Design and synthesis of luotonin A-derived topoisomerase targeting scaffold with potent antitumor effect and low genotoxicity.

Conventional topoisomerase (Topo) inhibitors typically usually exert their cytotoxicity by damaging the DNAs, which exhibit high toxicity and tend to result in secondary carcinogenesis risk. Molecules that have potent topoisomerase inhibitory activity but involve less DNA damage provide more desirable scaffolds for developing novel chemotherapeutic agents. In this work, we broke the rigid pentacyclic system of luotonin A and synthesized thirty-three compounds as potential Topo inhibitors based on the devised molecular motif. Further investigation disclose that two compounds with the highest antiproliferation activity against cancer cells, 5aA and 5dD, had a distinct Topo I inhibitory mechanism different from those of the classic Topo I inhibitors CPT or luteolin, and were able to obviate the obvious cellular DNA damage typically associated with clinically available Topo inhibitors. The animal model experiments demonstrated that even in mice treated with a high dosage of 50 mg/kg 5aA, there were no obvious signs of toxicity or loss of body weight. The tumor growth inhibition (TGI) rate was 54.3 % when 20 mg/kg 5aA was given to the T24 xenograft mouse model, and 5aA targeted the cancer tissue precisely without causing damage to the liver and other major organs.

Identification of O-arylated huperzinines as novel cholinergic anti-inflammatory pathway agonists against gout arthritis.

Lycodine alkaloids are important natural products with diverse biological effects. In this manuscript, we set out the first structural optimization of the 2-pyridone moiety of Lycodine alkaloid via selective O-arylation under metal-free conditions and obtained a series of potent bioactive molecules against monosodium urate (MSU)-induced IL-1ß production. Further investigations demonstrated that these natural product derivatives could activate the neuro-immunomodulatory cholinergic anti-inflammatory pathway (CAP) to block the initial phase of NLRP3 inflammasome activation. Compared with the clinical drugs hydrocortisone and indomethacin, as well as commercially available CAP agonists GTS-21 and pnu282987, 3k and 3q possessed greater potency against MSU-induced IL-1ß production. Meanwhile, these molecules possessed less cytotoxicity against promonocytic THP-1 macrophages when compared with colchicine. This work reports a concise strategy for direct modification of 2-pyridone moiety from natural Lycodine alkaloids, and provides novel frameworks for discovering CAP activators and drugs for gout arthritis.

Leisure-time activities and disability among Chinese community-dwelling oldest old: evidence from the Chinese Longitudinal Healthy Longevity Study.

With the acceleration of population aging, disability in older adults is a growing public health problem; however, little is known about the role of specific leisure-time activities in affecting disability. This study prospectively examined the association of leisure-time activities with disability among the Chinese oldest old. A total of 14 039 adults aged 80 years or older (median age of 89.8 years) were enrolled from the Chinese Longitudinal Healthy Longevity Survey from 1998 to 2014. Disability was defined as the presence of concurrent impairment in activities of daily living and physical performance. Cox proportional hazards models were used to estimate the associations between leisure-time activities and disability. During a mean of 4.2 years (2.7 years) of follow-up, 4487 participants developed disability. Compared with participants who never engaged in leisure-time activities, participants who engaged in almost daily activities, including gardening, keeping domestic animals or pets, playing cards or mahjong, reading books or newspapers, and watching TV or listening to the radio had a lower risk of disability, with HRs of 0.78 (0.69-0.88), 0.64 (0.58-0.70), 0.74 (0.63-0.86), 0.74 (0.65-0.84), and 0.84 (0.77-0.90), respectively. Moreover, the risk of disability gradually decreased with participation in an increasing number of those leisure-time activities (P for trend <0.001). Frequent engagement in leisure-time activities was associated with a lower risk of disability among the Chinese oldest old. This study highlights the importance of incorporating a broad range of leisure-time activities into the daily lives of older adults.

Rapid detection of hydrogen using narrow bandwidth fiber-optic spectral combs with a low limit of detection.

The all-fiber detection solutions are the key technology to detecting hydrogen leakage in time because of the low explosive limit of the hydrogen-air mixture gas. However, most of the fiber-optic-based hydrogen sensing platforms must disrupt their structure to achieve a special architecture for interacting with the hydrogen. Here, we report a promising non-damaged structure of fiber-optic narrow bandwidth spectral combs, that can be developed to determine the refractive change as low as 10-5 using its cut-off cladding resonance mode. Such high performance of response for the refractive index induces a rapid detection of hydrogen after a proper thickness of palladium was deposited on the device. An average response time of hydrogen of 4 min with a low limit of detection of 348 ppm was achieved. It is demonstrated that these narrow bandwidth fiber-optic resonance combs can be used for gas detection after being combined with functional materials.

Gamma-radiation enhancement of sensing properties of FBGs in a few-mode polymer CYTOP fiber.

We investigate the effect of γ-radiation on temperature (T) and relative humidity (RH) sensitivities of polymer perfluorinated fiber Bragg gratings (FBGs). To this aim, different γ-radiation doses (80, 120, 160, and 520 kGy) were applied to a set of FBGs. We show that irradiated FBGs demonstrate an RH sensitivity rise with the received dose: from 13.3 pm/%RH for a pristine FBG up to 56.8 pm/%RH for a 520-kGy dose at 30℃. In contrast, T sensitivity decreases with radiation dose with a subsequent change of sign from positive to negative. Therefore, by experimental interpolation, T sensitivity can be eliminated at around a 160-kGy dose. This opens the possibility of designing an RH sensor with enhanced sensitivity, which at the same time is insensitive to T.

Design and synthesis of pseudo-rutaecarpines as potent anti-inflammatory agents via regulating MAPK/NF-κB pathways to relieve inflammation-induced acute liver injury in mice.

Pseudo-natural products (PNPs) design strategy provides a great valuable entrance to effectively identify of novel bioactive scaffolds. In this report, novel pseudo-rutaecarpines were designed via the combination of several privileged structure units and 46 target compounds were synthesized. Most of them display moderate to potent inhibitory effect on LPS-induced NO production and low cytotoxicity in RAW264.7 macrophage. The results of the anti-inflammatory efficacy and action mechanism of compounds 7l and 8c indicated that they significantly reduced the release of IL-6, IL-1ß and TNF-α. Further studies revealed that they can strongly inhibit the activation of NF-κB and MAPK signal pathways. The LPS-induced acute liver injury mice model studies not only confirmed their anti-inflammatory efficacy in vivo but also could effectively relieve the liver injury in mice. The results suggest that compounds 7l and 8c might serve as lead compounds to develop therapeutic drugs for treatment of inflammation.

Synthesis of spiroindolenine-3,3'-pyrrolo[2,1-b]quinazolinones through gold(I)-catalyzed dearomative cyclization of N-alkynyl quinazolinone-tethered indoles.

A variety of functionalized spiroindolenine-3,3'-pyrrolo[2,1-b]quinazolinones were prepared in good to excellent yields through a gold(I)-catalyzed dearomative cyclization of N-alkynyl quinazolinone-tethered C2-substituted indoles. This reaction features a broad substrate scope, good functional group tolerance, and easy gram-scale preparation and transformations. Furthermore, biological activity studies showed that most of the obtained spiroindolenine-3,3'-pyrrolo[2,1-b]quinazolinone scaffolds showed potential as good anti-inflammatory agents.

Online Gamma Radiation Monitoring Using Few-Mode Polymer CYTOP Fiber Bragg Gratings.

We investigated the gamma radiation response of fiber Bragg gratings (FBGs) inscribed in a few-mode polymer optical fiber. The fiber had a graded-index CYTOP core of 20 µm and XYLEX overclad of 250 µm in diameter. Four FBGs were exposed to gamma radiation during four irradiation sessions at a 5.3 kGy/h dose rate. The FBGs showed a linear Bragg wavelength shift with the received dose with a mean sensitivity of -3.95 pm/kGy at 43 °C. The increased temperature provides a rise in the sensitivity: it reached -10.6 pm/kGy at 58 °C. After irradiation, the FBGs showed partial recovery, which increased with the received dose. Furthermore, the FBG's reflection power decreased with the dose. This attenuation is mainly due to insertion losses caused by the radiation induced attenuation in the CYTOP fiber. Linear response to the received dose makes CYTOP FBGs attractive for gamma radiation dosimetry. However, temperature dependence of the sensitivity should be compensated in practical applications.

Properties of Fiber Bragg Grating in CYTOP Fiber Response to Temperature, Humidity, and Strain Using Factorial Design.

The characteristics of fiber Bragg grating (FBG) in cyclic transparent fluoropolymer (CYTOP) optical fiber have attracted more and more attention in recent years. However, different results of the FBG response to environmental parameters are reported. This work presents a three-variable two-level factorial experimental method to investigate the FBG response to temperature, humidity, and strain in CYTOP fiber. Two uniform FBGs are inscribed separately in CYTOP fiber with and without over-clad. With only eight measuring points, the interactions among three variable parameters are computed and the parameter sensitivities and cross-sensitivities are estimated. Similar temperature and strain sensitivities were found for both gratings, whereas significant cross-sensitivity between humidity and temperature was present only in FBG inscribed in CYTOP fiber with over-clad.

Identification of long noncoding natural antisense transcripts (lncNATs) correlated with drought stress response in wild rice (Oryza nivara).

BACKGROUND: Wild rice, including Oryza nivara and Oryza rufipogon, which are considered as the ancestors of Asian cultivated rice (Oryza sativa), possess high genetic diversity and serve as a crucial resource for breeding novel cultivars of cultivated rice. Although rice domestication related traits, such as seed shattering and plant architecture, have been intensively studied at the phenotypic and genomic levels, further investigation is needed to understand the molecular basis of phenotypic differences between cultivated and wild rice. Drought stress is one of the most severe abiotic stresses affecting rice growth and production. Adaptation to drought stress involves a cascade of genes and regulatory factors that form complex networks. O. nivara inhabits swampy areas with a seasonally dry climate, which is an ideal material to discover drought tolerance alleles. Long noncoding natural antisense transcripts (lncNATs), a class of long noncoding RNAs (lncRNAs), regulate the corresponding sense transcripts and play an important role in plant growth and development. However, the contribution of lncNATs to drought stress response in wild rice remains largely unknown. RESULTS: Here, we conducted strand-specific RNA sequencing (ssRNA-seq) analysis of Nipponbare (O. sativa) and two O. nivara accessions (BJ89 and BJ278) to determine the role of lncNATs in drought stress response in wild rice. A total of 1246 lncRNAs were identified, including 1091 coding-noncoding NAT pairs, of which 50 were expressed only in Nipponbare, and 77 were expressed only in BJ89 and/or BJ278. Of the 1091 coding-noncoding NAT pairs, 240 were differentially expressed between control and drought stress conditions. Among these 240 NAT pairs, 12 were detected only in Nipponbare, and 187 were detected uniquely in O. nivara. Furthermore, 10 of the 240 coding-noncoding NAT pairs were correlated with genes enriched in stress responsive GO terms; among these, nine pairs were uniquely found in O. nivara, and one pair was shared between O. nivara and Nipponbare. CONCLUSION: We identified lncNATs associated with drought stress response in cultivated rice and O. nivara. These results will improve our understanding of the function of lncNATs in drought tolerance and accelerate rice breeding.

Ultra-fast fiber Bragg grating inscription in CYTOP polymer optical fibers using phase mask and 400 nm femtosecond laser.

Fiber Bragg gratings (FBGs) in cyclic transparent fluoropolymer (CYTOP) optical fiber are the subject of a lot of research as they can be of interest for many applications, such as temperature, humidity, strain, and radiation sensing. We report here a new technique to produce high quality FBGs in CYTOP fiber. It uses a femtosecond laser system operating at 400 nm and a phase mask. In contrast to previously reported results, the gratings are obtained in a few seconds with a writing power as low as 80 µW. With this setup, 2 mm-long gratings with reflectivity up to 92 % and full width at half maximum bandwidth around 0.5 nm were obtained in less than 10 s. The resonance wavelengths of the FBGs are confirmed by numerical computation in the graded-index multimode CYTOP fiber, and the mode selection characteristic of FBGs in CYTOP is investigated. Finally, the temperature sensitivity of CYTOP FBG is measured in different mode groups for heating up and cooling down, showing values independent of the mode group measured, but with a small hysteresis.

800 nm femtosecond pulses for direct inscription of FBGs in CYTOP polymer optical fiber.

We report the inscription of highly reflective fiber Bragg gratings in perfluorinated polymer (CYTOP) optical fibers using 800 nm femtosecond pulses and a line-by-line inscription method. We demonstrate that the energy for grating inscription without damage is below 27 nJ. After the writing process, we show that the grating reflectivity continues to rise for several hours. The obtained gratings show reflectivity degradation with temperature increase, while the Bragg wavelength undergoes a linear temperature dependence of 37.7 pm/°C when the humidity is controlled and the heating/cooling rate is relatively low (≤0.14∘C/min). The humidity sensitivity at a fixed temperature (25°C) is 22.3 pm/%RH. Finally, the axial strain sensitivity is determined to be 1.35 pm/µÉ›.

3-Arylamino-quinoxaline-2-carboxamides inhibit the PI3K/Akt/mTOR signaling pathways to activate P53 and induce apoptosis.

Thirty-eight new 3-arylaminoquinoxaline-2-carboxamide derivatives were in silico designed, synthesized and their cytotoxicity against five human cancer cell lines and one normal cells WI-38 were evaluated. Molecular mechanism studies indicated that N-(3-Aminopropyl)-3-(4-chlorophenyl) amino-quinoxaline-2-carboxamide (6be), the compound with the most potent anti-proliferation can inhibit the PI3K-Akt-mTOR pathway via down regulating the levels of PI3K, Akt, p-Akt, p-mTOR and simultaneously inhibit the phosphorylation of Thr308 and Ser473 residues in Akt kinase to servers as a dual inhibitor. Further investigation revealed that 6be activate the P53 signal pathway, modulated the downstream target gene of Akt kinase such p21, p27, Bax and Bcl-2, caused the fluctuation of intracellular ROS, Ca2+ and mitochondrial membrane potential to induce cell cycle arrest and apoptosis in MGC-803 cells. 6be also display moderate anti-tumor activity in vivo while displaying no obvious adverse signs during the drug administration. The results suggest that 3-arylaminoquinoxaline-2-carboxamide derivatives might server as new scaffold for development of PI3K-Akt-mTOR inhibitor.

Functional analysis of Cwc24 ZF-domain in 5' splice site selection.

The essential splicing factor Cwc24 contains a zinc-finger (ZF) domain required for its function in splicing. Cwc24 binds over the 5' splice site after the spliceosome is activated, and its binding prior to Prp2-mediated spliceosome remodeling is important for proper interactions of U5 and U6 with the 5' splice site sequence and selection of the 5' splice site. Here, we show that Cwc24 transiently interacts with the 5' splice site in formation of the functional RNA catalytic core during spliceosome remodeling, and the ZF-motif is required for specific interaction of Cwc24 with the 5' splice site. Deletion of the ZF domain or mutation of the conserved ZF residues greatly weakened the association of Cwc24 with the spliceosome, and lowered the affinity and specificity of its interaction with the 5' splice site, resulting in atypical interactions of U5, U6 and Prp8 with the 5' splice site, and aberrant cleavage at the 5' splice site. Our results reveal a crucial role of the Cwc24 ZF-motif for defining 5' splice site selection in the first splicing step.

Multi-UAV Reconnaissance Task Assignment for Heterogeneous Targets Based on Modified Symbiotic Organisms Search Algorithm.

This paper considers a reconnaissance task assignment problem for multiple unmanned aerial vehicles (UAVs) with different sensor capacities. A modified Multi-Objective Symbiotic Organisms Search algorithm (MOSOS) is adopted to optimize UAVs' task sequence. A time-window based task model is built for heterogeneous targets. Then, the basic task assignment problem is formulated as a Multiple Time-Window based Dubins Travelling Salesmen Problem (MTWDTSP). Double-chain encoding rules and several criteria are established for the task assignment problem under logical and physical constraints. Pareto dominance determination and global adaptive scaling factors is introduced to improve the performance of original MOSOS. Numerical simulation and Monte-Carlo simulation results for the task assignment problem are also presented in this paper, whereas comparisons with non-dominated sorting genetic algorithm (NSGA-II) and original MOSOS are made to verify the superiority of the proposed method. The simulation results demonstrate that modified SOS outperforms the original MOSOS and NSGA-II in terms of optimality and efficiency of the assignment results in MTWDTSP.

Variant GADL1 and response to lithium therapy in bipolar I disorder.

BACKGROUND: Lithium has been a first-line choice for maintenance treatment of bipolar disorders to prevent relapse of mania and depression, but many patients do not have a response to lithium treatment. METHODS: We selected subgroups from a sample of 1761 patients of Han Chinese descent with bipolar I disorder who were recruited by the Taiwan Bipolar Consortium. We assessed their response to lithium treatment using the Alda scale and performed a genomewide association study on samples from one subgroup of 294 patients with bipolar I disorder who were receiving lithium treatment. We then tested the single-nucleotide polymorphisms (SNPs) that showed the strongest association with a response to lithium for association in a replication sample of 100 patients and tested them further in a follow-up sample of 24 patients. We sequenced the exons, exon-intron boundaries, and part of the promoter of the gene encoding glutamate decarboxylase-like protein 1 (GADL1) in 94 patients who had a response to lithium and in 94 patients who did not have a response in the genomewide association sample. RESULTS: Two SNPs in high linkage disequilibrium, rs17026688 and rs17026651, that are located in the introns of GADL1 showed the strongest associations in the genomewide association study (P=5.50×10(-37) and P=2.52×10(-37), respectively) and in the replication sample of 100 patients (P=9.19×10(-15) for each SNP). These two SNPs had a sensitivity of 93% for predicting a response to lithium and differentiated between patients with a good response and those with a poor response in the follow-up cohort. Resequencing of GADL1 revealed a novel variant, IVS8+48delG, which lies in intron 8 of the gene, is in complete linkage disequilibrium with rs17026688 and is predicted to affect splicing. CONCLUSIONS: Genetic variations in GADL1 are associated with the response to lithium maintenance treatment for bipolar I disorder in patients of Han Chinese descent. (Funded by Academia Sinica and others.).

Comparison of Histological, Microbiological, and Molecular Methods in Diagnosis of Patients with TBLN Having Different Anti-TB Treatment Background.

OBJECTIVE: The influence of anti-tuberculosis (TB) treatment history on tuberculous lymphadenitis (TBLN) diagnosis is unclear. Therefore, this study aims to evaluate the diagnostic methods, including histology, microbiology, and molecular tests, used for TBLN. METHODS: In this study, suspected patients with TBLN and having different anti-TB treatment background were enrolled. All the samples were tested simultaneously by histology, Ziehl-Neelsen (ZN) staining, mycobacterial culture (culture), Xpert MTB/RIF (xpert), real-time PCR, and high-resolution melting curve PCR (HRM). Thereafter, the performance of these methods on samples with different anti-TB treatment background was assessed. RESULTS: In our study, 89 patients were prospectively included 82 patients with TBLN and 7 with other diseases. The overall sensitivities of Xpert, real-time PCR, histology, ZN staining, and culture were 86.6%, 69.5%, 58.5%, 43.9%, and 22.0%, respectively. The anti-TB treatment history revealed dramatic influences on the sensitivity of culture (P < 0.0001). In fact, the treatment that lasted over 3 months also influenced the sensitivity of Xpert (P < 0.05). However, the treatment history did not affect the performance of remaining tests (P > 0.05). For rifampicin drug susceptibility test (DST), the anti-TB treatment showed only significant influence on the success rate of culture DST (P = 0.001), but not on those of Xpert and HRM tests (P > 0.05). CONCLUSION: Other tests as well as culture should be considered for patients with TBLN having retreatment history or over 1-month treatment to avoid false negative results.

Diagnostic Value of Cerebrospinal Fluid T-SPOT.TB for Tuberculousis Meningitis in China.

The aim of this study was to evaluate the diagnostic value of the cerebrospinal fluid (CSF) T-SPOT.TB test for the diagnosis of TB meningitis (TBM). A retrospective analysis of 96 patients with manifested meningitis was conducted; T-SPOT.TB test was performed for diagnosing TBM to determine the diagnostic sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). A receiver operating characteristic (ROC) curve was also drawn to assess the diagnostic accuracy. The sensitivity, specificity, PPV, and NPV of CSF T-SPOT.TB test were 97.8%, 78.0%, 80.3%, and 97.5%, respectively, for 52 patients (54.2%) of the 96 enrolled patients. The area under the curve (AUC) was 0.910, and the sensitivities of CSF T-SPOT.TB for patients with stages I, II, and III of TBM were 96.7%, 97.2%, and 98.9%, respectively. CSF T-SPOT.TB test is a rapid and accurate diagnostic method with higher sensitivity and specificity for diagnosing TBM.

Visual and Haptic Perception Training to Improve Handwriting Skills in Children With Dysgraphia.

We investigated a visual-perceptual and haptic-perceptual training program to enhance motor skills and Chinese handwriting performance among children with handwriting difficulties. The participants were 28 first- and second-grade children with handwriting difficulties. They were matched according to age and then randomly assigned into a control group or an experimental group. Participants in the experimental group received 12 sessions of a training program, whereas those in the control group received conventional handwriting training. The Test of Visual Perceptual Skills-Third Edition (TVPS-3), Tactual Performance Test (TPT), and Battery of Chinese Basic Literacy (BCBL) were all administered before and after 6 wk of intervention. Repeated-measures analysis of variance revealed that the experimental group showed significant improvement on the TVPS-3 but not on the TPT. Along with the improved visual-perceptual skills, the experimental group showed a significant difference in far-point copy speed and handwriting accuracy, as reflected in the BCBL.

Characterization of graphomotor functions in individuals with Parkinson's disease and essential tremor.

In this study, we explored the relationship between the clinical features and motor impairments related to the graphomotor function of individuals with Parkinson's disease (PD) and essential tremor (ET). We recruited 46 participants: 12 with PD, 13 with ET, and 21 controls. All participants were asked to perform six graphomotor tasks on a digitizer tablet: drawing straight lines, cursive-connected loops, discrete circles, and continuous circles, and making goal-aimed movements with a stylus in two different directions with three different accuracy constraints. The results showed that although participants with PD were able to draw straight lines slightly faster than controls, they produced cursive-connected loops much slower than controls. In addition, in contrast to controls and individuals with ET, PDs also drew the cursive loops progressively smaller. In the aiming task, we found that equivalent movements with high accuracy constraints were drawn slower by individuals with ET or PD than by controls. However, when performing the equivalent movements with moderate or low accuracy constraints, PDs performed similarly to controls. In contrast to the equivalent movements, PD and ET participants both performed nonequivalent movements slower than controls, no matter the demands arising from the accuracy constraints. The present study shows that simple graphic tasks can differentiate impairments in fine motor function resulting from ET and PD.