Essential role of N-terminal SAM regions in STIM1 multimerization and function.

The single-pass transmembrane protein Stromal Interaction Molecule 1 (STIM1), located in the endoplasmic reticulum (ER) membrane, possesses two main functions: It senses the ER-Ca2+ concentration and directly binds to the store-operated Ca2+ channel Orai1 for its activation when Ca2+ recedes. At high resting ER-Ca2+ concentration, the ER-luminal STIM1 domain is kept monomeric but undergoes di/multimerization once stores are depleted. Luminal STIM1 multimerization is essential to unleash the STIM C-terminal binding site for Orai1 channels. However, structural basis of the luminal association sites has so far been elusive. Here, we employed molecular dynamics (MD) simulations and identified two essential di/multimerization segments, the α7 and the adjacent region near the α9-helix in the sterile alpha motif (SAM) domain. Based on MD results, we targeted the two STIM1 SAM domains by engineering point mutations. These mutations interfered with higher-order multimerization of ER-luminal fragments in biochemical assays and puncta formation in live-cell experiments upon Ca2+ store depletion. The STIM1 multimerization impeded mutants significantly reduced Ca2+ entry via Orai1, decreasing the Ca2+ oscillation frequency as well as store-operated Ca2+ entry. Combination of the ER-luminal STIM1 multimerization mutations with gain of function mutations and coexpression of Orai1 partially ameliorated functional defects. Our data point to a hydrophobicity-driven binding within the ER-luminal STIM1 multimer that needs to switch between resting monomeric and activated multimeric state. Altogether, these data reveal that interactions between SAM domains of STIM1 monomers are critical for multimerization and activation of the protein.

Integration of machine learning for developing a prognostic signature related to programmed cell death in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) presents a significant global health burden, characterized by a heterogeneous molecular landscape and various genetic and epigenetic alterations. Programmed cell death (PCD) plays a critical role in CRC, offering potential targets for therapy by regulating cell elimination processes that can suppress tumor growth or trigger cancer cell resistance. Understanding the complex interplay between PCD mechanisms and CRC pathogenesis is crucial. This study aims to construct a PCD-related prognostic signature in CRC using machine learning integration, enhancing the precision of CRC prognosis prediction. METHOD: We retrieved expression data and clinical information from the Cancer Genome Atlas and Gene Expression Omnibus (GEO) datasets. Fifteen forms of PCD were identified, and corresponding gene sets were compiled. Machine learning algorithms, including Lasso, Ridge, Enet, StepCox, survivalSVM, CoxBoost, SuperPC, plsRcox, random survival forest (RSF), and gradient boosting machine, were integrated for model construction. The models were validated using six GEO datasets, and the programmed cell death score (PCDS) was established. Further, the model's effectiveness was compared with 109 transcriptome-based CRC prognostic models. RESULT: Our integrated model successfully identified differentially expressed PCD-related genes and stratified CRC samples into four subtypes with distinct prognostic implications. The optimal combination of machine learning models, RSF + Ridge, showed superior performance compared with traditional methods. The PCDS effectively stratified patients into high-risk and low-risk groups, with significant survival differences. Further analysis revealed the prognostic relevance of immune cell types and pathways associated with CRC subtypes. The model also identified hub genes and drug sensitivities relevant to CRC prognosis. CONCLUSION: The current study highlights the potential of integrating machine learning models to enhance the prediction of CRC prognosis. The developed prognostic signature, which is related to PCD, holds promise for personalized and effective therapeutic interventions in CRC.

A dramatic decline in fruit citrate induced by mutagenesis of a NAC transcription factor, AcNAC1.

Citrate is a common primary metabolite which often characterizes fruit flavour. The key regulators of citrate accumulation in fruit and vegetables are poorly understood. We systematically analysed the dynamic profiles of organic acid components during the development of kiwifruit (Actinidia spp.). Citrate continuously accumulated so that it became the predominate contributor to total acidity at harvest. Based on a co-expression network analysis using different kiwifruit cultivars, an Al-ACTIVATED MALATE TRANSPORTER gene (AcALMT1) was identified as a candidate responsible for citrate accumulation. Electrophysiological assays using expression of this gene in Xenopus oocytes revealed that AcALMT1 functions as a citrate transporter. Additionally, transient overexpression of AcALMT1 in kiwifruit significantly increased citrate content, while tissues showing higher AcALMT1 expression accumulated more citrate. The expression of AcALMT1 was highly correlated with 17 transcription factor candidates. However, dual-luciferase and EMSA assays indicated that only the NAC transcription factor, AcNAC1, activated AcALMT1 expression via direct binding to its promoter. Targeted CRISPR-Cas9-induced mutagenesis of AcNAC1 in kiwifruit resulted in dramatic declines in citrate levels while malate and quinate levels were not substantially affected. Our findings show that transcriptional regulation of a major citrate transporter, by a NAC transcription factor, is responsible for citrate accumulation in kiwifruit, which has broad implications for other fruits and vegetables.

Switchable optical ring lattice in free space.

Optical lattices with spatially regular structures have recently attracted considerable attention across physics and optics communities. In particular, due to the increasing emergence of new structured light fields, diverse lattices with rich topology are being generated via multi-beam interference. Here, we report a specific ring lattice with radial lobe structures generated via superposition of two ring Airy vortex beams (RAVBs). We show that the lattice morphology evolves upon propagation in free space, switching from a bright-ring lattice to dark-ring lattice and even to fascinating multilayer texture. This underlying physical mechanism is related to the variation of the unique intermodal phase between the RAVBs as well as topological energy flow with symmetry breaking. Our finds provide an approach for engineering customized ring lattices to inspire a wide variety of new applications.

Topological spatial differentiation via complex amplitude filtering in Fourier space.

Various approaches to implementing optical analog differentiation have been studied extensively and applied in edge-based image processing. Here, we report a topological optical differentiation scheme based on complex amplitude filtering, i.e., amplitude and spiral phase modulation in Fourier space. The isotropic and anisotropic multiple-order differentiation operations are demonstrated both theoretically and experimentally. Meanwhile, we also achieve multiline edge detection corresponding to the differential order for the amplitude and phase objects. This proof-of-principle work could open up new avenues for engineering a nanophotonic differentiator and realizing a more compact image-processing system.

Construction and validation of a survival prognostic model for stage III hepatocellular carcinoma: a real-world, multicenter clinical study.

OBJECTIVE: To construct a survival prediction model for patients with TNM stage III hepatocellular carcinoma (HCC) to guide the clinical diagnosis and treatment of HCC patients and improve prognosis. METHODS: Based on data from patients with stage III (AJCC 7th TNM stage) recorded by the American Institute of Cancer Research from 2010 to 2013, risk factors affecting the prognosis were screened by Cox univariate and multivariate regression, line plots was constructed, and the credibility of the model was verified by Boostrap method. ROC operating curves, calibration curves and DCA clinical decision curves were used to evaluate the model, and Kaplan-Meier was used for survival analysis was used to evaluate the efficacy of the model. External survival data from patients newly diagnosed with stage III hepatocellular carcinoma during 2014-2015 were used to validate and fit the model and to optimize the model. RESULTS: Age > 75 years vs.18-53 years [HR = 1.502; 95%CI(1.134-1.990)], stage IIIC vs. Stage IIIA [HR = 1.930; 95%CI(1.509-2.470)], lobotomy vs. non-surgery [HR = 0.295; 95%CI(0.228-0.383)], radiotherapy vs. non-radiotherapy [HR = 0.481; 95%CI(0.373-0.619)], chemotherapy vs. Non-chemotherapy [HR = 0.443; 95%CI(0.381-0.515)], positive serum AFP before treatment vs. negative [HR = 1.667; 95%CI(1.356-2.049)], the above indicators are independent prognostic factors for patients with stage III hepatocellular carcinoma, and the P values for the above results were less than 0.05. A joint prediction model was constructed based on age, TNM stage, whether and how to operate, whether to receive radiotherapy, whether to receive chemotherapy, pre-treatment serum AFP status and liver fibrosis score. The consistency index of the improved prognosis model was 0.725. CONCLUSIONS: The traditional TNM staging has limitations for clinical diagnosis and treatment, while the Nomogram model modified by TNM staging has good predictive efficacy and clinical significance.

Sublethal effects of an indoxacarb enantiomer insecticide on Plutella xylostella caterpillar and Chrysoperla sinica predator.

Plutella xylostella (L.) is a migratory species and an important insect pest of cruciferous crops worldwide, and Chrysoperla sinica (Tjeder) is a predaceous insect of agricultural and forest pests in the field. Indoxacarb has two enantiomers: (+)-S-indoxacarb and (-)-R-indoxacarb. This study was conducted to clarify the selective toxicity and sublethal effects of both enantiomers on P. xylostella and C. sinica. The (+)-S-indoxacarb isomer had greater acute toxicity to P. xylostella and C. sinica, while (-)-R-indoxacarb had less toxicity to P. xylostella and low toxicity to C. sinica. Lethal concentration 25 % (LC25) of (+)-S-indoxacarb had significant effects on the development, population, and fecundity of P. xylostella and C. sinica. The LC25 concentration of (-)-R-indoxacarb had a significant effect on the oviposition of P. xylostella. The field recommended concentration of (-)-R-indoxacarb significantly affected the pupal stage, adult survival rate, oviposition, and larval survival rate of C. sinica. Both enantiomers could significantly affect the search efficiency, successful attack rate, prey handling time, and maximum predation of C. sinica larvae, and the effects of (+)-S-indoxacarb alone were greater than those of (-)-R-indoxacarb. This study provided evidence of the different selective toxicity, sublethal effects of indoxacarb enantiomers on P. xylostella and C. sinica, which of the results could provide a basis for more rational use of indoxacarb in ecosystems.

Targeting disordered-structured domain interactions in Galectin-3 based on NMR and enhanced MD.

Intrinsically disordered regions (IDRs) are common and important functional domains in many proteins. However, IDRs are difficult to target for drug development due to the lack of defined structures that would facilitate the identification of possible drug-binding pockets. Galectin-3 is a carbohydrate-binding protein of which overexpression has been implicated in a wide variety of disorders, including cancer and inflammation. Apart from its carbohydrate-recognition/binding domain (CRD), Galectin-3 also contains a functionally important disordered N-terminal domain (NTD) that contacts the C-terminal domain (CTD) and could be a target for drug development. To overcome challenges involved in inhibitor design due to lack of structure and the highly dynamic nature of the NTD, we used a protocol combining nuclear magnetic resonance data from recombinant Galectin-3 with accelerated molecular dynamics (MD) simulations. This approach identified a pocket in the CTD with which the NTD makes frequent contact. In accordance with this model, mutation of residues L131 and L203 in this pocket caused loss of Galectin-3 agglutination ability, signifying the functional relevance of the cavity. In silico screening was used to design candidate inhibitory peptides targeting the newly discovered cavity, and experimental testing of only three of these yielded one peptide that inhibits the agglutination promoted by wild-type Galectin-3. NMR experiments further confirmed that this peptide indeed binds to a cavity in the CTD, not within the actual CRD. Our results show that it is possible to apply a combination of MD simulations and NMR experiments to precisely predict the binding interface of a disordered domain with a structured domain, and furthermore use this predicted interface for designing inhibitors. This procedure can potentially be extended to many other targets in which similar IDR interactions play a vital functional role.

Global analysis of protein lysine 2-hydroxyisobutyrylation (Khib) profiles in Chinese herb rhubarb (Dahuang).

BACKGROUND: Lysine 2-hydroxyisobutyrylation (Khib) is a newly discovered protein posttranslational modification (PTM) and is involved in the broad-spectrum regulation of cellular processes that are found in both prokaryotic and eukaryotic cells, including in plants. The Chinese herb rhubarb (Dahuang) is one of the most widely used traditional Chinese medicines in clinical applications. To better understand the physiological activities and mechanism of treating diseases with the herb, it is necessary to conduct intensive research on rhubarb. However, Khib modification has not been reported thus far in rhubarb. RESULTS: In this study, we performed the first global analysis of Khib-modified proteins in rhubarb by using sensitive affinity enrichment combined with high-accuracy HPLC-MS/MS tandem spectrometry. A total of 4333 overlapping Khib modification peptides matched on 1525 Khib-containing proteins were identified in three independent tests. Bioinformatics analysis showed that these Khib-containing proteins are involved in a wide range of cellular processes, particularly in protein biosynthesis and central carbon metabolism and are distributed mainly in chloroplasts, cytoplasm, nucleus and mitochondria. In addition, the amino acid sequence motif analysis showed that a negatively charged side chain residue (E), a positively charged residue (K), and an uncharged residue with the smallest side chain (G) were strongly preferred around the Khib site, and a total of 13 Khib modification motifs were identified. These identified motifs can be classified into three motif patterns, and some motif patterns are unique to rhubarb and have not been identified in other plants to date. CONCLUSIONS: A total of 4333 Khib-modified peptides on 1525 proteins were identified. The Khib-modified proteins are mainly distributed in the chloroplast, cytoplasm, nucleus and mitochondria, and involved in a wide range of cellular processes. Moreover, three types of amino acid sequence motif patterns, including EKhib/KhibE, GKhib and k.kkk….Khib….kkkkk, were extracted from a total of 13 Khib-modified peptides. This study provides comprehensive Khib-proteome resource of rhubarb. The findings from the study contribute to a better understanding of the physiological roles of Khib modification, and the Khib proteome data will facilitate further investigations of the roles and mechanisms of Khib modification in rhubarb.

The role of TXNL1 in disease: treatment strategies for cancer and diseases with oxidative stress.

Thioredoxin-like protein-1 (TXNL1; also known as thioredoxin-related 32 kDa protein, TRP32) is a thioredoxin involved in the regulation of oxidative stress, which protects cells from damage through redox balance. Studies have shown that TXNL1 has a variety of functions, including cell signal transduction, cell cycle regulation, protein synthesis, modification and degradation, vesicle transport, transcriptional regulation, cell apoptosis, virus replication and oxidative stress regulation, etc., and plays an important role in the occurrence and development of human diseases. Therefore, TXNL1 has a strong correlation with the treatment of cancer and oxidative stress diseases. In this paper, the basic structure, function and potential application value of TXNL1 in diseases are reviewed, so as to open up new targets for the treatment of cancer and oxidative stress-related diseases.

The associations of birth outcome differences in twins with prenatal exposure to bisphenol A and its alternatives.

BACKGROUND: Bisphenol A (BPA) and its alternatives, including BPF and BPS, exhibit endocrine disruption activities. However, the effects of bisphenols on fetal growth in twins remain unclear. OBJECTIVE: To explore the associations of prenatal BPA, BPF, and BPS exposure with birth outcome differences in twins. METHODS: We recruited 289 twin pregnant women who visited the hospital for prenatal examination during the first trimester from 2013 to 2016. Urinary bisphenol levels were determined during the first, second, and third trimesters. The associations of maternal exposure to bisphenols with birth outcome differences in twins were analyzed after stratification by different trimesters. We applied the multiple informant model to estimate trimester-specific associations between urinary bisphenol concentrations and birth outcome differences in twins. RESULTS: We found low reproducibility (ICC<0.40) for maternal urinary BPA and moderate reproducibility (0.40 < ICC<0.75) for BPF and BPS. Urinary BPA concentrations were positively associated with within-pair twin birth weight difference when comparing the third vs. the first tertile in each of the three trimesters (i.e., 133.06 g, 95% CI: 68.19, 197.94; 144.5 g, 95%CI: 81.82-207.18 g; and 135.04 g, 95%CI: 71.37-198.71 g for the 1st, 2nd, and 3rd trimester, respectively). The effect of urinary BPA concentration on increased birth length difference within-pair twins were also observed across different trimesters (All P for trends < 0.05). Urinary BPA levels were positively associated with the within-pair birth weight and birth length differences across pregnancy trimesters (All of Type 3 P for values < 0.05). CONCLUSION: Maternal BPA exposure appeared to influence birth wight and birth length differences in twins. Our results warrant further confirmation.

MHC-mismatched mixed chimerism restores peripheral tolerance of noncross-reactive autoreactive T cells in NOD mice.

Autoimmune type 1 diabetes (T1D) and other autoimmune diseases are associated with particular MHC haplotypes and expansion of autoreactive T cells. Induction of MHC-mismatched but not -matched mixed chimerism by hematopoietic cell transplantation effectively reverses autoimmunity in diabetic nonobese diabetic (NOD) mice, even those with established diabetes. As expected, MHC-mismatched mixed chimerism mediates deletion in the thymus of host-type autoreactive T cells that have T-cell receptor (TCR) recognizing (cross-reacting with) donor-type antigen presenting cells (APCs), which have come to reside in the thymus. However, how MHC-mismatched mixed chimerism tolerizes host autoreactive T cells that recognize only self-MHC-peptide complexes remains unknown. Here, using NOD.Rag1-/-BDC2.5 or NOD.Rag1-/-BDC12-4.1 mice that have only noncross-reactive transgenic autoreactive T cells, we show that induction of MHC-mismatched but not -matched mixed chimerism restores immune tolerance of peripheral noncross-reactive autoreactive T cells. MHC-mismatched mixed chimerism results in increased percentages of both donor- and host-type Foxp3+ Treg cells and up-regulated expression of programmed death-ligand 1 (PD-L1) by host-type plasmacytoid dendritic cells (pDCs). Furthermore, adoptive transfer experiments showed that engraftment of donor-type dendritic cells (DCs) and expansion of donor-type Treg cells are required for tolerizing the noncross-reactive autoreactive T cells in the periphery, which are in association with up-regulation of host-type DC expression of PD-L1 and increased percentage of host-type Treg cells. Thus, induction of MHC-mismatched mixed chimerism may establish a peripheral tolerogenic DC and Treg network that actively tolerizes autoreactive T cells, even those with no TCR recognition of the donor APCs.

Insecticide resistance and resistance mechanisms in the melon aphid, Aphis gossypii, in Shandong, China.

The melon aphid, Aphis gossypii, is an important pest of vegetables. Insecticide resistance in A. gossypii has increased due to the frequent use of insecticides. We studied the levels and mechanisms of A. gossypii resistance to imidacloprid, acetamiprid and lambda-cyhalothrin here. The resistance levels of the three insecticides in 20 populations of A. gossypii varied. When compared to the susceptible strain (Lab-SS), there were two moderate resistance (MR) populations and nine low resistance (LR) populations to imidacloprid, respectively, two MR populations and two LR populations to acetamiprid, respectively, and, five MR populations and two LR populations to λ-cyhalothrin, respectively. Gene mutation detection in the MR level populations showed arginine to threonine substitution (R81T) in three populations and lysine to glutamine substitution (K264E) in the nicotinic acetylcholine receptor (nAChR) ß1 subunit in one population, respectively. No valine to isoleucine substitution (V62I) was found in the nAChR ß1 subunit in any of the tested populations. The leucine to phenylalanine substitution (L1014F) in sodium channel α subunit was found in five MR populations. The relative expression of the CYP6CY13 gene was significantly upregulated in the Daiyue and Shenxian populations. The CYP6CY14 gene was significantly upregulated in Daiyue, Dongchangfu, Shenxian, Mengyin and Anqiu populations. The CYP6CY19 gene was significantly upregulated in the Dongchangfu and Mengyin populations. The relative expressions of the esterase E4 or FE4 genes were significantly upregulated in most of the MR populations. These results provide insight into the current insecticide resistance of A. gossypii and may contribute to more effective resistance management strategies.

Highly Sensitive Detection of Multiple MicroRNAs by High-Performance Liquid Chromatography Coupled with Long and Short Probe-Based Recycling Amplification.

This report demonstrated the utility of high-performance liquid chromatography (HPLC)-fluorescence detection for selective separation and sensitive quantification of multiple microRNAs (miRNAs). A duplex specific nuclease (DSN)-assisted target recycling amplification strategy was developed to enhance the signals of miRNAs, which alleviates the low sensitivity of conventional HPLC to nucleic acids. To separate the signals of different miRNAs, DNA probes with different lengths and base sequences were immobilized on magnetic beads. The application of an effective magnetic separation minimized the background signal and extended the dynamic range. This assay achieved a limit of detection of 0.39 fM for miRNA-122, 0.30 fM for miRNA-155, and 0.26 fM for miRNA-21, respectively. The proposed assay was successfully applied to detect simultaneously miRNA-122, miRNA-155, and miRNA-21 in serum samples from healthy persons and cervical cancer patients, and the results were then compared with those of quantitative real-time-polymerase chain reaction amplification.

Magnetic Three-Phase Single-Drop Microextraction for Rapid Amplification of the Signals of DNA and MicroRNA Analysis.

The detection of nucleic acids usually suffers from a lengthy amplification process. To obtain an enhanced signal within several seconds, a magnetic three-phase single-drop microextraction (MTP-SDME) approach was developed for the quantification of nucleic acids. First, a target-triggered recycling amplification strategy was used to constitute magnetic branched DNA/Fe3O4 networks, which displayed peroxidase-like catalytic activity toward the 3,3',5,5'-tetramethylbenzidine colorimetric reaction. The networks were separated and enriched by rapid (6 s) MTP-SDME (with only 6 µL of solvent required), thereby producing highly sensitive signals for the quantification of nucleic acids. The signals were significantly amplified by the triple strategy (network formation, MTP-SDME, and catalytic reaction). The application of magnetic extraction minimized the background signal, avoided sample matrix effects, and enhanced the analyte signals. This assay achieved linear calibration curves of between 0.5 aM and 1 pM for microRNA-122 (miRNA-122) and between 1 aM and 1 pM for HBV-T (a DNA fragment from hepatitis B virus). Limits of detection of 0.15 aM for miRNA-122 and 0.34 aM for HBV-T were attained, with relative standard deviations of <5.0% (n = 3). Furthermore, the procedure was applied to determine miRNA-122 and HBV-T in genuine serum samples from hepatocellular carcinoma patients.

Surgery of the Primary Tumor Offers Survival Benefits of Breast Cancer with Synchronous Ipsilateral Supraclavicular Lymph Node Metastasis.

BACKGROUND: Controversy exists around the locoregional management of the primary tumor for breast cancer associated with synchronous ipsilateral supraclavicular lymph node metastasis (sISLM) due to the rarity of the disease and limited available data. This study aimed to compare outcomes of patients in the Surveillance, Epidemiology, and End Results (SEER) database with sISLM who underwent surgical resection and radiation of the primary tumor with those who did not. METHODS: This population-based retrospective study included breast cancer patients with sISLM without distant metastases from 2004 to 2016 in the SEER database. In this study, patients had been stratified by operative management, and propensity score matching (PSM) had been successfully applied. RESULTS: A total of 1172 breast cancer patients with sISLM were included in the study: 863 (73.6%) of patients underwent the primary tumor resection, and 309 (26.4%) patients did not undergo surgery. The median survival time in the surgery group was longer compared to the nonsurgery group in the overall cohort and the PSM cohort. We concluded that the primary tumor resection was associated with improved survival. Subgroup analysis further demonstrated that local surgery was not inferior to radical surgery. CONCLUSION: For selected breast cancer patients with sISLM, surgery is a promising local intervention which may improve the survival.

Increased Responses of Phenoloxidase in Chlorantraniliprole Resistance of Plutella xylostella (Lepidoptera: Plutellidae).

The diamondback moth (Plutella xylostella, DBM) is an important pest of cruciferous vegetables. The use of chlorantraniliprole has been essential in the management of the DBM. However, in many countries and areas, DBM has become highly resistant to chlorantraniliprole. Three different DBM strains, susceptible (S), chlorantraniliprole-selected (Rc), and field-collected (Rb) resistant strains/populations were studied for the role of phenoloxidase in resistance development to the insecticide. By assaying the activity of phenoloxidase (PO) in the three different DBM strains, the results showed that the PO activity in the Rc strain was increased significantly compared with the S strain. The synergistic effects of quercetin showed that the resistant ratio (RR) of the QRc larvae to chlorantraniliprole was decreased from 423.95 to 316.42-fold compared with the Rc larvae. Further studies demonstrated that the transcriptional and translational expression levels of PxPPO1 (P. xylostella prophenoloxidase-1 gene) and PxPPO2 (P. xylostella prophenoloxidase-2 gene) were increased to varying degrees compared with the S strain, such as the transcriptional expression levels of PxPPO2 were 24.02-fold that of the S strain. The responses of phenoloxidase were significantly different in chlorantraniliprole-resistant DBM.

Redox-Activated Porphyrin-Based Liposome Remote-Loaded with Indoleamine 2,3-Dioxygenase (IDO) Inhibitor for Synergistic Photoimmunotherapy through Induction of Immunogenic Cell Death and Blockage of IDO Pathway.

Immunotherapy through stimulating the host immune system has emerged as a powerful therapeutic strategy for various malignant and metastatic tumors in the clinic. However, harnessing the immune system for cancer treatment often fails to obtain a durable response rate due to the poor immunogenicity and the strong immunosuppressive milieu in the tumor site. Herein, a redox-activated liposome was developed from the self-assembly of the porphyrin-phospholipid conjugate and coencapsulation of indoleamine 2,3-dioxygenase (IDO) inhibitor into the interior lumen via remote-loading for simultaneous induction of immunogenic cell death (ICD) and reversing of suppressive tumor microenvironment. The nanoparticle exhibited prolonged blood circulation and enhanced tumor accumulation in the 4T1 tumor-bearing mice after intravenous injection. The nanovesicle could render exponential activation of fluorescence signal and photodynamic therapy (PDT) activity (>100-fold) in response to the high level of intracellular glutathione after endocytosed by tumor cells, thereby achieving effective inhibition of tumor growth and reduced phototoxicity to normal tissues owing to the activatable design of the nanoparticle. More importantly, redox-activated PDT induced intratumoral infiltration of cytotoxic T lymphocytes by induction of ICD of tumor cells. After combining with the IDO inhibitor, the systemic antitumor immune response was further augmented. Hence, we believe that the present nanovesicle strategy has the potential for the synergistic immunotherapy of the metastatic cancers.

Structural Mechanisms of Store-Operated and Mitochondrial Calcium Regulation: Initiation Points for Drug Discovery.

Calcium (Ca2+) is a universal signaling ion that is essential for the life and death processes of all eukaryotes. In humans, numerous cell stimulation pathways lead to the mobilization of sarco/endoplasmic reticulum (S/ER) stored Ca2+, resulting in the propagation of Ca2+ signals through the activation of processes, such as store-operated Ca2+ entry (SOCE). SOCE provides a sustained Ca2+ entry into the cytosol; moreover, the uptake of SOCE-mediated Ca2+ by mitochondria can shape cytosolic Ca2+ signals, function as a feedback signal for the SOCE molecular machinery, and drive numerous mitochondrial processes, including adenosine triphosphate (ATP) production and distinct cell death pathways. In recent years, tremendous progress has been made in identifying the proteins mediating these signaling pathways and elucidating molecular structures, invaluable for understanding the underlying mechanisms of function. Nevertheless, there remains a disconnect between using this accumulating protein structural knowledge and the design of new research tools and therapies. In this review, we provide an overview of the Ca2+ signaling pathways that are involved in mediating S/ER stored Ca2+ release, SOCE, and mitochondrial Ca2+ uptake, as well as pinpoint multiple levels of crosstalk between these pathways. Further, we highlight the significant protein structures elucidated in recent years controlling these Ca2+ signaling pathways. Finally, we describe a simple strategy that aimed at applying the protein structural data to initiating drug design.

Mixtures of fluopyram and abamectin for management of Meloidogyne incognita in tomato.

The southern root-knot nematode (RKN), Meloidogyne incognita, causes significant damage to vegetable production and is a major problem in greenhouse tomatoes. The effect of a combination of fluopyram and abamectin, at a mass ratio of 1:5, was studied for RKN control. Pot trials showed that fluopyram, abamectin, and their combination at three dosages increased the height, stem diameter, root fresh weight, shoot fresh weight, and the root length of tomato plants. The RKN control efficacy of the 1:5 combination at 450 g a.i./ha was 74.06% at 30 days after transplanting (DAT), and the control efficacy of the combination at 337.5 and 450 g a.i./ha differed significantly from those of other treatments at 60 DAT. The root-galling index (RGI) control efficacy of the combination at 450 g a.i./ha and of fluopyram (41.7% SC) only at 450 g a.i./ha were better than the control efficacies of other treatments, and these two treatments significantly increased root activity. Field trial results showed that the soil nematode control efficacy was similar to that of the pot trials at 30 and 60 DAT. The RGI control efficacy of the combination at 337.5 and 450 g a.i./ha and of fluopyram (41.7% SC) only at 450 g a.i./ha differed significantly from those of the two other treatments. The tomato yields of the 1:5 combination at 450 g a.i./ha were increased by 24.07 and 23.22% compared to the control in field trials during two successive years. The combination of fluopyram and abamectin provides good nematode measure, and it can increase tomato yields. It provides an effective solution for the integrated management of southern RKN.