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The specific ammonia uptake rates (SAUR) and ammonia oxidizing bacteria (AOB) community of influent sewage and activated sludge in the 2

Synthetic cannabinoids, as exemplified by SDB-001 (1), bind to both CB1 and CB2 receptors and exert cannabimimetic effects similar to (-)-trans-Δ9-tetrahydrocannabinol, the main psychoactive component present in the cannabis plant. As CB1 receptor ligands were found to have severe adverse psychiatric effects, increased attention was turned to exploiting the potential therapeutic value of the CB2 receptor. In our efforts to discover novel and selective CB2 receptor agonists, 1 was selected as a starting point for hit molecule identification and a class of 1H-pyrazole-3-carboxamide derivatives were thus designed, synthesized, and biologically evaluated. Systematic structure-activity relationship investigations resulted in the identification of the most promising compound 66 as a selective CB2 receptor agonist with favorable pharmacokinetic profiles. Especially, 66 treatment significantly attenuated dermal inflammation and fibrosis in a bleomycin-induced mouse model of systemic sclerosis, supporting that CB2 receptor agonists might serve as potential therapeutics for treating systemic sclerosis.

The long-term effects of a decreasing temperature on the nitrification performance, biofilm characteristics, and nitrifier community in a moving-bed biofilm reactor (MBBR) and integrated fixed-film activated sludge (IFAS) system were investigated at various temperatures (20, 15, and 10℃) to explore the adaptability of nitrifying biofilm systems to low temperatures. During the experiment, the extracellular polymeric substances (EPS) in the biofilms increased with decreasing temperature, which resulted in an increased biofilm mass and thickness. As there was only a biofilm phase in the MBBR to remove ammonia, the part of the carriers in the MBBR at 10℃ became plugged, which partially led to a deterioration in the effluent water quality. This indicated that the IFAS system was more adaptable to low temperatures than was the MBBR. Meanwhile, the results for the nitrifier activities showed that, although the nitrification contribution rate of the suspended phase in the IFAS system always dominated during the experiment, that of the fixed phase with regards to the ammonia uptake rate (AUR) gradually increased from 30.72% at 20℃ to 39.85% at 10℃. This indicated that the biofilm played an enhanced role in nitrification in the IFAS system. Moreover, the qPCR results revealed that the nitrifier copies of the number of biofilms increased slightly with decreased temperature, and coincided with an increase in biomass, which partially compensated for the decreased nitrification activity. These findings provide a theoretical basis for the application of the biofilm systems to wastewater treatment.

Middle East respiratory syndrome coronavirus (MERS-CoV) poses a serious threat to human health, and currently there are no effective or specific therapies available to treat it. Herein a series of 1-phenyl

We previously reported a series of coumestans−a naturally occurring tetracyclic scaffold containing a δ-lactone−that effectively target the thioesterase domain of polyketide synthase 13 (Pks13) in Mycobacterium tuberculosis (Mtb), resulting in superior anti-tuberculosis (TB) activity. Compared to the corresponding ‘open-form’ ethyl benzofuran-3-carboxylates, the enhanced anti-TB effects seen with the conformationally restricted coumestan series could be attributed to the extra π-π stacking interactions between the benzene ring of coumestans and the phenyl ring of F1670 residue located in the Pks13-TE binding domain. To further probe this binding feature, novel tetracyclic analogues were synthesized and evaluated for their anti-TB activity against the Mtb strain H37Rv. Initial comparison of the ‘open-form’ analogueues against the tetracyclic counterparts again showed that the latter is superior in terms of anti-TB activity. In particular, the δ-lactam-containing 5H-benzofuro [3,2-c]quinolin-6-ones gave the most promising results. Compound 65 demonstrated potent activity against Mtb H37Rv with MIC value between 0.0313 and 0.0625 μg/mL, with high selectivity to Vero cells (64–128 fold). The thermal stability analysis supports the notion that the tetracyclic compounds bind to the Pks13-TE domain as measured by nano DSF, consistent with the observed SAR trends. Compound 65 also showed excellent selectivity against actinobacteria and therefore unlikely to develop potential drug resistance to nonpathogenic bacteria.

Herein, we design and synthesize an array of benzofuro[3,2-c]quinolines starting from 3-(2-methoxyphenyl)quinolin-4(1H)ones via a sequential chlorination/demethylation, intramolecular cyclization pathway. This sequential transformation was efficient, conducted under metal-free and mild reaction conditions, and yielded corresponding benzofuro[3,2-c]quinolines in high yields. In vitro biological evaluation indicated that such type of compounds showed excellent antileukemia activity and selectivity, and therefore may offer a promising hit compound for developing antileukemia compounds.

Herein we reported a series of 14 novel derivatives based on the N-cyclobutylaminoethoxyisoxazole scaffold. In vitro binding studies of these compounds demonstrated their low nanomolar to subnanomolar potencies as σ1 receptor ligands, with moderate to excellent selectivity over the σ2 receptor as represented by compounds 17–30. The majority of the derivatives scored high (>4.7) in the CNS MPO appraisal system, indicating their high likelihood in penetrating the blood–brain barrier. A number of these compounds exhibited significant neurite outgrowth efficacy in N1E-115 neuronal cells and displayed excellent selectivity for σ1 receptors over the selected endogenous neurotransmitter transporters, such as DAT, NET and SERT. Among the mini-series, compound 28 (Ki σ1 = 0.2 nM, Ki σ2 = 198 nM, CNS MPO score = 5.4) emerged as a promising selective σ1 receptor ligand that warrants its further evaluation as a potential therapeutic for neurodegenerative diseases.

Selective CB2 agonists represent an attractive therapeutic strategy for the treatment of a variety of diseases without psychiatric side effects mediated by the CB1 receptor. We carried out a rational optimization of a black market designer drug SDB-001 that led to the identification of potent and selective CB2 agonists. A 7-methoxy or 7-methylthio substitution at the 3-amidoalkylindoles resulted in potent CB2 antagonists (27 or 28, IC50 = 16–28 nM). Replacement of the amidoalkyls from 3-position to the 2-position of the indole ring dramatically increased the agonist selectivity on the CB2 over CB1 receptor. Particularly, compound 57 displayed a potent agonist activity on the CB2 receptor (EC50 = 114–142 nM) without observable agonist or antagonist activity on the CB1 receptor. Furthermore, 57 significantly alleviated the clinical symptoms and protected the murine central nervous system from immune damage in an experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis.

Previously we identified a series of amidoalkylindoles as potent and selective CB(2) partial agonists. In the present study, we report our continuous effort to improve the aqueous solubility by introducing N atoms to the amidoalkylindole framework. Synthesis, characterization, and pharmacology evaluations were described. Bioisosteric replacements of the indole nucleus with an indazole, azaindole and benzimidazole were explored. Benzimidazole 43 (EC(50,CB(1)) = NA, EC(50,CB(2)) = 0.067 μM) and azaindole 24 (EC(50,CB(1)) = NA, EC(50,CB(2)) = 0.048 μM) were found to be potent and selective CB(2) receptor partial agonists, both with improved aqueous solubility.

Novel berberine derivatives with disubstituents on positions C9 and C13 were synthesized and evaluated for antiproliferative activities against human prostate cancer cell lines (PC3 and DU145), breast cancer cell line (MDA-MB-231) and human colon cancer cell lines (HT29 and HCT116). All compounds showed significantly enhanced antiproliferative activities compared with berberine. Notably, compound 18e exhibited the strongest cytotoxicity against PC3 cells with an IC50 value of 0.19 μM, and the highest selectivity index (SIPC3 > 20). Further studies showed that 18e could arrest the cell cycle at G1 phase, and significantly inhibit tumor cell colony forming and migration even at low concentrations. Interestingly, 18e could significantly induce cytoplasmic vacuolation, suggesting a different mode of action from berberine.

Warming winter and atmospheric nitrogen (N) deposition are expected to have effects on net primary production (NPP) of Chinese fir (Cunninghamia lanceolata) plantation and implications for plantation carbon sequestration. The effects of nongrowing-season warming on plant morphological and physiological traits were investigated in a greenhouse experiment with two-year-old C. lanceolata seedlings. Elevated temperature (ET) during the nongrowing season significantly increased the net photosynthetic characteristics. The strongest effects occurred during warming period from 1 December 2014 to 1 February 2015 (W1). Moreover, the carbohydrate concentration was elevated due to the warming during W1, but it declined during four months of the warming (from 1 December 2014 to 1 April 2015, W2). The seedlings kept under N deposition (CN) showed a positive effect in all the above-mentioned parameters except δ13C. Significant interactions between ET and N deposition were observed in most parameters tested. At the end of the experiment (W2), the seedlings exposed to a combined ET and N deposition treatment exhibited the highest carbon contents. Our results showed that N deposition might ameliorate the negative effects of the winter warming on the carbon content.

An efficient method for construction of 3-arylquinolin-4(1 H )-ones via in situ Meinwald rearrangement/intramolecular reductive cyclization of 2′-nitrochalcone epoxides has been developed. The practical approach is of excellent functional groups compatibility with as high as 98% yield under mild reaction conditions. Trapping and NMR analysis about the key intermediates of the transformation provided insights to propose a plausible mechanism for the intramolecular reductive cyclization. Moreover, further derivation successfully furnished hydroxyl substituted and N -methyl substituted derivatives which may provide a promising potential application in exploring biologically active compounds of 3-arylquinolin-4(1 H )-ones.

In recent years, melanoma has become a tumor with the fastest increase of morbidity in all malignant tumors, and its annual increase is 3%-5%. Both morbidity and mortality of melanoma are low in China, but they are showing an increasing tendency in recent years. However, the morbidity of melanoma is increasing in most European and American countries, but the mortality keeps stable and is not in an increasing tendency along with the increasing morbidity, demonstrating that there are great differences between China and Western countries in the diagnosis and treatment of melanoma. At present, melanoma has become one of the diseases that severely threaten human health. Compared with other common malignant tumors, there are significant differences in the clinical diagnosis and specific treatment of melanoma. To better adapt the rapid development of treatment for melanoma, and to make the clinical practice of melanoma more specific and internationalized in China, Expert Committee on Melanoma, Chinese Society of Clinical Oncology, has updated the Guidelines for Diagnosis and Treatment of Melanoma in China. Therefore, the editorial board of this journal interpreted this guideline in details, aiming to provide the latest and most practical evidence-based evidence for clinical oncologists in China.

A novel series of sigma (σ) receptor ligands based on an alkoxyisoxazole scaffold has been designed and synthesized. Preliminary receptor binding assays identified highly potent (Ki < 1 nM) and selective σ1 ligands devoid of binding interactions with the monoamine transporters DAT, NET, and SERT. In particular, compound 53 was shown to possess significant antinociceptive activity in the mouse formalin-induced inflammation pain model when administered intraperitoneally at 40 and 80 mg/kg. Initial pharmacokinetics evaluation indicated an excellent brain exposure following oral dosing in mice, suggesting that further investigation into the use of alkoxyisoxazoles as σ1 ligands for antinociception is warranted. This study supports the notion that selective σ1 antagonism could be a useful strategy in the development of novel antipain therapy.

A convenient and practical approach to coumestans has been successfully developed by using a one-pot tandem demethylation/annulation/oxidation reaction sequence that employs easily accessible 2,3-bis(2-methoxyphenyl)-3-oxopropanals as the starting material. This synthetic protocol provided a variety of coumestan derivatives in good to excellent yields under mild conditions. The exploration of biologically active coumestan compounds is a potential application of this synthetic method.

To address the emergency caused by multi-drug resistant Staphylococcus aureus, a series of novel capsaicin derivatives with nitrothiophene substituents have been designed and evaluated for the antibacterial activities against S. aureus Newman and multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108, and NRS-271). The structure-activity relationship was further revealed. Compound 13c, 13f, and 13g were highly active against staphylococcal growth, with minimal inhibition concentration (MIC) values of 0.39–1.56 μg/mL. The oxadiazole-derived compound 21, a bioisostere of ester 13f, is the most potent candidate for anti-growth of five multidrug-resistant S. aureus strains with MICs of 0.20–0.78 μg/mL, which is more active compared with vancomycin in vitro. Notably, these anti-staphylococcal compounds are much less cytotoxic to the normal kidney epithelial cell line (HK293T).

In recent years, the integrated ultrafiltration (UF) membrane process has been widely used due to its high removal efficiency, slight membrane fouling, and small land use. However, a number of problems gradually occurred regarding the integrated UF process caused by the granular adsorbents used, such as powdered activated carbon, carbon nano-tube, nanoscale zerovalent iron, etc. Severe membrane surface damage was easily caused by these granular adsorbents after a long running time, and the cost of most adsorbents was very high. In this study, to effectively overcome these problems, cheap and loose aluminum hydrolyzed flocs were directly injected into the membrane tank in the presence of humic acid (HA), with the aim of investigating the removal efficiency of HA and the corresponding membrane behavior. The results showed that the removal efficiency of HA could be influenced by aeration mode, floc injection frequency, and floc dosage. Compared with intermittent aeration and one-time injection, a loose "protection membrane" layer was formed with continuous aeration and batch injections. Therefore, HA molecules were largely removed, leading to the dramatic alleviation of membrane fouling. The transmembrane pressure significantly increased to 74.8 kPa in the absence of flocs after running for 5 days, but that only increased by 6.3 kPa with continuous aeration and an injection frequency of once every 2 d (each addition consisted of 5.4 mmol·L

The communities and activity of nitrifiers collected from the raw sewage of the 2

A nitrifying sequencing batch reactor (SBR) and continuous stirred-tank reactor (CSTR) were operated at 15℃ under the same conditions to investigate the effect of two typical flow patterns (plug flow and complete mixing) on the efficiency of nitrification enhancement. The results show that, during bioaugmentation, the ammonia utilized rate(AUR)and nitrite utilized rate(NUR)in the SBR were 2.34 and 2.39 times of that before bioaugmentation, and after bioaugmentation ceased, the AUR and NUR slightly decreased to 2.01 and 1.78 times of that before bioaugmentation. Meanwhile, the AUR and NUR in the CSTR were 2.63 and 2.44 times that before bioaugmentation, and after bioaugmentation ceased, the AUR and NUR decreased to 1.48 and 1.31 times that before bioaugmentation. Fluorescence In-Situ Hybridization (FISH) results showed that during bioaugmentation, the ammonia oxidizing bacteria (AOB) and nitrite oxidizing bacteria (NOB) in the SBR were 2.67 and 2.71 times of that before bioaugmentation, and after bioaugmentation ceased, the AUR and NUR slightly decreased to 2.14 and 1.95 times that before bioaugmentation. Meanwhile, the AUR and NUR in the CSTR were 2.91 and 1.77 times of that before bioaugmentation, and after bioaugmentation ceased, the AUR and NUR decreased to 1.25 and 1.50 times of that before bioaugmentation. Therefore, the efficiency of nitrification enhancement was similar between the two types of flow patterns during bioaugmentation, but the seeded nitrifiers were much more vulnerable to wash out in the CSTR than that in the SBR due to r/K selectivity of the flow patterns.

Inhibition of the mycolic acid pathway has proven a viable strategy in antitubercular drug discovery. The AccA3/AccD4/FadD32/Pks13 complex of Mycobacterium tuberculosis constitutes an essential biosynthetic mechanism for mycolic acids. Small molecules targeting the thioesterase domain of Pks13 have been reported, including a benzofuran-based compound whose X-ray cocrystal structure has been very recently solved. Its initial inactivity in a serum inhibition titration (SIT) assay led us to further probe other structurally related benzofurans with the aim to improve their potency and bioavailability. Herein, we report our preliminary structure-activity relationship studies around this scaffold, highlighting a natural product-inspired cyclization strategy to form coumestans that are shown to be active in SIT. Whole genome deep sequencing of the coumestan-resistant mutants confirmed a single nucleotide polymorphism in the pks13 gene responsible for the resistance phenotype, demonstrating the druggability of this target for the development of new antitubercular agents.

Herein we reported a series of 14 novel derivatives based on the

In our continued efforts to develop lithocholic acid (LCA) analogues as selective PTP1B inhibitors, 14 novel 2,3-pyrazole ring-substituted-4,4-dimethyl derivatives were synthesized and evaluated against PTP1B, as well as homologous protein tyrosine phosphatases (PTPs). All compounds were shown to be more potent and selective PTP1B inhibitors than LCA (IC50 = 12.74 μM) with IC50 values ranging between 0.42 to 4.49 μM. Moreover, treatment of CHO/hIR cells with 4,4-dimethyl-2′-(p-fluoro phenyl)-2′H-chola-2,5-dieno[3,2-c]pyrazol-24-oic acid (30) or 4,4-dimethyl-2′-(o-chloro phenyl)-2′H-chola-2,5-dieno[3,2-c]pyrazol-24-oic acid (34) increased the phosphorylation levels of IR and Akt in a dose dependent manner. The promising findings in this study suggest that further investigation of these compounds for the treatment of metabolic disorders is warranted.

Molecular markers are efficient tools for breeding and genetic studies. However, despite their ecological and economic importance, their development and application have long been hampered. In this study, we identified 524,170 simple sequence repeat (SSR), 267,636 intron length polymorphism (ILP), and 11,872 potential intron polymorphism (PIP) markers from 16 tree species based on recently available genome sequences. Larger motifs, including hexamers and heptamers, accounted for most of the seven different types of SSR loci. Within these loci, A/T bases comprised a significantly larger proportion of sequence than G/C. SSR and ILP markers exhibited an alternative distribution pattern. Most SSRs were monomorphic markers, and the proportions of polymorphic markers were positively correlated with genome size. By verifying with all 16 tree species, 54 SSR, 418 ILP, and four PIP universal markers were obtained, and their efficiency was examined by PCR. A combination of five SSR and six ILP markers were used for the phylogenetic analysis of 30 willow samples, revealing a positive correlation between genetic diversity and geographic distance. We also found that SSRs can be used as tools for duplication analysis. Our findings provide important foundations for the development of breeding and genetic studies in tree species.

Aberrant expression of lysine specific histone demethylase 1 (LSD1) has been increasingly associated with numerous cancer cells and several proof-of-concept studies are strongly suggestive of its potential as a druggable target. Tranylcypromine (TCP) is an antidepressant originally known to target the monoamine oxidases A and B (MAO-A and MAO-B), which are structurally related to LSD1. A number of TCP derivatives have been identified as potent LSD1 inhibitors, with a handful of them currently being tested in clinical trials. However, thus far the majority of structure-activity relationship studies reported on these TCP derivatives have been mostly limited to the racemates. In this study, we present the SAR data for a novel series of conformationally-restricted TCP-based LSD1 inhibitors, both in their racemic and enantiomerically pure forms. Compounds 18b and 19b were identified as the most potent LSD1 inhibitors within this series, possessing excellent selectivity (>10,000-fold) against MAO-A and MAO-B. These compounds activated CD86 expression on the human MV4-11 AML cells following 10 days of exposure, accompanied with the apparent cytotoxicity. Taken together, these findings are consistent with the pharmacological inhibition of LSD1 and further provide structural insights on the binding modes of these TCP derivatives and their enantiomers at the LSD1.

Originally thought to be nondruggable, kinases represent attractive drug targets for pharmaceutical companies and academia. To date, there are over 40 kinase inhibitors approved by the US FDA, with 32 of these being small molecules, in addition to the three mammalian target of rapamycin inhibitor macrolides (sirolimus, temsirolimus and everolimus). Despite the rapid development of kinase inhibitors for cancer, presently none of these agents are approved for CNS indications. This mini perspective highlights selected kinase targets for CNS disorders, of which brain-permeable small-molecule inhibitors are reported, with demonstrated preclinical proof-of-concept efficacy. This is followed by a brief discussion on the key challenges of blood–brain barrier penetration and selectivity profiles in developing kinase inhibitors for CNS disorders.

Death-associated protein kinase-related apoptosis-inducing kinase-2 (DRAK2) is a serine/threonine kinase that plays a key role in a wide variety of cell death signaling pathways. Inhibition of DRAK2 was found to efficiently protect islet β-cells from apoptosis and hence DRAK2 inhibitors represent a promising therapeutic strategy for the treatment of diabetes. Only very few chemical entities targeting DRAK2 are currently known. We carried out a high throughput screening and identified compound 4 as a moderate DRAK2 inhibitor with an IC50 value of 3.15 μM. Subsequent SAR studies of hit compound 4 led to the development of novel benzofuran-3(2H)-one series of DRAK2 inhibitors with improved potency and favorable selectivity profiles against 26 selected kinases. Importantly, most potent compounds 40 (IC50 = 0.33 μM) and 41 (IC50 = 0.25 μM) were found to protect islet β-cells from apoptosis in dose-dependent manners. These data support the notion that small molecule inhibitors of DRAK2 represents a promising strategy for the treatment of diabetes.

Nicotinic acetylcholine receptors (nAChRs) have been investigated for developing drugs that can potentially treat various central nervous system disorders. Considerable evidence supports the hypothesis that modulation of the cholinergic system through activation and/or desensitization/inactivation of nAChR holds promise for the development of new antidepressants. The introductory portion of this Miniperspective discusses the basic pharmacology that underpins the involvement of α4β2-nAChRs in depression, along with the structural features that are essential to ligand recognition by the α4β2-nAChRs. The remainder of this Miniperspective analyzes reported nicotinic ligands in terms of drug design considerations and their potency and selectivity, with a particular focus on compounds exhibiting antidepressant-like effects in preclinical or clinical studies. This Miniperspective aims to provide an in-depth analysis of the potential for using nicotinic ligands in the treatment of depression, which may hold some promise in addressing an unmet clinical need by providing relief from depressive symptoms in refractory patients.

An efficient and practical method for construction of 2-arylbenzo[b]furans from 2-methoxychalcone epoxides has been reported. Catalyzed by 2 mol % of BF3·Et2O, 2-methoxychalcone epoxides went through the Meerwein rearrangement, followed by deformylation in one-pot to successfully afforded 2-methoxydeoxybenzoins. Afterward, 2-arylbenzo[b]furans were obtained in high yields (87%–100%) via intermolecular cyclodehydration of 2-methoxydeoxybenzoins with 48% HBr. By utilization of this approach, the natural product stemofuran A and the key intermediate of eupomatenoid 6 have been synthesized conveniently.

AMP-activated protein kinase (AMPK), which is a pivotal guardian of whole-body energy metabolism, has become an attractive therapeutic target for metabolic syndrome. Previously, using a homogeneous scintillation proximity assay, we identified the small-molecule AMPK activator C24 from an optimization based on the original allosteric activator PT1. In this paper, the AMPK activation mechanism of C24 and its potential beneficial effects on glucose and lipid metabolism on db/db mice were investigated. C24 allosterically stimulated inactive AMPK α subunit truncations and activated AMPK heterotrimers by antagonizing autoinhibition. In primary hepatocytes, C24 increased the phosphorylation of AMPK downstream target acetyl-CoA carboxylase dose-dependently without changing intracellular AMP/ATP ratio, indicating its allosteric activation in cells. Through activating AMPK, C24 decreased glucose output by down-regulating mRNA levels of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in primary hepatocytes. C24 also decreased the triglyceride and cholesterol contents in HepG2 cells. Due to its improved bioavailability, chronic oral treatment with multiple doses of C24 significantly reduced blood glucose and lipid levels in plasma, and improved the glucose tolerance of diabetic db/db mice. The hepatic transcriptional levels of PEPCK and G6Pase were reduced. These results demonstrate that this orally effective activator of AMPK represents a novel approach to the treatment of metabolic syndrome.

A 3-pyridyl ether scaffold bearing a cyclopropane-containing side chain was recently identified in our efforts to create novel antidepressants that act as partial agonists at α4β2-nicotinic acetylcholine receptors. In this study, a systematic structure-activity relationship investigation was carried out on both the azetidine moiety present in compound 3 and its right-hand side chain, thereby discovering a variety of novel nicotinic ligands that retain bioactivity and feature improved chemical stability. The most promising compounds, 24, 26, and 30, demonstrated comparable or enhanced pharmacological profiles compared to the parent compound 4, and the N-methylpyrrolidine analogue 26 also exhibited robust antidepressant-like efficacy in the mouse forced swim test. The favorable ADMET profile and chemical stability of 26 further indicate this compound to be a promising lead as a drug candidate warranting further advancement down the drug discovery pipeline.

LF-3-88 (2-[5-[5-(2(S)-azetidinylmethoxyl)-3-pyridyl]-3-isoxazolyl] ethanol) was identified as a highly selective α4β2-nAChRs partial agonist, with a Ki value of 0.4 nM and EC50 value of 110 nM. A sensitive and selective ultra high pressure liquid chromatography-tandem mass spectrometry (UHPLC-MS-MS) method was developed and validated to study the pharmacokinetics profile of this compound in mice. Protein precipitation with acetonitrile was used to prepare the plasma and brain samples, and the recovery was greater than 90%. The inter-day and intra-day accuracy and precision of the quantitative method ranged from 95 % to 106 % for plasma and from 93 % to 105 % for brain homogenates. The precision of the assay was 93 %) for 24 h on the bench top at room temperature, and for at least 3 weeks at 4 °C and −80 °C. The UHPLC-MS-MS assay was applied to the measurement of plasma and brain levels of LF-3-88 following oral administration to male Balb/c mice. Plasma concentrations of LF-3-88 and brain levels were dose-dependent with half-lives of approximately 60 min and 180 min, respectively, indicating good oral bioavailability and penetration of the blood-brain barrier.

A series of novel 9, 13-disubstituted berberine derivatives have been synthesized and evaluated for the antibacterial activities against Staphylococcus aureus, including Newman strain and multidrug-resistant strains (NRS-1, NRS-70, NRS-100, NRS-108, and NRS-271). Compound 20 shows the most potent activity against the growth of Newman strain, with a MIC value of 0.78 μg/mL, which is comparable with the positive control vancomycin. In addition, compound 20, 21, and 33 are highly antistaphylococcal active against five strains of multidrug-resistant S. aureus, with MIC values of 0.78–1.56 μg/mL. Of note, theses antibacterial active compounds have no obvious toxicity to the viability of human fibroblast (HAF) cells at the MIC concentration.

We previously reported the cyclopropylpyridine and isoxazolylpyridine ether scaffolds to be versatile building blocks for creating potent α4β2 nicotinic acetylcholine receptor (nAChR) partial agonists with excellent selectivity over the α3β4 subtype. In our continued efforts to develop therapeutic nicotinic ligands, seven novel hybrid compounds were rationally designed, synthesized, and evaluated in [3H]epibatidine binding competition studies. Incorporation of a cyclopropane- or isoxazole-containing side chain onto the 5-position of 1-(pyridin-3-yl)-1,4-diazepane or 2-(pyridin-3-yl)-2,5-diazabicyclo[2.2.1]heptane led to highly potent and selective α4β2* nAChR partial agonists with Ki values of 0.5–51.4 nM for α4β2 and negligible affinities for α3β4 and α7. Moreover, compounds 21, 25, and 30 maintained the functional profiles (EC50 and IC50 values of 15–50 nM) of the parent azetidine-containing compounds 3 and 4 in the 86Rb+ ion flux assays. In vivo efficacy of the most promising compound 21 was confirmed in the mouse SmartCube® platform and classical forced swim tests, supporting the potential use of α4β2 partial agonists for treatment of depression.

Background: Few studies have addressed whether abnormalities in the lenticular nucleus (LN) are characteristic transcranial sonography (TCS) echo features in patients with primary dystonia. This study aimed to explore alterations in the basal ganglia in different forms of primary focal dystonia. Methods: cross-sectional observational study was performed between December 2013 and December 2014 in 80 patients with different forms of primary focal dystonia and 55 neurologically normal control subjects. TCS was performed in patients and control subjects. Multiple comparisons of multiple rates were used to compare LN hyperechogenicity ratios between control and patient groups. Results: Thirteen individuals were excluded due to poor temporal bone windows, and two subjects were excluded due to disagreement in evaluation by sonologists. Totally, 70 patients (cervical dystonia, n = 30; blepharospasm, n = 30; oromandibular dystonia, n = 10) and 50 normal controls were included in the final analysis. LN hyperechogenicity was observed in 51% (36/70) of patients with primary focal dystonia, compared with 12% (6/50) of controls (P < 0.001). Substantia nigra hyperechogenicity did not differ between the two groups. LN hyperechogenicity was observed in 73% (22/30) of patients with cervical dystonia, a greater prevalence than in patients with blepharospasm (33%, 10/30, P = 0.002) and oromandibular dystonia (40%, 4/10, P = 0.126). LN hyperechogenicity was more frequently observed in patients with cervical dystonia compared with controls (73% vs. 12%, P < 0.001); however, no significant difference was detected in patients with blepharospasm (33% vs. 12%, P = 0.021) or oromandibular dystonia (40% vs. 12%, P = 0.088). Conclusions: LN hyperechogenicity is more frequently observed in patients with primary focal dystonia than in controls. It does not appear to be a characteristic TCS echo feature in patients with blepharospasm or oromandibular dystonia.

A series of new seco-A ring bile acid diamides were synthesized, and their antiproliferative activities against PC3M (prostate), HT29 (colon) and ES-2 (ovarian) cancer cell lines were investigated using SRB assays. Most synthesized compounds presented improved antiproliferative activities compared to the parent bile acids (IC50 > 80 μM), especially the piperazine conjugated compound 27 with IC50 values of 1.07, 4.58 and 3.86 μM against PC3M, HT29 and ES-2 cancer cell lines, respectively. In addition, all the tested compounds showed less cytotoxic activity on a noncancerous cell line (HAF), and the most active compound 27 exhibited the highest selectivity (Selectivity Index, SI(PC3M) = 26.3). Furthermore, 27 could also enhance G1 arrest in PC3M cell, revealed by cell cycle analysis, and increase anti-migration activity on PC3M cells, confirmed by transwell migration assay.

Comparative analyses of the pharmacophoric elements required for σ1 and nicotinic ligands led to the identification of a potent and selective σ1 ligand (15). Compound 15 displayed high selectivity for the σ1 receptor (Ki, σ1 = 4.1 nM; Ki, σ2 = 1312 nM) with moderate binding affinity for the DAT (Ki = 373 nM) and NET (Ki = 203 nM) in the PDSP broad screening panel of common CNS neurotransmitter transporters and receptors. The key finding in this present work is that a subtle structural modification could be used as a tool to switch a ligand’s selectivity between nAChRs and sigma receptors.

Different fiber materials were modified and the effects of modified fiber on paper performance were evaluated. It’s shown that the strength of paper can be promoted by modified fiber. When the mixing ratio of modified NBKP fiber was 5%, the tensile index was increased from 38.28 N•m/g to 47.21 N•m/g. When the addition ratio of modified HYP fiber was 1.5%, the internal bond strength of paper was increased from 49.41 J/ m2 to 55.30 J/ m2, and the tensile index was increased by 48.06%. When the addition ratio of modified fiber of sawdust was 1.5% and mixed with OCC, the tensile index of paper was increased from 18.89N•m/g to 27.55N•m/g, and the ring crush index was increased by 13.99%.

There was a certain amount of fibers in paper sludge, including the short fiber and small fiber. Collagen fiber was a compound with high bond energy, which can be reused from the leather solid waste, and contained many polar groups. Both fibers can be well combined with Hydrogen bond. So the collagen fiber and paper sludge were studied as raw materials, mixed with plant fiber, to make corrugated paper. The results showed that, when the wastes were used to make the corrugated paper, its central pressure indicators could reach its national standard.

There is considerable evidence to support the hypothesis that the blockade of nAChR is responsible for the antidepressant action of nicotinic ligands. The nicotinic acetylcholine receptor (nAChR) antagonist, mecamylamine, has been shown to be an effective add-on in patients that do not respond to selective serotonin reuptake inhibitors. This suggests that nAChR ligands may address an unmet clinical need by providing relief from depressive symptoms in refractory patients. In this study, a new series of nAChR ligands based on an isoxazole-ether scaffold have been designed and synthesized for binding and functional assays. Preliminary structure-activity relationship (SAR) efforts identified a lead compound 43, which possesses potent antidepressant-like activity (1 mg/kg, IP; 5 mg/kg, PO) in the classical mouse forced swim test. Early stage absorption, distribution, metabolism, excretion, and toxicity (ADME-Tox) studies also suggested favorable drug-like properties, and broad screening towards other common neurotransmitter receptors indicated that compound 43 is highly selective for nAChRs over the other 45 neurotransmitter receptors and transporters tested.

Depression, a common neurological condition, is one of the leading causes of disability and suicide worldwide. Standard treatment, targeting monoamine transporters selective for the neurotransmitters serotonin and noradrenaline, is not able to help many patients that are poor responders. This study advances the development of sazetidine-A analogues that interact with α4β2 nicotinic acetylcholine receptors (nAChRs) as partial agonists and that possess favorable antidepressant profiles. The resulting compounds that are highly selective for the α4β2 subtype of nAChR over α3β4-nAChRs are partial agonists at the α4β2 subtype and have excellent antidepressant behavioral profiles as measured by the mouse forced swim test. Preliminary absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies for one promising ligand revealed an excellent plasma protein binding (PPB) profile, low CYP450-related metabolism, and low cardiovascular toxicity, suggesting it is a promising lead as well as a drug candidate to be advanced through the drug discovery pipeline.

Deji Reservoir is situated in the middle of Taiwan on the upstream catchment of the Dajia stream with an area of over 60,160 ha. The embankment stands 180 m high and is the tallest concrete arch dam in Taiwan. This dam stores 1.7 billion cubic meters of valid volume water. It provides over 370 million kilowatt-hours of electricity annually. It is also an important facility for operating flood control, hydroelectricity, irrigation, public water supply, etc. Seventy-two percent of the terrain is at 2,000- to 3,000-m altitude, and 5.2% is above 3,200-m altitude. More than 59% of the area is covered with steep topography of 55% slope. Only 7.9% of the area is shown with gentle slopes of less than 30% slope, which are located among the two banks of main streams with the altitudes ranging from 1,500 to 2,500 m. Most of the gentle slopes are used for temperate zone fruit, vegetable, and tea plantations. This land-use immediately adjoins a reservoir catchment region, resulting in an enormous impact on the mountainous environment. This study reviewed human-developed land-use area to properly address and evaluate norms for mitigating the impacts on the reservoir. The initial investigation brought up the parameters of gradient, slope movement types and processes, distance to the reservoir, location of developed area and distance with the farm road, etc. Local investigation and global information system technology were conducted in this research. We focused on segregating the terrain types of indisposed land-use. A different land-use management strategy is also analyzed.