Photodynamic therapy (PDT) combined with oxygenating strategies is widely employed in cancer treatment; however, oxygen-boosted PDT has failed to achieve an ideal effect due to the complexity, ...heterogeneity, and irreversible hypoxic environment generated by tumor tissues. With the emergence of Fe-dependent ferroptosis boasting reactive oxygen species (ROS) cytotoxicity as well, such a chemodynamic approach to cancer therapy has drawn extensive attention. In this study, hemoglobin (Hb) is connected with the photosensitizer chlorin e6 (Ce6) to construct a 2-in-1 nanoplatform (SRF@Hb-Ce6) with Sorafenib (SRF, ferroptosis promotor) loaded, combining oxygen-boosted PDT and potent ferroptosis. Benefiting from the intrinsic presence of Fe capable of binding oxygen, hemoglobin concurrently furnishes oxygen for oxygen-dependent PDT and Fe for Fe-dependent ferroptosis. Furthermore, amphiphilic MMP2-responsive peptide is incorporated into the skeleton of the nanoplatform to ensure drug-release specificity for safety improvement. Correlative measurements demonstrate the potentiation of PDT and ferroptosis with SRF@Hb-Ce6. More importantly, PDT strengthens ferroptosis by recruiting immune cells to secrete IFN-γ, which can sensitize the tumor to ferroptosis in our findings. The therapeutic effect of synergistic treatment with SRF@Hb-Ce6 in vitro and in vivo was proven significant, revealing the promising prospects of combined PDT and ferroptosis therapy with the 2-in-1 nanoplatform.
Low-density, flexible and high-performance electromagnetic interference (EMI) shielding materials are urgently required to address the increasingly serious problem of radiation pollution. Ni-Co ...alloys with intrinsic conductivity and magnetism are good candidates for providing excellent EMI shielding performance. However, their high density and poor flexibility severely restrict their further applications in some specific fields. Herein, lightweight and flexible Ni-Co alloy nanoparticle-coated PAN-PU (P@Ni-Co) nanofiber membrane is fabricated through the combination of the electrospinning technique and the electroless deposition process, and it is employed as an effective EMI shielding material. Due to its remarkable conductivity of 1139.6 S/cm and the satisfactory saturation magnetization value of 49.6 emu/g, P@Ni-Co hybrid membrane with a thickness of 0.180 mm and a density of 0.59 g cm−3 exhibits excellent electromagnetic interference shielding effectiveness (EMI SE) of >68 dB over a wide frequency band (8–26.5 GHz); moreover, the average EMI SE reached as high as 77.8 dB with an absolute EMI shielding effectiveness (SSET) of 7325.8 dB cm2·g−1, which are higher than those for most of the reported EMI shielding materials. Compared to reflection, absorption makes a much larger contribution to the total EMI shielding effectiveness. These results suggest that Ni-Co alloy nanoparticle-coated PAN-PU nanofiber membrane would be very promising for applications as a thinner and lighter EMI shielding material.
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•P@Ni-Co nanofiber membrane is prepared via electrospinning and electroless plating.•P@Ni-Co exhibits remarkable conductivity and satisfying magnetism.•P@Ni-Co is employed as lightweight and flexible EMI shielding material.•The average EMI SE could reach 77.8 dB over wide frequency band (8–26.5 GHz).•Absorption makes much larger contribution to total EMI shielding effectiveness.
Feed-forward loops (FFLs), consisting of miRNAs, transcription factors (TFs) and their common target genes, have been validated to be important for the initialization and development of complex ...diseases, including cancer. Esophageal Carcinoma (ESCA) and Stomach Adenocarcinoma (STAD) are two types of malignant tumors in the digestive tract. Understanding common and distinct molecular mechanisms of ESCA and STAD is extremely crucial.
In this paper, we presented a computational framework to explore common and distinct FFLs, and molecular biomarkers for ESCA and STAD. We identified FFLs by combining regulation pairs and RNA-seq data. Then we constructed disease-specific co-expression networks based on the FFLs identified. We also used random walk with restart (RWR) on disease-specific co-expression networks to prioritize candidate molecules. We identified 148 and 242 FFLs for these two types of cancer, respectively. And we found that one TF, E2F3 was related to ESCA, two genes, DTNA and KCNMA1 were related to STAD, while one TF ESR1 and one gene KIT were associated with both of the two types of cancer.
This proposed computational framework predicted disease-related biomolecules effectively and discovered the correlation between two types of cancers, which helped develop the diagnostic and therapeutic strategies of Esophageal Carcinoma and Stomach Adenocarcinoma.
In view of the existing verification methods of electric meters, there are problems such as high maintenance cost, poor accuracy, and difficulty in full coverage, etc. Starting from the perspective ...of analyzing the large-scale measured data collected by user-side electric meters, an online estimation method for the operating error of electric meters was proposed, which uses the recursive least squares (RLS) and introduces a double-parameter method with dynamic forgetting factors λa and λb to track the meter parameters changes in real time. Firstly, the obtained measured data are preprocessed, and the abnormal data such as null data and light load data are eliminated by an appropriate clustering method, so as to screen out the measured data of the similar operational states of each user. Then equations relating the head electric meter in the substation and each users’ electric meter and line loss based on the law of conservation of electric energy are established. Afterwards, the recursive least squares algorithm with double-parameter is used to estimate the parameters of line loss and the electric meter error. Finally, the effects of double dynamic forgetting factors, double constant forgetting factors and single forgetting factor on the accuracy of estimated error of electric meter are discussed. Through the program-controlled load simulation system, the proposed method is verified with higher accuracy and practicality.
The process of ripening and softening in grape begins at veraison and is closely related to the depolymerization of pectin components. A variety of enzymes are involved in pectin metabolism and one ...class of enzyme, pectin lyases (PLs), have been reported to play an important role in softening in many fruits; however, little information is available on the
gene family in grape. In this study, 16
genes were identified in the grape genome using bioinformatics methods. Among them,
,
, and
had the highest expression levels during grape ripening, which suggests that these genes are involved in grape ripening and softening. Furthermore, overexpression of
affects the contents of water-soluble pectin (WSP) and acid-soluble pectin (ASP) in the leaves of Arabidopsis and significantly changes the growth of Arabidopsis plants. The relationship between
and pectin content was further determined by antisense expression of
. In addition, we also studied the effect of
on fruit in transgenic tomato plants, which showed that
accelerated fruit ripening and softening. Our results indicate that
plays an important role in grape berry softening during ripening by depolymerizing pectin.
Soil microbial communities are fundamental to maintaining key soil processes associated with litter decomposition, nutrient cycling, and plant productivity and are thus integral to human well-being. ...Recent technological advances have exponentially increased our knowledge concerning the global ecological distributions of microbial communities across space and time and have provided evidence for their contribution to ecosystem functions. However, major knowledge gaps in soil biogeography remain to be addressed over the coming years as technology and research questions continue to evolve. In this minireview, we state recent advances and future directions in the study of soil microbial biogeography and discuss the need for a clearer concept of microbial species, projections of soil microbial distributions toward future global change scenarios, and the importance of embracing culture and isolation approaches to determine microbial functional profiles. This knowledge will be critical to better predict ecosystem functions in a changing world.
The mTORC1 pathway coordinates nutrient and growth factor signals to maintain organismal homeostasis. Whether nutrient signaling to mTORC1 regulates stem cell function remains unknown. Here, we show ...that SZT2--a protein required for mTORC1 downregulation upon nutrient deprivation--is critical for hematopoietic stem cell (HSC) homeostasis. Ablation of SZT2 in HSCs decreased the reserve and impaired the repopulating capacity of HSCs. Furthermore, ablation of both SZT2 and TSC1--2 repressors of mTORC1 on the nutrient and growth factor arms, respectively--led to rapid HSC depletion, pancytopenia, and premature death of the mice. Mechanistically, loss of either SZT2 or TSC1 in HSCs led to only mild elevation of mTORC1 activity and reactive oxygen species (ROS) production. Loss of both SZT2 and TSC1, on the other hand, simultaneously produced a dramatic synergistic effect, with an approximately 10-fold increase of mTORC1 activity and approximately 100-fold increase of ROS production, which rapidly depleted HSCs. These data demonstrate a critical role of nutrient mTORC1 signaling in HSC homeostasis and uncover a strong synergistic effect between nutrient- and growth factor-mediated mTORC1 regulation in stem cells.
The COVID‐19 pathogen, SARS‐CoV‐2, requires its main protease (SC2MPro) to digest two of its translated long polypeptides to form a number of mature proteins that are essential for viral replication ...and pathogenesis. Inhibition of this vital proteolytic process is effective in preventing the virus from replicating in infected cells and therefore provides a potential COVID‐19 treatment option. Guided by previous medicinal chemistry studies about SARS‐CoV‐1 main protease (SC1MPro), we have designed and synthesized a series of SC2MPro inhibitors that contain β‐(S‐2‐oxopyrrolidin‐3‐yl)‐alaninal (Opal) for the formation of a reversible covalent bond with the SC2MPro active‐site cysteine C145. All inhibitors display high potency with Ki values at or below 100 nM. The most potent compound, MPI3, has as a Ki value of 8.3 nM. Crystallographic analyses of SC2MPro bound to seven inhibitors indicated both formation of a covalent bond with C145 and structural rearrangement from the apoenzyme to accommodate the inhibitors. Virus inhibition assays revealed that several inhibitors have high potency in inhibiting the SARS‐CoV‐2‐induced cytopathogenic effect in both Vero E6 and A549/ACE2 cells. Two inhibitors, MPI5 and MPI8, completely prevented the SARS‐CoV‐2‐induced cytopathogenic effect in Vero E6 cells at 2.5–5 μM and A549/ACE2 cells at 0.16–0.31 μM. Their virus inhibition potency is much higher than that of some existing molecules that are under preclinical and clinical investigations for the treatment of COVID‐19. Our study indicates that there is a large chemical space that needs to be explored for the development of SC2MPro inhibitors with ultra‐high antiviral potency.
Small but strong: A series of SARS‐CoV‐2 MPro covalent inhibitors exhibit excellent activity. Protein crystallography analysis and a live virus‐based microneutralization assay found two of the most potent anti‐SARS‐CoV‐2 small molecules so far. Due to the urgent matter of the COVID‐19 pandemic, these two inhibitors could be quickly advanced to preclinical and clinical tests for COVID‐19.
•MAMDC2 is upregulated significantly in microglia upon neurotropic herpesvirus infection.•MAMDC2 is upregulated remarkably in microglia isolated from a series of AD mice.•MAMDC2 enhances the ...polymerization of STING, facilitating the expression of type I interferon.•MAMDC2 interacts with STING via its first MAM domain.•MAMDC2 is a possible link between HSV-1 infection and AD pathogenesis.
Microglia, as central nervous system (CNS)-resident macrophages, are the first line of defense against neurotropic virus infection, the immune response of which is implicated in numerous CNS diseases, including Alzheimer's disease (AD). Indeed, the infectious hypothesis for AD has long been recognized, of note herpes simplex virus type 1 (HSV-1), the most common human neurotropic virus. However, the mechanism linking HSV-1 and AD remains obscure. In this study, we analyzed the transcriptome data of microglia in AD mice. We found that MAM domain containing 2 (MAMDC2) is significantly upregulated in microglia isolated from both a series of AD mice established by numerous genetic strategies and mice with HSV-1 infection. Mamdc2-deficient (Mamdc2−/−) mice are susceptible to HSV-1 infection and show an impaired type I interferon (I-IFN)-based innate antiviral response upon neurotropic HSV-1 infection. The in vitro experiments suggest a similar result. Moreover, lentivirus-mediated overexpression of Mamdc2 in mouse brains enhances the innate antiviral response in microglia and ameliorates herpes simplex encephalitis (HSE) symptoms. Mechanistically, MAMDC2 interacts with STING via its first MAM domain within and enhances the polymerization of STING, activating downstream TBK1-IRF3 signaling to facilitate the expression of I-IFNs. The sulfated glycosaminoglycan-mediated polymerization of STING also largely depends on MAMDC2. Our study uncovers the function of MAMDC2 in the innate antiviral response in microglia, revealing a potential mechanism linking HSV-1 and AD, especially the contribution of Mamdc2 overexpression to the upregulation of I-IFN in the AD brain.
Infection of HSV-1 in human and mouse microglia induces the expression of MAMDC2. The accumulated MAMDC2 enhances the polymerization of STING, activating TBK1-IRF3 downstream signaling to initiate the expression of type I interferon (I-IFN). MAMDC2 interacts with STING via the first MAM domain within MAMDC2. In the absence of MAMDC2, the polymerization of STING induced by cGAMP or HSV-1 in fection is impaired significantly, leading to a reduced expression of I-IFN. Display omitted
Although increased early detection, diagnosis and treatment have improved the outcome of breast cancer patients, prognosis estimation still poses challenges due to the disease heterogeneity. ...Accumulating data indicated an evident correlation between tumor immune microenvironment and clinical outcomes.
To construct an immune-related signature that can estimate disease prognosis and patient survival in breast cancer.
Gene expression profiles and clinical data of breast cancer patients were collected from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, which were further divided into a training set (n = 499), a testing set (n = 234) and a Meta-validation set (n = 519). In the training set, immune-related genes were recognized using combination of gene expression data and ESTIMATE algorithm-derived immune scores. An immune-related prognostic signature was generated with LASSO Cox regression analysis. The prognostic value of the signature was validated in the testing set and the Meta-validation set.
A total of 991 immune-related genes were identified. Twelve genes with non-zero coefficients in LASSO analysis were used to construct an immune-related prognostic signature. The 12-gene signature significantly stratified patients into high and low immune risk groups in terms of overall survival independent of clinical and pathologic factors. The signature also significantly stratified overall survival in clinical defined groups, including stage I/II disease. Several biological processes, such as immune response, were enriched among genes in the immune-related signature. The percentage of M
macrophage infiltration was significantly different between low and high immune risk groups. Time-dependent ROC curves indicated good performance of our signature in predicting the 1-, 3- and 5-year overall survival for patients from the full TCGA cohort. Furthermore, the composite signature derived by integrating immune-related signature with clinical factors, provided a more accurate estimation of survival relative to molecular signature alone.
We developed a 12-gene prognostic signature, providing novel insights into the identification of breast cancer with a high risk of death and assessment of the possibility of immunotherapy incorporation in personalized breast cancer management.
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