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Here, we discover an FLT3/CHK1 dual inhibitor (30) that exhibits excellent kinase potency and antiproliferative activity against MV4-11 cells. Simultaneously, 30possesses high selectivity over c-Kit enzyme and low hERG inhibitory ability. Compound 30, meanwhile, overcomes varied resistance in BaF3 cell lines carrying FLT3-TKD and FLT3-ITD mutations. Moreover, 30demonstrates favorable oral PK properties and kinase selectivity. These conclusions support that compound 30may be a promising potential FLT3/CHK1 dual agent for further development.

Large eddy simulations have been conducted to study upward transitional flows and heat transfer characteristics of supercritical CO2in a vertical mini-channel. The numerical simulation was carried out on a modified buoyantPimpleFOAM solver in OpenFOAM 7, and was verified using experiment data. Numerical results indicate that increasing the Grashof numbers can reduce the flow stability and make the flow transition earlier. There are four stages of heat transfer in the transition process, i.e., weakened, improved, recovered and normal heat transfer. These heat transfer phenomena in the transition process were explained from three perspectives: thermal boundary layer theory, turbulent transport and pseudo-boiling theory. Heat transfer enhancement during transition is related to the transport of supercritical molecular clusters, and these molecular clusters are regarded as pseudo-bubbles in pseudo-boiling theory. The flow pattern of the pseudo-phases in the dia-Widom process contains single-phase flow, steady pseudo-film flow, unsteady pseudo-film flow, partial pseudo-bubbles flow and flocculent pseudo-film flow. Pseudo-bubbles have similar behaviors to subcritical bubbles, i.e., break-up, deformation, condensation and coalescence. Relevant researches in this work are favorable for understanding the heat transfer mechanism of supercritical fluids during flow transition.

The incorporation of chirality endows Pt(II)-based metal–organic complexes (MOCs) with unique potentials in several fields such as nonlinear optics and chiral catalysis. However, the exploration of chiral Pt(II) metallacycles in biological responses remains underdeveloped. Herein, we designed and synthesized two chiral Pt(II) metallacycles 1and 2via the coordination-driven self-assembly of chiral 1,1′-spirobiindane-7,7′-diol (SPINOL)-derived ligands and cis-Pt(PEt3)2(OTf)2(90°Pt). Their structures were well characterized by 1H NMR, 31P{1H} NMR, ESI-TOF-MS, and X-ray crystallography, and their photophysical properties were investigated by UV–vis absorption, fluorescence, and circular dichroism (CD) spectroscopies. Then, the antitumor activity of the two chiral metallacycles in vitrowas further tested. Complexes 1and 2exhibited strong cytotoxicity, especially toward the A549 cells. The destruction of the mitochondrial function, the inhibition of the glutathione (GSH)/glutathione disulfide (GSSG) level, and the inactivation of superoxide dismutase (SOD) induced by complexes 1and 2led to the massive accumulation of reactive oxygen species (ROS). The overloaded ROS then triggered apoptotic cell death, and the release of damage-associated molecular patterns (DAMPs) further induced immunogenic cell death (ICD). To the best of our knowledge, this is the first example of Pt(II)-based metallacycles that can induce immunogenic cell death, providing a new strategy for the future design and construction of immune-modulating platinum agents in cancer therapy.

The development of procedural competencies by interventional cardiology fellows for minimally invasive treatment of cardiac diseases depends on their effective training and evaluation. Learning tool manipulation for safe robotic PCIs requires expert supervision and use of high-fidelity systems, however, with limited proficiency for real-time hand motion recognition. Therefore, this study proposes a deep learning-based model for identifying operators’ actions. The proposed model is based on the convolutional neural network (CNN) that consists of 1-D convolutional layers for automatic feature map extraction, downsampling, and fully connected layers (FCLs) for inference. The developed models were evaluated using a multimodal dataset collected from sensory glove, electromagnetic (EM), and surface electromyography (sEMG) sensors and real-time angiograms in the course of in vivo catheterization trials performed by nine subjects (two experts and seven novices) using a custom-built robotic catheter system (RCS). The results indicate that the model achieves a 92%–96% accuracy in identifying five actions across four clusters compared with a recognition performance of 83% when recognizing all six actions. Furthermore, we compared the proposed model performance with the existing studies, and the analyses show that our model has a 2%–3% higher accuracy for five-action recognition. Therefore, the proposed model could be employed for real-time hand motion recognition in robot-assisted percutaneous coronary intervention (R-PCI) trials.

Robot-assisted intravascular interventions have evolved as unique treatments approach for cardiovascular diseases. However, the technology currently has low potentials for catheterization skill evaluation, slow learning curve, and inability to transfer experience gained from manual interventions. This study proposes a new weighting-based deep ensemble model for recognizing interventionalists' hand motions in manual and robotic intravascular catheterization. The model has a module of neural layers for extracting features in electromyography data, and an ensemble of machine learning methods for classifying interventionalists' hand gestures as one of the six hand motions used during catheterization. A soft-weighting technique is applied to guide the contributions of each base learners. The model is validated with electromyography data recorded during in-vitro and in-vivo trials and labeled as many-to-one sequences. Results obtained show the proposed model could achieve 97.52% and 47.80% recognition performances on test samples in the in-vitro and in-vivo data, respectively. For the latter, transfer learning was applied to update weights from the in-vitro data, and the retrained model was used for recognizing the hand motions in the in-vivo data. The weighting-based ensemble was evaluated against the base learners and the results obtained shows it has a more stable performance across the six hand motion classes. Also, the proposed model was compared with four existing methods used for hand motion recognition in intravascular catheterization. The results obtained show our model has the best recognition performances for both the in-vitro and in-vivo catheterization datasets. This study is developed toward increasing interventionalists' skills in robot-assisted catheterization.

In this study, a 1-D distal force sensor design is proposed for minimally invasive surgery (MIS) based on the fiber Bragg grating (FBG) sensing principle. The sensor is made with a miniaturized force-sensitive flexure within which an optical fiber is embedded. The former includes a spiral elastomer utilized for high axial force sensitivity, while the fiber includes dual FBGs that are tightly suspended around the distal parts of the flexure and along elastomer’s centerline, respectively. The theoretical model of the flexure was derived based on its components and a design approach for decoupling strain and temperature cross effects during sensor usage. In addition, design parameters of the flexure were analyzed on physics-based model optimization using a fmincon function, while the static and dynamic properties were analyzed in-silico using the finite-element method. Further experiments were also carried out to analyze the sensor’s performance, and the data obtained was used for calibration study. The latter was done by training a feed-forward neural network designed for predicting the force versus wavelength-shift relationship. The experimental results show the designed force sensor can sense force values in a range of 1 N with an average relative error less than 2% of full scale. Ex-vivo tissue palpation study was also done on a pig liver to verify the effectiveness and applicability of the proposed sensor.

Many real-world video-text tasks involve different levels of granularity to represent local and global information with distinct semantics, such as frames and words, clips and sentences, or videos and paragraphs. Most existing multimodal representation learning methods suffer from limitations: (i) Adopting expert systems or manual design to extract more fine-grained local information (such as objects and actions in a video frame) for supervision may lead to information asymmetry since there may no corresponding information among modalities; (ii) Neglecting the hierarchical nature of the data to aggregate different levels of information from different modalities will cause insufficient representations. To alleviate the above issues, in this paper, we propose a Multi-Granularity Aggregation Transformer (MGAT) for joint video-audio-text representation learning. Specifically, for intra-modality, we first design a multi-granularity transformer module to relieve information asymmetry by making full use of local and global information within a single modality from different perspectives. Then, for inter-modality, we develop an attention-guided aggregation module to fuse audio and video information hierarchically. Last, we align the aggregated information with text information at different hierarchical levels via intra- and inter-modality consistency loss and contrastive loss. With the help of more granularity of information, we are able to obtain a well-performed representation model for a variety of tasks, e.g., video-paragraph retrieval and video captioning. Extensive experiments on two challenging benchmarks, i.e., ActivityNet-captions and Youcook2, demonstrate the superiority of our proposed method.

High-temperature warnings frequently occurred at the Power Distribution System (PDS) of the Alpha Magnetic Spectrometer (AMS). To investigate the fundamental reasons, a theoretical model for the AMS PDS was established under the International Space Station (ISS) normal and special operating conditions. With the model, the study investigated the external heat fluxes and the temperature responses of the PDS. The effects of ISS special operations on the PDS’s thermal environment were also investigated. Results reveal that the total external heat flux at the PDS reaches its maximum value when the angle βis around −25°, where high-temperature warning frequently occurs. Under the ISS normal operating condition, the temperature response hysteresis at the PDS varies from 116 s to 230 s. When the ISS performed special operations, locking the ISS solar arrays had the greatest influence on the PDS’s external heat fluxes, and the average temperature at the PDS fell by 1.7°C. When the ISS performed multiple special operations, simultaneously locking the ISS solar arrays and adjusting the ISS flight attitude were the most frequent operations, of which the influences on the PDS temperature were the largest, i.e., the changes in peak temperature reached up to +2.5°C.

ABSTRACTLong non-coding RNA (lncRNA) growth arrest specific 5 (GAS5) and microRNA (miR)-146a both have inhibitory effects on LPS-induced inflammation, suggesting the crosstalk between them. In this study, the expression of GAS5 and miR-146a in patients with sepsis-induced acute lung injury (sepsis-ALI), sepsis patients without obvious complications (sepsis) and healthy controls were studied by RT-qPCR. The role of GAS5 in the expression and methylation of miR-146a in human bronchial epithelial cells (HBEpCs) were studied by RT-qPCR and methylation-specific PCR (MSP), respectively. Cell apoptosis was analyzed by flow cytometry. We found that GAS5 and miR-146a were downregulated in sepsis-ALI and the expression of these two were correlated. LPS induced the downregulation of GAS5 and miR-146a in HBEpCs. In HBEpCs, overexpression of GAS5 increased the expression levels of miR-146a and reduced the methylation of miR-146a gene. Under lipopolysaccharide (LPS) treatment, overexpression of GAS5 and miR-146a decreased the apoptotic rate of HBEpCs. Moreover, the combined overexpression of GAS5 and miR-146a showed stronger effects. Therefore, GAS5 is downregulated in sepsis-ALI and inhibits cell apoptosis by up-regulating the expression of miR-146a.

AbstractIn our previous study, we firstly cloned the gene of a novel ReNHase (NHase from Rhodococcus erythropolisCCM2595), and the strain was shown to degrade only phenol, hydroxybenzoate, p-chlorophenol, aniline and other aromatic compounds. Here in, we further purified the ReNHase from R. erythropolisCCM2595 and detected its properties of biodegradation. We constructed a plasmid with the gene of ReNHase with His-tag. The encoding ReNHase was cloned and overexpressed in recombinant Escherihia coliand confirmed by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE). The substrate scope of the new heterologous ReNHase was tested and the efficiency of degradation of nitriles by the ReNHase was also investigated by high efficiency liquid chromatography. We also studied the effect of temperature and pH on the catalysis of adiponitrile by the purified ReNHase. The recombinant E.colishowed high catalytic regioselectivity with high substrate affinity towards dinitriles (especially for adiponitrile) whereas lower affinity towards mononitriles. Compared to whole-cell catalysis, the catalytic time was shortened significantly with the purified ReNHase. The enzyme activity of crude recombinant E.coliwas 635 U g−1(DCW), while the specific activity of purified ReNHase was 63.107 U mg−1. The apparent Kmvalue for the purified ReNHase is 6.6252 mmol L−1, which revealed the good affinity between the purified ReNHase and adiponitrile. The reaction Kcatis 82.77 s−1and Kcat/Kmis 1.249 × 104(mol−1L s−1), which showed high catalytic activity towards adiponitrile. We propose that this purified ReNHase may be applied for the industry and sewage treatment for environmental protection.

We present new high‐resolution oxygen isotope (δ18O) records from three NW African speleothems located at ~31°N. The present‐day rainfall patterns at 31°N in NW Africa are linked to negative winter North Atlantic Oscillation phases. However, on multimillennial time scales, our δ18O records, together with other hydroclimate records, provide new evidence of humid conditions during the mid‐Holocene, a period that was presumably characterized by arid climate. Thus, the apparent increase in moisture during the mid‐Holocene is interpreted better as an increase in summer rainfall. This is most likely linked to the expansion of the West African summer monsoon fringe during the African Humid Period, which terminated in our record abruptly around 4 Kyr BP. The temporospatial difference with speleothem records from N Morocco suggests that the High‐Atlas Mountains might have been a topographic barrier to further expansion of the West African summer monsoon fringe into higher latitudes. The Holocene African Humid Period in North Africa, characterized by the expansion of vegetation into the Green Sahara, has been linked to the intensification of the West African summer monsoon (WASM). However, the temporospatial pattern of the African Humid Period, especially the northernmost expansion of the WASM, remain a matter of controversy, largely owing to the lack of precisely dated and high‐resolution paleoclimatic records. This study presents new high‐resolution paleoclimate data based on speleothem oxygen isotope records from a key site at ~31°N in NW Africa. Our data suggest that the WASM expanded to 31°N in NW Africa during the mid‐Holocene and terminated abruptly at 4 Kyr BP. Holocene rainfall variability in NW Africa is inferred from precisely dated and high‐resolution speleothem δ18O recordsThe West African summer monsoon expanded to 31°N in NW Africa during the mid‐HoloceneThe African Humid Period ended with an abrupt interval of megadrought around 4 Kyr BP in NW Africa

Cancer cells exhibit altered and usually increased metabolic processes to meet their high biogenetic demands1,2. Under these conditions, ammonia is concomitantly produced by the increased metabolic processing. However, it is unclear how tumour cells dispose of excess ammonia and what outcomes might be caused by the accumulation of ammonia. Here we report that the tumour suppressor p53, the most frequently mutated gene in human tumours, regulates ammonia metabolism by repressing the urea cycle. Through transcriptional downregulation of CPS1, OTCand ARG1, p53 suppresses ureagenesis and elimination of ammonia in vitro and in vivo, leading to the inhibition of tumour growth. Conversely, downregulation of these genes reciprocally activates p53 by MDM2-mediated mechanism(s). Furthermore, the accumulation of ammonia causes a significant decline in mRNA translation of the polyamine biosynthetic rate-limiting enzyme ODC, thereby inhibiting the biosynthesis of polyamine and cell proliferation. Together, these findings link p53 to ureagenesis and ammonia metabolism, and further reveal a role for ammonia in controlling polyamine biosynthesis and cell proliferation.

The characteristics of flow and heat transfer of shell-and-tube heat exchangers with overlapped helical baffles (STHXsHB) were illustrated through a theoretical analysis and numerical simulation. The ideal helical flow model was constructed to demonstrate parts of the flow characteristics of the STHXsHB, providing theoretical evidence of short-circuit and back flows in a triangular zone. The numerical simulation was adopted to describe the characteristics of helical, leakage, and bypass streams. In a fully developed section, the distribution of velocity and wall heat transfer coefficient has a similar trend, which presents the effect of leakage and bypass streams. The short-circuit flow accelerates the axial velocity of the flow through the triangular zone. Moreover, the back flow enhances the local heat transfer and causes the ascent of flow resistance. This study shows the detailed features of helical flow in STHXsHB, which can inspire a reasonable optimization on the shell-side structure.

The composite structure of Co beads (200–300 nm) threaded by carbon nanotubes has been synthesized through a facile solvothermal method followed by a carbon reduction process. A carbon layer of ca. 5 nm was coated on the surface of Co beads to form a core-shell structure (CNTs/Co@C), in favor of the anti-oxidation of Co nanoparticles. The CNTs/Co@C hybrid showed a saturation magnetization (Ms) of 82.5 emu g−1and a larger Hcvalue of 258.8 Oe than bulk Co (ca. 10 Oe). Served as an EM wave absorption material, the epoxy resin composites consisting of 60 wt% and 40 wt% CNTs/Co@C hybrid exhibited effective EM absorption (RL < − 10 dB) over the frequency ranges of 1.5–15 and 1.6–20 GHz with the matching thicknesses of 1.0–7.5 and 1.0–10.0 mm, respectively. The superior EM absorption performances of CNTs/Co@C hybrid containing strong absorption, wide frequency range, thin thickness, and light weight are mainly attributed to the synergy of magnetic loss from Co beads and dielectric loss from carbon nanotubes, as well as remarkable impedance matching. Graphical abstractThe composite structure of Co beads threaded by carbon nanotubes synthesized through a facile solvothermal method followed by a carbon reduction process exhibit superior electromagnetic wave absorption properties.

Increased metabolic activity usually provides energy and nutrients for biomass synthesis and is indispensable for the progression of the cell cycle. Here, we find a role for α-ketoglutarate (αKG) generation in regulating cell-cycle gene transcription. A reduction in cellular αKG levels triggered by malic enzyme 2 (ME2) or isocitrate dehydrogenase 1 (IDH1) depletion leads to a pronounced arrest in G1 phase, while αKG supplementation promotes cell-cycle progression. Mechanistically, αKG directly binds to RNA polymerase II (RNAPII) and increases the level of RNAPII binding to the cyclin D1 gene promoter via promoting pre-initiation complex (PIC) assembly, consequently enhancing cyclin D1 transcription. Notably, αKG addition is sufficient to restore cyclin D1 expression in ME2- or IDH1-depleted cells, facilitating cell-cycle progression and proliferation in these cells. Therefore, our findings indicate a function of αKG in gene transcriptional regulation and cell-cycle control.

Neovasculogenesis induced by stem cell therapy is an innovative approach to improve critical limb ischemia (CLI) in diabetes. Mesenchymal stem cells (MSCs) are ideal candidates due to their angiogenic and immunomodulatory features. The aim of this study is to determine the therapeutic effects of human placenta-derived MSCs (P-MSCs) on diabetic CLI, with or without exogenous insulin administration, and the underlying mechanism of any effect. A series of in vitro experiments were performed to assess the stemness and vasculogenic activity of P-MSCs. P-MSCs were intramuscularly injected at two different doses with and without the administration of insulin. The efficacy of P-MSC transplantation was evaluated by ischemia damage score, ambulatory score, laser Doppler perfusion image (LDPI), capillary, and vascular density. In vivo imaging was applied to track the implanted P-MSCs. In vivo differentiation and in situ secretion of angiogenic cytokines were determined. In vitro experimental outcomes showed the differentiation potential and potent paracrine effect of P-MSCs. P-MSCs survived in vivo for at least 3 weeks and led to the acceleration of ischemia recovery, due to newly formed capillaries, increased arterioles, and secretion of various proangiogenic factors. P-MSCs participate in angiogenesis and vascularization directly through differentiation and cytokine expression.

•Hierarchical Co-doped NiO microspheres have been synthesized for the first time.•Hierarchical Co-NiO microspheres shows ultrahigh specific surface areas and reduced grain sizes.•The 1 mol% Co-doped NiO sensor exhibits enhanced H2S gas-sensing properties at 200 °C.•The improved sensing mechanism of hierarchical Co-NiO microspheres are further studied.

•Conductive polyacrylonitrile-modified NaTi2(PO4)3(NTP/PAN) was firstly fabricated.•N-doped carbon coating layer from PAN enhanced the electronic conductivity of NTP.•Defects induced by N-doping in NTP lattice facilitates Li+-ions diffusion.•This designed NTP/PAN anode displayed outstanding rate capability and cycling stability.

A conduction heat transfer process is enhanced by filling prescribed quantity and optimized-shaped high thermal conductivity materials to the substrate. Numerical simulations and analyses are performed on a volume to point conduction problem based on the principle of minimum entropy generation. In the optimization, the arrangement of high thermal conductivity materials is variable, the quantity of high thermal-conductivity material is constrained, and the objective is to obtain the maximum heat conduction rate as the entropy is the minimum. A novel algorithm of thermal conductivity discretization is proposed based on large quantity of calculations. Compared with other algorithms in literature, the average temperature in the substrate by the new algorithm is lower, while the highest temperature in the substrate is in a reasonable range. Thus the new algorithm is feasible. The optimization of volume to point heat conduction is carried out in a rectangular model with radiation boundary condition and constant surface temperature boundary condition. The results demonstrate that the algorithm of thermal conductivity discretization is applicable for volume to point heat conduction problems.

Energy metabolism is significantly reprogrammed in many human cancers, and these alterations confer many advantages to cancer cells, including the promotion of biosynthesis, ATP generation, detoxification and support of rapid proliferation. The pentose phosphate pathway (PPP) is a major pathway for glucose catabolism. The PPP directs glucose flux to its oxidative branch and produces a reduced form of nicotinamide adenine dinucleotide phosphate (NADPH), an essential reductant in anabolic processes. It has become clear that the PPP plays a critical role in regulating cancer cell growth by supplying cells with not only ribose-5-phosphate but also NADPH for detoxification of intracellular reactive oxygen species, reductive biosynthesis and ribose biogenesis. Thus, alteration of the PPP contributes directly to cell proliferation, survival and senescence. Furthermore, recent studies have shown that the PPP is regulated oncogenically and/or metabolically by numerous factors, including tumor suppressors, oncoproteins and intracellular metabolites. Dysregulation of PPP flux dramatically impacts cancer growth and survival. Therefore, a better understanding of how the PPP is reprogrammed and the mechanism underlying the balance between glycolysis and PPP flux in cancer will be valuable in developing therapeutic strategies targeting this pathway.

Shape and quantity of helical baffles have great impact on the shell-side performance of helical baffled heat exchangers (HBHE). In this work, three physical models of HBHE with baffles of different shape (trisection, quadrant and sextant sector) were investigated. Numerical simulations were performed on HBHE at three helix angles (10°, 25° and 40°) by the software ANSYS CFX. Analyses of numerical results indicate that the sextant HBHE shows relatively better fluid flow performance because the leakage flow in the triangle area is evidently reduced and the fluid streamline appears much closer to an ideal spiral flow, while the trisection and quadrant HBHE show more scattered and disordered streamline distributions. The convective heat transfer coefficient and pressure drop in three types of HBHE were presented. Further investigations on the shell side performance with different helical baffles were implemented by the field synergy theory. Both theoretical and numerical analyses gave support on the relations between helical baffle shape and shell-side performance. This paper may provide useful reference for the selection of baffle shape and quantity in HBHE.

The pentose phosphate pathway (PPP) provides ribose and NADPH that support biosynthesis and antioxidant defense. Our recent findings suggest that the p53-related protein TAp73 enhances the PPP flux. TAp73 stimulates the expression of glucose-6-phophate dehydrogenase (G6PD), the rate-limiting enzymes of the PPP. Through this regulation, TAp73 promotes the accumulation of macromolecules and increases cellular capability to withstand oxidative stresses. TAp73 also regulates other metabolic enzymes, and the relative importance of these targets in TAp73-mediated cell growth is not well understood. Here we show that, like in other cell lines, TAp73 is required for supporting proliferation and maintaining the expression of G6PD in the human lung cancer H1299 cells. Restoration of G6PD expression almost fully rescues the defects in cell growth caused by TAp73 knockdown, suggesting that G6PD is the major proliferative target of TAp73 in these cells. G6PD expression is elevated in various tumors, correlating with the upregulation of TAp73. These results indicate that TAp73 may function as an oncogene, and that G6PD is likely a focal point of regulation in oncogenic growth.

Abstract: Loop heat pipes (LHPs) were designed for the alpha magnetic spectrometer (AMS-02) to dissipate heat from the cryocoolers. A bypass valve is applied to the LHP to keep the cryocooler temperature above its limit (−20°C) in cold environment. Extensive experiments were performed on operation characteristics of LHPs with the bypass valve for AMS-02 during thermal vacuum and thermal balance (TVTB) test. We found that the bypass valve can start up successfully in cold environment. With the bypass valve, the evaporator temperature is stable and can meet the requirement of the cryocooler. We analyzed three operating modes of the bypass valve. Set point temperature and regulation temperature shifts were observed and their relations with the bypass valve temperature were given.

In Fig. 1c of this Letter, the labels p53+/+and p53-/-were inadvertently swapped. The original figure has been corrected online.