Effect of stent treatment on hemodynamics in iliac vein compression syndrome with collateral vein.

BACKGROUND: Iliac vein compression syndrome (IVCS) leads to blood flow obstruction in the lower extremities and is usually treated with stents, but stenting may worsen the hemodynamics and increase the risk of thrombosis in the iliac vein. The present work evaluates the advantages and disadvantages of the stent on IVCS with a collateral vein. METHODS: The computational fluid dynamics method is adopted to analyze the preoperative and postoperative flow fields in a typical IVCS. The geometric models of the iliac vein are constructed from medical imaging data. The porous model is used to simulate the flow obstruction in IVCS. RESULTS: The preoperative and postoperative hemodynamic characteristics in the iliac vein are obtained, e.g., the pressure gradient at two ends of the compressive region and the wall shear stress. It is found that the stenting restores the blood flow in the left iliac vein. CONCLUSION: Impacts of the stent are classified into short-term and long-term effects. The short-term effects are beneficial in relieving IVCS, i.e., shortening the blood stasis and reducing the pressure gradient. The long-term effects increase the risk of thrombosis in the stent, i.e., enlarging wall shear stress due to a large corner and a diameter constriction in the distal vessel, and suggests the need to develop a venous stent for IVCS.

Dynamical analysis of a modified Leslie-Gower Holling-type II predator-prey stochastic model in polluted environments with interspecific competition and impulsive toxicant input.

In this paper, we use a mean-reverting Ornstein-Uhlenbeck process to simulate the stochastic perturbations in the environment, and then a modified Leslie-Gower Holling-type II predator-prey stochastic model in a polluted environment with interspecific competition and pulse toxicant input is proposed. Through constructing V-function and applying Ito^'s formula, the sharp sufficient conditions including strongly persistent in the mean, persistent in the mean and extinction are established. In addition, the theoretical results are verified by numerical simulation.

Design, Synthesis, and Biological Evaluation of Pyrrole-2-carboxamide Derivatives as Mycobacterial Membrane Protein Large 3 Inhibitors for Treating Drug-Resistant Tuberculosis.

In this work, pyrrole-2-carboxamides were designed with a structure-guided strategy based on the crystal structure of MmpL3 and a pharmacophore model. The structure-activity relationship studies revealed that attaching phenyl and pyridyl groups with electron-withdrawing substituents to the pyrrole ring and attaching bulky substituents to the carboxamide greatly improved anti-TB activity. Most compounds showed potent anti-TB activity (MIC < 0.016 µg/mL) and low cytotoxicity (IC50 > 64 µg/mL). Compound 32 displayed excellent activity against drug-resistant tuberculosis, good microsomal stability, almost no inhibition of the hERG K+ channel, and good in vivo efficacy. Furthermore, the target of the pyrrole-2-carboxamides was identified by measuring their potency against M. smegmatis expressing wild-type and mutated variants of the mmpL3 gene from M. tuberculosis (mmpL3tb) and determining their effect on mycolic acid biosynthesis using a [14C] acetate metabolic labeling assay. The present study provides new MmpL3 inhibitors that are promising anti-TB agents.

Resonant signals in the lithosphere-atmosphere-ionosphere coupling.

A study in the lithosphere, atmosphere and ionosphere (LAI) coupling often troubles scientists due to a certain distance between distinct instruments, which monitor geophysical parameters in different spheres. An instrumental system was established in southwest China (Leshan; LESH) for monitoring vibrations and perturbations in LAI (MVP-LAI). A ground-based Global Navigation Satellite System (GNSS) receiver at the YADU station locates ~ 260 km away that continuously receives electromagnetic signals transmitted from the BeiDou navigation System (BDS) geostationary satellites to monitor the total electron content (TEC) at the ionospheric pierce point right over the MVP-LAI system. The employment of YADU TEC benefits in elimination of possible shaking effects happening on multiple instruments at the LESH station and mitigation the troubles due to the discrepancy in observation places. Through a stacking process on the retrieved data for increase of signal to noise ratios, a novel phenomenon of the resonant LAI coupling at a fundamental mode of ~ 3.4 mHz and its multiples persists in ground vibrations, atmospheric pressure and TEC retrieved from the MVP-LAI system and the YADU station. The retrieved data share frequencies during the operational period of 1.5 months that is irrelevant to obvious events in the lithosphere, atmosphere and ionosphere. The persistence of the resonant LAI coupling is essential in the Earth's system.

A Multiobjective Hybrid Optimization Algorithm for Path Planning of Coal Mine Patrol Robot.

In the complex underground environment, the paths planned for coal mine patrol robot are often too long and unsmooth under the influence of low visibility and poor road conditions. To solve the problems, this paper improves the hybrid algorithm between the improved artificial fish swarm algorithm (AFSA) and the dynamic window algorithm (DWA) for global path planning of coal mine patrol robot and introduces the improved genetic algorithm (GA) to enhance the path planning accuracy. Based on the global optimal path, the improved DWA was adopted to design a new adaptive trajectory evaluation function, which improves the ability of the patrol robot to avoid local obstacles. The proposed optimization algorithm was proved feasible through simulations. In addition, a simulation platform for the control of coal mine patrol robot was established, using the software development platform for coal mine patrol robot and robot operating system (ROS). The simulation results show that the improvement shortened the path length by 0.12 m, reduced the time by 3.14 s, and removed many turning points and redundant points. Therefore, the proposed improved hybrid path planning algorithm is effective and superior.

Persistence and extinction of a modified Leslie-Gower Holling-type II two-predator one-prey model with Lévy jumps.

This paper is concerned with a modified Leslie-Gower and Holling-type II two-predator one-prey model with Lévy jumps. First, we use an Ornstein-Uhlenbeck process to describe the environmental stochasticity and prove that there is a unique positive solution to the system. Moreover, sufficient conditions for persistence in the mean and extinction of each species are established. Finally, we give some numerical simulations to support the main results.

Persistence and extinction of a modified Leslie-Gower Holling-type â ¡ predator-prey stochastic model in polluted environments with impulsive toxicant input.

In this paper, a modified Leslie-Gower Holling-type Ⅱ two-predator one-prey stochastic model in polluted environments with impulsive toxicant input is proposed where we use an Ornstein-Uhlenbeck process to improve the stochasticity of the environment. The sharp sufficient conditions for persistence in the mean and extinction are established. The results reveal that the persistence and extinction of the species have close relationships with the toxicant and environmental stochasticity. In addition, the theoretical results are verified by numerical simulation.

Discovery of a Candidate Containing an (S)-3,3-Difluoro-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden Scaffold as a Highly Potent Pan-Inhibitor of the BCR-ABL Kinase Including the T315I-Resistant Mutant for the Treatment of Chronic Myeloid Leukemia.

BCR-ABL kinase inhibition is an effective strategy for the treatment of chronic myeloid leukemia (CML). Herein, we report compound 3a-P1, bearing a difluoro-indene scaffold, as a novel potent pan-inhibitor against BCR-ABL mutants, including the most refractory T315I mutant. As the privileged (S)-isomer compared to its (R)-isomer 3a-P2, 3a-P1 exhibited potent antiproliferative activities against K562 and Ku812 CML cells and BCR-ABL and BCR-ABLT315I BaF3 cells, with IC50 values of 0.4, 0.1, 2.1, and 4.7 nM, respectively. 3a-P1 displayed a good safety profile in a battery of assays, including single-dose toxicity, hERG K+, and genotoxicity. It also showed favorable mice pharmacokinetic properties with a good oral bioavailability (32%), a reasonable half-life (4.61 h), and a high exposure (1386 h·ng/mL). Importantly, 3a-P1 demonstrated a higher potency than ponatinib in a mice xenograft model of BaF3 harboring BCR-ABLT315I. Overall, the results indicate that 3a-P1 is a promising drug candidate for the treatment of CML to overcome the imatinib-resistant T315I BCR-ABL mutation.

Determining Essential Requirements for Fluorophore Selection in Various Fluorescence Applications Taking Advantage of Diverse Structure-Fluorescence Information of Chromone Derivatives.

Herein, we report our work exploring the essential requirements for fluorophore selection during the development of various fluorescence applications. We assembled a library of chromone-derived fluorophores with diverse structure-fluorescence properties, which allowed us to choose the fluorophore pairs with similar structures but differing fluorescence properties and compared the performance of the selected fluorophore pairs in three types of commonly used fluorescence applications. We found that the selection standard of a suitable fluorophore is variable depending on the application. (1) In fluorescence imaging, fluorophores with strong and constant fluorescence under various conditions, such as a large pH range, are preferred. Notably, (2) in the detection of bioactive species, fluorophores with relatively lower fluorescence quantum yield favor the detection sensitivity. Furthermore, (3) in enzymatic assays employing fluorescence, the key parameter is the binding affinity between the fluorophore and the enzyme.

Broadband thin sound absorber based on hybrid labyrinthine metastructures with optimally designed parameters.

Broadband acoustic absorbers with thin thickness are highly desired in practical situations such as architectural acoustics, yet it is still challenging to achieve high absorption by using structure with limited thickness. Here we report the theoretical optimal design, numerical simulation and experimental demonstration of a planar acoustic absorber capable of producing broadband sound absorption with deep-subwavelength thickness. The mechanism is that, we use a hybrid design of individual unit cell comprising multiple resonators with a coiled configuration for expanding the working bandwidth and downscaling the resulting device, and, on the other hand, the geometries of the constituent resonance elements are optimally designed by using genetic algorithm. Based on an analytical formula we derive for an efficient prediction of the absorption efficiency, the optimization process is accelerated and gives rise to an optimally maximized amount of absorbed energy with limited device thickness. As a result, the proposed absorber features planar profile, broad bandwidth, wide absorbing angle (the absorber works well when the incident angle of sound wave reaches 60°) and thin thickness (< 1/25 wavelength). In addition, the proposed scheme does not rely on extra sound-absorptive materials or the type of constituent solid material, which significantly simplifies the sample fabrication and improves the application potential of resulting device. The measured data agree well with the theoretical predictions, showing high sound absorption in the prescribed frequency range. We envision our design to further improve the performance of acoustic absorbers and find applications in practical situations in need of elimination of broadband acoustic waves within limited spaces.

Taking advantage of the aromatisation of 7-diethylamino-4-methyl-3,4-dihydrocoumarin in the fluorescence sensing of superoxide anion.

The aromatisation of 7-diethylamino-3,4-dihydrocoumarin provides an alternative fluorescent probing technique to selectively detect the concentration of superoxide anion in solution. In addition, we reported the advantage of evaluating O2˙- sensing probes in anhydrous DMSO instead of in aqueous buffers when using KO2 as the surrogate of O2˙-.

Cysteine and methionine contribute differentially to regulate alternative oxidase in leaves of poplar (Populus deltoides x Populus euramericana 'Nanlin 895') seedlings exposed to different salinity.

The effects of different doses of NaCl on the expression profiles of genes involved in the mitochondrial electron transport chain (miETC), H2O2 and O2- levels, and antioxidant enzymes and amino acid metabolism were investigated in the leaves of poplar (Populus deltoides x Populus euramericana 'Nanlin 895'). In the miETC, complexes II and III and bypasses of the cytochrome c pathway including AOX and UCP displayed higher transcript abundance, whereas COX6b encoding cytochrome c oxidase were suppressed at 200 and 400 mM. H2O2 accumulated at 200 mM NaCl but O2- was generated at 400 mM. Accordingly, CAT was enhanced at 200 and 400 mM, while G-POD strengthened only at 400 mM. In addition, cysteine was reduced at 400 mM but did not change at 200 mM, although methionine was accumulated at 200 mM but not altered at 400 mM. Exogenous cysteine accumulated H2S and methionine increased ACC at 200 mM NaCl. At 400 mM NaCl, cysteine elevated the expression of CGS encoding cystathionine gamma-synthase and MS2 encoding methionine synthase as well as ACC and H2S levels, and methionine increased ACC content with repressed CGS and MS2. Moreover, exogenous KCN decreased cysteine levels, with an augment in H2S and up-regulation of CYS C1 encoding ß-cyanoalanine synthase at all salinity conditions, whereas antimycin A (AA) and salicylhydroxamic acid (SHAM) affected neither the levels of cysteine or H2S, nor the CYS C1 expression. However, neither KCN, AA nor SHAM affected ACC content. AOX1b was induced both by exogenous cysteine and methionine as well as KCN and AA but suppressed by SHAM at 200 and 400 mM NaCl, in negative correlation with MDA content. These results suggest that poplar leaf evolved diverse strategies in amino acid metabolism of manipulating the AOX pathway to defend against different levels of salt stress.

Longitudinal Examination of Bone Loss in Male Rats After Moderate-Severe Contusion Spinal Cord Injury.

To elucidate mechanisms of bone loss after spinal cord injury (SCI), we evaluated the time-course of cancellous and cortical bone microarchitectural deterioration via microcomputed tomography, measured histomorphometric and circulating bone turnover indices, and characterized the development of whole bone mechanical deficits in a clinically relevant experimental SCI model. 16-weeks-old male Sprague-Dawley rats received T9 laminectomy (SHAM, n = 50) or moderate-severe contusion SCI (n = 52). Outcomes were assessed at 2-weeks, 1-month, 2-months, and 3-months post-surgery. SCI produced immediate sublesional paralysis and persistent hindlimb locomotor impairment. Higher circulating tartrate-resistant acid phosphatase 5b (bone resorption marker) and lower osteoblast bone surface and histomorphometric cancellous bone formation indices were present in SCI animals at 2-weeks post-surgery, suggesting uncoupled cancellous bone turnover. Distal femoral and proximal tibial cancellous bone volume, trabecular thickness, and trabecular number were markedly lower after SCI, with the residual cancellous network exhibiting less trabecular connectivity. Periosteal bone formation indices were lower at 2-weeks and 1-month post-SCI, preceding femoral cortical bone loss and the development of bone mechanical deficits at the distal femur and femoral diaphysis. SCI animals also exhibited lower serum testosterone than SHAM, until 2-months post-surgery, and lower serum leptin throughout. Our moderate-severe contusion SCI model displayed rapid cancellous bone deterioration and more gradual cortical bone loss and development of whole bone mechanical deficits, which likely resulted from a temporal uncoupling of bone turnover, similar to the sequalae observed in the motor-complete SCI population. Low testosterone and/or leptin may contribute to the molecular mechanisms underlying bone deterioration after SCI.

A Mild Aqueous Sonogashira Reaction as a Fluorescent Labeling Strategy for 5-Bromide-2'-Deoxyuridine.

C5-modified uridines are a valuable class of nucleoside analogues, both as potent chemotherapy agents and through their use as the conjunction site in DNA labeling strategies. As an important C5-modified uridine, BrdU has been used in cell proliferation assays since the 1980s. Currently, the detection of BrdU relies on traditional immunostaining; however, this approach has its limitations. Thus, it is desirable, albeit difficult, to develop chemistry methods to fluorescently label BrdU in a cellular context. In the present study, we report our efforts toward developing a robust chemistry methodology for BrdU fluorescent labeling. The Sonogashira reaction was chosen as the key reaction, and various alkynyl groups (aliphatic or aryl) containing fluorescent dyes were synthesized to cross-couple with BrdU. Various bases and catalyst systems were screened to evaluate the optimum conditions. A mild aqueous Sonogashira reaction (K2PdCl4, S-Phos, n-Bu4N⁺OH-, Sodium d-isoascorbate, EtOH/H2O = 1:1, 37 °C, Ar) was obtained to enable high-yielding BrdU fluorescent labeling.

Usability of a Medication Event Reminder Monitor System (MERM) by Providers and Patients to Improve Adherence in the Management of Tuberculosis.

Poor initiation and implementation and premature discontinuation of anti-tuberculous therapy, all forms of nonadherence, are major reasons for treatment failure, the development of drug-resistant tuberculosis, and transmission to other non-infected individuals. Directly Observed Therapy (DOT) has been the worldwide standard, but implementation of DOT is burdensome for providers and patients, especially in resource-limited settings, where most of the burden of active TB is located. Among the alternatives to DOT is electronic monitoring (EM) of drug dosing histories. Here we report a usability study of a newly-designed, modular electronic monitor product, called the MERM (Medication Event and Reminder Monitor), that is compatible with TB medication formats and supply chains in resource-limited settings. This study, done in a rural setting in China, showed that the use of the MERM for EM of TB medications was associated with a high degree of user performance, acceptability, and satisfaction among both TB patients and medical staff. Based on these data, EM is becoming the standard of care for drug-susceptible TB patients in China and scaled implementations in several other countries with high TB burden have begun. In addition, the MERM is being used in MDR-TB patients and in clinical trials involving patients with TB/HIV and latent TB.

Enantiomerization and stereoselectivity in bioaccumulation of furalaxyl in Tenebrio molitor larvae.

Furalaxyl is a chiral pesticide and widely used in modern agriculture as racemate mixture. The enantiomerization and enantioselecive bioaccumulation by a single dose of furalaxyl to Tenebrio molitor larvae under laboratory conditions were studied using a high-performance liquid chromatography tandem mass spectroscopy method based on a ChiralPAK IC column. Our results showed that a significant enantiomerization (interconversion between R-enantiomer and S-enantiomer) was observed in Tenebrio molitor larvae under R- or S-furalaxyl exposure. Though the two furalaxyl enantiomers exhibited low-capacity of bioaccumulation in Tenebrio molitor larvae, bioaccumulation of rac-furalaxyl was enantioselective with a preferential accumulation of S-furalaxyl at 10mg/kg dosage exposure. In addition, enantiomerization and enantioselective degradation of the two enantiomers was not observed in wheat bran. These results showed that enantioselectivtiy of furalaxyl enantiomers was an important process combined with degradation, metabolism and enatiomerization in organisms.

Enantioselective bioaccumulation and toxic effects of fipronil in the earthworm Eisenia foetida following soil exposure.

BACKGROUND: Enantiomers of chiral pesticides often have different bioactivity, toxicity and environmental behaviours. Fipronil has been used in racemate for agricultural purposes against soil insects, leading to increased inputs into soil environments and complex biota exposures. To understand the potential risk associated with fipronil enantiomer exposure, subchronic toxicity and bioaccumulation tests with earthworms (Eisenia foetida) in fipronil-spiked soils were evaluated under laboratory conditions. RESULTS: Enantioselective toxicity was measured in E. foetida biomass after 28 days of subchronic exposure, with increased toxicity from racemate and S-fipronil compared with R-fipronil. The bioaccumulation of fipronil in earthworm tissues was also enantioselective, with a preferential accumulation of S-fipronil, and the enantiomer fraction was approximately 0.56-0.60. During soil exposure, fipronil was transformed primarily into fipronil sulfide, sulfone and amide, and E. foetida rapidly accumulated fipronil and sulfone. CONCLUSION: This work demonstrates the enantioselective subchronic toxicity and bioaccumulation of enantiomers of fipronil in E. foetida. The earthworm tissues exhibited a relative enrichment of fipronil and fipronil sulfone, and these compounds might biomagnify (with a biota-to-soil accumulation factor of ≥1.0 kgOCkglip-1), allowing for the possible trophic transfer and/or bioaccumulation of all these chemicals if earthworms were consumed by predator organisms.

Stereoselectivity in bioaccumulation and excretion of epoxiconazole by mealworm beetle (Tenebrio molitor) larvae.

Stereoselectivity in bioaccumulation and excretion of stereoisomers of epoxiconazole by mealworm beetle (Tenebrio molitor) larvae through dietary exposure was investigated. Liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method that use a ChiralcelOD-3R[cellulosetris-Tris-(3, 5-dichlorophenyl-carbamate)] chromatography column was applied to carry out chiral separation of the stereoisomers. Wheat bran was spiked with racemic epoxiconazole at two dose levels of 20mg/kg and 2mg/kg (dry weight) to feed T. molitor larvae. The results showed that both the doses of epoxiconazole were taken up by Tenebrio molitor larvae rapidly at the initial stages. There was a significant trend of stereoselective bioaccumulation in the larvae with a preferential accumulation of (-)-epoxiconazole in the 20mg/kg dose. The stereoselectivity in bioaccumulation in the 2mg/kg dosage was not obvious compared to the 20mg/kg group. Results of excretion indicated an active excretion is an important pathway for the larvae to eliminate epoxiconazole which was a passive transport process with non stereoselectivity. The faster elimination might be the reason for the low accumulation of epoxiconazole, as measured by bioaccumulation factor (BAF).

Enantioselective acute toxicity effects and bioaccumulation of furalaxyl in the earthworm (Eisenia foetida).

The enantioselectivities of individual enantiomers of furalaxyl in acute toxicity and bioaccumulation in the earthworm (Eisenia foetida) were studied. The acute toxicity was tested by filter paper contact test. After 48 h of exposure, the calculated LC50 values of the R-form, rac-form, and S-form were 2.27, 2.08, and 1.22 µg cm(-2), respectively. After 72 h of exposure, the calculated LC50 values were 1.90, 1.54, and 1.00 µg cm(-2), respectively. Therefore, the acute toxicity of furalaxyl enantiomers was enantioselective. During the bioaccumulation experiment, the enantiomer fraction of furalaxyl in earthworm tissue was observed to deviate from 0.50 and maintained a range of 0.55-0.60; in other words, the bioaccumulation of furalaxyl was enantioselective in earthworm tissue with a preferential accumulation of S-furalaxyl. The uptake kinetic of furalaxyl enantiomers fitted the first-order kinetics well and the calculated kinetic parameters were consistent with the low accumulation efficiency.

Stereoselective degradation and toxic effects of benalaxyl on blood and liver of the Chinese lizard Eremias argus.

Benalaxyl as a xylem-systemic fungicide is usually direct sprayed on the soil surface, which is potential harm to the animals lived in the soil. However, the stereoselectivity of benalaxyl in reptiles have rarely been studied. In this study, Chinese lizards (Eremias argus) were firstly used to evaluate the stereoselectivity in biodegradation and toxicity of racemate and individual enantiomers of benalaxyl. A method for determining residues of the two enantiomers of benalaxyl in lizard blood and liver by high-performance liquid chromatography coupled with triple quadrupole mass spectrometry (HPLC-MS/MS) was developed. The degradation followed pseudo first-order kinetics and the degradation of the (S)-(+)-benalaxyl was faster than its antipode in blood and liver (Half-time t1/2 of (R)-(-)-benalaxyl and (S)-(+)-benalaxyl were 5.08 h and 3.75 h in blood, 6.21 h and 4.45 h in liver, separately). Moreover, antioxidant defenses consisting of activities of superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST) and lipid peroxide malondialdehyde (MDA) were determined in 24h acute exposure. Enantioselectivity of acute toxicity depended on the concentration and form of benalaxyl. In addition, cellular degeneration, decrease of cell number, clustering phenomena of cell nuclei and preliminary liver fibrosis were observed in pathological detection at the termination of 21-d subchronic exposure (20 mg/kg(-bw) of racemate and individual enantiomers of benalaxyl). The enantiomer fractions (EFs) in racemate and individual enantiomer groups were approached both in blood and liver caused by the chiral conversion. The chiral conversion from (R)-(-)-benalaxyl to (S)-(+)-benalaxyl and (S)-(+)-benalaxyl to (R)-(-)-benalaxyl were the primary cause for no remarkable differences in toxicity between the enantiomers of benalaxyl.