Wavelet denoising of fiber optic monitoring signals in permafrost regions.

To address the noise issue in fiber optic monitoring signals in frozen soil areas, this study employs wavelet denoising techniques to process the fiber optic signals. Since existing parameter choices for wavelets are typically based on conventional environments, selecting suitable parameters for frozen soil regions becomes crucial. In this work, an index library is constructed based on commonly used wavelet basis functions in civil engineering. An optimal wavelet basis function is objectively selected through specific criteria. Considering the characteristic of small root mean square error in fiber optic signals in frozen soil areas, a multi-index fusion approach is applied to determine the optimal decomposition level. Field observations validate that denoised signals, with parameters set appropriately, can more accurately identify locations where settlement occurs.

Instant p-doping and pore elimination of the spiro-OMeTAD hole-transport layer in perovskite solar cells.

An instant p-doping strategy employing 4-tert-butyl-2-chloropyridine and tert-butyl peroxybenzoate for the spiro-OMeTAD hole-transport layer (HTL) in perovskite solar cells (PSCs) is proposed to replace the conventional 4-tert-butylpyridine-doped HTL. The novel doping process eliminates the formation of pores in the HTL. Meanwhile, a 21.4% efficiency is achieved on the corresponding absolute methylammonium-free PSCs with significantly improved thermal and moisture stability.

mRNA-Laden Lipid-Nanoparticle-Enabled in Situ CAR-Macrophage Engineering for the Eradication of Multidrug-Resistant Bacteria in a Sepsis Mouse Model.

Sepsis, which is the most severe clinical manifestation of acute infection and has a mortality rate higher than that of cancer, represents a significant global public health burden. Persistent methicillin-resistant Staphylococcus aureus (MRSA) infection and further host immune paralysis are the leading causes of sepsis-associated death, but limited clinical interventions that target sepsis have failed to effectively restore immune homeostasis to enable complete eradication of MRSA. To restimulate anti-MRSA innate immunity, we developed CRV peptide-modified lipid nanoparticles (CRV/LNP-RNAs) for transient in situ programming of macrophages (MΦs). The CRV/LNP-RNAs enabled the delivery of MRSA-targeted chimeric antigen receptor (CAR) mRNA (SasA-CAR mRNA) and CASP11 (a key MRSA intracellular evasion target) siRNA to MΦs in situ, yielding CAR-MΦs with boosted bactericidal potency. Specifically, our results demonstrated that the engineered MΦs could efficiently phagocytose and digest MRSA intracellularly, preventing immune evasion by the "superbug" MRSA. Our findings highlight the potential of nanoparticle-enabled in vivo generation of CAR-MΦs as a therapeutic platform for multidrug-resistant (MDR) bacterial infections and should be confirmed in clinical trials.

Selective grain boundary passivation by ammonium nitrate for enhanced performance and stability of FA-Cs based perovskite solar cells.

Grain boundaries of metal halide perovskites contain massive defects that are detrimental to photovoltaics applications. This work demonstrates that inorganic NH4NO3 can selectively passivate the grain boundaries of perovskite films and improve their moisture resistance simultaneously, resulting in enhanced performance and stability of the methylammonium-free perovskite solar cells.

Intracavitary Spraying of Nanoregulator-Encased Hydrogel Modulates Cholesterol Metabolism of Glioma-Supportive Macrophage for Postoperative Glioblastoma Immunotherapy.

Glioblastoma multiforme (GBM) is notoriously resistant to immunotherapy due to its intricate immunosuppressive tumor microenvironment (TME). Dysregulated cholesterol metabolism is implicated in the TME and promotes tumor progression. Here, it is found that cholesterol levels in GBM tissues are abnormally high, and glioma-supportive macrophages (GSMs), an essential "cholesterol factory", demonstrate aberrantly hyperactive cholesterol metabolism and efflux, providing cholesterol to fuel GBM growth and induce CD8+ T cells exhaustion. Bioinformatics analysis confirms that high 7-dehydrocholesterol reductase (DHCR7) level in GBM tissues associates with increased cholesterol biosynthesis, suppressed tumoricidal immune response, and poor patient survival, and DHCR7 expression level is significantly elevated in GSMs. Therefore, an intracavitary sprayable nanoregulator (NR)-encased hydrogel system to modulate cholesterol metabolism of GSMs is reported. The degradable NR-mediated ablation of DHCR7 in GSMs effectively suppresses cholesterol supply and activates T-cell immunity. Moreover, the combination of Toll-like receptor 7/8 (TLR7/8) agonists significantly promotes GSM polarization to antitumor phenotypes and ameliorates the TME. Treatment with the hybrid system exhibits superior antitumor effects in the orthotopic GBM model and postsurgical recurrence model. Altogether, the findings unravel the role of GSMs DHCR7/cholesterol signaling in the regulation of TME, presenting a potential treatment strategy that warrants further clinical trials.

Dual mRNA co-delivery for in situ generation of phagocytosis-enhanced CAR macrophages augments hepatocellular carcinoma immunotherapy.

Hepatocellular carcinoma (HCC) is a prevalent and lethal disease, and tumor regression rarely occurs in advanced HCC patients due to limited effective therapies. Given the enrichment of macrophages in HCC and their role in tumor immunity, transforming them into chimeric antigen receptor macrophages (CAR-Ms) is thought to increase HCC cell-directed phagocytosis and tumoricidal immunity. To test this hypothesis, mRNA encoding CAR is encapsulated in a lipid nanoparticle (LNP) that targets liver macrophages. Notably, the LNPs adsorb specific plasma proteins that enable them to target HCC-associated macrophages. Moreover, mRNA encoding Siglec-G lacking ITIMs (Siglec-GΔITIMs) is codelivered to liver macrophages by LNP to relieve CD24-mediated CAR-Ms immune suppression. Mice treated with LNPs generating CAR-Ms as well as CD24-Siglec-G blockade significantly elevate the phagocytic function of liver macrophages, reduce tumor burden and increase survival time in an HCC mouse model. Arguably, our work suggests an efficacious and flexible strategy for the treatment of HCC and warrants further rigorous evaluation in clinical trials.

Reversing immune evasion using a DNA nano-orchestrator for pancreatic cancer immunotherapy.

Immune evasion caused by the paucity of MHCI is a prominent characteristic of pancreatic adenocarcinoma (PAAD), which is thought to underlie dysfunctional even absent adaptive T cell immunity and is responsible for ineffective immunotherapy. Here, we report a ROS-responsive DNA nano-orchestrator to cascade reverse MHC I-associated immune evasion and boost anti-tumor T cell stimulation, stimulating the activation of tumoricidal immunity against PAAD. Chloroquine phosphate (CQP) as an autophagy inhibitor was first encapsulated with ferritin, and via DNA modular self-assembly technology, the generated ferritin nanocores (FNC) were then caged into ROS-responsive CpG-DNA nanoframe. After systemic injection, the FNC-laden DNA nanoframe (FNC@NF) was passively enriched in tumor tissues in which the DNA nanoframe was cleaved upon the ROS stimulation. Oligodeoxynucleotide (ODN) with CpG motifs was detached and functioned as a TLR9 agonist. The liberated FNC was then endocytosed in an actively targeted manner by binding to transferrin receptor 1. In the lysosome, CQP was burst released from FNC due to acid-triggering. Through CQP-mediated autophagy abrogation, MHC-I molecules were preserved. We demonstrated that cascade inhibiting autophagy and boosting TLR9 stimulation via our proposed DNA-based hybrid nanosystem restored MHC I on the tumor cell surface and reshaped the antigen presentation of DCs, and ultimately reversed immune evasion and synergistically reinforced the activation of cytotoxic T cells against PAAD cells. In sum, our work provides an alternative strategy for cascade reversing immune evasion and boosting anti-tumor T cell stimulation and holds great potential for pancreatic cancer immunotherapy. STATEMENT OF SIGNIFICANCE: A DNA nano-orchestrator was created by sequentially assembling chloroquine phosphate-laden ferritin nanocores with ROS-responsive CpG-DNA nanoframe. Through cascade inhibiting autophagy and boosting TLR9 stimulation, the nano-orchestrator efficiently reversed MHC I-associated immune evasion and augmented anti-tumor T cell stimulation, which ultimately activated tumoricidal immunity against pancreatic adenocarcinoma.

Surficial nano-deposition locoregionally yielding bactericidal super CAR-macrophages expedites periprosthetic osseointegration.

Tracking and eradicating Staphylococcus aureus in the periprosthetic microenvironment are critical for preventing periprosthetic joint infection (PJI), yet effective strategies remain elusive. Here, we report an implant nanoparticle coating that locoregionally yields bactericidal super chimeric antigen receptor macrophages (CAR-MΦs) to prevent PJI. We demonstrate that the plasmid-laden nanoparticle from the coating can introduce S. aureus-targeted CAR genes and caspase-11 short hairpin RNA (CASP11 shRNA) into macrophage nuclei to generate super CAR-MΦs in mouse models. CASP11 shRNA allowed mitochondria to be recruited around phagosomes containing phagocytosed bacteria to deliver mitochondria-generated bactericidal reactive oxygen species. These super CAR-MΦs targeted and eradicated S. aureus and conferred robust bactericidal immunologic activity at the bone-implant interface. Furthermore, the coating biodegradability precisely matched the bone regeneration process, achieving satisfactory osteogenesis. Overall, our work establishes a locoregional treatment strategy for priming macrophage-specific bactericidal immunity with broad application in patients suffering from multidrug-resistant bacterial infection.

Association between the systemic immune inflammation index and recurrence or metastasis after interventional therapy in patients with primary liver cancer- a retrospective cohort study.

Background: The systemic immune inflammation index has been used to evaluate the prognosis of patients with a variety of malignant tumors. However, studies were limited in primary liver cancer (PLC) patients. This study aimed to investigate the association between the systemic immune inflammation index and recurrence or metastasis after interventional therapy in patients with PLC. Methods: From January 2016 to December 2017, 272 patients with PLC admitted to the 941st Hospital of PLA Joint Logistics Support Force were retrospectively collected. All patients received interventional treatment, there were no residual lesions after interventional treatment. The patients were followed up for 5 years to monitor the rates of recurrence or metastasis. The patients were divided into a recurrence or metastasis group (n=112) and a control group (n=160). The differences in clinical features between the 2 groups were compared, and the predictive value of systemic immune inflammation index on recurrence or metastasis after interventional treatment in patients with PLC was analyzed. Results: Compared with the control group (8.12%), the proportion of patients with ≥2 lesions in the recurrence or metastasis group (19.64%) was significantly increased (P=0.005); the proportion of patients with vascular invasion was significantly increased in the recurrence or metastasis group (10.71% vs. 4.38%, P=0.044); albumin decreased significantly in the recurrence or metastasis group (39.69±6.17 vs. 41.69±6.82 g/L, P=0.014); neutrophils (%) were significantly increased in the recurrence or metastasis group (0.70±0.08 vs. 0.64±0.08, P<0.001); lymphocytes (%) were significantly reduced in the recurrence or metastasis group (0.25±0.06 vs. 0.30±0.06, P<0.001); and platelet count was significantly increased in the recurrence or metastasis group (179.22±39.52 vs. 160.81±34.13 109/L, P<0.001). The systemic immune inflammation index was significantly increased in the recurrence or metastasis group (535.23±174.05 vs. 357.84±120.21, P<0.001). Systemic immune inflammation index was valuable in predicting recurrence or metastasis, and the area under the curve was 0.795 (95% CI: 0.742-0.848, P<0.001). Systemic immune inflammation index >405.08 was an independent risk factor of recurrence or metastasis [relative risk (95% CI: 1.878-5.329), P=0.000]. Conclusions: Elevated systemic immune inflammation index is associated with recurrence or metastasis after interventional therapy in patients with PLC.

Risk factors of lymph node metastasis in patients with T1 stage colorectal cancer-a retrospective cohort study based on the Surveillance, Epidemiology, and End Results database.

Background: Patients with T1 stage early colorectal cancer (CRC) can be treated with radical surgery or endoscopic surgery. Endoscopic surgery has a number of advantages, including minimal trauma and a rapid recovery. However, it cannot remove regional lymph nodes to assess whether there is lymph node metastasis. Thus, the analysis of the risk factors of lymph node metastasis in patients with T1 stage CRC is of great significance in the selection of appropriate treatment methods. Although previous studies have explored the risk factors for lymph node metastasis in T1 stage CRC patients, the number of cases were relatively insufficient, and further exploration is necessary. Methods: A total of 2,085 patients who had been pathologically diagnosed with CRC from 2015 to 2017 from the Surveillance, Epidemiology, and End Results (SEER) database. Among the patients, 324 had lymph node metastasis. A multivariate logistic regression analysis was conducted to analyze the risk factors of lymph node metastasis in patients with T1 stage CRC. Next, we established a prediction model to predict lymph node metastasis in patients with T1 stage CRC. Results: The results of the multivariate logistic regression analysis showed that age at diagnosis, rectosigmoid cancer, poorly differentiated or undifferentiated tumor cells, and distant metastasis were independent factors of lymph node metastasis in patients with T1 stage CRC (P<0.05). This study used the R4.0.3 statistical software for the statistical analysis. The data set was randomly divided into a training set and verification set. The training set comprised 1,460 patients, and the verification set comprised 625 patients. The area under the receiver operating characteristic curve (AUC) of the training set was 0.675 [95% confidence interval (CI): 0.635-0.714], and the AUC of the verification set was 0.682 (95% CI: 0.617-0.747). In the validation set, the model was tested by the Hosmer-Lemeshow Goodness-of-Fit Test (χ2=4.018, P=0.855), and the results showed that the model was reliable at predicting lymph node metastasis in patients with T1 stage CRC. Conclusions: For CRC patients with high risk factors of lymph node metastasis, endoscopic physicians should carefully evaluate the advantages and disadvantages of the endoscopic surgery before deciding whether to perform this surgery.

Comparison of NOD-like and Toll-like receptors gene expression levels in blood monocytes of colon cancer patients.

Colon cancer is one of the most common cancers affecting many people worldwide. This disease can be treated if diagnosed in the early stages. Therefore, with the hypothesis that the level of expression of inflammatory genes in peripheral blood monocytes of patients with colon cancer is different from that of healthy people, this research was done to find out the role of inflammation in the development of colon cancer by relying on its immunopathological profile to help diagnose it in the early stages. In this case-control study, the expression levels of TLR4, TLR2, NLRP3, and NOS2 genes in 15 patients with confirmed stage II colon cancer were determined by the TNM method. Also, 15 healthy people referred for this cancer screening were selected as the control group. First, RNA was extracted from the blood monocytes of two groups, and after making cDNA, the comparison was created using the qPCR method. In this study, the ß-actin gene was used as a reference gene. The expression levels of TLR2 and TLR4 at the mRNA level were significantly lower in colon cancer patients compared to the healthy control group (P<0.05). The expression level of NLRP3 in the group of colon cancer patients showed a relative increase. Still, it was not significant, while the expression level of the NOS2 gene in the group of colon cancer patients increased significantly compared to the healthy control group (P<0.05). Considering the significant changes in TLR4, TLR2, and NOS2 gene expression in monocytes of patients with grade II colon cancer and the role of inflammatory reactions in the development of this cancer, these findings can be used to diagnose and determine the prognosis. However, this requires further studies.

Improved PGC demodulation algorithm to eliminate modulation depth and intensity disturbance.

In this paper, an improved phase generated carrier (PGC) demodulation algorithm based on frequency mixing and division difference is proposed. The effects of phase modulation depth variation and light intensity disturbance of the light source on the demodulated phase signal are investigated theoretically and experimentally. Compared to the traditional PGC differential-cross-multiplying (PGC-DCM) and PGC arctangent (PGC-Arctan) demodulation algorithms, the ameliorated demodulation algorithm eliminates the harmonic distortion of the demodulated signal by extracting the carrier modulation depth through frequency mixing. The demodulation error caused by the light intensity disturbance of the light source is suppressed by division difference. The stability of the demodulation system is improved. To verify the algorithm, a PGC demodulation system is built based on a Michelson interferometer. The experimental results show that when the frequency and amplitude of the sensed signal are set to 1 kHz and 0.4 rad, respectively, the signal-to-noise ratio with the proposed algorithm achieves a gain of 35.66 dB over the PGC-Arctan algorithm and 26.26 dB over the PGC-DCM algorithm.

Design, synthesis, and antiviral evaluation of novel piperidine-substituted arylpyrimidines as HIV-1 NNRTIs by exploring the hydrophobic channel of NNIBP.

Herein, alkenylpiperidine and alkynylpiperidine moieties were introduced into the left wing of DAPYs (diarylpyrimidines) to explore the new site of the NNIBP (non-nucleoside inhibitor binding pocket) protein-solvent interface region via the structure-based drug design strategy. All the synthesized compounds displayed nanomolar to submicromolar activity against WT (wild-type) HIV-1. Among all, compound FT1 (EC50 = 19 nM) was found to be the most active molecule, which is better than NVP (EC50 = 0.10 µM). In addition, most of the compounds displayed micromolar activity against K103N and E138K mutant strains, while FT1 (EC50(K103N) = 50 nM, EC50(E138K) = 0.19 µM) still has the most effective activity. The molecular dynamics simulation studies revealed that the presence of pyridine moiety of FT1 was essential and played a significant role in its binding with RT (reverse transcriptase).

Exploiting the hydrophobic channel of the NNIBP: Discovery of novel diarylpyrimidines as HIV-1 NNRTIs against wild-type and K103N mutant viruses.

To further explore the chemical space surrounding the "hydrophobic channel" of the NNRTI binding pocket (NNIBP), a new series of diarylpyrimidines (DAPYs) were designed and synthesized as potent HIV-1 non-nucleoside RT inhibitors (NNRTIs). The target compounds were evaluated for anti-HIV potency in MT-4 cells. Most of the synthesized DAPYs exhibited moderate to excellent activity against the HIV-1 wild-type (WT) strain with EC50 values ranging from 16 nM to 0.722 µM. Interestingly, few compounds displayed remarkable activity in inhibiting K103N mutant virus with EC50 values ranging from 39 nM to 1.708 µM. Notably, FS2 (EC50(IIIB) = 16 nM, EC50(K103N) = 39 nM, SI = 294) was identified as the most significant compound, which was considerably more potent than nevirapine, lamivudine, and comparable to zidovudine. Additionally, the HIV-1 RT inhibition assay confirmed their binding target. Preliminary structure-activity relationships (SARs) and molecular modeling studies were also performed, providing significant suggestions for further optimization.

The development of an effective synthetic route of rilpivirine.

BACKGROUND: Rilpivirine (RPV) was approved by the U.S. FDA (Food and Drug Administration) in 2011 to treat individuals infected with human immunodeficiency virus 1 (HIV-1). Significantly, rilpivirine is three fold more potent than etravirine. Once-daily, it is used with a low oral dose (25 mg/tablet), decreasing the drug administration and bringing a better choice to the patients. However, there are many shortcomings in the existing synthesis route of RPV, such as the high cost, prolonged reaction time and low yield (18.5%). RESULTS: This article describes our efforts to develop an efficient and practical microwave-promoted method to synthesize rilpivirine using less toxic organic reagents and low boiling solvents. The last step's reaction time decreased from 69 h to 90 min through this optimized synthetic procedure, and the overall yield improved from 18.5 to 21%. In addition, the yield of intermediate 3 increased from 52 to 62% compared to the original patent. CONCLUSION: Overall, through a series of process optimization, we have developed a practical synthesis method of rilpivirine, which is easy to scale with higher yield and shorter reaction time.

Targeting dual tolerant regions of binding pocket: Discovery of novel morpholine-substituted diarylpyrimidines as potent HIV-1 NNRTIs with significantly improved water solubility.

To address the intractable issues of drug resistance and poor solubility, a novel series of morpholine-substituted diarylpyrimidines targeting the tolerant region I and tolerant region II of NNIBP were rationally designed by utilizing the available crystallography studies. The biological evaluation results showed that four most promising compounds (14e1, 14g1, 14g2 and 14j2) displayed excellent potency against WT HIV-1 strain with EC50 values ranging from 58 to 87 nM, being far more potent than NVP and comparable to ETV. Besides, some derivatives exhibited moderate activity in inhibiting the mutant HIV-1 strains. More encouragingly, 14d2 (RF = 0.4) possessed higher antiresistance profile than ETV (RF = 6.3) and K-5a2 (RF = 3.0) toward the double mutant strain F227L + V106A. The HIV-1 RT inhibition assay confirmed their binding target. The molecular docking studies were conducted and discussed in detail to rationalize the preliminary SARs. Further test indicated that morpholine could indeed promote the improvement of water solubility. Additionally, the in silico prediction of physicochemical properties and CYP enzymatic inhibitory ability were investigated to evaluate their drug-like features.

Targeting the hydrophobic channel of NNIBP: discovery of novel 1,2,3-triazole-derived diarylpyrimidines as novel HIV-1 NNRTIs with high potency against wild-type and K103N mutant virus.

Enlightened by our previous efforts to modify diarylpyrimidines as HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) and the reported crystallographic studies, we designed and synthesized novel 1,2,3-triazole-derived diarylpyrimidine derivatives via the CuAAC "click reaction", to make additional interactions with the hydrophobic channel in the NNRTI binding pocket. The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells. All the compounds showed favorable activity against the wild-type HIV-1 strain with an EC50 of 0.013-5.62 µM. Interestingly, some compounds displayed remarkable potency in inhibiting K103N mutant virus, a key drug-resistant mutant to NNRTIs. Among them, meta-methylbenzoate (ZL2, EC50(IIIB) = 0.020 µM, EC50(K103N) = 0.043 µM, CC50 > 241.52 µM), para-methylbenzoate (ZL3, EC50(IIIB) = 0.013 µM, EC50 (K103N) = 0.022 µM, CC50 > 241.52 µM) and para-phenol (ZL7, EC50(IIIB) = 0.014 µM, EC50 (K103N) = 0.054 µM, CC50 = 2.1 µM) derivatives are the three most promising compounds which are superior to the first-line antiretroviral drug efavirenz (EC50(IIIB) = 0.003 µM, EC50 (K103N) = 0.11 µM, CC50 > 6.34 µM) against the K103N mutant strain. More encouragingly, ZL2 and ZL3 exhibited much lower cytotoxicity and a high selection index of >10 000 compared with all the control drugs (AZT, 3TC, NVP, EFV, and ETV). The detailed structure-activity relationship (SAR), enzymatic inhibitory activity and docking study of the representative compounds are also discussed. Furthermore, the preliminary physicochemical properties and the early metabolic stability of representative compounds were examined to evaluate their drug-like properties.

[Application of mutual information to variable selection in diagnosis of phosphorus nutrition in rice].

The present study obtained data of rice canopy spectrum, and P and chlorophyll content at typical growth stages with different rates of P supply by means of solution experiment. The effects of P treatments on leaf P and chlorophyll content were analyzed statistically using LSD's multiple comparison at a probability of 0.05; By mutual information (MI) variable selection procedure, the optimal spectral variables were identified at 536, 630, 1040, 551 and 656 nm, and their corresponding mutual information values were 1.0575, 1.1039, 1.135 3, 1.1417 and 1.1494 respectively; based on these sensitive bands, the built feed-forward artificial neural network model (ANN) had higher precision for P content estimation than the multiple linear regression model (MLR). Its RMSE of cross-validation and R were 0.038 8 and 0.9882, respectively, for the calibration data set, and the RMSE of prediction and R were 0.0505 and 0.9892, respectively, for the test data set. Therefore, it was suggested that MI was encouraged for quantitative prediction of leaf P content in rice with visible/near infrared hyperspectral information without assumption on the relationship between independent and dependent variables. But more work is needed to explain why these bands are sensitive to leaf P content in rice.