in multiple tumor nodules in the same patient has not been reported. Sintilimab, a monoclonal antiprogrammed cell death receptor-1 (PD-1) antibody, was used to treat patients with unresectable hepatocellular carcinoma (HCC). In the present study, we report a case of therapeutic heterogeneity in relapsed HCC with lung metastases. A 57-year-old female patient was diagnosed with HCC and underwent radical hepatectomy. One and a half years later, imaging scans found multiple metastatic tumors in the lung, which were accompanied by an increased α-fetoprotein (AFP) level. The patient then started to receive sintilimab. In the first 6 months after sintilimab treatment, all the metastatic nodules regressed gradually and ultimately disappeared, except for one nodule, which remained stable in the following 3 months. Finally, the patient underwent pulmonary lobectomy to remove the remaining nodule. Thereafter, follow-up visits showed the AFP level decreased to normal and imaging scans showed no signs of recurrence, confirming that the patient exhibited a clinically complete response. Pathological assessments showed that in the primary tumor site, the tumor comprised moderately differentiated HCC with a few infiltrated cytotoxic T cells and negative PD-L1 expression. While in the metastatic site, the nodule was composed of poorly differentiated HCC with cytotoxic T-cell infiltration with few cells inside the tumor and expressed PD-L1 in some areas of the tumor. There were dynamic alterations of PD-L1 expression and cytotoxic T-cell infiltration in the primary and relapsed HCC lesions after anti-PD-1 treatment. This case presented the heterogeneities of both the tumor microenvironment and the following antitumor response among the metastatic nodules in the same patient and revealed the importance of comprehensive therapy in cancer treatment.

Dispositional pessimism is related to reduced respiratory sinus arrhythmia reactivity to a psychosocial stressor.

The associations among dispositional optimism/pessimism, baseline RSA and RSA reactivity were investigated in the current study. Physiological data were collected from 102 young adults during baseline, social stress task (i.e., a public speaking task) and recovery periods in the laboratory. Dispositional optimism and pessimism were assessed using the revised Life Orientation Test. Results showed that higher dispositional pessimism is significantly related to lower levels of RSA reactivity to the social stress task. Finding highlight that individuals with higher levels of pessimism may be at elevated risk for physiological maladjustment.

Increasing Performances of 1-3 Piezocomposite Ultrasonic Transducer by Alternating Current Poling Method.

Ultrasonic transducers are the basic core component of diagnostic imaging devices, wherein the piezoelectric materials are the active element of transducers. Recent studies showed that the alternating current poling (ACP) method could develop the properties of piezocomposites, which had great potential to improve transducer performance. Herein, transducers (fc = 3 MHz) made of DCP and ACP 1-3 piezocomposites (prepared by PZT-5H ceramics and PMN-PT single crystals) were fabricated. The effect of the ACP method on the bandwidth and insertion loss (sensitivity) was explored. The results indicate that the ACP method can significantly enhance the bandwidth and slightly increase the insertion loss of transducers. Particularly, a superhigh bandwidth of 142.8% was achieved in the transducer of ACP 1-3 PMN-PT single crystal combined with suitable matching and backing layers. This bandwidth is higher than that of all reported transducers with similar center frequency. Moreover, the optimization mechanism of transducer performance by the ACP method was discussed. The obtained results suggested that the ACP is an effective and convenient technology to improve transducer performances, especially for the bandwidth.

Engineered Cell Membrane-Derived Nanoparticles in Immune Modulation.

Immune modulation is one of the most effective approaches in the therapy of complex diseases, including public health emergency. However, most immune therapeutics such as drugs, vaccines, and cellular therapy suffer from the limitations of poor efficacy and adverse side effects. Fortunately, cell membrane-derived nanoparticles (CMDNs) have superior compatibility with other therapeutics and offer new opportunities to push the limits of current treatments in immune modulation. As the interface between cells and outer surroundings, cell membrane contains components which instruct intercellular communication and the plasticity of cytomembrane has significantly potentiated CMDNs to leverage our immune system. Therefore, cell membranes employed in immunomodulatory CMDNs have gradually shifted from natural to engineered. In this review, unique properties of immunomodulatory CMDNs and engineering strategies of emerging CMDNs for immune modulation, with an emphasis on the design logic are summarized. Further, this review points out some pressing problems to be solved during clinical translation and put forward some suggestions on the prospect of immunoregulatory CMDNs. It is anticipated that this review can provide new insights on the design of immunoregulatory CMDNs and expand their potentiation in the precise control of the dysregulated immune system.

Prediction of asymptomatic COVID-19 infections based on complex network.

Novel coronavirus pneumonia (COVID-19) epidemic outbreak at the end of 2019 and threaten global public health, social stability, and economic development, which is characterized by highly contagious and asymptomatic infections. At present, governments around the world are taking decisive action to limit the human and economic impact of COVID-19, but very few interventions have been made to target the transmission of asymptomatic infected individuals. Thus, it is a quite crucial and complex problem to make accurate forecasts of epidemic trends, which many types of research dedicated to deal with it. In this article, we set up a novel COVID-19 transmission model by introducing traditional SEIR (susceptible-exposed-infected-removed) disease transmission models into complex network and propose an effective prediction algorithm based on the traditional machine learning algorithm TrustRank, which can predict asymptomatic infected individuals in a population contact network. Our simulation results show that our method largely outperforms the graph neural network algorithm for new coronary pneumonia prediction and our method is also robust and gives good results even if the network information is incomplete.

[Seasonal Removal Efficiency and Degradation Products of Two Typical PPCPs in Subsurface Flow Constructed Wetlands].

The pollution of surface waters by pharmaceuticals and personal care products (PPCPs) has aroused widespread concern. Constructed wetlands (CWs) have outstanding advantages in the removal of PPCPs; however, few studies have focused on the interaction of different types of PPCPs in CWs. In this study, two typical PPCPs[broad-spectrum antimicrobial agents triclosan (TCS) and non-steroidal anti-inflammatory drug diclofenac (DCF)] were selected as target pollutants and their removal behavior in subsurface flow CWs was analyzed. The effects of different seasons and influent conditions (i.e., single and combined addition of TCS and DCF) on removal efficiency was also examined. The main parameters of the CW system were as follows:the up-flow subsurface CW had a hydraulic load of 0.20 m·d-1 and a hydraulic residence time of 3 d with a continuous flow inlet. The initial influent concentration of PPCPs was 80 g·L-1 for TCS and 25 g·L-1 for DCF. The results showed that the average removal efficiencies for TCS and DCF in summer (91.72% and 85.86%, respectively) were significantly higher than in winter (52.88% and 32.47%, respectively). Independent sample t-tests confirmed that there was no significant difference in the removal efficiency of TCS and DCF under the different influent conditions (single and combined addition). The degradation products of TCS and DCF were also no different between the influent systems, and the representative degradation products of TCS were not detected in all systems. The main degradation products of DCF in the different systems were 3,5-dichlorobenzoic acid and m-dichlorobenzene. The two studied PPCPs showed no significant antagonism and competition effects at trace levels.

Mn oxides changed nitrogen removal process in constructed wetlands with a microbial electrolysis cell.

Intensified Mn redox cycling could enhance nutrient removal in constructed wetlands (CWs). In this study, Mn oxides (birnessite-coated sand) were used as the matrix in horizontal flow CWs (HFCWs) with a microbial electrolysis cell (MEC) (E-B-CW) or without an MEC (B-CW). The model CWs were developed to investigate the capacities and mechanisms of nitrogen removal with increased Mn redox cycling. The results showed that E-B-CW had the highest average removal efficiencies for NH4-N, NO3-N and TN, followed by B-CW and control HFCW (C-CW). The Mn(III) oxides (MnOOH or Mn2O3) and the Mn(IV) oxide (MnO2) were all detected in E-B-CW and B-CW, while the matrix in E-B-CW had much more Mn(IV) oxides than B-CW. Interestingly, clustering heat map showed that ammonification and nitrate reduction were related to Mn-oxidizing bacteria and the relative abundance of Mn-oxidizing bacteria in E-B-CW was highest due to the re-oxidation of Mn(II) by the MEC.