Grim-19 plays a key role in mitochondrial steroidogenic acute regulatory protein stability and ligand-binding properties in Leydig cells.

Grim-19 (gene associated with retinoid-IFN-induced mortality 19), the essential component of complex I of mitochondrial respiratory chain, functions as a noncanonical tumor suppressor by controlling apoptosis and energy metabolism. However, additional biological actions of Grim-19 have been recently suggested in male reproduction. We investigated here the expression and functional role of Grim-19 in murine testis. Testicular Grim-19 expression was detected from mouse puberty and increased progressively thereafter, and GRIM-19 protein was observed to be expressed exclusively in interstitial Leydig cells (LCs), with a prominent mitochondrial localization. In vivo lentiviral vector-mediated knockdown of Grim-19 resulted in a significant decrease in testosterone production and triggered aberrant oxidative stress in testis, thus impairing male fertility by inducing germ cell apoptosis and oligozoospermia. The control of testicular steroidogenesis by GRIM-19 was validated using the in vivo knockdown model with isolated primary LCs and in vitro experiments with MA-10 mouse Leydig tumor cells. Mechanistically, we suggest that the negative regulation exerted by GRIM-19 deficiency-induced oxidative stress on steroidogenesis may be the result of two phenomena: a direct effect through inhibition of phosphorylation of steroidogenic acute regulatory protein (StAR) and subsequent impediment to StAR localization in mitochondria and an indirect pathway that is to facilitate the inhibiting role exerted by the extracellular matrix on the steroidogenic capacity of LCs via promotion of integrin activation. Altogether, our observations suggest that Grim-19 plays a potent role in testicular steroidogenesis and that its alterations may contribute to testosterone deficiency-related disorders linked to metabolic stress and male infertility.

DeepHPV: a deep learning model to predict human papillomavirus integration sites.

Human papillomavirus (HPV) integrating into human genome is the main cause of cervical carcinogenesis. HPV integration selection preference shows strong dependence on local genomic environment. Due to this theory, it is possible to predict HPV integration sites. However, a published bioinformatic tool is not available to date. Thus, we developed an attention-based deep learning model DeepHPV to predict HPV integration sites by learning environment features automatically. In total, 3608 known HPV integration sites were applied to train the model, and 584 reviewed HPV integration sites were used as the testing dataset. DeepHPV showed an area under the receiver-operating characteristic (AUROC) of 0.6336 and an area under the precision recall (AUPR) of 0.5670. Adding RepeatMasker and TCGA Pan Cancer peaks improved the model performance to 0.8464 and 0.8501 in AUROC and 0.7985 and 0.8106 in AUPR, respectively. Next, we tested these trained models on independent database VISDB and found the model adding TCGA Pan Cancer performed better (AUROC: 0.7175, AUPR: 0.6284) than the model adding RepeatMasker peaks (AUROC: 0.6102, AUPR: 0.5577). Moreover, we introduced attention mechanism in DeepHPV and enriched the transcription factor binding sites including BHLHA15, CHR, COUP-TFII, DMRTA2, E2A, HIC1, INR, NPAS, Nr5a2, RARa, SCL, Snail1, Sox10, Sox3, Sox4, Sox6, STAT6, Tbet, Tbx5, TEAD, Tgif2, ZNF189, ZNF416 near attention intensive sites. Together, DeepHPV is a robust and explainable deep learning model, providing new insights into HPV integration preference and mechanism. Availability: DeepHPV is available as an open-source software and can be downloaded from https://github.com/JiuxingLiang/DeepHPV.git, Contact: huzheng1998@163.com, liangjiuxing@m.scnu.edu.cn, lizheyzy@163.com.

Patients without Increased Lymphocyte Counts and Decreased CT Scores During the Early 2nd Week of Illness Onset may Develop to Severe COVID-19.

BACKGROUND: Lymphopenia and high CT score is associated with COVID-19 severity. Herein we describe the change pattern in lymphocyte count and CT score during hospitalization and explore a possible association with the severity of COVID-19. METHODS: In this retrospective study, 13 non-severe COVID-19 patients diagnosed at admission were enrolled. One patient progressed to severe disease. Change patterns in lymphocyte counts and CT scores of all patients were analyzed. RESULTS: Lymphocyte count increased gradually from day 5 post-illness onset (day 5 vs. day 15, p = 0.001). Lymphocyte count of the severe patient fluctuated at low levels throughout the 15-day period. Chest CT scores of non-severe patients increased significantly during the first 5 days of illness onset, but decreased gradually beginning day 9 (illness onset vs. day 5, p = 0.002, day 9 vs. day 15, p = 0.015). In the severe patient, CT score continued to increase over the 11 days post-illness onset period. CONCLUSIONS: Non-severe COVID-19 patients had significantly increased lymphocyte counts and decreased CT scores beginning day 5 and day 9 of illness onset, respectively. The patients without increased lymphocyte counts and decreased CT scores during the early 2nd week of illness onset may develop to severe COVID-19.

Dynamic contrast-enhanced MRI perfusion parameters are imaging biomarkers for angiogenesis in lung cancer.

BACKGROUND: Quantitative parameters of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) may have the potential to reflect angiogenesis and proliferation of pulmonary neoplasms. PURPOSE: To verify whether DCE-MRI can identify pulmonary neoplasm property and evaluate the correlation of DCE-MRI perfusion parameters with microvessel density (MVD) and Ki-67 in lung cancer. MATERIAL AND METHODS: This study enrolled 65 patients with one pulmonary neoplasm who underwent computed tomography-guided percutaneous lung biopsy with pathological diagnosis (43 malignant, 22 benign; mean age = 59.71 ± 11.72 years). All patients did DCE-MRI before biopsy. Quantitative MRI parameters including endothelial transfer constant (Ktrans), flux rate constant (Kep), and fractional extravascular extracellular space (EES) volume (Ve) were calculated by extended Tofts linear model. MVD was evaluated by CD34-expressing tumor vessels. Proliferation was assessed by Ki-67 staining. The correlations of parameters with MVD and Ki-67 expression were analyzed. RESULTS: Ktrans and Kep values were significantly increased in malignant lesions compared to benign lesions (P = 0.001 and 0.022, respectively), whereas no statistical difference in Ve was found. The CD34 expression was positively correlated to Ktrans (r = 0.608; P = 0.004) and Kep (r = 0.556; P = 0.001). Subsequent subtype analyses also showed positive correlations of Ktrans and Kep with MVD in adenocarcinoma group (r = 0.550 and 0.563; P = 0.012 and 0.015, respectively). No significant correlation was found between these parameters and Ki-67. CONCLUSION: Ktrans and Kep may distinguish benign and malignant pulmonary neoplasm. Ktrans and Kep, with their positive correlation to MVD, can be used as non-invasive parameters reflecting lung cancer angiogenesis.

All electrospun fabrics based piezoelectric tactile sensor.

Tactile sensors have been widely used in the areas of health monitoring and intelligent human-machine interface. Flexible tactile sensors based on nanofiber mats made by electrospinning can meet the requirements of comfortability and breathability for wearing the body very well. Here, we developed a flexible and self-powered tactile sensor that was sandwich assembled by electrospun organic electrodes and a piezoelectric layer. The metal-free organic electrodes of thermal plastic polyurethane (PU) nanofibers decorated with multi-walled carbon nanotubes were fabricated by electrospinning followed by ultrasonication treatment. The electrospun polyvinylidene fluoride-trifluoroethylene (PVDF-TrFE) mat was utilized as the piezoelectric layer, and it was found that the piezoelectric performance of PVDF-TrFE nanofiber mat added with barium titanate (BaTiO3) nanoparticles was enhanced about 187% than that of the pure PVDF-TrFE nanofiber mat. For practical application, the as-prepared piezoelectric tactile sensor exhibited an approximative linear relationship between the external force and the electrical output. Then the array of fabricated sensors was attached to the fingertips of a glove to grab a cup of water for tactile sensing, and the mass of water can be directly estimated according to the outputs of the sensor array. Attributed to the integrated merits of good flexibility, enhanced piezoelectric performance, light weight, and efficient gas permeability, the developed tactile sensor could be widely used as wearable devices for robot execution end or prosthesis for tactile feedback.

Does laser treatment restore the bond strength of resin composites to recently bleached enamel? A systematic review and meta-analysis.

PURPOSE: To do a systematic review and meta-analysis to determine whether laser treatment affects the bond strength of resin composites to recently bleached enamel. METHODS: This report follows the Preferred Reporting Items for Systematic Reviews and Qualitative Analyses (PRISMA) statement. Medline via PubMed, Embase, Web of Science, and the Cochrane Library databases were searched with no limits on publication year. Two reviewers independently screened all titles and abstracts to perform the study selection, data extraction, and risk-of-bias assessments. A random-effects meta-analysis model was performed using Review Manager software (version 5.3, Cochrane Collaboration). RESULTS: From the 93 records identified, seven articles that met all the inclusion criteria were included in the systematic review, and six studies were included in the meta-analysis. The overall results showed a statistically significant difference in bond strength between the control group and laser-treated group (P= 0.04; mean difference: 5.27; 95% confidence interval: 0.28 to 10.27), favoring the laser-treated group. Subgroup analyses revealed that the tooth source (bovine or human teeth) contributed to the effect of laser treatment on the bleached enamel. CLINICAL SIGNIFICANCE: Laser treatment may increase the bond strength of resin composites to recently bleached enamel. Pretreatment with a laser, preferably with Nd:YAG (1 W, frequency of 10 Hz, irradiation time of 60 seconds) or CO2 lasers (0.5 W, frequency of 10 Hz, irradiation time of 60 seconds), may be recommended to restore the bond strength of recently bleached enamel.

A coordinate positioning puncture method under robot-assisted CT-guidance: phantom and animal experiments.

PURPOSE: To evaluate the accuracy of the robot-assisted computed tomography (CT)-guided coordinate positioning puncture method by phantom and animal experiments. MATERIAL AND METHODS: In the phantom experiment, seven robot-assisted punctures were made to evaluate the accuracy of the method. In the animal experiment, 18 punctures (nine robotic and nine manual) were made in the livers of nine rabbits. The indicators, such as needle-tract length, angle deviation, puncture accuracy, number of scans required, and radiation exposure dose were compared between manual and robotic punctures. The paired-samples t-test was used for analysis. RESULTS: In the phantom experiment, the mean accuracy of seven punctures was 2.67 mm. In the animal experiment, there was no significant difference in needle-tract length (32.58 mm vs. 34.04 mm, p = .606), angle deviation (17.21° vs. 21.23° p = .557) and puncture accuracy (8.42 vs. 8.77 mm, p = .851) between the two groups. However, the number CT scans required (2.44 vs. 3.33, p = .002), and the radiation exposure dose (772.98 vs. 1077.89 mGy/cm, p = .003) were lower in the robot group than in the manual group. CONCLUSIONS: The coordinate positioning puncture method under robot-assisted CT-guidance can reach an accuracy that is comparable to that of the traditional manual CT-guided puncture method and with fewer CT scanning times accompanied with a lower radiation dosage.

Direction Matters: On Influence-Preserving Graph Summarization and Max-Cut Principle for Directed Graphs.

Summarizing large-scale directed graphs into small-scale representations is a useful but less-studied problem setting. Conventional clustering approaches, based on Min-Cut-style criteria, compress both the vertices and edges of the graph into the communities, which lead to a loss of directed edge information. On the other hand, compressing the vertices while preserving the directed-edge information provides a way to learn the small-scale representation of a directed graph. The reconstruction error, which measures the edge information preserved by the summarized graph, can be used to learn such representation. Compared to the original graphs, the summarized graphs are easier to analyze and are capable of extracting group-level features, useful for efficient interventions of population behavior. In this letter, we present a model, based on minimizing reconstruction error with nonnegative constraints, which relates to a Max-Cut criterion that simultaneously identifies the compressed nodes and the directed compressed relations between these nodes. A multiplicative update algorithm with column-wise normalization is proposed. We further provide theoretical results on the identifiability of the model and the convergence of the proposed algorithms. Experiments are conducted to demonstrate the accuracy and robustness of the proposed method.

Information-Theoretic Representation Learning for Positive-Unlabeled Classification.

Recent advances in weakly supervised classification allow us to train a classifier from only positive and unlabeled (PU) data. However, existing PU classification methods typically require an accurate estimate of the class-prior probability, a critical bottleneck particularly for high-dimensional data. This problem has been commonly addressed by applying principal component analysis in advance, but such unsupervised dimension reduction can collapse the underlying class structure. In this letter, we propose a novel representation learning method from PU data based on the information-maximization principle. Our method does not require class-prior estimation and thus can be used as a preprocessing method for PU classification. Through experiments, we demonstrate that our method, combined with deep neural networks, highly improves the accuracy of PU class-prior estimation, leading to state-of-the-art PU classification performance.

Ultra-low-dose CT-guided lung biopsy in clinic: radiation dose, accuracy, image quality, and complication rate.

BACKGROUND: Computed tomography (CT)-guided percutaneous lung biopsy is usually performed by helical scanning. However, there are no studies on radiation dose, diagnostic accuracy, image quality, and complications based on axial scan mode. PURPOSE: To determine radiation dose, accuracy, image quality, and complication rate following an ultra-low-dose (ULD) protocol for CT-guided lung biopsy in clinic. MATERIAL AND METHODS: A total of 105 patients were enrolled to receive CT-guided lung biopsy. The use of an ULD protocol (axial scan) for CT-guided biopsy was initiated. Patients were randomly assigned to axial mode (Group A) and conventional helical mode (Group B) CT groups. 64-slice CT was performed for CT-guided pulmonary biopsy with an 18-G coaxial cutting biopsy needle. The radiation dose, accuracy, image quality, and complication rate were measured. RESULTS: Ninety-seven patients were selected for the final phase of the study. There was no significant difference between the two groups for pulmonary nodule characteristics (P > 0.05). The mean effective dose in group A (0.077 ± 0.010 mSv) was significantly reduced relative to group B (0.653 ± 0.177 mSv, P < 0.001). There was no significant difference in accuracy, image quality, and complication rate (P > 0.050) between the two modes. CONCLUSION: An ULD protocol for CT-guided lung nodule biopsy yields a reduction in the radiation dose without significant change in the accuracy, image quality, and complication rate relative to the conventional helical mode scan.

Endoplasmic Reticulum Targeting to Amplify Immunogenic Cell Death for Cancer Immunotherapy.

Immunogenic cell death (ICD) elicited by photodynamic therapy (PDT) is mediated through generation of reactive oxygen species (ROS) that induce endoplasmic reticulum (ER) stress. However, the half-life of ROS is very short and the intracellular diffusion depth is limited, which impairs ER localization and thus limits ER stress induction. To solve the problem, we synthesized reduction-sensitive Ds-sP NPs (PEG-s-s-1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[amino(polyethylene glycol)-2000] nanoparticles) loaded with an efficient ER-targeting photosensitizer TCPP-TER (4,4',4″,4'″-(porphyrin-5,10,15,20-tetrayl)tetrakis(N-(2-((4-methylphenyl)sulfonamido)ethyl)benzamide). The resulting Ds-sP/TCPP-TER NPs could selectively accumulate in the ER and locally generate ROS under near-infrared (NIR) laser irradiation, which induced ER stress, amplified ICD, and activated immune cells, leading to augmented immunotherapy effect. This study presents a novel ICD amplifying, ER-targeting PDT strategy that can effectively eradicate primary tumors under NIR exposure, as well as distant tumors through an abscopal effect.

FgPal1 regulates morphogenesis and pathogenesis in Fusarium graminearum.

Ascospores are the primary inoculum in Fusarium graminearum, a causal agent of wheat head blight. In a previous study, FgPAL1 was found to be upregulated in the Fgama1 mutant and important for ascosporogenesis. However, the biological function of this well-conserved gene in filamentous ascomycetes is not clear. In this study, we characterized its functions in growth, differentiation and pathogenesis. The Fgpal1 mutant had severe growth defects and often displayed abnormal hyphal tips. It was defective in infectious growth in rachis tissues and spreading in wheat heads. The Fgpal1 mutant produced conidia with fewer septa and more nuclei per compartment than the wild type. In actively growing hyphal tips, FgPal1-GFP mainly localized to the subapical collar and septa. The FgPal1 and LifeAct partially co-localized at the subapical region in an interdependent manner. The Fgpal1 mutant was normal in meiosis with eight nuclei in developing asci but most asci were aborted. Taken together, our results showed that FgPal1 plays a role in maintaining polarized tip growth and coordination between nuclear division and cytokinesis, and it is also important for infectious growth and developments of ascospores by the free cell formation process.

In Situ Polymerized Hollow Mesoporous Organosilica Biocatalysis Nanoreactor for Enhancing ROS-Mediated Anticancer Therapy.

The combination of reactive oxygen species (ROS)-involved photodynamic therapy (PDT) and chemodynamic therapy (CDT) holds great promise for enhancing ROS-mediated cancer treatment. Herein, we reported an in situ polymerized hollow mesoporous organosilica nanoparticle (HMON) biocatalysis nanoreactor to integrate the synergistic effect of PDT/CDT for enhancing ROS-mediated pancreatic ductal adenocarcinoma treatment. HPPH photosensitizer was hybridized within the framework of HMON via an "in situ framework growth" approach. Then, the hollow cavity of HMONs was exploited as a nanoreactor for "in situ polymerization" to synthesize the polymer containing thiol groups, thereby enabling the immobilization of ultrasmall gold nanoparticles, which behave like glucose oxidase-like nanozyme, converting glucose into H2O2 to provide self-supplied H2O2 for CDT. Meanwhile, Cu2+-tannic acid complexes were further deposited on the surface of HMONs (HMON-Au@Cu-TA) to initiate Fenton-like reaction to covert the self-supplied H2O2 into •OH, a highly toxic ROS. Finally, collagenase (Col), which can degrade the collagen I fiber in the extracellular matrix (ECM), was loaded into HMON-Au@Cu-TA to enhance the penetration of HMONs and O2 infiltration for enhanced PDT. This study provides a good paradigm for enhancing ROS-mediated anti-tumor efficacy. Meanwhile, this research offers a new method to broaden the application of silica based nanotheranostics.

Alantolactone suppresses inflammation, apoptosis and oxidative stress in cigarette smoke-induced human bronchial epithelial cells through activation of Nrf2/HO-1 and inhibition of the NF-κB pathways.

BACKGROUND: It is well established that airway remodeling and inflammation are characteristics for chronic obstructive pulmonary disease (COPD). Moreover, cigarette smoke extract (CSE) promots inflammation, apoptosis and oxidative stress in COPD. And, there is evidence suggested that alantolactone (ALT), a sesquiterpene lactone isolated from Inula helenium, plays an adverse role in inflammation, apoptosis and oxidative stress. However, few studies have investigated the function and mechanism of ALT treatment on the COPD pathological process. METHODS: The levels of IL-1 ß, TNF-α, IL-6 and IFN-γ were examined by ELISA. Cells' apoptosis and caspase-3 activity were detected by Cell Death Detection PLUS enzyme-linked immunosorbent assay and caspase-Glo 3/7 Assay, respectively. The content of malondialdehyde (MDA) and superoxide dismutase (SOD) were determined by using MDA and SOD assay kits. Reactive oxygen species (ROS) generation was measured by DCFH-DA assay. Protein expression was assayed by Western blot. RESULTS: In the present study, we aimed to observe the protective effects of ALT against inflammation, apoptosis and oxidative stress in human bronchial epithelial Beas-2B and NHBE cells. Our results showed that different doses of CSE exposure induced Beas-2B and NHBE cell inflammatory cytokines IL-1 ß, TNF-α, IL-6 and IFN-γ expression, cell apoptosis, caspase-3 activity and mediated oxidative stress markers MDA, ROS and SOD levels, while ALT treatment counteracted the effects of CSE. Further studies suggested that ALT attenuated NF-κB pathway activation. ALT also activated the Nrf2/HO-1 signal pathway through promoting Nrf2 nuclear aggregation and downstream HO-1 protein expression. HO-1 inhibitor tin protoporphyrin IX (SnPP IX) reversed the effects of ALT on Beas-2B and NHBE cell inflammation, apoptosis and oxidative stress. CONCLUSIONS: The above results collectively suggested that ALT suppressed CSE-induced inflammation, apoptosis and oxidative stress by modulating the NF-ĸB and Nrf2/ HO-1 axis.

Crucial Impact of Hydrophilicity on the Self-Assembled 2D Colloidal Crystals Using Langmuir-Blodgett Method.

Large-scale close-packed two-dimensional (2D) colloidal crystal with high coverage is indispensable for various promising applications. The Langmuir-Blodgett (LB) method is a powerful technique to prepare 2D colloidal crystals. However, the self-assembly and movement of microspheres during the whole LB process are less analyzed. In this study, we clarify the crucial impact of hydrophilicity of the microspheres on their self-assembly in the LB process and on the properties of the prepared 2D colloidal crystals. The characteristic surface pressure-area isotherms of the microspheres have been analyzed and adjusted by only counting the quantity of the microspheres on the water surface, which leads to more accurate results. The critical surface pressures for hydrophilic and hydrophobic microspheres are about 61 and 46 mN/m, respectively. The decrease of the surface hydrophilicity of microspheres facilitates their self-assembly on the water surface, which further leads to higher coverage and less defects of the 2D colloidal crystals. A coverage of as high as 97% was obtained using hydrophobic microspheres. Entropy and intersphere capillary forces drive the self-assembly and transportation of the microspheres, respectively. Caused by the diffraction of visible light, opposite contrasts at local adjacent regions on the surface of the 2D colloidal crystals have been observed. The understanding of self-assembly of the microspheres during the LB process paves the way to fabricate the high-quality 2D colloidal crystals for various applications such as photonic papers and inks, stealth materials, biomimetic coatings, and related nanostructures.

PTPN14 acts as a candidate tumor suppressor in prostate cancer and inhibits cell proliferation and invasion through modulating LATS1/YAP signaling.

Protein tyrosine phosphatase, non-receptor type 14 (PTPN14) exerts a profound effect in the progression of multiple malignant tumors. However, whether PTPN14 plays a role in prostate cancer has not been well investigated. Herein, we evaluated the function and potential underlying mechanism of PTPN14 in prostate cancer. Decreased PTPN14 expression was detected in prostate cancer, and restoration of PTPN14 expression in prostate cancer cells inhibited the proliferative and invasive potential. Mechanistically, PTPN14 increased the phosphorylation of Yes-associated protein (YAP) by activation of large tumor suppressor 1 (LATS1), an action that resulted in a significant reduction in YAP-mediated transcriptional activity. Inactivation of YAP by its inhibitor markedly abrogated the PTPN14-knockdown-induced promotion effect on prostate cancer cell proliferation and invasion. Notably, PTPN14 up-regulation also exerted a remarkable suppressive impact on tumorigenesis of prostate cancer in vivo. Taken together, the study reveals a tumor-inhibition role of PTPN14 that represses the proliferation and invasion of prostate cancer by down-regulating YAP activation.

Reliable resistive switching of epitaxial single crystalline cubic Y-HfO2 RRAMs with Si as bottom electrodes.

Previous studies have mainly focused on the resistive switching (RS) of amorphous or polycrystalline HfO2-RRAM. The RS of single crystalline HfO2 films has been rarely reported. Yttrium doped HfO2 (YDH) thin films were fabricated and successful Y incorporation into HfO2 was confirmed by x-ray photoemission spectroscopy. A pure cubic phase of YDH and an abrupt YDH/Si interface were obtained and verified by x-ray diffraction, Raman spectroscopy and transmission electron microscopy. A Pt/YDH/n++-Si heterostructure using Si as the bottom electrode was fabricated, which shows stable RS with an ON/OFF ratio of 100 and a reliable data retention (104 s). The electron transport mechanism was investigated in detail. It indicates that hopping conduction is dominating when the device is at a high resistance state, while space charge limited conduction acts as the dominant factor at a low resistance state. Such behavior, which is different from devices using TiN or Ti as electrodes, was attributed to the Y doping and specific YDH/Si interface. Our results demonstrate a proof of concept study to use highly doped Si as bottom electrodes along with single crystalline YDH as insulator layer for such RRAM applications as wireless sensors and synaptic simulation.

TWIRLS, a knowledge-mining technology, suggests a possible mechanism for the pathological changes in the human host after coronavirus infection via ACE2.

Faced with the current large-scale public health emergency, collecting, sorting, and analyzing biomedical information related to the "SARS-CoV-2" should be done as quickly as possible to gain a global perspective, which is a basic requirement for strengthening epidemic control capacity. However, for human researchers studying viruses and hosts, the vast amount of information available cannot be processed effectively and in a timely manner, particularly if our scientific understanding is also limited, which further lowers the information processing efficiency. We present TWIRLS (Topic-wise inference engine of massive biomedical literatures), a method that can deal with various scientific problems, such as liver cancer, acute myeloid leukemia, and so forth, which can automatically acquire, organize, and classify information. Additionally, this information can be combined with independent functional data sources to build an inference system via a machine-based approach, which can provide relevant knowledge to help human researchers quickly establish subject cognition and to make more effective decisions. Using TWIRLS, we automatically analyzed more than three million words in more than 14,000 literature articles in only 4 hr. We found that an important regulatory factor angiotensin-converting enzyme 2 (ACE2) may be involved in host pathological changes on binding to the coronavirus after infection. On triggering functional changes in ACE2/AT2R, the cytokine homeostasis regulation axis becomes imbalanced via the Renin-Angiotensin System and IP-10, leading to a cytokine storm. Through a preliminary analysis of blood indices of COVID-19 patients with a history of hypertension, we found that non-ARB (Angiotensin II receptor blockers) users had more symptoms of severe illness than ARB users. This suggests ARBs could potentially be used to treat acute lung injury caused by coronavirus infection.

Synthesis of Copper Peroxide Nanodots for H2O2 Self-Supplying Chemodynamic Therapy.

Chemodynamic therapy (CDT) employs Fenton catalysts to kill cancer cells by converting intracellular H2O2 into hydroxyl radical (•OH), but endogenous H2O2 is insufficient to achieve satisfactory anticancer efficacy. Despite tremendous efforts, engineering CDT agents with specific and efficient H2O2 self-supplying ability remains a great challenge. Here, we report the fabrication of copper peroxide (CP) nanodot, which is the first example of a Fenton-type metal peroxide nanomaterial, and its use as an activatable agent for enhanced CDT by self-supplying H2O2. The CP nanodots were prepared through coordination of H2O2 to Cu2+ with the aid of hydroxide ion, which could be reversed by acid treatment. After endocytosis into tumor cells, acidic environment of endo/lysosomes accelerated the dissociation of CP nanodots, allowing simultaneous release of Fenton catalytic Cu2+ and H2O2 accompanied by a Fenton-type reaction between them. The resulting •OH induced lysosomal membrane permeabilization through lipid peroxidation and thus caused cell death via a lysosome-associated pathway. In addition to pH-dependent •OH generation property, CP nanodots with small particle size showed high tumor accumulation after intravenous administration, which enabled effective tumor growth inhibition with minimal side effects in vivo. Our work not only provides the first paradigm for fabricating Fenton-type metal peroxide nanomaterials, but also presents a new strategy to improve CDT efficacy.

Bench to Bedside: Albumin Binders for Improved Cancer Radioligand Therapies.

Radioligand therapy (RLT) relies on the use of pharmacophores to selectively deliver ionization energy to cancers to exert its tumoricidal effects. Cancer cells that are not directly targeted by a radioconjugate remain susceptible to RLT because of the crossfire effect. This is significant given the inter- and intra-heterogeneity of tumors. In recent years, reversible albumin binders have been used as simple "add-ons" for radiopharmaceuticals to modify pharmacokinetics and to enhance therapeutic efficacy. In this Review, we discuss recent advances in albumin binder platforms used in RLT, with an emphasis on 4-( p-iodophenyl)butyric acid and Evans blue derivatives. We focus on four biological systems pertinent to oncology that utilize this class of compounds: folate receptor, integrin αvß3, somatostatin receptor, and prostate-specific membrane antigen. Finally, we offer our perspectives on albumin binders for RLT, highlighting future areas of research that will help propel the technology further for clinical use.