Lysosomal cation channel TRPML1 suppression sensitizes acute myeloid leukemia cells to chemotherapeutics by inhibiting autophagy.

Despite the implementation of novel therapeutic regimens and extensive research efforts, chemoresistance remains a formidable challenge in the treatment of acute myeloid leukemia (AML). Notably, the involvement of lysosomes in chemoresistance has sparked interest in developing lysosome-targeted therapies to sensitize tumor cells to currently approved chemotherapy or as innovative pharmacological approaches. Moreover, as ion channels on the lysosomal membrane are critical regulators of lysosomal function, they present potential as novel targets for enhancing chemosensitivity. Here, we discovered that the expression of a lysosomal cation channel, namely transient receptor potential mucolipin 1 (TRPML1), was elevated in AML cells. Inhibiting TRPML1 individually does not impact the proliferation and apoptosis of AML cells. Importantly, inhibition of TRPML1 demonstrated the potential to modulate the sensitivity of AML cells to chemotherapeutic agents. Exploration of the underlying mechanisms revealed that suppression of TRPML1 impaired autophagy while concurrently increasing the production of reactive oxygen species (ROS) and ROS-mediated lipid peroxidation (Lipid-ROS) in AML cells. Finally, the knockdown of TRPML1 significantly reduced OCI-AML3 tumor growth following chemotherapy in a mouse model of human leukemia. In summary, targeting TRPML1 represents a promising approach for combination therapy aimed at enhancing chemosensitivity in treating AML.

Longitudinal Serum Proteomics Characterization of CD19-CAR-T Cell Therapy for B-Cell Malignancies.

Chimeric antigen receptor (CAR)-modified T cells have demonstrated remarkable efficacy in treating B-cell leukemia. However, treated patients may potentially develop side effects, such as cytokine release syndrome (CRS), the mechanisms of which remain unclear. Here, we collected 43 serum samples from eight patients with B-cell acute lymphoblastic leukemia (B-ALL) before and five time points after CD19-specific CAR-T cell treatment. Using TMTpro 16-plex-based quantitative proteomics, we quantified 1151 proteins and profiled the longitudinal proteomes analysis of each patient. Seven days after therapy, we found the most dysregulated inflammatory proteins. Lipid metabolism proteins, including APOA1, decreased after therapy, reached their minimum after 7 days, and then gradually recovered. Hence, APOA1 has been selected as a potential biomarker of the CRS disease progression. Furthermore, we identified CD163 as a potential biomarker of CRS severity. These two biomarkers were successfully validated using targeted proteomics in an independent cohort. Our study provides new insights into CAR-T cell therapy-induced CRS. The biomarkers we identified may help develop targeted drugs and monitoring strategies.

Keap1-Nrf2/ARE Pathway-based Investigation into the Mechanism of Edaravone Dexborneol in Cerebral Infarction Model Neuroprotection.

The neuroprotection of acute cerebral infarction (ACI) model by edaravone dexborneol (ED)-mediated Keap1-Nrf2/ARE signal pathway was investigated. Sham operation was set as a control to prepare the ACI model with cerebral artery occlusion. The abdominal cavity was injected with edaravone (ACI+Eda group) and ED (ACI+ED group). Then, neurological deficit scores, cerebral infarct volume, oxidative stress ability, inflammatory reaction level, and the status of the Keap1-Nrf2/ARE signal pathway of rats in all groups were explored. It was demonstrated that the neurological deficit score and cerebral infarct volume of rats in the ACI group apparently increased versus those in the Sham group (P<0.05), suggesting that the ACI model was successfully prepared. Versus those in the ACI group, the neurological deficit score and cerebral infarct volume of rats in the ACI+Eda and ACI+ED groups decreased. In contrast, the activity of cerebral oxidative stress superoxide dismutase (SOD) and glutathione-peroxidase (GSH-Px) increased. Malondialdehyde (MDA) and the expressions of cerebral inflammation indicators (interleukin (IL)-1ß, IL-6, and tumor necrosis factor-α messenger ribonucleic acid (TNF-α mRNA)) and cerebral Keap1 reduced. The expressions of Nrf2 and ARE increased (P<0.05). Versus those in the ACI+Eda group, all indicators of rats in the ACI+ED group were improved more apparently and were more similar to those in the Sham group (P<0.05). The above findings suggested that both edaravone and ED could mediate Keap1-Nrf2/ARE signal pathway to play a neuroprotective role in ACI. Versus edaravone, ED improved ACI oxidative stress and inflammatory reaction level and played a neuroprotective role more apparently.

Joint communication interference system design based on parameter modulation.

In this paper, a joint communication interference integration signal waveform is proposed to satisfy the need of electronic system integration in civil and military uses, and mitigate the tension of spectrum resource. We design the system structure of the integrated signal model and propose the communication receiving processing flow of the integrated system. We utilize the dense false-target jamming style to raise the constant false alarm rate detection threshold via the delay superposition of multiple groups of frequency modulation (FM) slope mismatch jamming signals, which can play a role in protecting our target from being detected. Furthermore, linear frequency modulation (LFM) signals with different FM slopes and Doppler frequencies are obtained via the modulation mapping of communication data; thus, a single LFM signal can carry n bit data. Through correlation processing and frequency detection, code sequence information can be obtained to achieve communication function. The simulation results show that the integrated signal has the effect of shielding and jamming the pulse compression radar. Moreover, the system has a better bit error rate and a high communication rate, which can ensure that the communication task of sending accurate instructions is completed while implementing effective interference.

Thermal Deformation Modeling for Phased Array Antenna Compensation Control.

Thermal compensation control can correct errors caused by the thermal deformation of phased array antenna (PAA) panels. Thermal deformation of the panel is needed to calculate the compensation value. While the PAA is working, thermal deformation is unconditional to measure, but predicting it by temperature is feasible. However, thermal deformation is also affected by other factors, such as the structural shape, assembly method, and material parameters, and it is difficult to measure these parameters of PAA because of the complex structure. In contrast, the measurement method of the temperature and thermal deformation of the PAA in the laboratory is much easier. Therefore, a comprehensive influence parameters (CIPs)-finite element method (FEM) method was proposed in this study, it can extract the influence of above parameters on thermal deformation from temperature and thermal deformation measurement data and build a thermal deformation prediction model. Experiments have verified that the CIPs-FEM can greatly reduce the difficulty of thermal deformation modeling and have a high prediction accuracy.

MIMO Radar Parallel Simulation System Based on CPU/GPU Architecture.

The data volume and computation task of MIMO radar is huge; a very high-speed computation is necessary for its real-time processing. In this paper, we mainly study the time division MIMO radar signal processing flow, propose an improved MIMO radar signal processing algorithm, raising the MIMO radar algorithm processing speed combined with the previous algorithms, and, on this basis, a parallel simulation system for the MIMO radar based on the CPU/GPU architecture is proposed. The outer layer of the framework is coarse-grained with OpenMP for acceleration on the CPU, and the inner layer of fine-grained data processing is accelerated on the GPU. Its performance is significantly faster than the serial computing equipment, and satisfactory acceleration effects have been achieved in the CPU/GPU architecture simulation. The experimental results show that the MIMO radar parallel simulation system with CPU/GPU architecture greatly improves the computing power of the CPU-based method. Compared with the serial sequential CPU method, GPU simulation achieves a speedup of 130 times. In addition, the MIMO radar signal processing parallel simulation system based on the CPU/GPU architecture has a performance improvement of 13%, compared to the GPU-only method.

The risk factor assessment of the spread of foot-and-mouth disease in mainland China.

In China, foot-and-mouth disease (FMD) serotype O remains prevalent, and its main host is pigs. Infected but undiscovered pigs can carry foot-and-mouth disease virus (FMDV) for a longtime. And, the virus can spread among farms through pig trade. Although individual vaccination at least 2 times a year and monthly monitoring disease and culling all individual in same group for pigs are adopted vigorously in China, the epidemic remains prevalent. Therefore, in this paper, based on these propagation characteristics and control measures of the epidemic in China, we take the pig farms as research individuals, the trade among farms as transmission routes to establish a dynamic model with nonlinear incidence. In addition, we use this model to assess the impact of trade and transport of pigs among farms on the spread of foot-and-mouth disease virus (FMDV), and to assess the effect of the immunization, monitoring and culling adopted presently in China on the control of the epidemic. By the dynamical analysis of the model, it is found that there will appear backward branching under some conditions, which means that there are two spreading thresholds for the disease, and the disease development trend is also related to the current epidemic situation. Besides, we give the threshold conditions of key parameters to control the spread of FMD. By carrying out data fitting and parameter estimation, we confirm the model rationality, and give four evaluation indexes: the basic reproduction number R0 of FMD serotype O in China, the value of the infected farms at the equilibria, annual probability of a susceptible farm being infected and annual transmission intensity of an infected farm. By carrying out the sensitivity analysis of key parameters on four evaluation indexes, the effect of parameters on the spread of the disease can be intuitively observed. All these can provide a theoretical basis for understanding of the trading-based transmission mechanism, control and prevention of foot-and-mouth disease in pigs in China.

Modeling the outbreak and control of African swine fever virus in large-scale pig farms.

African swine fever virus (ASFV) leads to a highly contagious, lethal and economically devastating disease among pigs. Since no effective treatment for the disease, it is crucial to investigate its transmission mechanism and control strategies in large-scale pig farms. We first established a toy model to explore ASFV spread in one pig unit. Then a switching patch model was developed to capture its spread from one initial epidemic pig house consecutively to others, even the whole farm. Assessing innocent culling rates of three large-scale epidemic pig farms in Jiangsu Province showed that it is unnecessary to slaughter all pigs in the farms compulsively. Then we explored how the disinfection and fixation of employees impact ASFV spread in the farms. To control ASFV, we can block or slow down its spreading by improving the efficiency of disinfection and decreasing employee population to some extend. We can also shrink potential areas to be infected by properly improving the matching refinement degree among employees and houses. Some essential requirements for large-scale pig farms are presented to reduce their ASFV spreading risk, which can be helpful for animal health authorities in establishing regulation to standardize large-scale pig farms.

Application of N-carbamylglutamate in Rex rabbits to reduce body fat deposition and its possible mechanism.

N-Carbamylglutamate (NCG) has been shown to enhance arginine synthesis and improve growth performance in animals. However, the effect of NCG on body fat deposition remains unknown. This study examined the effects of NCG on body fat deposition and evaluated the potential mechanisms involved. Rex rabbits (3 months old) were assigned to one of four dietary groups and supplemented with NCG at the following different concentrations in a feeding trial that lasted 67 d: 0 (control), 0·04, 0·08, and 0·12 %. NCG supplementation increased serum concentrations of arginine and proline by activating intestinal carbamoylphosphate synthase-І at the posttranscriptional level. Final body weights and growth performance were not affected by dietary NCG levels. However, NCG-treated rabbits had lower perirenal and subcutaneous fat percentages, serum TAG content, and hepatic fatty acid synthase (FAS) activity and increased NO synthase activity and serum levels of NO, growth hormone (GH), and insulin-like growth factor 1 (IGF-1). There were significant positive correlations between TAG content and perirenal fat percentage, as well as FAS activity and perirenal fat percentage, but significant negative correlations between TAG and NO levels, and FAS activity and IGF-1 level in rabbits after NCG treatment. NCG supplementation did not affect hepatic health indicators, except for serum ammonia concentrations, which were decreased in NCG-treated rabbits. Our results suggest that NCG can serve as a dietary supplement to reduce unfavourable fat deposition through inhibiting hepatic lipogenesis in animals since it appears to have no negative effects on growth performance or hepatic health.

3-Nitro-3,4-dihydrocoumarins: valuable precursors for the synthesis of enantiomerically enriched masked quaternary α-amino acid derivatives with a 3,4-dihydrocoumarin scaffold.

A bifunctional squaramide catalyzed enantioselective formal [2 + 4] annulation reaction with 3-nitro-3,4-dihydrocoumarins and ortho-quinone methide has been developed. Novel chiral masked quaternary α-amino acid derivatives with a 3,4-dihydrocoumarin scaffold are obtained in a highly stereocontrolled manner. Representative transformation of the annulation product to a biologically important quaternary α-amino acid derivative is achieved without any appreciable loss in the diastereo- and enantioselectivity.

Protective Effect of Low Molecular Weight Seleno-Aminopolysaccharide on the Intestinal Mucosal Oxidative Damage.

Low molecular weight seleno-aminopolysaccharide (LSA) is an organic selenium compound comprising selenium and low molecular weight aminopolysaccharide (LA), a low molecular weight natural linear polysaccharide derived from chitosan. LSA has been found to exert strong pharmacological activity. In this study, we aimed to investigate the protective effect of LSA on intestinal mucosal oxidative stress in a weaning piglet model by detecting the growth performance, intestinal mucosal structure, antioxidant indices, and expression level of intracellular transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) and its related factors. Our results indicated that LSA significantly increased the average daily gain and feed/gain (p < 0.05), suggesting that LSA can effectively promote the growth of weaning piglets. The results of scanning electron microscope (SEM) microscopy showed that LSA effectively reduced intestinal damage, indicating that LSA improved the intestinal stress response and protected the intestinal structure integrity. In addition, diamine oxidase (DAO) and d-lactic acid (d-LA) levels remarkably decreased in LSA group compared with control group (p < 0.05), suggesting that LSA alleviated the damage and permeability of weaning piglets. LSA significantly increased superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and total antioxidant capacity (T-AOC) levels, but decreased malondialdehyde (MDA) level, indicating that LSA significantly enhanced the antioxidant capacity and reduced oxidative stress in weaning piglets. RT-PCR results showed that LSA significantly increased GSH-Px1, GSH-Px2, SOD-1, SOD-2, CAT, Nrf2, HO-1, and NQO1 gene expression (p < 0.05). Western blot analysis revealed that LSA activated the Nrf2 signaling pathway by downregulating the expression of Keap1 and upregulating the expression of Nrf2 to protect intestinal mucosa against oxidative stress. Collectively, LSA reduced intestinal mucosal damage induced by oxidative stress via Nrf2-Keap1 pathway in weaning stress of infants.

Effectiveness of Market-Level Biosecurity at Reducing Exposure of Poultry and Humans to Avian Influenza: A Systematic Review and Meta-Analysis.

Background: In this study, we aimed to identify the effect of market-level risk factors on avian influenza (AI) infection in poultry and humans and generate evidence that will inform AI prevention and control programs at live bird markets (LBMs). Methods: We performed a systematic literature review in both English and Chinese search engines. We estimated the pooled odds ratios of biosecurity indicators relating to AI infections at market level using a quality effects (QE) meta-analysis model. Results: Biosecurity measures effective at reducing AI market contamination and poultry infection at LBMs include smaller market size, selling single poultry species and separating different species, performing cleaning and disinfection and market closures, ban on overnight storage, and sourcing poultry from local areas. Our meta-analysis indicates that higher risk of exposure to AI infection occurs in workers at retail LBMs, female workers, and those who contact ducks, conduct cleaning, slaughtering, defeathering, or evisceration. Conclusions: The most effective strategies to reduce AI market contamination identified in this study should target larger LBMs that are located at noncentral city areas and sell and slaughter multispecies of live poultry. Live bird market workers directly involved in cleaning and poultry processing tasks should participate in occupational health and safety programs.

Asymmetric Formal [4 + 2] Annulation of o-Quinone Methides with ß-Keto Acylpyrazoles: A General Approach to Optically Active trans-3,4-Dihydrocoumarins.

An asymmetric cascade reaction between ß-keto acylpyrazoles and o-quinone methides in a formal [4 + 2] fashion to access potentially pharmacological active trans-3,4-dihydrocoumarins has been achieved efficiently by using a quinine-based chiral squaramide as the catalyst. The desired products were obtained in high yields with excellent diastereo- and enantioselectivities (up to 96% yield, >19/1 dr and 96% ee) under mild reaction conditions.

Organocatalyzed Asymmetric Michael Addition of 1-Acetylindolin-3-ones to ß,γ-Unsaturated α-Ketoesters: An Access to Chiral Indolin-3-ones with Two Adjacent Tertiary Stereogenic Centers.

Asymmetric Michael addition of 1-acetylindolin-3-ones to ß,γ-unsaturated α-ketoesters was investigated for the synthesis of chiral indolin-3-ones with two adjacent tertiary stereogenic centers. Under the catalysis of a chiral bifunctional squaramide derived from l-tert-leucine, a wide range of 1-acetylindolin-3-ones and ß,γ-unsaturated α-ketoesters were well-tolerated in this transformation to provide the corresponding novel densely functionalized chiral indolin-3-one derivatives in high yield with excellent diastereo- and enantioselectivity under mild reaction conditions.

Stereocontrolled Construction of Tetrahydropyrano[2,3-c]pyrazole Scaffold via an Organocatalyzed Formal [3 + 3] Annulation.

A bifunctional squaramide catalyzed enantioselective formal [3 + 3] annulation reaction with pyrazolin-5-ones and nitroallylic acetates has been developed. Densely substituted tetrahydropyrano[2,3-c]pyrazoles with two adjacent stereogenic centers are obtained in a highly stereocontrolled manner. Representative transformation of the annulation product to a biologically important fused dihydroisoquinoline is achieved without any appreciable loss in the diastereo- and enantioselectivity.

Community-based interventions to enhance knowledge, protective attitudes and behaviors towards canine rabies: results from a health communication intervention study in Guangxi, China.

BACKGROUND: In China canine rabies poses a serious public health problem in that human mortality ranks the second highest globally. While rabies health education interventions are advocated by WHO to be critical components of modern rabies control and prevention programs, available studies have not adequately investigated the relative efficacy of their implementation in at-risk populations. This study aims to measure and compare the effect on knowledge and protective behavior towards rabies of health education interventions that include a novel Short Messaging Service via cell phone (SMS) and rabies health information sessions (IS). METHODS: The study used a between-subject design involving repeated measures of rabies-related KAP (knowledge, attitude and practice). A total of 350 randomly selected villagers were randomly allocated into three intervention (SMS, IS and SMS + IS) and one control group. The content of SMS and IS covered topics about rabies prevention and route of transmission. The SMS intervention consisted of ten separate messages delivered three times two weeks after the pretest; the IS intervention was conducted once immediately after the pretest. A validated questionnaire was used to capture demographic information and KAP information. Ordinary Least Squares regression was used to contrast the effects of interventions. RESULTS: Our results indicate that overall SMS outperforms IS at improving knowledge and protective behavior against rabies. Our results suggest that a combined intervention of SMS and IS can result in higher scores than any of the two in isolation. The impact of SMS, IS and SMS + IS is greatest on knowledge, followed by attitude and practice scores. CONCLUSION: This study demonstrated that health communication modes based on SMS, IS and a combination of the two are all effective to improve rabies-related KAP in the short term. These findings highlight the potential usefulness of SMS as an additional tool for public health communication and promotion; further studies are needed to investigate the long term benefits of these interventions on the reduction of dog bites and resulting human rabies incidence.

Glycyrrhizic Acid Promotes M1 Macrophage Polarization in Murine Bone Marrow-Derived Macrophages Associated with the Activation of JNK and NF-κB.

The roots and rhizomes of Glycyrrhiza species (licorice) have been widely used as natural sweeteners and herbal medicines. The aim of this study is to investigate the effect of glycyrrhizic acid (GA) from licorice on macrophage polarization. Both phenotypic and functional activities of murine bone marrow-derived macrophages (BMDMs) treated by GA were assessed. Our results showed that GA obviously increased the cell surface expression of CD80, CD86, and MHCII molecules. Meanwhile, GA upregulated the expression of CCR7 and the production of TNF-α, IL-12, IL-6, and NO (the markers of classically activated (M1) macrophages), whereas it downregulated the expression of MR, Ym1, and Arg1 (the markers of alternatively activated (M2) macrophage). The functional tests showed that GA dramatically enhanced the uptake of FITC-dextran and E. coli K88 by BMDMs and decreased the intracellular survival of E. coli K88 and S. typhimurium. Moreover, we demonstrated that JNK and NF-κB activation are required for GA-induced NO and M1-related cytokines production, while ERK1/2 pathway exhibits a regulatory effect via induction of IL-10. Together, these findings indicated that GA promoted polarization of M1 macrophages and enhanced its phagocytosis and bactericidal capacity. The results expanded our knowledge about the role of GA in macrophage polarization.

Effect of avian influenza scare on transmission of zoonotic avian influenza: A case study of influenza A (H7N9).

Avian influenza scare is a human psychological factor that asserts both positive and negative effects on the transmission of zoonotic avian influenza. In order to study the dichotomous effect of avian influenza scare on disease transmission, taking H7N9 avian influenza as a typical case, a two-patch epidemic model is proposed. The global dynamics and the threshold criteria are established by LaSalle invariant principle and the theory of asymptotic autonomous system. To mitigate the negative effects and curb illegal poultry trade, a game-theoretic model is adopted to explore the optimal policy of culling subsidies to reasonably compensate stakeholders for their economic losses resulting from the scare. The optimal policy of culling subsidy is found to heavily depend on the penalty of illegal poultry trade, the stakeholders' income, the intensity of control measures, and the prevalence level of the disease. The negative effect of avian influenza scare on disease transmission is considerably more significant than the positive effect. In order to avoid a widespread outbreak of zoonotic avian influenza across the region, a comprehensive national global control strategy is essential and effective, even in the presence of the negative effect of the avian influenza scare.