Photonic-assisted multiple microwave frequency measurement with improved robustness.

A multiple microwave frequency measurement approach based on frequency-to-time mapping (FTTM) is reported. The FTTM is constructed by optical sideband sweeping and electric-domain intermediate frequency envelope monitoring. Two optimized operations are implemented. First, the use of balanced photodetection cancels out the beat components generated by the signals under test (SUT) themselves, so as to exclude frequency misjudgment. Second, a reference signal is introduced to map the SUT frequency to a relative time difference instead of an absolute time value, avoiding the measuring bias caused by time synchronization. As a result, the proposed scheme with improved robustness could be attractive for future practical applications. An experiment is performed. Microwave frequency measurement from 16 to 26 GHz is demonstrated, with an average error of 7.53 MHz.

Design, Synthesis and In Vivo Fluorescence Imaging Study of a Cytochrome P450 1B1 Targeted NIR Probe Containing a Chelator Moiety.

Cytochrome P450 (CYP) 1B1 has been found to be overexpressed specifically in tumor tissues at an early stage, which makes it a potential cancer biomarker for molecular imaging. Multimodal imaging combines different imaging modalities and offers more comprehensive information. Thus, imaging probes bearing more than one kind of signal fragment have been extensively explored and display great promise. Herein, we developed a near infrared (NIR) probe with a chelator moiety targeting CYP1B1 by conjugating α-naphthoflavone (ANF) derivatives with both an NIR dye and a chelator for potential application in bimodal imaging. Enzymatic inhibitory studies demonstrated inhibitory activity against CYP1B1 and selectivity among CYP1 were successfully retained after chemical modification. Cell-based saturation studies indicated nanomolar range binding affinity between the probe and CYP1B1 overexpressed cancer cells. In vitro competitive binding assays monitored by confocal microscopy revealed that the probe could specifically accumulate in tumor cells. In vivo and ex vivo imaging studies demonstrated that the probe could effectively light-up the tumor tissues as early as 2 hours post-injection. In addition, the fluorescence was significantly blocked by co-injection of CYP1B1 inhibitor, which indicated the probe accumulation in tumor sites was due to specific binding to CYP1B1.

Lateralized Cerebral Processing of Abstract Linguistic Structure in Clear and Degraded Speech.

Human cortical activity measured with magnetoencephalography (MEG) has been shown to track the temporal regularity of linguistic information in connected speech. In the current study, we investigate the underlying neural sources of these responses and test the hypothesis that they can be directly modulated by changes in speech intelligibility. MEG responses were measured to natural and spectrally degraded (noise-vocoded) speech in 19 normal hearing participants. Results showed that cortical coherence to "abstract" linguistic units with no accompanying acoustic cues (phrases and sentences) were lateralized to the left hemisphere and changed parametrically with intelligibility of speech. In contrast, responses coherent to words/syllables accompanied by acoustic onsets were bilateral and insensitive to intelligibility changes. This dissociation suggests that cerebral responses to linguistic information are directly affected by intelligibility but also powerfully shaped by physical cues in speech. This explains why previous studies have reported widely inconsistent effects of speech intelligibility on cortical entrainment and, within a single experiment, provided clear support for conclusions about language lateralization derived from a large number of separately conducted neuroimaging studies. Since noise-vocoded speech resembles the signals provided by a cochlear implant device, the current methodology has potential clinical utility for assessment of cochlear implant performance.

Estimation of positioning sparsity for Sagnac correction in fiber-optic time transfer.

The Sagnac effect is an important factor that leads to nonreciprocity in long-haul fiber-optic time and a frequency transfer system. For high-precision time transfer, correction must be performed to eliminate the time difference based on the trajectory of the path. However, the routing information may be not detailed enough to guarantee sufficient precision for Sagnac correction. Thus, nodes along the path must be surveyed with a certain sparsity. We provide a practical method for estimating the average distance of these nodes. Six simulated paths are generated to validate the method for different uncertainties.

The Efficacy of Resin Hemoperfusion Cartridge on Inflammatory Responses during Adult Cardiopulmonary Bypass.

AIM: This study aimed to evaluate the efficacy of the resin hemoperfusion device (HA380 hemoperfusion cartridge) on inflammatory responses during adult cardiopulmonary bypass (CPB). METHODS: Sixty patients undergoing surgical valve replacement were randomized into the HP group (n = 30) with an HA380 hemoperfusion cartridge in the CPB circuit or the control group (n = 30) with the conventional CPB circuit. The results of routine blood tests, blood biochemical indexes, and inflammatory factors were analyzed at V0 (pre-CPB), V1 (CPB 30 min), V2 (ICU 0 h), V3 (ICU 6 h), and V4 (ICU 24 h). RESULTS: The HP group had significantly lower levels of IL-6, IL-8, and IL-10. Significant estimation of group differences in the generalized estimating equation (GEE) models was also observed in IL-6 and IL-10. The HP group had significantly lower levels of creatinine (Cr), aminotransferase (AST), and total bilirubin (TBil) compared to the control group. The estimation of differences of Cr, AST, and TBil all reached statistical significance in GEE results. The HP group had significantly less vasopressor requirement and shorter mechanical ventilation time and ICU stay time as compared to the control group. CONCLUSION: The HA380 hemoperfusion cartridge could effectively reduce the systemic inflammatory responses and improve postoperative recovery of patients during adult CPB.

Identification of Phelligridin-Based Compounds as Novel Human CD73 Inhibitors.

As an emerging immune checkpoint, CD73 has received more attention in the past decade. Inhibition of CD73 enzymatic activity can enhance antitumor immunity. Several CD73 inhibitors have been identified by in vitro assays in recent years, but they remain premature for clinical application, indicating that more novel CD73 inhibitors should be studied. Herein, we aimed to identify novel CD73 inhibitors that hopefully are suitable drug candidates by using computer-aided drug discovery and enzymatic-based assays. Five-hundred molecules with high binding affinity were retrieved from the Chemdiv-Plus database by using a structure-based virtual screening approach. Then, we analyzed the drug properties of these molecules and obtained 68 small molecules based on the oral noncentral nervous system (CNS) drug profile. The inhibition rates of these molecules against CD73 enzymatic activities were determined at a concentration of 100 µM, and 20 molecules had an inhibition rate greater than 20%, eight of which were dose-dependent, with IC50 values of 6.72-172.1 µM. Among the screening hits, phelligridin-based compounds had the best experimental inhibition values. Modeling studies indicate that the phelligridin group is sandwiched by the rings of F417 and F500 residues. The identified inhibitors have a molecular weight of approximately 500 Dal and are predicted to form primarily hydrogen bonds with CD73 in addition to hydrophobic stacking interactions. In conclusion, novel inhibitors with satisfactory drug properties may serve as lead compounds for the development of CD73-targeting drugs, and the binding modes may provide insight for phelligridin-based drug design.

Speciation, toxicity mechanism and remediation ways of heavy metals during composting: A novel theoretical microbial remediation method is proposed.

Heavy metals (HM) pollution is a major limitation to the application of composting products. Therefore, mitigating the toxicity of HM has attracted wide attention during composting. The toxicity of HM is mainly acted on microorganisms during composting, and the toxicity of different HM speciation is obviously various. There are many pathways to change the speciation to reduce the toxicity during composting. Therefore, in this review, the speciation distribution, toxicity mechanism and remediation ways of HM during composting were discussed in order to better solve HM pollution. The microbial remediation technology holds enormous potential to remediate for HM without damaging composting, however, it is hard to extract HM. The innovation of this review was to outline microbial remediation strategies for HM during composting based on two mechanisms of microbial remediation: extracellular adsorption and intracellular sequestration, to solve the problem how to extract microbial agents from the compost. Ultimately, a novel theoretical method of microbial remediation was proposed to remove HM from the compost.

Exploring the Potential of Hydrophilic Matrix Combined with Insoluble Film Coating: Preparation and Evaluation of Ambroxol Hydrochloride Extended Release Tablets.

To explore the potential utility of combination of hydrophilic matrix with membrane-controlled technology, the present study prepared tablets of a water-soluble model drug (ambroxol hydrochloride), through process of direct compression and spray coating. Single-factor experiments were accomplished to optimize the formulation. In vivo pharmacokinetics was then performed to evaluate the necessity and feasibility of further development of this simple process and low-cost approach. Various release rates could be easily obtained by adjusting the viscosity and amount of hypromellose, pore-former ratios in coating dispersions and coating weight gains. Dissolution profiles of coated tablets displayed initial delay, followed by near zero-order kinetics. The pharmacokinetic study of different formulations showed that lag time became longer as the permeability of coating membrane decreased, which was consistent with the in vitro drug release trend. Besides, in vitro/in vivo correlation study indicated that coated tablets exhibited a good correlation between in vitro release and in vivo absorption. The results, therefore, demonstrated that barrier-membrane-coated matrix formulations were extremely promising for further application in industrialization and commercialization.

DMAKO-20 as a New Multitarget Anticancer Prodrug Activated by the Tumor Specific CYP1B1 Enzyme.

To reduce the pervasive toxicity of natural shikonin, alkannin, and their synthetic analogues and to enhance the selectivity of these chemotherapeutics toward cancer cells, a novel 5,8-dimethyl alkannin oxime derivative (DMAKO-20) was designed, synthesized, and evaluated for its strong antitumor activity both in vitro and in vivo. It showed potent growth inhibitory effects against HCT-15, HCT-116, and K562 cells (IC50 < 1 µM), moderate antiproliferative activity toward MDA-MB-231, HepG2, PANC, Bel7402, and MGC803 cancer cells (IC50 < 10 µM), and was nontoxic to the human normal VEC and HSF cells. In vivo efficacy studies demonstrated that DMAKO-20 (10 mg/kg, i.v. on every the other day, 8 times in 14 days) resulted in 59.3% reduction in HCT-15 xenograft volume. It was as effective as the toxic antimetabolite 5-FU but revealed neither toxicity nor death in mice. The mechanistic investigations indicated that DMAKO-20 underwent the tumor-specific CYP1B1-catalyzed bioactivation to afford nitric oxide and active naphthoquinone mono-oximes, which exhibited combined anticancer effects. It was defined as a representative of the "Multi-target Anticancer Prodrugs Activated by Specific Enzymes in cancer cells". The produced active metabolites exerted anticancer effects by the direct nucleophilic alkylation and the induction of the apoptosis of cancer cells through activation of the mitochondrial pathway. The discovery of DMAKO-20 and the illustration of its molecular mechanisms may provide a new strategy to overcome the nonselective toxicity of the current chemotherapeutics.

Cytotoxicity of Synthesized 1,4-Naphthoquinone Oxime Derivatives on Selected Human Cancer Cell Lines.

In an effort to develop potent and selective antitumor agents, a series of 1,4-naphthoquinone oxime derivatives were designed and synthesized. The cytotoxicity of these compounds were evaluated against five human cancer cell lines (colorectal cancer cell: HCT-15, breast cancer cell: MDA-MB-231, liver cancer cell: BEL-7402, colorectal cancer cell: HCT-116 and ovarian cancer cell: A2780) in vitro. Among them, compound 14 was found to be the most potent cytotoxic compound against three cell lines (MDA-MB-231, BEL-7402 and A2780) with IC50 values of 0.66±0.05, 5.11±0.12 and 8.26±0.22 µM, respectively. Additionally, the length of the side chains and the position of the substituent may also affect the cytotoxic activity of the naphthoquinone oxime derivatives. In general, compound 14 effectively inhibited breast cancer cell proliferation and may become a promising anticancer agent.

Development of a Mouse Model of Metabolic Syndrome, Pulmonary Hypertension, and Heart Failure with Preserved Ejection Fraction.

Pulmonary hypertension (PH) associated with heart failure with preserved ejection fraction (PH-HFpEF; World Health Organization Group II) secondary to left ventricular (LV) diastolic dysfunction is the most frequent cause of PH. It is an increasingly recognized clinical complication of the metabolic syndrome. To date, no effective treatment has been identified, and no genetically modifiable mouse model is available for advancing our understanding for PH-HFpEF. To develop a mouse model of PH-HFpEF, we exposed 36 mouse strains to 20 weeks of high-fat diet (HFD), followed by systematic evaluation of right ventricular (RV) and LV pressure-volume analysis. The HFD induces obesity, glucose intolerance, insulin resistance, hyperlipidemia, as well as PH, in susceptible strains. We observed that certain mouse strains, such as AKR/J, NON/shiLtJ, and WSB/EiJ, developed hemodynamic signs of PH-HFpEF. Of the strains that develop PH-HFpEF, we selected AKR/J for further model validation, as it is known to be prone to HFD-induced metabolic syndrome and had low variability in hemodynamics. HFD-treated AKR/J mice demonstrate reproducibly higher RV systolic pressure compared with mice fed with regular diet, along with increased LV end-diastolic pressure, both RV and LV hypertrophy, glucose intolerance, and elevated HbA1c levels. Time course assessments showed that HFD significantly increased body weight, RV systolic pressure, LV end-diastolic pressure, biventricular hypertrophy, and HbA1c throughout the treatment period. Moreover, we also identified and validated 129S1/SvlmJ as a resistant mouse strain to HFD-induced PH-HFpEF. These studies validate an HFD/AKR/J mouse model of PH-HFpEF, which may offer a new avenue for testing potential mechanisms and treatments for this disease.

Figure of Merit Enhancement of a Surface Plasmon Resonance Sensor Using a Low-Refractive-Index Porous Silica Film.

In this paper; the surface plasmon resonance (SPR) sensor with a porous silica film was studied. The effect of the thickness and porosity of the porous silica film on the performance of the sensor was analyzed. The results indicated that the figure of merit (FOM) of an SPR sensor can be enhanced by using a porous silica film with a low-refractive-index. Particularly; the FOM of an SPR sensor with 40 nm thick 90% porosity porous silica film; whose refractive index is 1.04 was improved by 311% when compared with that of a traditional SPR sensor. Furthermore; it was found that the decrease in the refractive index or the increase in the thickness of the low-refractive-index porous silica film can enlarge the FOM enhancement. It is believed that the proposed SPR sensor with a low-refractive-index porous silica film will be helpful for high-performance SPR sensors development.

An HDAC-Targeted Imaging Probe LBH589-Cy5.5 for Tumor Detection and Therapy Evaluation.

Histone deacetylases (HDACs) are overexpressed in various cancers. In vivo imaging to measure the expression and functions of HDACs in tumor plays an important role for tumor diagnosis and HDAC-targeted therapy evaluation. The development of stable and highly sensitive HDAC targeting probe is highly desirable. Near-infrared (NIR) fluorescence optical imaging is a powerful technology for visualizing disease at the molecular level in vivo with high sensitivity and no ionizing radiation. We report here the design, synthesis, and bioactivity evaluation of LBH589-Cy5.5 for in vivo NIR fluorescence imaging of HDACs. The IC50 value of the resulting NIR probe to HDACs was determined to be 9.6 nM. In vitro fluorescence microscopic studies using a triple-negative breast cancer cell line, MDA-MB-231, established the binding specificity of LBH589-Cy5.5 to HDACs. An in vivo imaging study performed in MDA-MB-231 tumor xenografts demonstrated accumulation of the probe in tumor with good contrast from 2 h to 48 h postinjection. Furthermore, the fluorescent signal of LBH589-Cy5.5 in tumor was successfully blocked by coinjection of nonfluorescent LBH589 with the probe. In a following therapy evaluation study, the administration of SAHA, a clinically used HDAC inhibitor, decreased LBH589-Cy5.5 accumulation in tumor, demonstrating the potential application of LBH589-Cy5.5 for evaluating therapeutic response of HDAC inhibitors in cancer treatment.

Antitumor activity of DMAKO-05, a novel shikonin derivative, and its metabolism in rat liver microsome.

The antitumor activity of shikonin derivatives is largely dependent on the generation of superoxide radicals and the alkylation activity of their naphthoquinone moiety. However, our recent study showed that 1,4-dioxime-5,8-dimethoxynaphthalene (DMAKO-05), a novel shikonin derivative, displayed more potential antitumor activity and less toxicity compared to fluorouracil (5-FU) both in vitro and in vivo, even though the hydroxyl and carbonyl groups of its naphthoquinone structure were shielded. To understand the underlying mechanisms, we investigated the metabolism of DMAKO-05 in rat liver microsomes. The kinetic analysis indicated that DMAKO-05 underwent a biphasic metabolism in rat liver microsomes. The inhibition experiments showed that CYP1A and CYP3A were the major enzymes in the metabolism of DMAKO-05, along with partial contribution from CYP2A. In addition, the structures of eight DMAKO-05 metabolites, which were characterized by accurate mass and MS/MS fragmentograms, implied that DMAKO-05 was mainly metabolized through the oxygenation of its naphthoquinone nucleus and the hydrolysis of its side chain, instead of the oxidation of hydroxyimine to ketone. Therefore, DMAKO-05 should not be considered as a traditional naphthoquinone prodrug.

In silico discovery of aminoacyl-tRNA synthetase inhibitors.

Aminoacyl-tRNA synthetases (aaRSs) are enzymes that catalyze the transfer of amino acids to their cognate tRNA. They play a pivotal role in protein synthesis and are essential for cell growth and survival. The aaRSs are one of the leading targets for development of antibiotic agents. In this review, we mainly focused on aaRS inhibitor discovery and development using in silico methods including virtual screening and structure-based drug design. These computational methods are relatively fast and cheap, and are proving to be of great benefit for the rational development of more potent aaRS inhibitors and other pharmaceutical agents that may usher in a much needed generation of new antibiotics.

Preparation of Nanoparticles Loaded with Quercetin and Effects on Bacterial Biofilm and LPS-Induced Oxidative Stress in Dugesia japonica.

Quercetin is a kind of flavonol compound, which has been widely concerned because of its good pharmacological effects. However, its poor water solubility and poor oral absorption limit its application. To address the above problems, the optimal technological conditions for preparing quercetin-loaded chitosan sodium alginate nanoparticles (Q-CSNPs) were obtained through single-factor experiment method. Q-CSNPs were characterized by particle size analyzer, scanning electron microscope (SEM), transmission electron microscope (TEM), and Fourier transform infrared spectroscopy (FTIR). Biofilm experiment evaluated the antibacterial activity of five different concentrations of Q-CSNPs against Escherichia coli and Staphylococcus aureus. DPPH and hydroxyl radical scavenging experiments determined their antioxidant activity. The effect of Q-CSNPs labeled with FITC on the oxidative stress of planarian was determined. The results showed that quercetin was successfully encapsulated and had good antibacterial and antioxidant capacity in vitro. In vivo experiments of planarians also showed that Q-CSNPs could inhibit the oxidative stress induced by lipopolysaccharide (LPS) and especially alleviate the decrease of CAT activity and the increase of MDA content in planarians induced by LPS. After being supported by future in vivo studies, this preparation will provide research possibilities for the development of quercetin nano-drugs, quercetin dietary supplement, and so on.

Profound metabolic acidosis in association with sodium thiosulfate therapy in a patient with calcific uremic arteriolopathy: a case report and literature review.

Calciphylaxis, also known as Calcific uremic arteriolopathy (CUA), is a serious disorder that presents with skin necrosis due to calcification of dermal and subcutaneous adipose tissue capillaries and arterioles. The condition occurs primarily in patients with end-stage renal disease (ESRD) on dialysis, and it carries high morbidity and mortality, primarily due to sepsis, with an estimated six-month survival of approximately 50%. Although there are no high-quality studies to guide the optimal treatment approach for patients with calciphylaxis, many retrospective studies and case series support treatment with sodium thiosulfate (STS). Despite the frequent use of STS as an off-label treatment, data regarding its safety and efficacy are limited. STS has generally been considered a safe drug with mild side effects. However, severe metabolic acidosis associated with STS is a rare and life-threatening complication of STS treatment and is often unpredictable. Herein, we report a 64-year-old female with ESRD on peritoneal dialysis (PD) who presented with a profound high anion gap metabolic acidosis and severe hyperkalemia while on STS treatment for CUA. No other etiology for her severe metabolic acidosis other than STS was identified. ESRD patients receiving STS should be monitored closely for this side effect. Dose reduction, increasing the duration of infusion, or even discontinuing STS treatment should be considered if severe metabolic acidosis develops.

Study on the mechanism and degradation behavior of Encifer adhaerens DNM-S1 capturing dimethyl phthalate.

The global concern surrounding pollution caused by phthalates is escalating, with dimethyl phthalate (DMP) emerging as one of the most prevalent contaminants within the phthalates (PAEs) category. Although the biodegradation of DMP is considered both safe and efficient, its underlying degradation mechanism is not yet fully elucidated, and the degradation performance can be somewhat inconsistent. To address this issue, our study isolated a DMP-degrading bacterium (DNM-S1) from a vegetable greenhouse. The resulting data revealed that DNM-S1 exhibited a remarkable degradation performance, successfully degrading 84.98% of a 2000 mg L-1 DMP solution within 72 h. Remarkably, it achieved complete degradation of a 50 mg L-1 DMP solution within just 3 h. DMP degradation by DNM-S1 was also found to be efficient even under low-temperature conditions (10 °C). Our research further indicates that DNM-S1 is capable of capturing DMP through the ester bond in the bacterium's cell wall fatty acids, forming hydrogen bonds through hydrophobic interactions. The DMP was then transported into the DNM-S1 protoplasm using an active transport mechanism. Interestingly, the secondary metabolites of DNM-S1 contained natural carotenoids, which could potentially counteract the damaging effects of PAEs on cell membrane permeability. In summary, these findings highlight the potential of DNM-S1 in addressing PAEs pollution and provide new insights into the metabolic mechanism of PAEs degradation.

Photonics-Based Simultaneous DFS and AOA Measurement System without Direction Ambiguity.

A novel scheme that can simultaneously measure the Doppler frequency shift (DFS) and angle of arrival (AOA) of microwave signals based on a single photonic system is proposed. At the signal receiving unit (SRU), two echo signals and the reference signal are modulated by a Sagnac loop structure and sent to the central station (CS) for processing. At the CS, two low-frequency electrical signals are generated after polarization control and photoelectric conversion. The DFS without direction ambiguity and wide AOA measurement can be real-time acquired by monitoring the frequency and power of the two low-frequency electrical signals. In the simulation, an unambiguous DFS measurement with errors of ±3 × 10-3 Hz and a -90° to 90° AOA measurement range with errors of less than ±0.5° are successfully realized simultaneously. It is compact and cost-effective, as well as has enhanced system stability and improved robustness for modern electronic warfare systems.

Design and Synthesis of Novel Near-Infrared Fluorescence Probes Based on an Open Conformation of a Cytochrome P450 1B1 Complex for Molecular Imaging of Colorectal Tumors.

Cytochrome P450 1B1 (CYP1B1) is induced during the early stage of cancer and is universally overexpressed in tumors. Thus, it was considered as a potential biomarker for the monitoring of cancer. In this study, we designed and synthesized CYP1B1-targeted near-infrared (NIR) fluorescence molecular probes based on the latest reported open conformation of the CYP1B1-α-naphthoflavone (ANF) complex. According to the architecture of the open channel, we introduced linkers and a Cy5.5 fragment at the 5' position of ANF derivatives with strong CYP1B1 inhibitory activity to obtain probes 19-21. Then, in vitro cell-based studies showed that the probes could be enriched in tumor cells by binding to CYP1B1. During in vivo and ex vivo imaging in a xenograft mouse model, probe 19 with the best binding affinity was proven to be able to identify tumor sites in both fluorescence imaging and photoacoustic imaging modes.