Deformation and breakup of single drop in laminar and transitional jet flows

The authors gratefully acknowledge the financial support from the National Key R&D Program of China (2017YFB0306701), National Natural Science Foundation of China (No.21676007)，the Fundamental Research Funds for the Central Universities (XK1802-1), and Scientific Research and Technology Development Projects of China National Petroleum Corporation (No. 2016B-2605).Peer reviewedPostprin

Direction of Arrival Estimation and Sensor Array Error Calibration Based on Blind Signal Separation

We consider estimating the direction of arrival (DOA) in the presence of sensor array error. In the proposed method, a blind signal separation method, the Joint Approximation and Diagonalization of Eigenmatrices (JADE) algorithm, is implemented to separate the signal vector and the mixing matrix consisting of the array manifold matrix and the sensor array error matrix. Based on a new mixing matrix and the reconstruction of the array output vector of each individual signal, we propose a novel DOA estimation method and sensor array error calibration procedure. This method is independent of array phase errors and performs well against difference of SNR of signals. Numerical simulations verify the effectiveness of the proposed method

Analysis of transient characteristics and design improvement of the passive residual heat removal system of NHR-200-II

NHR-200-II is a small integrated pressurized water reactor with 200 MW core thermal power. The core heat is transferred to two independent intermediate circuits via fourteen in-vessel primary heat exchangers (PHE), and the heat in the intermediate circuits is transferred to feedwater by two steam generators (SG) in the two intermediate circuits respectively. A passive residual heat removal (PRHR) branch is connected to each intermediate circuit to remove core decay heat under postulated accidents. During normal operation, PRHR branches are isolated by valves while SG branches in intermediate circuits are open. The valves in PRHR branches will be opened and the isolation valves of SG branches will be closed during decay heat removal scenarios. The decay heat removal capacity of NHR-200-II PRHRS could be seriously deteriorated once the isolation valves for SG branches fail to close, which was confirmed in a scaled integral test loop previously. Current understanding of PRHRS’s thermal-hydraulic characteristics with possible isolation failure in SG branches is limited. In this paper, the NHR-200-II PRHRS is modeled with RELAP5 considering the case of success and fail to isolate SG branches. A series of numerical simulations are carried out to study the impact of various parameters, such as the initial temperature, the size of the intermediate circuits’ header, and the initial flow direction in the intermediate circuits. Oscillatory flow is found when SG branches fail to be isolated under certain parameters combinations. An improved PRHRS design is purposed to eliminate possible flow oscillations, and the purposed improved design are tested by numerical simulations

Somatic mutation of the cohesin complex subunit confers therapeutic vulnerabilities in cancer

A synthetic lethality-based strategy has been developed to identify therapeutic targets in cancer harboring tumor-suppressor gene mutations, as exemplified by the effectiveness of poly ADP-ribose polymerase (PARP) inhibitors in BRCA1/2-mutated tumors. However, many synthetic lethal interactors are less reliable due to the fact that such genes usually do not perform fundamental or indispensable functions in the cell. Here, we developed an approach to identifying the "essential lethality" arising from these mutated/deleted essential genes, which are largely tolerated in cancer cells due to genetic redundancy. We uncovered the cohesion subunit SA1 as a putative synthetic-essential target in cancers carrying inactivating mutations of its paralog, SA2. In SA2-deficient Ewing sarcoma and bladder cancer, further depletion of SA1 profoundly and specifically suppressed cancer cell proliferation, survival, and tumorigenic potential. Mechanistically, inhibition of SA1 in the SA2-mutated cells led to premature chromatid separation, dramatic extension of mitotic duration, and consequently, lethal failure of cell division. More importantly, depletion of SA1 rendered those SA2-mutated cells more susceptible to DNA damage, especially double-strand breaks (DSBs), due to reduced functionality of DNA repair. Furthermore, inhibition of SA1 sensitized the SA2-deficient cancer cells to PARP inhibitors in vitro and in vivo, providing a potential therapeutic strategy for patients with SA2-deficient tumors

Gou Qi Zi inhibits proliferation and induces apoptosis through the PI3K/AKT1 signaling pathway in non-small cell lung cancer

BackgroundGou Qi Zi (Lycium barbarum) is a traditional herbal medicine with antioxidative effects. Although Gou Qi Zi has been used to prevent premature aging and in the treatment of non-small cell lung cancer (NSCLC), its mechanism of action in NSCLC remains unclear. The present study utilized network pharmacology to assess the potential mechanism of action of Gou Qi Zi in the treatment of NSCLC.MethodsThe TCMSP, TCMID, SwissTargetPrediction, DrugBank, DisGeNET, GeneCards, OMIM and TTD databases were searched for the active components of Gou Qi Zi and their potential therapeutic targets in NSCLC. Protein-protein interaction networks were identified and the interactions of target proteins were analyzed. Involved pathways were determined by GO enrichment and KEGG pathway analyses using the Metascape database, and molecular docking technology was used to study the interactions between active compounds and potential targets. These results were verified by cell counting kit-8 assays, BrdU labeling, flow cytometry, immunohistochemistry, western blotting, and qRT-PCR.ResultsDatabase searches identified 33 active components in Gou Qi Zi, 199 predicted biological targets and 113 NSCLC-related targets. A network of targets of traditional Chinese medicine compounds and potential targets of Gou Qi Zi in NSCLC was constructed. GO enrichment analysis showed that Gou Qi Zi targeting of NSCLC was mainly due to the effect of its associated lipopolysaccharide. KEGG pathway analysis showed that Gou Qi Zi acted mainly through the PI3K/AKT1 signaling pathway in the treatment of NSCLC. Molecular docking experiments showed that the bioactive compounds of Gou Qi Zi could bind to AKT1, C-MYC and TP53. These results were verified by experimental assays.ConclusionGou Qi Zi induces apoptosis and inhibits proliferation of NSCLC in vitro and in vivo by inhibiting the PI3K/AKT1 signaling pathway

Targeted immunotherapy for HER2-low breast cancer with 17p loss

The clinical challenge for treating HER2 (human epidermal growth factor receptor 2)-low breast cancer is the paucity of actionable drug targets. HER2-targeted therapy often has poor clinical efficacy for this disease due to the low level of HER2 protein on the cancer cell surface. We analyzed breast cancer genomics in the search for potential drug targets. Heterozygous loss of chromosome 17p is one of the most frequent genomic events in breast cancer, and 17p loss involves a massive deletion of genes including the tumor suppressor TP53 Our analyses revealed that 17p loss leads to global gene expression changes and reduced tumor infiltration and cytotoxicity of T cells, resulting in immune evasion during breast tumor progression. The 17p deletion region also includes POLR2A, a gene encoding the catalytic subunit of RNA polymerase II that is essential for cell survival. Therefore, breast cancer cells with heterozygous loss of 17p are extremely sensitive to the inhibition of POLR2A via a specific small-molecule inhibitor, α-amanitin. Here, we demonstrate that α-amanitin-conjugated trastuzumab (T-Ama) potentiated the HER2-targeted therapy and exhibited superior efficacy in treating HER2-low breast cancer with 17p loss. Moreover, treatment with T-Ama induced immunogenic cell death in breast cancer cells and, thereby, delivered greater efficacy in combination with immune checkpoint blockade therapy in preclinical HER2-low breast cancer models. Collectively, 17p loss not only drives breast tumorigenesis but also confers therapeutic vulnerabilities that may be used to develop targeted precision immunotherapy

Safety and efficacy of a novel double-lumen tracheal tube in neonates with RDS: A prospective cohort study

BackgroundThe purpose of this study was to assess the safety and efficacy of a new double-lumen tracheal tube for neonates, with a conventional tracheal tube as a control.MethodNewborns with respiratory distress syndrome (RDS) requiring endotracheal intubation admitted to the tertiary neonatal intensive care unit (NICU) of Qujing Maternal and Child Healthcare Hospital in Yunnan Province between March 2021 and May 2022 were enrolled in this prospective cohort study. Outcome indicators related to effectiveness included mainly the number of intubations, duration of ventilation, duration of oxygenation, and length of stay; safety indicators included any clinical adverse effects during and after intubation. Appropriate stratified and subgroup analyses were performed according to the purpose of intubation, gestational age, and whether the drug was administered via endotracheal tube.ResultA total of 101 neonates were included and divided into two groups based on the choice of tracheal tube: the conventional (n = 50) and new (n = 51) tracheal tube groups. There was no statistical difference between the two groups in terms of adverse effects during and after intubation (p > 0.05). In neonates who were mechanically ventilated without endotracheal surfactant therapy or newborns receiving InSurE technique followed by non-invasive ventilation, no significant differences were found between the two groups regarding any of the efficacy indicators (p > 0.05). However, for neonates on invasive mechanical ventilation, the new tracheal tube allowed for a significant reduction in the duration of mechanical ventilation (96.50[74.00, 144.00] vs. 121.00[96.00, 196.50] hours, p = 0.037) and total ventilation (205.71 ± 80.24 vs. 277.56 ± 117.84 h, p = 0.027), when used as a route for endotracheal drug delivery. Further analysis was performed according to gestational age for newborns requiring intratracheal surfactant administration during mechanical ventilation, and the data showed that for preterm infants, the new tracheal tube not only shortened the duration of mechanical ventilation (101.75 ± 39.72 vs. 155.50 ± 51.49 h, p = 0.026) and total ventilation (216.00 ± 81.60 vs. 351.50 ± 113.79 h, p = 0.010), but also demonstrated significant advantages in reducing the duration of oxygen therapy (9.75 ± 6.02 vs. 17.33 ± 8.43 days, p = 0.042); however, there was no statistical difference in efficacy outcomes between the two groups in full-term infants (p > 0.05).ConclusionThe efficacy and safety of this new tracheal tube are promising in neonates with RDS, especially those requiring surfactant administration via a tracheal tube during mechanical ventilation. Given the limitations of this study, however, the clinical feasibility of this catheter needs to be further confirmed in prospective randomized trials with larger sample sizes.Clinical Trial Registrationhttp://www.chictr.org.cn/showproj.aspx?proj=12207

Medulloblastomas overexpress the p53-inactivating oncogene WIP1/PPM1D

Medulloblastoma is the most common malignant brain tumor of childhood. Despite numerous advances, clinical challenges range from recurrent and progressive disease to long-term toxicities in survivors. The lack of more effective, less toxic therapies results from our limited understanding of medulloblastoma growth. Although TP53 is the most commonly altered gene in cancers, it is rarely mutated in medulloblastoma. Accumulating evidence, however, indicates that TP53 pathways are disrupted in medulloblastoma. Wild-typep53-induced phosphatase 1 (WIP1 or PPM1D) encodes a negative regulator of p53. WIP1 amplification (17q22-q23) and its overexpression have been reported in diverse cancer types. We examined primary medulloblastoma specimens and cell lines, and detected WIP1 copy gain and amplification prevalent among but not exclusively in the tumors with 17q gain and isochromosome 17q (i17q), which are among the most common cytogenetic lesions in medulloblastoma. WIP1 RNA levels were significantly higher in the tumors with 17q gain or i17q. Immunoblots confirmed significant WIP1 protein in primary tumors, generally higher in those with 17q gain or i17q. Under basal growth conditions and in response to the chemotherapeutic agent, etoposide, WIP1 antagonized p53-mediated apoptosis in medulloblastoma cell lines. These results indicate that medulloblastoma express significant levels of WIP1 that modulate genotoxic responsiveness by negatively regulating p53

MAL2 drives immune evasion in breast cancer by suppressing tumor antigen presentation

Immune evasion is a pivotal event in tumor progression. To eliminate human cancer cells, current immune checkpoint therapy is set to boost CD8+ T cell-mediated cytotoxicity. However, this action is eventually dependent on the efficient recognition of tumor-specific antigens via T cell receptors. One primary mechanism by which tumor cells evade immune surveillance is to downregulate their antigen presentation. Little progress has been made toward harnessing potential therapeutic targets for enhancing antigen presentation on the tumor cell. Here, we identified MAL2 as a key player that determines the turnover of the antigen-loaded MHC-I complex and reduces the antigen presentation on tumor cells. MAL2 promotes the endocytosis of tumor antigens via direct interaction with the MHC-I complex and endosome-associated RAB proteins. In preclinical models, depletion of MAL2 in breast tumor cells profoundly enhanced the cytotoxicity of tumor-infiltrating CD8+ T cells and suppressed breast tumor growth, suggesting that MAL2 is a potential therapeutic target for breast cancer immunotherapy

Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation

One of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine that potentiate T cell–mediated cytotoxicity, we identified atractylenolide I (ATT-I), which substantially promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8+ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non–ATPase 4 (PSMD4), an essential component of the immunoproteasome complex, as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigen-processing activity of immunoproteasome, leading to enhanced MHC-I–mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient–derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8+ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation and empowers T cell cytotoxicity, thus elevating the tumor response to immunotherapy