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[Display omitted] The majority of acute myeloid leukemia (AML) patients respond to intensive induction therapy, consisting of cytarabine (AraC) and an anthracycline, though more than half experience relapse. Relapsed/refractory (R/R) AML patients are difficult to treat, and their clinical outcomes remain dismal. Venetoclax (VEN) in combination with azacitidine (AZA) has provided a promising treatment option for R/R AML, though the overall survival (OS) could be improved (OS ranges from 4.3 to 9.1 months). Overexpression of c-Myc is associated with chemoresistance in AML. Histone deacetylase (HDAC) inhibitors have been shown to suppress c-Myc and enhance the antileukemic activity of VEN, as well as AZA, though combination of all three has not been fully explored. In this study, we investigated the HDAC inhibitor, panobinostat, in combination with VEN + AZA against AraC-resistant AML cells. Panobinostat treatment downregulated c-Myc and Bcl-xL and upregulated Bim, which enhanced the antileukemic activity of VEN + AZA against AraC-resistant AML cells. In addition, panobinostat alone and in combination with VEN + AZA suppressed oxidative phosphorylation and/or glycolysis in AraC-resistant AML cells. These findings support further development of panobinostat in combination with VEN + AZA for the treatment of AraC-resistant AML. [ABSTRACT FROM AUTHOR]

Da-Cheng-Qi-Decoction (DCQD) has been used in the treatment of acute pancreatitis (AP) in China for many years. The aim of the current study was to examine the principal ingredient rhubarb of DCQD and its potential link to the pancreatic repair effects in rats with AP. The pancreatitis was induced in SD rats by intraperitoneal injections of cerulein. The results showed that rhubarb significantly increased blood perfusion of pancreatic tissue, reversed mitochondrial damage, and promoted pancreatic acinar and stellate cell proliferation. In addition, the rhein (from rhubarb) had high distribution in pancreas tissue and protected mitochondria in AR42J cells via the activation of PI3K/AKT/mTOR signaling pathway and activity inhibition of AMPK (P < 0.05). The results provide some preclinical evidence on the protective effects of DCQD for the treatment of acute pancreatitis. Rhein is regarded to be the active compound of rhubarb and can be expected to be a new compound for the treatment of AP. [ABSTRACT FROM AUTHOR]

• Comparing with the existing 'combined' QZS designs with parallel arrangement of both negative- and positive-stiffness elements, a 'monolithic' beam-like QZS design was proposed with balanced ultra-low stiffness and nonlinear behaviors, which has the obvious benefits in terms of lightweightness and integration. • The 1–3D configurations of the metastructure with different combinations of the QZS unit cells in series or/and in parallel were investigated, which provides the design guidelines for the 3D metastructure with customizable level of load-carrying capacity and deformation space. • The developed optimization design method was a powerful tool to achieve targeted QZS feature with complex geometry of the flexural beam microstructure, and it was successfully utilized to quantitatively control the metastructure's load-carrying capacity and vibration isolation ability. • A practical engineering application was presented with the metastructure's vibration isolation performance being successfully demonstrated on a real spacecraft's control moment gyros (CMG) (up to 90% reduction in 100–600 Hz frequency range with only a 4.5% gain in mass). Quasi-zero stiffness (QZS) isolators have demonstrated appropriate low-frequency vibration isolation performance without sacrificing the load-bearing capacity. The current 'combined' design of QZS isolators, however, suffers from complex mechanisms and cumbersome assembly, requiring the parallel arrangement of both negative-stiffness and positive-stiffness elements. Inspired by the multi-functional integration ability of metastructure, this study explores a lightweight design of three-dimensional (3D) QZS metastructure with 'monolithic' beam-like unit cells. The study begins with the optimization design method to reach customizable QZS features in the vibration isolation metastructure for complex working environments. Then, it turns to rapid manufacturing to fabricate the metastructure prototypes, whose static and vibration test results demonstrate good agreements with the analytical and numerical results. In an experiment for the vibration isolation of a typical control moment gyro (CMG) of spacecraft, the QZS metastructure exhibited excellent vibration isolation performance (up to 90% reduction in 100–600 Hz frequency range) with only a 4.5% gain in mass. As such, the proposed 3D QZS metastructure paves a new way to the design of lightweight, compact and broadband vibration isolators. [Display omitted] [ABSTRACT FROM AUTHOR]

The impairment of intestinal motility and related infectious complications are the predominant clinical phenomenon in patients with severe acute pancreatitis (SAP). We aimed to investigate the effects of Da-Cheng-Qi decoction (DCQD) on the gastrointestinal injury in SAP patients and the potential mechanism involved in rats. DCQD was enema administered to 70 patients for 7 days in West China Hospital. Mortality and organ failure during admission were observed and blood samples for laboratory analysis were collected. We also experimentally examined plasma inflammatory cytokines in rat serum and carried the morphometric studies of the gut. Intestinal propulsion index and serum and tissue vasoactive intestinal peptide (VIP) were also detected. Though DCQD did not affect the overall incidence of organ failure, it shortened the average time of paralytic intestinal obstruction and decreased the morbidity of infectious complications in patients with SAP. Compared with untreated rats, the DCQD lowered the levels of proinflammatory cytokine and decreased the mean pathological intestinal lesion scores. The VIP level in intestinal tissue or serum in DCQD group was obviously lowered and intestinal propulsion index was significantly improved. In conclusion, DCQD has good effect on pancreatitis-associated intestinal dysmotility in patients and in rat models. [ABSTRACT FROM AUTHOR]

Background: The traditional herbal medicinal formula Da-Cheng-Qi decoction (DCQD) has long been used to treat pancreatitis in China; however, the underlying mechanisms remain unclear. Aim: To investigate whether DCQD is beneficial to the patients with lung injury in severe acute pancreatitis (SAP); if it is, then to explore the lung protective effect of DCQD and the mechanism involved in rats. Methods: DCQD was enema administered to 70 patients for 7 days. Mortality, (multi)organ failure during admission were observed, blood samples for laboratory analysis were drawn on admission, on Days 3, 7, and 14 of the treatment. We also experimentally examined the function of two doses of DCQD in SAP rat models. IL-1β, IL-6, and IL-10 mRNA expression in rat lungs was measured quantitatively by the RT-PCR method and confirmed by morphometric studies of the lungs. Results: It was demonstrated that the administration of DCQD did shorten the average time that patients suffered acute respiratory distress syndrome (ARDS). Compared with untreated rats, the lungs of rats treated with DCQD showed significantly lower levels of proinflammatory cytokine IL-1β and IL-6 mRNA. Rats treated with DCQD had lower mean pathological lung lesion scores than those in SAP rats. Conclusion: DCQD has good prospects in the treatment for SAP because it did shorten the average time that patients suffered ARDS in the clinic. It exerts therapeutic effects on this disease through inhibiting the production of inflammatory mediators, decreasing the anti-inflammatory factors, and mitigating the pathological damage of the lung injury in SAP model. [ABSTRACT FROM AUTHOR]

• A design model of hybrid constellations for Earth discontinuous coverage is established. • An analytical method for coverage analysis of hybrid constellations is proposed. • The superiority of hybrid constellations is demonstrated. This paper mainly deals with the configuration design of hybrid constellations for Earth discontinuous coverage. Firstly, a general design model of the hybrid constellation with synchronous orbital precession and multiple repeating ground tracks is developed. Then, to cope with the massive coverage calculation during the constellation design process, an analytical method for rapid coverage analysis of hybrid constellations is proposed. Finally, numerical examples are carried out, and several hybrid constellation design cases are proposed. Results indicate that the proposed coverage analysis method is demonstrated to be of high precision, and the designed hybrid constellations can achieve superior coverage performance compared with conventional Walker constellations. This research can be conducive to hybrid constellations design and Earth discontinuous coverage analysis. [ABSTRACT FROM AUTHOR]

This paper explores the potential application of simultaneously transmitting and reflecting reconfigurable intelligent surface (STAR‐RIS) in improving the physical layer security (PLS) of millimetre wave (mmWave) non‐orthogonal multiple access (NOMA) uplink communications. In particular, the legitimate users on both sides of STAR‐RIS send confidential information simultaneously to the base station (BS) while keeping it secret from the eavesdroppers near the BS by exploiting the STAR‐RIS to proactively regulate the electromagnetic propagation environment. By jointly designing the transmit power, the active beamforming at the BS, and the reflecting/transmitting coefficients at the STAR‐RIS, the authors' goal is to maximize the minimum secrecy capacity subject to the successive interference cancellation decoding order constraints. Due to the non‐convexity of the formulated problem, an efficient algorithm is proposed by capitalizing on alternating optimization, a penalty‐based approach, successive convex approximation, and semi‐definite relaxation. Firstly, a two‐layer iterative algorithm based on the penalty for the joint beamforming optimization sub‐problem is proposed. Then, the non‐convex problem is transformed into a convex positive semi‐definite programming problem for the transmit power sub‐problem. Numerical simulation results reveal that the STAR‐RIS‐aided system has more tremendous advantages and effectiveness in improving the PLS of mmWave NOMA uplink communication compared with the benchmark schemes. [ABSTRACT FROM AUTHOR]

The secure communication scheme based on physical layer non‐reconciled keys receives extensive attention due to its high encryption rate. However, the mismatched secret bit sequences between the two users leads to higher BER and lower coding efficiency for this type of scheme. To solve this problem, this paper proposes an efficient and secure communication scheme for OFDM system with non‐reconciled keys. Initially, an adaptive coding method is designed to encode information blocks with different code rates to improve the overall efficiency. Then, on this basis, a sorting xor encryption algorithm is designed to reduce the bit error rate by sorting the channel estimation value and mapping them to corresponding sub‐channels. Theoretical analysis and simulation results indicate that this scheme can effectively reduce the bit error rate and improve the efficiency of information coding compared to the existing method. [ABSTRACT FROM AUTHOR]

The human males absent on the first (MOF)-containing non-specific lethal (NSL) histone acetyltransferase (HAT) complex acetylates histone H4 at lysine K5, K8, and K16. This complex shares several subunits with other epigenetic regulatory enzymes, which highlights the complexity of its intracellular function. However, the effect of the NSL HAT complex on the genome and target genes in human cells is still unclear. By using a CRISPR/Cas9-mediated NSL3-knockout 293T cell line and chromatin immunoprecipitation-sequencing (ChIP-Seq) approaches, we identified more than 100 genes as NSL HAT transcriptional targets, including several transcription factors, such as Yin Yang 1 (YY1) which are mainly involved in cell proliferation, biological adhesion, and metabolic processes. We found here that the ChIP-Seq peaks of MOF and NSL3 co-localized with H4K16ac, H3K4me2, and H3K4me3 at the transcriptional start site of YY1. In addition, both the mRNA and protein expression levels of YY1 were regulated by silencing or overexpressing NSL HAT. Interestingly, the expression levels of cell division cycle 6, a downstream target gene of YY1, were regulated by MOF or NSL3. In addition, the suppressed clonogenic ability of HepG2 cells caused by siNSL3 was reversed by overexpressing YY1, suggesting the involvement of YY1 in NSL HAT functioning. Additionally, de novo motif analysis of MOF and NSL3 targets indicated that the NSL HAT complex may recognize the specific DNA-binding sites in the promoter region of target genes in order to regulate their transcription. [ABSTRACT FROM AUTHOR]

[Display omitted] Venetoclax (VEN), in combination with low dose cytarabine (AraC) or a hypomethylating agent, is FDA approved to treat acute myeloid leukemia (AML) in patients who are over the age of 75 or cannot tolerate standard chemotherapy. Despite high response rates to these therapies, most patients succumb to the disease due to relapse and/or drug resistance, providing an unmet clinical need for novel therapies to improve AML patient survival. ME-344 is a potent isoflavone with demonstrated inhibitory activity toward oxidative phosphorylation (OXPHOS) and clinical activity in solid tumors. Given that OXPHOS inhibition enhances VEN antileukemic activity against AML, we hypothesized that ME-344 could enhance the anti-AML activity of VEN. Here we report that ME-344 enhanced VEN to target AML cell lines and primary patient samples while sparing normal hematopoietic cells. Cooperative suppression of OXPHOS was detected in a subset of AML cell lines and primary patient samples. Metabolomics analysis revealed a significant reduction of purine biosynthesis metabolites by ME-344. Further, lometrexol, a purine biosynthesis inhibitor, synergistically enhanced VEN-induced apoptosis in AML cell lines. Interestingly, AML cells with acquired AraC resistance showed significantly increased purine biosynthesis metabolites and sensitivities to ME-344. Furthermore, synergy between ME-344 and VEN was preserved in these AraC-resistant AML cells. In vivo studies revealed significantly prolonged survival upon combination therapy of ME-344 and VEN in NSGS mice bearing parental or AraC-resistant MV4-11 leukemia compared to the vehicle control. This study demonstrates that ME-344 enhances VEN antileukemic activity against preclinical models of AML by suppressing OXPHOS and/or purine biosynthesis. [ABSTRACT FROM AUTHOR]

• Longitudinally excited metastructures with periodically distributed internal oscillators are considered. • A theoretical concept is presented for the tuning condition between the metastructure as a whole and internal oscillators. • The original and explicit expression for the stiffness of internal oscillators is derived as the design criterion. • The theoretical concept is shown to be general and adjustable, covering a desirable resonance or several of them. • Experimental and numerical verifications of the theoretical concept are provided. A longitudinally excited metastructure with periodically distributed internal oscillators is considered with a view to determining how the tuning condition between their frequency and the frequency of the metastructure as a whole affects vibration attenuation. First, the mechanical model is created, and the tuning condition related to the first resonance frequency of the metastructure with blocked internal oscillators and the first resonance frequency of internal oscillators themselves is obtained in an original analytical form. Then, this condition is used to design the stiffness of the internal oscillators and they are allowed to oscillate in the metastructure, yielding vibration attenuation around the first resonance. The influence of the number of internal oscillators as well as the mass ratio between the mass of one internal oscillator and external oscillator of the metastructure is investigated. Experimental validations, accompanied with numerical results, of these theoretical results are provided subsequently. In addition, the theoretical concept is extended to other resonances, demonstrating its adaptivity and generality, and these cases are then validated via numerical experiments in FEM simulations. [ABSTRACT FROM AUTHOR]

[Display omitted] The combination of venetoclax (VEN) and azacitidine (AZA) has become the standard of care for acute myeloid leukemia (AML) patients who are ≥ 75 years or unfit for intensive chemotherapy. Though initially promising, resistance to the combination therapy is an issue and VEN + AZA-relapsed/refractory patients have dismal outcomes. To better understand the mechanisms of resistance, we developed VEN + AZA-resistant AML cell lines, MV4-11/VEN + AZA-R and ML-2/VEN + AZA-R, which show > 300-fold persistent resistance compared to the parental lines. We demonstrate that these cells have unique metabolic profiles, including significantly increased levels of cytidine triphosphate (CTP) and deoxycytidine triphosphate (dCTP), changes in fatty acid and amino acid metabolism and increased utilization and reliance on glycolysis. Furthermore, fatty acid transporter CD36 is increased in the resistant cells compared to the parental cells. Inhibition of glycolysis with 2-Deoxy-D-glucose re-sensitized the resistant cells to VEN + AZA. In addition, the VEN + AZA-R cells have increased levels of the antiapoptotic protein Mcl-1 and decreased levels of the pro-apoptotic protein Bax. Overexpression of Mcl-1 or knockdown of Bax result in resistance to VEN + AZA. Our results provide insight into the molecular mechanisms contributing to VEN + AZA resistance and assist in the development of novel therapeutics to overcome this resistance in AML patients. [ABSTRACT FROM AUTHOR]

Objective. To identify the herbal formula compatibility law based on the effects of the absorbed components from DCQD on the cerulein-injured AR42J cells. Methods. AR42J cells were pretreated for 30 min with or without the different concentrations of the absorbed components from DCQD individually or in combination or DCQD and coincubated with cerulein (10 nM) for a further 24 h. Cell viability, lactate dehydrogenase (LDH) release, and the levels of apoptosis and necrosis were measured. Results. Compared to DCQD, the individual or combination components partially protected cerulein-injured AR42J cells by increasing cell viability, reducing LDH release, and promoting apoptosis. Rhein, naringin, and honokiol were the main absorbed components from DCQD in cerulein-induced pancreatitis. Moreover, rhein in combination with naringin and honokiol had synergistic effects in protecting cerulein-injured AR42J cells and was better than the individual or the pairwise combination of the three components. Conclusions. The ten effective components from DCQD may elicit similar protective effects as DCQD on cerulein-induced pancreatitis. The principle of the formula compatibility of DCQD may be identified based on the effects of its absorbed components in cerulein-injured AR42J cells. [ABSTRACT FROM AUTHOR]

Estimation and control of wheel slip is a critical consideration in preventing loss of traction, minimizing power consumptions, and reducing soil disturbance. An approach to wheel slip estimation and control, which is robust to sensor noises and modeling imperfection, has been investigated in this study. The proposed method uses a simplified form of wheels longitudinal dynamic and the measurement of wheel and vehicle speeds to estimate and control the optimum slip. The longitudinal wheel forces were estimated using a robust sliding mode observer. A straightforward and simple interpolation method, which involves the use of Burckhardt tire model, instantaneous values of wheel slip, and the estimate of longitudinal force, was used to determine the optimum slip ratio that guarantees maximum friction coefficient between the wheel and the road surface. An integral sliding mode control strategy was also developed to force the wheel slip to track the desired optimum value. The algorithm was tested in Matlab/Simulink environment and later implemented on an autonomous electric vehicle test platform developed by the Nanjing agricultural university. Results from simulation and field tests on surfaces with different friction coefficients (μ) have proved that the algorithm can detect an abrupt change in terrain friction coefficient; it can also estimate and track the optimum slip. More so, the result has shown that the algorithm is robust to bounded variations on the weight on the wheels and rolling resistance. During simulation and field test, the system reduced the slip from non-optimal values of about 0.8 to optimal values of less than 0.2. The algorithm achieved a reduction in slip ratio by reducing the torque delivery to the wheel, which invariably leads to a reduction in wheel velocity. [ABSTRACT FROM AUTHOR]