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The urgent demand for high-bandwidth wireless services in enhanced mobile broadband networks needs innovative solutions for mobile front-haul systems. The terahertz (THz) band offers a promising candidate for ultrahigh-capacity data transmission. This study investigates the integration of photonics-aided THz signal generation with MIMO and PDM technologies. We proposed a novel, to the best of our knowledge, space-time domain equalization algorithm based on MIMO-complex-valued neural networks (CVNN), which can preserve the signal phase and the relation between the X- and Y-polarization. We experimentally demonstrate the transmission of 60-GBaud PDM-QPSK and 30-GBaud PDM-16QAM signals over a 100-m 2 × 2 wireless MIMO link at 320â GHz with BER below 3.8 × 10-3 and 1.56 × 10-2 for QPSK and 16QAM signals, respectively. Compared with the MIMO-Volterra, our MIMO-CVNN has an advantage in terms of calculation complexity and decision accuracy due to its effective handling of phase information and inter-polarization relationships simultaneously.
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In this experiment, we demonstrated an intensity modulation and direct-detection (IM/DD) system based on a field-programmable gate array (FPGA). The PAM8 signals are successfully delivered at 44.2368 Gbit/s over a 45-km standard single-mode fiber (SSMF), satisfying the soft-decision forward error correction (SD-FEC) criterion of 2.4 × 10-2, and the net bit rate may reach 36.864 Gbit/s without the need of optical amplifiers. At the transmitter, we used a pruned pre-equalization algorithm to process the PAM8 signals, and the high-speed parallel PAM8 signals were processed at the receiver using 64 parallel constant modulus algorithm (CMA) and decision-directed least mean square (DD-LMS) equalizers. Additionally, we analyzed the bit error rate (BER) performance of the DD-LMS equalizer in FPGA simulation with various data lengths, both before and after equalization.
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This Letter proposes a probabilistic shaping delta-sigma modulation technique. By performing delta-sigma modulation on the probability shaping signal at the transmitting end, under the same transmit power and the same net bit rate, the delta-sigma modulation signal based on probability shaping can obtain better anti-noise capability than the delta-sigma modulation signal only. Under the same information entropy conditions, the bit error rate performance of the PS-based 131072QAM signal modulated by delta-sigma modulation is better than that of the ordinary 65536QAM signal using the delta-sigma modulation scheme, and lower than that of soft decision-forward error correction (4 × 10-2).
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Dual inhibitors of JAK2 and FLT3 can synergistically control the development of acute myeloid leukemia (AML), and overcome secondary drug resistance of AML that is associated with FLT3 inhibition. We therefore designed and synthesized a series of 4-piperazinyl-2-aminopyrimidines as dual inhibitors of JAK2 and FLT3, and improved their selectivity for JAK2. Screening cascades revealed that compound 11r exhibited inhibitory activity with IC50 values of 2.01, 0.51, and 104.40 nM against JAK2, FLT3, and JAK3, respectively. Compound 11r achieved a high selectivity for JAK2 at a ratio of 51.94, and also showed potent antiproliferative activity in HEL (IC50 = 1.10 µM) and MV4-11 (IC50 = 9.43 nM) cell lines. In an in vitro metabolism assay, 11r exhibited moderate stability in human liver microsomes (HLMs), with a half-life time of 44.4 min, and in rat liver microsomes (RLMs), with a half-life of 143 min. In pharmacokinetic studies, compound 11r showed moderate absorption (Tmax = 5.33 h), with a peak concentration of 38.7 ng/mL and an AUC of 522 ng h/mL in rats, and an oral bioavailability of 25.2%. In addition, 11r induced MV4-11 cell apoptosis in a dose-dependent manner. These results indicate that 11r is a promising selective JAK2/FLT3 dual inhibitor.
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Antineoplásicos , Leucemia Mieloide Aguda , Ratas , Humanos , Animales , Relación Estructura-Actividad , Línea Celular Tumoral , Inhibidores de Proteínas Quinasas/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/metabolismo , Microsomas Hepáticos/metabolismo , Apoptosis , Tirosina Quinasa 3 Similar a fms/metabolismo , Proliferación Celular , Antineoplásicos/uso terapéutico , Janus Quinasa 2/metabolismoRESUMEN
For W-band long-range mm-wave wireless transmission systems, nonlinearity issues resulting from photoelectric devices, optical fibers, and wireless power amplifiers can be handled by deep learning equalization algorithms. In addition, the PS technique is considered an effective measure to further increase the capacity of the modulation-constraint channel. However, since the probabilistic distribution of m-QAM varies with the amplitude, there have been difficulties in learning valuable information from the minority class. This limits the benefit of nonlinear equalization. To overcome the imbalanced machine learning problem, we propose a novel two-lane DNN (TLD) equalizer using the random oversampling (ROS) technique in this paper. The combination of PS at the transmitter and ROS at the receiver improved the overall performance of the W-band wireless transmission system, and our 4.6-km ROF delivery experiment verified its effectiveness for the W-band mm-wave PS-16QAM system. Based on our proposed equalization scheme, we achieved single-channel 10-Gbaud W-band PS-16QAM wireless transmission over a 100 m optical fiber link and a 4.6 km wireless air-free distance. The results show that compared with the typical TLD without ROS, the TLD-ROS can improve the receiver's sensitivity by 1 dB. Furthermore, a reduction of 45.6% in complexity was achieved, and we were able to reduce training samples by 15.5%. Considering the actual wireless physical layer and its requirements, there is much to be gained from the joint use of deep learning and balanced data pre-processing techniques.
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A series of novel biaryloxazolidinone derivatives containing amide and acrylamide structure were designed, synthesized and evaluated for their antibacterial activity. Most compounds generally exhibited potent antibacterial activity with MIC values of 1⯵g/mL against S. aureus, MRSA, MSSA, LREF and VRE pathogens, using linezolid and radezolid as positive controls. Compound 17 exhibited good antibacterial activity with MIC values of 0.5⯵g/mL against S. aureus, MRSA, MSSA and VRE and 0.25⯵g/mL against LREF. The results indicated that compound 17 might serve as a potential hit-compound for further investigation.
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Acrilamida/síntesis química , Amidas/síntesis química , Antibacterianos/uso terapéutico , Bacterias Grampositivas/efectos de los fármacos , Antibacterianos/farmacología , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Novel biaryloxazolidinone derivatives containing a rhodanine or thiohydantoin moiety were designed, synthesized and evaluated for their antibacterial activity. The key compounds 7 and 9 were synthesized by the knoevenagel condensation of intermediate aldehyde 5 with rhodanine derivatives 6a-6b. The preliminary study showed that compounds 7, 9 and 10e exhibited potent antibacterial activity with MIC values of 0.125⯵g/mL against S. aureus, MRSA, MSSA, LREF and VRE pathogens, using linezolid and radezolid as the positive controls. The most promising compound 10e exhibited potent antibacterial activity against tested clinical isolates of MRSA, MSSA, VRE and LREF with MIC values in the range of 0.125-0.5⯵g/mL, and the potency of 10e against clinical isolates of LREF was 64-fold higher than that of linezolid. Moreover, compound 10e was non-cytotoxic with an IC50 value of 91.04⯵M against HepG2 cell. Together, compound 10e might serve as a novel antibacterial agent for further investigation.
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Antibacterianos/farmacología , Diseño de Fármacos , Bacterias Grampositivas/efectos de los fármacos , Inhibidores de la Monoaminooxidasa/farmacología , Oxindoles/farmacología , Rodanina/farmacología , Tiohidantoínas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Monoaminooxidasa/metabolismo , Inhibidores de la Monoaminooxidasa/síntesis química , Inhibidores de la Monoaminooxidasa/química , Oxindoles/síntesis química , Oxindoles/química , Rodanina/química , Relación Estructura-Actividad , Tiohidantoínas/químicaRESUMEN
OBJECTIVE: To investigate the effects of Danmu Extract Syrup (DMS) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and explore the mechanism. METHODS: Seventy-two male Balb/C mice were randomly divided into 6 groups according to a random number table (n=12), including control (normal saline), LPS (5 mg/kg), LPS+DMS 2.5 mL/kg, LPS+DMS 5 mL/kg, LPS+DMS 10 mL/kg, and LPS+Dexamethasone (DXM, 5 mg/kg) groups. After pretreatment with DMS and DXM, the ALI mice model was induced by LPS, and the bronchoalveolar lavage fluid (BALF) were collected to determine protein concentration, cell counts and inflammatory cytokines. The lung tissues of mice were stained with hematoxylin-eosin, and the wet/dry weight ratio (W/D) of lung tissue was calculated. The levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1 ß in BALF of mice were detected by enzyme linked immunosorbent assay. The expression levels of Claudin-5, vascular endothelial (VE)-cadherin, vascular endothelial growth factor (VEGF), phospho-protein kinase B (p-Akt) and Akt were detected by Western blot analysis. RESULTS: DMS pre-treatment significantly ameliorated lung histopathological changes. Compared with the LPS group, the W/D ratio and protein contents in BALF were obviously reduced after DMS pretreatment (P<0.05 or P<0.01). The number of cells in BALF and myeloperoxidase (MPO) activity decreased significantly after DMS pretreatment (P<0.05 or P<0.01). DMS pre-treatment decreased the levels of TNF-α, IL-6 and IL-1 ß (P<0.01). Meanwhile, DMS activated the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway and reversed the expressions of Claudin-5, VE-cadherin and VEGF (P<0.01). CONCLUSIONS: DMS attenuated LPS-induced ALI in mice through repairing endothelial barrier. It might be a potential therapeutic drug for LPS-induced lung injury.
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Lesión Pulmonar Aguda , Medicamentos Herbarios Chinos , Proteínas Proto-Oncogénicas c-akt , Ratones , Masculino , Animales , Proteínas Proto-Oncogénicas c-akt/metabolismo , Lipopolisacáridos , Fosfatidilinositol 3-Quinasas/metabolismo , Interleucina-1beta/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Claudina-5/metabolismo , Lesión Pulmonar Aguda/tratamiento farmacológico , Lesión Pulmonar Aguda/inducido químicamente , Pulmón/patología , Interleucina-6/metabolismoRESUMEN
BACKGROUND: Acute lung injury (ALI) is a severe inflammatory disease, underscoring the urgent need for novel treatments. Nauclea officinalis Pierre ex Pitard (Danmu in Chinese, DM) is effective in treating inflammatory respiratory diseases. However, there is still no evidence of its protective effect against ALI. METHODS: Metabolomics was applied to identify the potential biomarkers and pathways in ALI treated with DM. Further, network pharmacology was introduced to predict the key targets of DM against ALI. Then, the potential pathways and key targets were further verified by immunohistochemistry and western blot assays. RESULTS: DM significantly improved lung histopathological characteristics and inflammatory response in LPS-induced ALI. Metabolomics analysis showed that 16 and 19 differential metabolites were identified in plasma and lung tissue, respectively, and most of these metabolites tended to recover after DM treatment. Network pharmacology analysis revealed that the PI3K/Akt pathway may be the main signaling pathway of DM against ALI. The integrated analysis of metabolomics and network pharmacology identified 10 key genes. These genes are closely related to inflammatory response and cell apoptosis of lipopolysaccharide (LPS)-induced ALI in mice. Furthermore, immunohistochemistry and western blot verified that DM could regulate inflammatory response and cell apoptosis by affecting the PI3K/Akt pathway, and expression changes in Bax and Bcl-2 were also triggered. CONCLUSION: This study first integrated metabolomics, network pharmacology and biological verification to investigate the potential mechanism of DM in treating ALI, which is related to the regulation of inflammatory response and cell apoptosis. And the integrated analysis can provide new strategies and ideas for the study of traditional Chinese medicines in the treatment of ALI.
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Pediatric central nervous system (CNS) tumors are the second most common cancer diagnosis among children. Long noncoding RNAs (lncRNAs) emerge as critical regulators of gene expression, and they play fundamental roles in immune regulation. However, knowledge on epigenetic changes in lncRNAs in diverse types of pediatric CNS tumors is lacking. Here, we integrated the DNA methylation profiles of 2,257 pediatric CNS tumors across 61 subtypes with lncRNA annotations and presented the epigenetically regulated landscape of lncRNAs. We revealed the prevalent lncRNA methylation heterogeneity across pediatric pan-CNS tumors. Based on lncRNA methylation profiles, we refined 14 lncRNA methylation clusters with distinct immune microenvironment patterns. Moreover, we found that lncRNA methylations were significantly correlated with immune cell infiltrations in diverse tumor subtypes. Immune-related lncRNAs were further identified by investigating their correlation with immune cell infiltrations and potentially regulated target genes. LncRNA with methylation perturbations potentially regulate the genes in immune-related pathways. We finally identified several candidate immune-related lncRNA biomarkers (i.e., SSTR5-AS1, CNTN4-AS1, and OSTM1-AS1) in pediatric cancer for further functional validation. In summary, our study represents a comprehensive repertoire of epigenetically regulated immune-related lncRNAs in pediatric pan-CNS tumors, and will facilitate the development of immunotherapeutic targets.
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Neoplasias del Sistema Nervioso Central , ARN Largo no Codificante , Neoplasias del Sistema Nervioso Central/genética , Niño , Epigénesis Genética , Epigenoma , Regulación Neoplásica de la Expresión Génica , Humanos , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Microambiente Tumoral/genéticaRESUMEN
Inhibition of the soluble epoxide hydrolase (sEH) is a promising new therapeutic approach in the treatment of inflammation. Driven by the in-house database product lead 1, a hybridization strategy was utilized for the design of a series of novel benzo [d]thiazol derivatives. To our delight, D016, a byproduct of compound 9, was obtained with an extraordinarily low IC50 value of 0.1 nM but poor physical and chemical properties. After removal of a non-essential urea moiety or replacement of the urea group by an amide group, compounds 15a, 17p, and 18d were identified as promising sEH inhibitors, and their molecular binding modes to sEH were constructed. Furthermore, compounds 15a and 18d exhibited more effective in vivo anti-inflammatory effect than t-AUCB in carrageenan-induced mouse paw edema. Compound 15a also showed moderate metabolic stability with a half-time of 34.7 min. Although 18d was unstable in rat liver microsomes, it might be a "prodrug". In conclusion, this study could provide valuable insights into discovery of new sEH inhibitors, and compounds 15a and 18d were worthy of further development as potential drug candidates to treat inflammation.
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Antiinflamatorios no Esteroideos/farmacología , Benzotiazoles/farmacología , Edema/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Epóxido Hidrolasas/antagonistas & inhibidores , Inflamación/tratamiento farmacológico , Animales , Antiinflamatorios no Esteroideos/síntesis química , Antiinflamatorios no Esteroideos/química , Benzotiazoles/síntesis química , Benzotiazoles/química , Carragenina , Supervivencia Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Edema/inducido químicamente , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Epóxido Hidrolasas/metabolismo , Células Hep G2 , Humanos , Inflamación/inducido químicamente , Ligandos , Masculino , Ratones , Ratones Endogámicos BALB C , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Simulación del Acoplamiento Molecular , Estructura Molecular , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Clinically, a single agent that simultaneously inhibits multiple targets has been widely used in cancer treatment to overcome complicated dose design and anti-cancer resistance. Inspired by the synergistic effects between c-Met and HDAC in tumor development, a novel series of c-Met/HDAC bifunctional inhibitors was designed and synthesized by merging the pharmacophores of HDAC inhibitor into a c-Met inhibitor. All the target compounds were evaluated for their biological activity, the most potent compound, 14x, exhibited strong inhibition against HDAC1 with an IC50 of 18.49 nM and remarkable inhibitory activity against c-Met with an IC50 of 5.40 nM, respectively. In addition, 14x efficiently inhibited the proliferation of HCT-116, MCF-7 and A549 cell lines with IC50 values of 0.22 µM, 1.59 µM and 0.22 µM, respectively, which were superior to the reference compounds Cabozantinib and SAHA. Futhermore, 14x induced apoptosis and cause cell cycle arrest in G2/M phase. Docking experiments on c-Met and HDAC enzymes revealed the key interactions between 14x with the target protein. These results indicated that 14x was a potent dual c-Met/HDAC inhibitor and deserved for further investigation.
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Histona Desacetilasa 1/efectos de los fármacos , Inhibidores de Histona Desacetilasas/farmacología , Proteínas Proto-Oncogénicas c-met/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Simulación por Computador , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Inhibidores de Histona Desacetilasas/administración & dosificación , Humanos , Simulación del Acoplamiento MolecularRESUMEN
Using the principle of bioisosteric replacement, we present a structure-based design approach to obtain new Axl kinase inhibitors with significant activity at the kinase and cellular levels. Through a stepwise structure-activity relationships exploration, a series of 6,7-disubstituted quinoline derivatives, which contain 1,3,4-oxadiazol acetamide moiety as novel Linker, were ultimately synthesized with Axl as the primary target. Most of them exhibited moderate to excellent activity, with IC50 values ranging from 0.032 to 1.54⯵M against the tested cell lines. Among them, the most promising compound 47e, as an Axl kinase inhibitor (IC50â¯=â¯10â¯nM), shows remarkable cytotoxicity against A549, HT-29, PC-3, MCF-7, H1975 and MDA-MB-231â¯cell lines. More importantly, 47e also shows a significant inhibitory effect on EGFR-TKI resistant NSCLC cell lines H1975/gefitinib. Meanwhile, this study provides a novel type of linker for Axl kinase inhibitors, namely 1,3,4-oxadiazol acetamide moiety, which is out of the scope of the "5- atoms role ".
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Acetamidas/farmacología , Antineoplásicos/farmacología , Diseño de Fármacos , Oxadiazoles/farmacología , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Proto-Oncogénicas/antagonistas & inhibidores , Proteínas Tirosina Quinasas Receptoras/antagonistas & inhibidores , Acetamidas/síntesis química , Acetamidas/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Estructura Molecular , Oxadiazoles/síntesis química , Oxadiazoles/química , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Tirosina Quinasas Receptoras/metabolismo , Relación Estructura-Actividad , Tirosina Quinasa del Receptor AxlRESUMEN
N6-methyladenosine (m6A) plays critical roles in human development and cancer progression. However, our knowledge regarding the dynamic expression of m6A regulators during human tissue development is still lacking. Here, we comprehensively analyzed the dynamic expression alterations of m6A regulators during seven tissue development and eight cancer types. We found that m6A regulators globally exhibited decreased expression during development. In addition, IGF2BP1/2/3 (insulinlike growth factor 2 MRNA-binding protein 1/2/3) exhibited reverse expression pattern in cancer progression, suggesting an oncofetal reprogramming in cancer. The expressions of IGF2BP1/2/3 were regulated by genome alterations, particularly copy number amplification in cancer. Clinical association analysis revealed that higher expressions of IGF2BP1/2/3 were associated with worse survival of cancer patients. Finally, we found that genes significantly correlated with IGF2BP1/2/3 were significantly enriched in cancer hallmark-related pathways. In summary, dynamic expression analysis will guide both mechanistic and therapeutic roles of m6A regulators during tissue development and cancer progression.