New Insights into PI3K Inhibitor Design using X-ray Structures of PI3Kα Complexed with a Potent Lead Compound

Abstract Phosphatidylinositol 3-kinase α is an attractive target to potentially treat a range of cancers. Herein, we described the evolution of a reported PI3K inhibitor into a moderate PI3Kα inhibitor with a low molecular weight. We used X-ray crystallography to describe the accurate binding mode of the compound YXY-4F. A comparison of the p110α–YXY-4F and apo p110α complexes showed that YXY-4F induced additional space by promoting a flexible conformational change in residues Ser773 and Ser774 in the PI3Kα ATP catalytic site. Specifically, residue 773(S) in PI3Kα is quite different from that of PI3Kβ (D), γ (A), and δ (D), which might guide further optimization of substituents around the NH group and phenyl group to improve the selectivity and potency of PI3Kα

Realization of robust boundary modes and non-contractible loop states in photonic Kagome lattices

Corbino-geometry has well-known applications in physics, as in the design of graphene heterostructures for detecting fractional quantum Hall states or superconducting waveguides for illustrating circuit quantum electrodynamics. Here, we propose and demonstrate a photonic Kagome lattice in the Corbino-geometry that leads to direct observation of non-contractible loop states protected by real-space topology. Such states represent the "missing" flat-band eigenmodes, manifested as one-dimensional loops winding around a torus, or lines infinitely extending to the entire flat-band lattice. In finite (truncated) Kagome lattices, however, line states cannot preserve as they are no longer the eigenmodes, in sharp contrast to the case of Lieb lattices. Using a continuous-wave laser writing technique, we experimentally establish finite Kagome lattices with desired cutting edges, as well as in the Corbino-geometry to eliminate edge effects. We thereby observe, for the first time to our knowledge, the robust boundary modes exhibiting self-healing properties, and the localized modes along toroidal direction as a direct manifestation of the non-contractible loop states

Mendelian randomization analysis identified tumor necrosis factor as being associated with severe COVID-19

Background: Observational studies have shown that anti-tumor necrosis factor (TNF) therapy may be beneficial for patients with coronavirus disease 2019 (COVID-19). Nevertheless, because of the methodological restrictions of traditional observational studies, it is a challenge to make causal inferences. This study involved a two-sample Mendelian randomization analysis to investigate the causal link between nine TNFs and COVID-19 severity using publicly released genome-wide association study summary statistics.Methods: Summary statistics for nine TNFs (21,758 cases) were obtained from a large-scale genome-wide association study. Correlation data between single-nucleotide polymorphisms and severe COVID-19 (18,152 cases vs. 1,145,546 controls) were collected from the COVID-19 host genetics initiative. The causal estimate was calculated by inverse variance-weighted (IVW), MR–Egger, and weighted median methods. Sensitivity tests were conducted to assess the validity of the causal relationship.Results: Genetically predicted TNF receptor superfamily member 6 (FAS) positively correlated with the severity of COVID-19 (IVW, odds ratio = 1.10, 95% confidence interval = 1.01–1.19, p = 0.026), whereas TNF receptor superfamily member 5 (CD40) was protective against severe COVID-19 (IVW, odds ratio = 0.92, 95% confidence interval = 0.87–0.97, p = 0.002).Conclusion: Genetic evidence from this study supports that the increased expression of FAS is associated with the risk of severe COVID-19 and that CD40 may have a potential protective effect against COVID-19

Salmon Calcitonin Exerts an Antidepressant Effect by Activating Amylin Receptors

Depressive disorder is defined as a psychiatric disease characterized by the core symptoms of anhedonia and learned helplessness. Currently, the treatment of depression still calls for medications with high effectiveness, rapid action, and few side effects, although many drugs, including fluoxetine and ketamine, have been approved for clinical usage by the Food and Drug Administration (FDA). In this study, we focused on calcitonin as an amylin receptor polypeptide, of which the antidepressant effect has not been reported, even if calcitonin gene-related peptides have been previously demonstrated to improve depressive-like behaviors in rodents. Here, the antidepressant potential of salmon calcitonin (sCT) was first evaluated in a chronic restraint stress (CRS) mouse model of depression. We observed that the immobility duration in CRS mice was significantly increased during the tail suspension test and forced swimming test. Furthermore, a single administration of sCT was found to successfully rescue depressive-like behaviors in CRS mice. Lastly, AC187 as a potent amylin receptor antagonist was applied to investigate the roles of amylin receptors in depression. We found that AC187 significantly eliminated the antidepressant effects of sCT. Taken together, our data revealed that sCT could ameliorate a depressive-like phenotype probably via the amylin signaling pathway. sCT should be considered as a potential therapeutic candidate for depressive disorder in the future

Ubiquitous International Volume

Abstract. Compressed sensing has been paid a lot of attention for its contribution for image restoration, image reconstruction and image representation. Two most common research orientations are the basic theory research and the application research respectively. A novel design for compressed sensing frame based on the wavelet frame and dictionary is proposed in this paper. It belongs to the basic theory research and the good performance in the experiments show its efficiency

An Integrated Spatio-Temporal Features Analysis Approach for Ocean Turbulence Using an Autonomous Vertical Profiler

Turbulent energy cascade and intermittency are very important characteristics in the turbulent energy evolution process. However, understanding the temporal–spatial features of kinetic energy transfer and quantifying the correlations between different scales of turbulent energy remains an outstanding challenge. To deeply understand the spatial–temporal features in the energy transfer process, an integrated features identification and extraction method is proposed to quantitatively investigate the correlations using the ocean shear turbulence measured by an autonomous vertical reciprocating profiler (AVRP). The proposed integrated method mainly contains two parallel features analysis modules: first, temporal multiscale features structures of the nonlinear and nonstationary turbulent cascade are identified by Variational Mode Decomposition (VMD); then, the ocean microstructure shear fluctuation data are decomposed into a series of intrinsic mode functions (IMFs), which are characterized by different time scales and frequency bandwidths. The local features of energy transfer are identified when the local intermittency peaks overlap and the phase-synchronization case occurs between two neighboring scales; second, the spatial statistical characteristics of the turbulent energy dissipation are quantitatively studied. The cumulative probability distribution functions (CPDFs) of kinetic energy dissipation are approximated well by a normal distribution, indicating that the turbulent dissipation process exhibits a robust spatial scaling correlation and a few intense dissipation locations dominate the integrated process. Finally, the proposed integrated method is evaluated through experiments using an autonomous vertical reciprocating profiler deployed in the South China Sea. Preliminary experimental results show that the proposed novel method is useful to improve our understanding of turbulent energy transfer and the evolution process in the ocean dynamic systems

A Multifractal Cascade Model for Energy Evolution and Dissipation in Ocean Turbulence

Scale properties and energy dissipation in the turbulent energy transfer process play an important role in deeply understanding the features of ocean turbulence. In this paper, a universal multifractal cascade model is applied to investigate scale and intermittency properties of a turbulent flow, and two sets of measured turbulence datasets in horizontal and vertical directions are performed for comprehensive experimental verification. First, an empirical mode decomposition method is utilized to adaptively decompose microstructure shear time series into several intrinsic mode functions. Then, the multifractal spectrum is calculated to extract multifractal features for different time scales. The ocean microstructure field shows an asymmetric structure with a left truncation and a long right tail in different directions. This proves that most energy transfer processes occur on small scales. Finally, the calculated multifractal indexes of all intrinsic mode functions for two datasets show that the intermittency of turbulence decreases with the increase in time scales, which reflects the multifractal intensity and the level of intermittency of turbulence. The multifractal cascade model can successfully build a bridge between intermittency and dissipation in the multiscale energy cascade process

A New Cross-Platform Instrument for Microstructure Turbulence Measurements

This study developed a new cross-platform instrument for microstructure turbulence measurement (CPMTM) and evaluated its performance. The CPMTM is designed as an “all-in-one” payload that can be easily integrated with a variety of marine instrumentation platforms. The sensors in the CPMTM include two shear probes, a fast-response temperature probe, and an accelerometer for monitoring vibrations. In addition, a custom-designed flexible connection vibration-damping device is used to isolate platform vibrations. To validate the CPMTM performance, a direct comparison was carried out with a reference acoustic Doppler velocimeter in a controlled flume for four background turbulence levels. The results of the comparison show that the velocity spectra measured by the CPMTM and ADV w components are in agreement, which demonstrates the ability of the CPMTM to acquire accurate turbulence data. Furthermore, the CPMTM was integrated into the long-range Sea-Whale 2000 AUV and tested in the northern South China Sea in September 2020. The data collected by the CPMTM show that the measured shear spectrum of the noise reduction agrees well with the empirical Nasmyth spectrum. Turbulent kinetic energy dissipation rates as low as 7 × 10−10 W kg−1 can be resolved. Laboratory and field experiments illustrate that the CPMTM has an extraordinarily low noise level and is validated for turbulence measurements

Gambogic acid sensitizes gemcitabine efficacy in pancreatic cancer by reducing the expression of ribonucleotide reductase subunit-M2 (RRM2)

Abstract Background Pancreatic cancer is susceptible to gemcitabine resistance, and patients receive less benefit from gemcitabine chemotherapy. Previous studies report that gambogic acid possesses antineoplastic properties; however, to our knowledge, there have been no specific studies on its effects in pancreatic cancer. Therefore, the purpose of this study was to explore whether increases the sensitivity of pancreatic cancer to gemcitabine, and determine the synergistic effects of gambogic acid and gemcitabine against pancreatic cancer. Methods The effects of gambogic acid on cell viability, the cell cycle, and apoptosis were assessed using 4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) and flow cytometry in pancreatic cancer cell lines. Protein expression was detected by western blot analysis and mRNA expression was detected using q-PCR. A xenograft tumor model of pancreatic cancer was used to investigate the synergistic effects of gambogic acid and gemcitabine. Results Gambogic acid effectively inhibited the growth of pancreatic cancer cell lines by inducing S-phase cell cycle arrest and apoptosis. Synergistic activity of gambogic acid combined with gemcitabine was observed in PANC-1 and BxPC-3 cells based on the results of MTT, colony formation, and apoptosis assays. Western blot results demonstrated that gambogic acid sensitized gemcitabine-induced apoptosis by enhancing the expression of cleaved caspase-3, cleaved caspase-9, cleaved-PARP, and Bax, and reducing the expression of Bcl-2. In particular, gambogic acid reduced the expression of the ribonucleotide reductase subunit-M2 (RRM2) protein and mRNA, a trend that correlated with resistance to gemcitabine through inhibition of the extracellular signal-regulated kinase (ERK)/E2F1 signaling pathway. Treatment with gambogic acid and gemcitabine significantly repressed tumor growth in the xenograft pancreatic cancer model. Immunohistochemistry results demonstrated a downregulation of p-ERK, E2F1, and RRM2 in mice receiving gambogic acid treatment and combination treatment. Conclusions These results demonstrate that gambogic acid sensitizes pancreatic cancer cells to gemcitabine in vitro and in vivo by inhibiting the activation of the ERK/E2F1/RRM2 signaling pathway. The results also indicate that gambogic acid treatment combined with gemcitabine might be a promising chemotherapy strategy for pancreatic cancer

De Novo HER2 S310Y mutation associates with poor response to EGFR tyrosine kinase inhibitor in activating EGFR-mutant NSCLC patient: A case report

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are highly effective in treating lung cancer patients with epidermal growth factor receptor (EGFR)-activating mutations. However, intrinsic resistances of tyrosine kinase inhibitor (TKI) have been reported in 20%–30% of cases. The majority of patients who have primary resistance to EGFR-TKI harbor an insertion in EGFR exon 20 and T790M mutation. Other previously described primary resistance mechanisms include MET amplification, ALK fusion, and KRAS mutation. However, other primary resistance mechanisms have not been fully investigated. Here, we present a 68-year-old Chinese never smoke female with postoperative recurrence of bone and liver metastases after 3 years of surgery, exhibiting combined EGFR and HER2 S310Y mutation by next-generation sequencing panel analysis. The patient responded to gefitinib treatment poorly and showed progressive disease with rapid growth of lung and liver metastasis. This is the first report of activated EGFR mutation patient with a HER2 S310Y mutation had progressed on EGFR-TKI. We suggest that HER2 S310Y mutation probably leads to EGFR-TKI primary resistance in EGFR-mutated NSCLC