Effect and mechanism of gomisin D on the isoproterenol induced myocardial injury in H9C2 cells and mice.

We established myocardial injury models in vivo and in vitro to investigate the cardioprotective effect of gomisin D obtained from Schisandra chinensis. Gomisin D significantly inhibited isoproterenol-induced apoptosis and hypertrophy in H9C2 cells. Gomisin D decreased serum BNP, ANP, CK-MB, cTn-T levels and histopathological alterations, and inhibited myocardial hypertrophy in mice. In mechanisms research, gomisin D reversed ISO-induced accumulation of intracellular ROS and Ca2+. Gomisin D further improved mitochondrial energy metabolism disorders by regulating the TCA cycle. These results demonstrated that gomisin D had a significant effect on isoproterenol-induced myocardial injury by inhibiting oxidative stress, calcium overload and improving mitochondrial energy metabolism.

Cavity-enhanced optical bistability of Rydberg atoms.

Optical bistability (OB) of Rydberg atoms provides a new, to the best of our knowledge, platform for studying nonequilibrium physics and a potential resource for precision metrology. To date, the observation of Rydberg OB has been limited in free space. Here, we explore cavity-enhanced Rydberg OB with a thermal cesium vapor cell. The signal of Rydberg OB in a cavity is enhanced by more than one order of magnitude compared with that in free space. The slope of the phase transition signal at the critical point is enhanced more than 10 times that without the cavity, implying an enhancement of two orders of magnitude in the sensitivity for Rydberg-based sensing and metrology.

Realization of Strong Coupling between Deterministic Single-Atom Arrays and a High-Finesse Miniature Optical Cavity.

We experimentally demonstrate strong coupling between a one-dimensional (1D) single-atom array and a high-finesse miniature cavity. The atom array is obtained by loading single atoms into a 1D optical tweezer array with dimensions of 1×11. Therefore, a deterministic number of atoms is obtained, and the atom number is determined by imaging the atom array on a CCD camera in real time. By precisely controlling the position and spacing of the atom array in the high finesse Fabry-Perot cavity, all the atoms in the array are strongly coupled to the cavity simultaneously. The vacuum Rabi splitting spectra are discriminated for deterministic atom numbers from 1 to 8, and the sqrt[N] dependence of the collective enhancement of the coupling strength on atom number N is validated at the single-atom level.

Severe hematuria in a patient receiving bevacizumab and pembrolizumab for metastatic cervical cancer: a case report.

BACKGROUND: Bevacizumab is a monoclonal antibody drug targeting Vascular Endothelial Growth Factor (VEGF), which binds to VEGF receptors to inhibit vascular endothelial cell proliferation and angiogenesis, thus inhibiting tumorigenesis. Pembrolizumab is a monoclonal antibody that can bind to the programmed death-1 (PD-1) receptor, which can block the binding of the PD-1 receptor to its ligands PD-L1 and PD-L2, and release PD-1 pathway-mediated suppression of immune responses. By blocking the activity of PD-1, the purpose of inhibiting tumor growth is achieved. CASE PRESENTATION: We report a severe hematuria of bevacizumab plus pembrolizumab, in a 58-year-old woman with metastatic cervical cancer. After three cycles every three weeks of consolidation chemotherapy (carboplatin, paclitaxel, bevacizumab) and following three cycles consolidation chemotherapy (carboplatin, paclitaxel, bevacizumab, pembrolizumab), the patient presented a worsening state. Manifested as massive gross hematuria with blood clots. After stopping chemotherapy, cefoxitin, tranexamic acid and hemocoagulase atrox therapy was administered resulting in rapid clinical improvement. The patient was a cervical cancer with bladder metastasis that increases the risk of development of hematuria. Inhibition of VEGF, which has anti-apoptotic, anti-inflammatory, and pro-survival influences on endothelial cells, weakens their regenerative capacity and increases expression of proinflammatory genes leading to weakened supporting layers of blood vessels and, hence, to damaged vascular integrity. In our patient, the development of hematuria may result from the anti-VEGF effect of bevacizumab. In addition, pembrolizumab may also cause bleeding, and the mechanism of bleeding caused by pembrolizumab is currently unclear, which may be related to immune mediation. CONCLUSION: To our knowledge, this is the first case reporting on the development of severe hematuria during bevacizumab plus pembrolizumab treatment, which should alert the clinicians in case of bleeding adverse events onset in older patients under bevacizumab plus pembrolizumab therapy.

General and robust covalently linked graphene oxide affinity grids for high-resolution cryo-EM.

Affinity grids have great potential to facilitate rapid preparation of even quite impure samples in single-particle cryo-electron microscopy (EM). Yet despite the promising advances of affinity grids over the past decades, no single strategy has demonstrated general utility. Here we chemically functionalize cryo-EM grids coated with mostly one or two layers of graphene oxide to facilitate affinity capture. The protein of interest is tagged using a system that rapidly forms a highly specific covalent bond to its cognate catcher linked to the grid via a polyethylene glycol (PEG) spacer. Importantly, the spacer keeps particles away from both the air-water interface and the graphene oxide surface, protecting them from potential denaturation and rendering them sufficiently flexible to avoid preferential sample orientation concerns. Furthermore, the PEG spacer successfully reduces nonspecific binding, enabling high-resolution reconstructions from a much cruder lysate sample.

NCAPG2 contributes to the progression of malignant melanoma through regulating proliferation and metastasis.

Malignant melanoma is a highly aggressive cutaneous neoplasm with increasing incidence worldwide. Non-SMC condensin II complex subunit G2 (NCAPG2) exerts import biological function in the pathogenesis of several tumors. In this study, the functional roles of NCAPG2 knockdown in malignant melanoma were revealed in in vitro and in vivo experiments. In vitro study demonstrated that NCAPG2 depletion could inhibit proliferation and migration and promote apoptosis of malignant melanoma cells. Our in vivo date further confirmed that NCAPG2 knockdown attenuated tumor growth of malignant melanoma. Interestingly, NCAPG2 drove tumor development of malignant melanoma through activating the signal transducer and activator of transcription 3 (STAT3). In conclusion, this study elaborated the tumor-promoting effects of NCAPG2 on malignant melanoma, and NCAPG2 may be a potential therapeutic target for malignant melanoma therapy.

SAF-248, a novel PI3Kδ-selective inhibitor, potently suppresses the growth of diffuse large B-cell lymphoma.

PI3Kδ is expressed predominately in leukocytes and overexpressed in B-cell-related malignances. PI3Kδ has been validated as a promising target for cancer therapy, and specific PI3Kδ inhibitors were approved for clinical practice. However, the substantial toxicity and relatively low efficacy as a monotherapy in diffuse large B-cell lymphoma (DLBCL) limit their clinical use. In this study, we described a novel PI3Kδ inhibitor SAF-248, which exhibited high selectivity for PI3Kδ (IC50 = 30.6 nM) over other PI3K isoforms at both molecular and cellular levels, while sparing most of the other human protein kinases in the kinome profiling. SAF-248 exhibited superior antiproliferative activity against 27 human lymphoma and leukemia cell lines compared with the approved PI3Kδ inhibitor idelalisib. In particular, SAF-248 potently inhibited the proliferation of a panel of seven DLBCL cell lines (with GI50 values < 1 µM in 5 DLBCL cell lines). We demonstrated that SAF-248 concentration-dependently blocked PI3K signaling followed by inducing G1 phase arrest and apoptosis in DLBCL KARPAS-422, Pfeiffer and TMD8 cells. Its activity against the DLBCL cells was negatively correlated to the protein level of PI3Kα. Oral administration of SAF-248 dose-dependently inhibited the growth of xenografts derived from Pfeiffer and TMD8 cells. Activation of mTORC1, MYC and JAK/STAT signaling was observed upon prolonged treatment and co-targeting these pathways would potentiate the activity of SAF-248. Taken together, SAF-248 is a promising selective PI3Kδ inhibitor for the treatment of DLBCL and rational drug combination would further improve its efficacy.

Characteristics of gastric cancer gut microbiome according to tumor stage and age segmentation.

With the development of 16S rRNA technology, gut microbiome evaluation has been performed in many diseases, including gastrointestinal tumors. Among these cancers, gastric cancer (GC) exhibits high morbidity and mortality and has been extensively studied in its pathogenesis and diagnosis techniques. The current researches have proved that the gut microbiome may have the potential to distinguish GC patients from healthy patients. However, the change of the gut microbiome according to tumor node metastasis classification (TNM) has not been clarified. Besides, the characteristics of gut microbiome in GC patients and their ages of onset are also ambiguous. To address the above shortcomings, we investigated 226 fecal samples and divided them according to their tumor stage and onset age. The findings revealed that surgery and tumor stage can change the characteristic of GC patients' gut microbiota. In specific, the effect of surgery on early gastric cancer (EGC) was greater than that on advanced gastric cancer (AGC), and the comparison of postoperative microflora with healthy people indicated that EGC has more differential bacteria than AGC. Besides, we found that Collinsella, Blautia, Anaerostipes, Dorea, and Lachnospiraceae_ND3007_group expressed differently between EGC and AGC. More importantly, it is the first time revealed that the composition of gut microbiota in GC is different between different onset ages. KEY POINTS: •Gut microbiota of gastric cancer (GC) patients are either highly associated with TNM stage and surgery or not. It shows surgery has more significant changes in early gastric cancer (EGC) than advanced gastric cancer (AGC). •There existed specific gut microbiota between EGC and AGC which may have potential to distinguish the early or advanced GC. •Onset age of GC may influence the gut microbiota: the composition of gut microbiota of early-onset gastric cancer (EOGC) and late-onset gastric cancer (LOGC) is significantly different.

Post-Marketing Safety of Vemurafenib: A Real-World Pharmacovigilance Study of the FDA Adverse Event Reporting System.

PURPOSE: Vemurafenib received approval for treatment of BRAF V600 variation metastatic melanoma in August 2011. This study analyzed Vemurafenib-related adverse events (AEs) to detect and characterize relevant safety signals using the real-word-data through the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: Disproportionality analyses, including the reporting odds ratio (ROR), the healthcare products regulatory agency (MHRA), the Bayesian confidence propagation neural network (BCPNN), and the multiitem gamma Poisson shrinker (MGPS) algorithms, were applied to quantify the signals of vemurafenib-related AEs. RESULTS: Out of 8,042,244 reports gathered from the FAERS, 9554 reports of vemurafenib as the 'primary suspected (PS)' AEs were recognized. Vemurafenib-induced AEs occurrence targeted 23 system organ class (SOC). A total of 138 significant disproportionality PTs was simultaneously reserved according to the four algorithms. Unexpected significant AEs such as sarcoidosis and kidney fibrosis might also occur. The median onset time of vemurafenib-related AEs was 26 days (interquartile range [IQR] 8-97 days), and most of the cases occurred within the first one and two months after vemurafenib initiation. CONCLUSION: Our study detected potential new AEs signals and might provide powerful support for clinical monitoring and risk identification of vemurafenib.

Gas permeation rates of ultrathin graphite sealed SiO2 cavities.

Despite the proven impermeability of graphene toward most standard gases, graphene/graphite sealed SiO2 cavities always exhibit a nonzero leak rate, and the physical leakage mechanism is still unclear. By measuring leak rates of different gases for the same cavities sealed by ultrathin graphite under identical conditions, we find that the leak rates generally depend on the kinetic diameter of the gas molecules, which implies that the leakage is caused by a molecular sieving mechanism. By comparing different samples, we find that the leak rate of any gas in a particular sample is well predicted by the leak rate of N2 in that sample. In addition, we observe enhanced leak rates of water-soluble molecules. We infer that the leakage path (i.e., the graphene/graphite-SiO2 interface) favors hydrophilic species.

Evaluating the Structural Robustness of Large-Scale Emerging Industry with Blurring Boundaries.

The present large-scale emerging industry evolves into a form of an open system with blurring boundaries. However, when complex structures with numerous nodes and connections encounter an open system with blurring boundaries, it becomes much more challenging to effectively depict the structure of an emerging industry, which is the precondition for robustness evaluation. Therefore, this study proposes a novel framework based on a data-driven percolation process and complex network theory to depict the network skeleton and thus evaluate the structural robustness of large-scale emerging industries. The empirical data we used are actual firm-level transaction data in the Chinese new energy vehicle industry in 2019, 2020, and 2021. We applied our method to explore the transformation of structural robustness in the Chinese new energy vehicle industry in pre-COVID (2019), under-COVID (2020), and post-COVID (2021) eras. We unveil that the Chinese new energy vehicle industry became more robust against random attacks in the post-COVID era than in pre-COVID.

[Community-based Home Hospice Care Model under the Guidance of Tertiary Hospitals].

Community-based home hospice care provided by community service centers and family physician teams aims to alleviate the suffering of terminally ill patients and help them to receive end-of-life care and pass away at home.The Puhuangyu Community Health Service Center established the home hospice care model of PUMCH-Puhuangyu Coordination at the end of 2019.The model has been practiced and improved to date.This paper introduces this model of home hospice care.

[Experience of Community-based Home Hospice Care Practice for 24 Patients in Beijing Puhuangyu Community].

Objective To investigate the feasibility of home hospice care based on the practical experience in Puhuangyu community of Beijing.Methods We selected the patients assessed by hospice care team and receiving home hospice care from Puhuangyu Community Health Service Center of Beijing from January 1,2020 to December 31,2021.The clinical manifestations,hospice services received,and place of death of the patients were analyzed. Results A total of 24 patients were included in this study.They mainly suffered from malignant tumors(18 patients,75.0%),with pain as the most common symptom(12 patients,50.0%).The patients received a variety of hospice services through a combination of outpatient visits,home visits,and WeChat follow-up.The service time of each patient was(2.8±1.7) h each week on average and 57.9%(11/19) of the patients passed away at home. Conclusions The home hospice care in Puhuangyu community has a stable source of patients.The members of this hospice team can provide a variety of home hospice services.With this model,the wish to pass away at home can be achievable for most patients.Therefore,this model of community-based home hospice care is feasible.

ANOX: A robust computational model for predicting the antioxidant proteins based on multiple features.

As an indispensable component of various living organisms, the antioxidant proteins have been studied for anti-aging and prevention of various diseases, such as altitude sickness, coronary heart disease, and even cancer. However, the traditional experimental methods for identifying the antioxidant proteins are very expensive and time-consuming. Thus, to address the challenge, a new predictor, named ANOX, was developed in this study. Multiple features, such as frequency matrix features (FRE), amino acid and dipeptide composition (AADP), evolutionary difference formula features (EEDP), k-separated bigrams (KSB), and PSI-PRED secondary structure (PRED), were extracted to generate the original feature space. To find the optimized feature subset, the Max-Relevance-Max-Distance (MRMD) algorithm was implemented for feature ranking and our model received the best performance with the top 1170 features. Rigorous tests were performed to evaluate the performance of ANOX, and the results showed that ANOX achieved a major improvement in the prediction accuracy of the antioxidant proteins (AUC:0.930 and 0.935 using 5-fold cross-validation or the jackknife test) compared to the state-of-the-art predictor AOPs-SVM (AUC:0.869 and 0.885). The dataset used in this study and the source code of ANOX are all available at https://github.com/NWAFU-LiuLab/ANOX.

The mitochondrial HSP90 paralog TRAP1 forms an OXPHOS-regulated tetramer and is involved in mitochondrial metabolic homeostasis.

BACKGROUND: The molecular chaperone TRAP1, the mitochondrial isoform of cytosolic HSP90, remains poorly understood with respect to its pivotal role in the regulation of mitochondrial metabolism. Most studies have found it to be an inhibitor of mitochondrial oxidative phosphorylation (OXPHOS) and an inducer of the Warburg phenotype of cancer cells. However, others have reported the opposite, and there is no consensus on the relevant TRAP1 interactors. This calls for a more comprehensive analysis of the TRAP1 interactome and of how TRAP1 and mitochondrial metabolism mutually affect each other. RESULTS: We show that the disruption of the gene for TRAP1 in a panel of cell lines dysregulates OXPHOS by a metabolic rewiring that induces the anaplerotic utilization of glutamine metabolism to replenish TCA cycle intermediates. Restoration of wild-type levels of OXPHOS requires full-length TRAP1. Whereas the TRAP1 ATPase activity is dispensable for this function, it modulates the interactions of TRAP1 with various mitochondrial proteins. Quantitatively by far, the major interactors of TRAP1 are the mitochondrial chaperones mtHSP70 and HSP60. However, we find that the most stable stoichiometric TRAP1 complex is a TRAP1 tetramer, whose levels change in response to both a decline and an increase in OXPHOS. CONCLUSIONS: Our work provides a roadmap for further investigations of how TRAP1 and its interactors such as the ATP synthase regulate cellular energy metabolism. Our results highlight that TRAP1 function in metabolism and cancer cannot be understood without a focus on TRAP1 tetramers as potentially the most relevant functional entity.

A Robust and Low-Power Bismuth Doped Tin Oxide Memristor Derived from Coaxial Conductive Filaments.

Memristor, processing data storage and logic operation all-in-one, is an advanced configuration for next generation computer. In this work, a bismuth doped tin oxide (Bi:SnO2 ) memristor with ITO/Bi:SnO2 /TiN structure has been fabricated. Observing from transmission electron microscope (TEM) for the Bi:SnO2 device, it is found that the bismuth atoms surround the surface of SnO2 crystals to form the coaxial Bi conductive filament. The self-compliance current, switching voltage and operating current of Bi:SnO2 memristor are remarkably smaller than that of ITO/SnO2 /TiN device. With the content of 4.8% Bi doping, the SET operating power of doped device is 16 µW for ITO/Bi:SnO2 /TiN memory cell of 0.4 × 0.4 µm2 , which is cut down by two orders of magnitude. Hence, the findings in this study suggest that Bi:SnO2 memristors hold significant potential for application in low power memory and broadening the understanding of existing resistive switching (RS) mechanism.

Designed peptides that assemble into cross-α amyloid-like structures.

Amyloids adopt 'cross-ß' structures composed of long, twisted fibrils with ß-strands running perpendicular to the fibril axis. Recently, a toxic peptide was proposed to form amyloid-like cross-α structures in solution, with a planar bilayer-like assembly observed in the crystal structure. Here we crystallographically characterize designed peptides that assemble into spiraling cross-α amyloid-like structures, which resemble twisted ß-amyloid fibrils. The peptides form helical dimers, stabilized by packing of small and apolar residues, and the dimers further assemble into cross-α amyloid-like fibrils with superhelical pitches ranging from 170 Å to 200 Å. When a small residue that appeared critical for packing was converted to leucine, it resulted in structural rearrangement to a helical polymer. Fluorescently tagged versions of the designed peptides form puncta in mammalian cells, which recover from photobleaching with markedly different kinetics. These structural folds could be potentially useful for directing in vivo protein assemblies with predetermined spacing and stabilities.

Triply Magic Conditions for Microwave Transition of Optically Trapped Alkali-Metal Atoms.

We report the finding of "triply magic" conditions (the doubly magic frequency-intensity conditions of an optical dipole trap plus the magic magnetic field) for the microwave transitions of optically trapped alkali-metal atoms. The differential light shift (DLS) induced by a degenerate two-photon process is adopted to compensate a DLS associated with the one-photon process. Thus, doubly magic conditions for the intensity and frequency of the optical trap beam can be found. Moreover, the DLS decouples from the magnetic field in a linearly polarized optical dipole trap, so that the magic condition of the magnetic field can be applied independently. Therefore, the triply magic conditions can be realized simultaneously. We also experimentally demonstrate the doubly magic frequency-intensity conditions as well as the independence of the magnetic field. When the triply magic conditions are fulfilled, the inhomogeneous and homogeneous decoherences for the optically trapped atom will be dramatically suppressed, and the coherence time can be extended significantly.

Pharmacological inhibition of SUMO-1 with ginkgolic acid alleviates cardiac fibrosis induced by myocardial infarction in mice.

BACKGROUND AND PURPOSE: Protein modification by small ubiquitin-like modifier (SUMO) plays a critical role in the pathogenesis of heart diseases. The present study was designed to determine whether ginkgolic acid (GA) as a SUMO-1 inhibitor exerts an inhibitory effect on cardiac fibrosis induced by myocardial infarction (MI). EXPERIMENTAL APPROACH: GA was delivered by osmotic pumps in MI mice. Masson staining, electron microscopy (EM) and echocardiography were used to assess cardiac fibrosis, ultrastructure and function. Expression of SUMO-1, PML, TGF-ß1 and Pin1 was measured with Western blot or Real-time PCR. Collagen content, cell viability and myofibroblast transformation were measured in neonatal mouse cardiac fibroblasts (NMCFs). Promyelocytic leukemia (PML) protein was over-expressed by plasmid transfection. KEY RESULTS: GA improved cardiac fibrosis and dysfunction, and decreased SUMO-1 expression in MI mice. GA (>20 µM) inhibited NMCF viability in a dose-dependent manner. Nontoxic GA (10 µM) restrained angiotensin II (Ang II)-induced myofibroblast transformation and collagen production. GA also inhibited expression of TGF-ß1 mRNA and protein in vitro and in vivo. GA suppressed PML SUMOylation and PML nuclear body (PML-NB) organization, and disrupted expression and recruitment of Pin1 (a positive regulator of TGF-ß1 mRNA), whereas over-expression of PML reversed that. CONCLUSIONS AND IMPLICATIONS: Inhibition of SUMO-1 by GA alleviated MI-induced heart dysfunction and fibrosis, and the SUMOylated PML/Pin1/TGF-ß1 pathway is crucial for GA-inhibited cardiac fibrosis.

The lncRNA SNHG5/miR-32 axis regulates gastric cancer cell proliferation and migration by targeting KLF4.

Long noncoding RNAs (lncRNAs) are emerging as important regulators in cellular processes, including the development, proliferation, and migration of cancer cells. We have demonstrated in a prior study that small nucleolar RNA host gene 5 (SNHG5) is dysregulated in gastric cancer (GC). To further explore the underlying mechanisms of SNGH5 function in the development of GC, in this study, we screened the microRNAs interacting with SNHG5 and elucidated their roles in GC. We showed that SNHG5 contains a putative miR-32-binding site and that deletion of this site abolishes the responsiveness to miR-32. Suppression of SNHG5 expression by miR-32 was found to be Argonaute (Ago)2-dependent. Immunoprecipitation showed that SNHG5 could be pulled down from the Ago-2 complex with miR-32. Furthermore, it was reported that Kruppel-like factor 4 (KLF4) is a target gene of miR-32. In agreement with SNHG5 being a decoy for miR-32, we showed that KLF4 suppression by miR-32 could be partially rescued by SNHG5 overexpression, whereas miR-32 mimic rescued SNHG5 overexpression-mediated suppression of GC cell migration. In addition, we identified a negative correlation between the expression of SNHG5 and miR-32 in GC tissues. Furthermore, KLF4 expression was significantly downregulated in GC specimens, and a negative correlation between miR-32 and KLF4 expression and a positive correlation between KLF4 and SNHG5 expression levels were detected. Overall, this study demonstrated, for the first time, that the SNHG5/miR-32/KLF4 axis functions as an important player in GC cell migration and potentially contributes to the improvement of GC diagnosis and therapy.-Zhao, L., Han, T., Li, Y., Sun, J., Zhang, S., Liu, Y., Shan, B., Zheng D., Shi, J. The lncRNA SNHG5/miR-32 axis regulates gastric cancer cell proliferation and migration by targeting KLF4.