Increase in CFC-11 emissions from eastern China based on atmospheric observations.

The recovery of the stratospheric ozone layer relies on the continued decline in the atmospheric concentrations of ozone-depleting gases such as chlorofluorocarbons1. The atmospheric concentration of trichlorofluoromethane (CFC-11), the second-most abundant chlorofluorocarbon, has declined substantially since the mid-1990s2. A recently reported slowdown in the decline of the atmospheric concentration of CFC-11 after 2012, however, suggests that global emissions have increased3,4. A concurrent increase in CFC-11 emissions from eastern Asia contributes to the global emission increase, but the location and magnitude of this regional source are unknown3. Here, using high-frequency atmospheric observations from Gosan, South Korea, and Hateruma, Japan, together with global monitoring data and atmospheric chemical transport model simulations, we investigate regional CFC-11 emissions from eastern Asia. We show that emissions from eastern mainland China are 7.0 ± 3.0 (±1 standard deviation) gigagrams per year higher in 2014-2017 than in 2008-2012, and that the increase in emissions arises primarily around the northeastern provinces of Shandong and Hebei. This increase accounts for a substantial fraction (at least 40 to 60 per cent) of the global rise in CFC-11 emissions. We find no evidence for a significant increase in CFC-11 emissions from any other eastern Asian countries or other regions of the world where there are available data for the detection of regional emissions. The attribution of any remaining fraction of the global CFC-11 emission rise to other regions is limited by the sparsity of long-term measurements of sufficient frequency near potentially emissive regions. Several considerations suggest that the increase in CFC-11 emissions from eastern mainland China is likely to be the result of new production and use, which is inconsistent with the Montreal Protocol agreement to phase out global chlorofluorocarbon production by 2010.

Estimation of the proximal temperature rise of an excited upconversion particle by detecting the wavefront of emission.

Monitoring the temperature distribution within a local environment at the micro and nanoscale is vital as many processes are solely thermal. Various thermometric techniques have been explored in the community, and out of these, fluorescent nano/micro particle-based mechanisms are accepted widely (fluorescence intensity ratio (FIR) techniques, where the ratio of populations in two consecutive energy levels is compared with Boltzmann distribution). We describe a new technique to account for the temperature rise near an illuminated upconverting particle (UCP) using wavefront imaging, which is more sensitive than the conventional thermometric techniques on the microscale. We rely on a thermo-optical phase microscopic technique by reconstructing the wavefront of emission from an upconverting particle using a Shack-Hartmann wavefront sensor. The wavefront maps the local phase distribution, which is an indicator of the surroundings' optical parameters, particularly the suspended medium's temperature-induced refractive index in the presence of convection currents. We describe how these extracted phase values can provide information about the optical heating due to the particle and hence its local environment along the direction of the emission. Our findings demonstrate the detection of a minimum temperature rise of 0.23 K, while the FIR methods indicate a minimum of 0.3 K rise. This technique is used to study the temperature increase in the backscattered direction for an upconverting particle illuminated on pump resonance. We also estimate the Soret coefficient for an upconverting particle optically trapped on pump resonance and experiencing anisotropic heating across the body.

Phytochemicals in Drug Discovery-A Confluence of Tradition and Innovation.

Phytochemicals have a long and successful history in drug discovery. With recent advancements in analytical techniques and methodologies, discovering bioactive leads from natural compounds has become easier. Computational techniques like molecular docking, QSAR modelling and machine learning, and network pharmacology are among the most promising new tools that allow researchers to make predictions concerning natural products' potential targets, thereby guiding experimental validation efforts. Additionally, approaches like LC-MS or LC-NMR speed up compound identification by streamlining analytical processes. Integrating structural and computational biology aids in lead identification, thus providing invaluable information to understand how phytochemicals interact with potential targets in the body. An emerging computational approach is machine learning involving QSAR modelling and deep neural networks that interrelate phytochemical properties with diverse physiological activities such as antimicrobial or anticancer effects.

Caudiquinol: A Meroterpenoid with an Intact C20 Geranylgeranyl Chain Isolated from Garcinia caudiculata.

The tropical Garcinia genus of flowering plants is a prolific producer of aromatic natural products including polyphenols, flavonoids, and xanthones. In this study, we report the first phytochemical investigation of Garcinia caudiculata Ridl. from the island of Borneo. Fractionation, purification, and structure elucidation by MS and NMR resulted in the discovery of two meroterpenoids. One was a benzofuranone lactone previously isolated from Iryanthera grandis and Rhus chinensis, and the second was a new hydroquinone methyl ester that we named caudiquinol. Both natural products are rare examples of plant meroterpenoids with an intact geranylgeranyl chain.

Growth vector elaboration of fragments: regioselective functionalization of 5-hydroxy-6-azaindazole and 3-hydroxy-2,6-naphthyridine.

This article discusses the reactivity of 6-azaindazole (1) and 2,6-naphthyridine (2), proposed to be "heteroaromatic rings of the future," which would be useful for fragment-based drug discovery (FBDD) campaigns, developing growth vectors for fragment elaboration by selectively functionalizing different positions on the rings. The pyridone oxygens and pyrazole nitrogen can be functionalized selectively. Arylation at the α-carbon of the pyridone moiety was achieved by a transition metal-free radical cross-coupling using aryl hydrazines. This method proceeded under mild conditions without the need for protection of the hydroxypyridine. Additionally, we developed a method for the regioselective C-3 functionalization of heterocycle 1via N-sulfonamide rearrangement. This method involved a novel regioselective base-mediated N-C migration of the N-1 sulfonamide to yield the C-3 sulfone. This procedure is also applicable for indazole C-3 functionalization and mechanistic studies of the rearrangement suggest that an intermolecular process is involved. These reactions enable the fragment elaboration of heterocycles 1 and 2 in several growth vectors to facilitate their use in FBDD.

Synthesis of [1-8-NαC]-zanriorb A1, alanine-containing analogues, and their cytotoxic and anti-inflammatory activity.

The synthesis of the orbitide[1-8-NαC]-zanriorb A1, isolated from the medicinal plant Zanthoxylum riedelianum, was investigated by solution-phase macrocyclization of a linear peptide and on-resin solid-phase macrocyclization with an acylsulfonamide safety-catch linker. The solution-phase route produced a mixture of proline rotamers, and the main component was assigned as the trans, cis rotamer, identical to the natural product. The on-resin cyclization was less successful, producing mainly a linear peptide, and minor cyclic products as rotameric mixtures. Although the natural product was reported to be significantly cytotoxic against Jurkat leukemia T cells, our synthetic peptides were inactive, suggesting the presence of other rotamers or impurities in the naturally isolated material. Additional analogues of zanriorb A1 were synthesized in which proline and glycine residues were replaced with alanine. While these analogues were not cytotoxic, several of them inhibited the production of nitric oxide in lipopolysaccharide (LPS)-stimulated macrophages. The most active compound, cyclic[Ala5,6,8 ]-zanriorb A1 had an IC50 of 22 µM and was more potent compared with the standard NG-monomethyl-l-arginine acetate (L-NMMA) with an IC50 of 98 µM, indicating their strong anti-inflammatory potential.

Interaction of molecular nitrogen with vanadium oxide in the absence and presence of water vapor at room temperature: Near-ambient pressure XPS.

Interactions of N2 at oxide surfaces are important for understanding electrocatalytic nitrogen reduction reaction (NRR) mechanisms. Interactions of N2 at the polycrystalline vanadium oxide/vapor interface were monitored at room temperature and total pressures up to 10-1 Torr using Near-Ambient Pressure X-ray Photoelectron Spectroscopy (NAP-XPS). The oxide film was predominantly V(IV), with V(III) and V(V) components. XPS spectra were acquired in environments of both pure N2 and equal pressures of N2 and H2O vapor. In pure N2, broad, partially resolved N1s features were observed at binding energies of 401.0 and 398.7 eV, with a relative intensity of ∼3:1, respectively. These features remained upon subsequent pumpdown to 10-9 Torr. The observed maximum N surface coverage was ∼1.5 × 1013 cm-2-a fraction of a monolayer. In the presence of equal pressures of H2O, the adsorbed N intensity at 10-1 Torr is ∼25% of that observed in the absence of H2O. The formation of molecularly adsorbed H2O was also observed. Density functional theory-based calculations suggest favorable absorption energies for N2 bonding to both V(IV) and V(III) cation sites but less so for V(V) sites. Hartree-Fock-based cluster calculations for N2-V end-on adsorption show that experimental XPS doublet features are consistent with the calculated shake-up and normal, final ionic configurations for N2 end-on bonding to V(III) sites but not V(IV) sites. The XPS spectra of vanadium oxide transferred in situ between electrochemical and UHV environments indicate that the oxide surfaces studied here are stable upon exposure to the electrolyte under NRR-relevant conditions.

Euglenatides, Potent Antiproliferative Cyclic Peptides Isolated from the Freshwater Photosynthetic Microalga Euglena gracilis.

By limiting the nitrogen source to glutamic acid, we isolated cyclic peptides from Euglena gracilis containing asparagine and non-proteinogenic amino acids. Structure elucidation was accomplished through spectroscopic methods, mass spectrometry and chemical degradation. The euglenatides potently inhibit pathogenic fungi and cancer cell lines e.g., euglenatide B exhibiting IC50 values of 4.3 µM in Aspergillus fumigatus and 0.29 µM in MCF-7 breast cancer cells. In an unprecedented convergence of non-ribosomal peptide synthetase and polyketide synthase assembly-line biosynthesis between unicellular species and the metazoan kingdom, euglenatides bear resemblance to nemamides from Caenorhabditis elegans and inhibited both producing organisms E. gracilis and C. elegans. By molecular network analysis, we detected over forty euglenatide-like metabolites in E. gracilis, E. sanguinea and E. mutabilis, suggesting an important biological role for these natural products.

Insights into the Structure-Activity Relationship of Glycosides as Positive Allosteric Modulators Acting on P2X7 Receptors.

P2X7 is an important ligand-gated ion channel expressed in multiple immune cell populations. This study aimed to investigate the chemical requirements of triterpenoid glycosides within a new binding pocket to characterize the structure-activity relationship. A set of glycosides were screened for positive modulator activity at human P2X7 using a YO-PRO-1 dye uptake assay in HEK-293 cells stably expressing the wild-type human P2X7 variant (HEK-hP2X7 cells). The highest positive modulator activity was with ginsenoside-compound K (CK), containing a monosaccharide (glucose) attached at carbon-20. Ginsenoside-20(S)-Rg3, containing a disaccharide group (glucose-glucose) at carbon-3, displayed positive modulator activity with a reduced EC50 for ATP and increased maximal response at human P2X7. The epimer 20(R)-Rg3 was inactive. A similar stereo-specific pattern was observed for 20(S)-Rh2. Ginsenoside-F1, highly similar to ginsenoside-CK but containing a single additional hydroxyl group, was also inactive at P2X7. Computational docking suggests hydrophobic residues in the pocket are involved in steric discrimination between triterpenoids, whereas the position and identity of the carbohydrate group are important for positive modulator activity at human P2X7. Ginsenosides containing monosaccharide attachments perform better than di- or trisaccharide glycosides. Additional modifications to the triterpenoid scaffold at carbon-6 are not tolerated. Gypenosides from plant sources other than Panax ginseng (gypenoside XVII, gypenoside XLIX, stevenleaf) can also act as positive allosteric modulators of P2X7. We also investigated the effect of positive allosteric modulators on endogenous P2X7 in THP-1 monocytes and confirmed our findings in a calcium response assay. A cell viability assay showed potentiation of ATP-induced cell death with ginsenoside-CK in THP-1 and HEK-hP2X7 cells. SIGNIFICANCE STATEMENT: Ginsenosides are active as positive allosteric modulators at P2X7, and this study determines the chemical features important for mediating this effect. The position and identity of the sugar group is important for activity, as is the position of a number of hydroxyl groups on the triterpenoid scaffold. Diastereomers of ginsenoside-Rg3 and ginsenoside-Rh2 demonstrate the importance of the location of hydroxyl groups relative to the hydrophobic face of the predicted binding pocket.

Factors associated with erectile dysfunction diagnosis in men with HIV infection: a case-control study.

OBJECTIVES: HIV infection is associated with increased risk of erectile dysfunction (ED); however, factors associated with ED remain unclear. We evaluated the prevalence of ED among men living with HIV and factors associated with ED diagnosis in the US Military HIV Natural History Study (NHS). METHODS: A retrospective cohort study evaluated participants in the NHS, a cohort of HIV-positive active duty members and beneficiaries with HIV infection. Men with a diagnosis of ED after HIV diagnosis were included. Cohort controls without ED diagnosis were matched 2:1 by age at HIV diagnosis and duration of follow-up. Multivariate logistic regression models were used to identify factors associated with ED. RESULTS: A total of 543 of 5682 male participants (9.6% prevalence) had a diagnosis of ED, of whom 488 were included in the analysis. The median (interquartile range, IQR) age at ED diagnosis was 43 (37.0-49.0) years and the time from HIV diagnosis to antiretroviral therapy (ART) start was longer for cases (5.0 years, IQR: 2.0-9.0) than for controls (3.0 years, 1.0-6.0; P < 0.01). Cases had higher proportions of multiple comorbid conditions, including depression (33.4% vs. 21.7%), tobacco use (19.7% vs. 9.0%) and sleep apnoea (14.8% vs. 4.2%) compared with controls (P < 0.01 for all). Logistic regression showed increased odds of ED for delayed ART initiation > 4 years [odds ratio (OR) = 2.05, 95% confidence interval (CI): 1.56-2.71], protease inhibitor use ≥ 1 year (OR = 1.81, 95% CI: 1.38-2.38) and sleep apnoea (OR = 2.60, 95% CI: 1.68-4.01). CONCLUSIONS: Erectile dysfunction was common in men with HIV and associated factors included both HIV-related and traditional factors.

New tranylcypromine derivatives containing sulfonamide motif as potent LSD1 inhibitors to target acute myeloid leukemia: Design, synthesis and biological evaluation.

Lysine-specific demethylase 1 (LSD1) is frequently elevated in acute myeloid leukemia (AML) and often leads to tumorigenesis. In recent years, numerous LSD1 inhibitors based on tranylcypromine (TCP) scaffolding have reached clinical trials. Most TCP derivatives were modified at the amino site of cyclopropane motif. Herein, we for the first time introduced a sulfonamide group in TCP benzene ring of series a compounds and performed a systematical study on structure and activity relationships by varying sulfonamide groups. The introduction of sulfonamide significantly increased the targeting capacity of TCP against LSD1. Moreover, we discovered that the Boc attached LSD1 inhibitors (labelled as series b compounds) substantially improved their anti-proliferation capacity towards AML cells. The intracellular thermal shift and LC-MS/MS results implied that Boc enhanced the drug lipophilicity and might be removed under the cancerous acidic environment to release the real pharmacophore, evidenced by the fact that a structurally similar but acidic inert pivaloyl to replace Boc dramatically dropped the cellular anti-proliferation effect. Finally, a benzyl group installed at the amino site to appropriately increase lipophilicity led to trans-4-(2-(benzylamino)-cyclopropyl)-N,N-diethylbenzenesulfonamide a10 that showed better anti-proliferation activity in AML cells and enzymatic inhibition against LSD1. Taken together, our work offers a novel TCP-based structure and provides a prodrug strategy for the discovery of potent LSD1 inhibitors by having appropriate lipophilicity.

Immune microenvironments in solid tumors: new targets for therapy.

Leukocytes and their soluble mediators play important regulatory roles in all aspects of solid tumor development. While immunotherapeutic strategies have conceptually held clinical promise, with the exception of a small percentage of patients, they have failed to demonstrate effective, consistent, and durable anti-cancer responses. Several subtypes of leukocytes that commonly infiltrate solid tumors harbor immunosuppressive activity and undoubtedly restrict the effectiveness of these strategies. Several of these same immune cells also foster tumor development by expression of potent protumor mediators. Given recent evidence revealing that immune-based mechanisms regulate the response to conventional cytotoxic therapy, it seems reasonable to speculate that tumor progression could be effectively diminished by combining cytotoxic strategies with therapies that blunt protumor immune-based effectors and/or neutralize those that instead impede development of desired anti-tumor immunity, thus providing synergistic effects between traditional cytotoxic and immune-modulatory approaches.

Detection of the presence of Coxiella burnetii in a case of goat abortion: a first report from India.

Abortion is a major cause of economic loss to the goat industry. Coxiella burnetii the causative agent of Q fever is an important zoonotic agent known to be prevalent worldwide. In the present investigation, we detected the presence of Coxiella burnetii by the modified Ziehl Neelsen method of staining and its DNA by trans-PCR assay in the placenta obtained from the aborted goat. We also ruled out other common causes of abortion in this case. Based on a literature survey, this is the first report on the direct detection of Coxiella burnetii from an aborted goat to be reported from India.

LSD1 inhibition attenuates androgen receptor V7 splice variant activation in castration resistant prostate cancer models.

BACKGROUND: Castrate resistant prostate cancer (CRPC) is often driven by constitutively active forms of the androgen receptor such as the V7 splice variant (AR-V7) and commonly becomes resistant to established hormonal therapy strategies such as enzalutamide as a result. The lysine demethylase LSD1 is a co-activator of the wild type androgen receptor and a potential therapeutic target in hormone sensitive prostate cancer. We evaluated whether LSD1 could also be therapeutically targeted in CRPC models driven by AR-V7. METHODS: We utilised cell line models of castrate resistant prostate cancer through over expression of AR-V7 to test the impact of chemical LSD1 inhibition on AR activation. We validated findings through depletion of LSD1 expression and in prostate cancer cell lines that express AR-V7. RESULTS: Chemical inhibition of LSD1 resulted in reduced activation of the androgen receptor through both the wild type and its AR-V7 splice variant forms. This was confirmed and validated in luciferase reporter assays, in LNCaP and 22Rv1 prostate cancer cell lines and in LSD1 depletion experiments. CONCLUSION: LSD1 contributes to activation of both the wild type and V7 splice variant forms of the androgen receptor and can be therapeutically targeted in models of CRPC. Further development of this approach is warranted.

Continued Emissions of the Ozone-Depleting Substance Carbon Tetrachloride From Eastern Asia.

Carbon tetrachloride (CCl4) is an ozone-depleting substance, accounting for about 10% of the chlorine in the troposphere. Under the terms of the Montreal Protocol, its production for dispersive uses was banned from 2010. In this work we show that, despite the controls on production being introduced, CCl4 emissions from the eastern part of China did not decline between 2009 and 2016. This finding is in contrast to a recent bottom-up estimate, which predicted a significant decrease in emissions after the introduction of production controls. We find eastern Asian emissions of CCl4 to be 16 (9-24) Gg/year on average between 2009 and 2016, with the primary source regions being in eastern China. The spatial distribution of emissions that we derive suggests that the source distribution of CCl4 in China changed during the 8-year study period, indicating a new source or sources of emissions from China's Shandong province after 2012.

Nanoscale tilt measurement using a cyclic interferometer with polarization phase stepping and multiple reflections.

High-accuracy tilt or roll angle measurement is required for a variety of engineering and scientific applications. A cyclic interferometer with multiple reflections has been developed to measure small tilt angles. To accomplish this task, a novel and simple method, phase shift by polarization, was developed. The results of these studies show that the multiple reflection cyclic interferometers can be used to measure object tilts on the order of 0.2 nano-radians. We develop the theory for polarization phase step and show that accurate measurements can be made with the cyclic interferometer.

Systematic Analysis of the Relationship among 3D Structure, Bioactivity, and Membrane Permeability of PF1171F, a Cyclic Hexapeptide with Paralyzing Effects on Silkworms.

PF1171 hexapeptides, a family of cyclic hexapeptides produced by fungi, exhibit paralyzing effects on the larvae of silkworms via oral administration. To elucidate the structural features of PF1171 hexapeptides that are crucial for bioactivity, the relationship among 3D structure, bioactivity, and membrane permeability of PF1171F (the peptide with the highest bioavailability) was systematically analyzed through the synthesis of 22 analogues. The PF1171F analogues were prepared by the solid-phase synthesis of a linear precursor and subsequent solution-phase macrolactamization. Analysis by NMR spectroscopy and molecular modeling indicated that the major 3D conformations of PF1171F in various solvents resemble its X-ray crystal structure. The analogues with this conformation tend to exhibit potent paralysis against silkworms, indicating the significance of the conformation in the paralysis. The biological activity was dependent on the mode of administration, varying between hemolymph injection and oral administration. Parallel artificial membrane permeability assay (PAMPA) of the analogues revealed a correlation between membrane permeabilities and paralytic activity by hemolymph injection, indicating that the target molecule of PF1171F is present inside the cell membrane.

Comparative Study of the Synthesis and Structural and Physicochemical Properties of Diketopiperazines vs Aza-diketopiperazines.

Aza-diketopiperazines (aza-DKPs) represent an underprivileged motif obtained by scaffold hopping of 2,5-diketopiperazines (2,5-DKPs). Herein, we compare the synthesis and the structural and physicochemical properties of aza-DKP 4 vs 2,5-DKP 7. Thus, X-ray and 1H NMR studies show that aza-DKP 4 is a rigid and nonflat scaffold like the 2,5-DKP 7. Moreover, the replacement of one Cα-stereogenic center by a nitrogen atom results in a significant improvement of both the water solubility and the microsomal stability.

Fluorinated tranylcypromine analogues as inhibitors of lysine-specific demethylase 1 (LSD1, KDM1A).

We report a series of tranylcypromine analogues containing a fluorine in the cyclopropyl ring. A number of compounds with additional m- or p-substitution of the aryl ring were micromolar inhibitors of the LSD1 enzyme. In cellular assays, the compounds inhibited the proliferation of acute myeloid leukemia cell lines. Increased levels of the biomarkers H3K4me2 and CD86 were consistent with LSD1 target engagement.

Total synthesis, structural, and biological evaluation of stylissatin A and related analogs.

The natural product cyclic peptide stylissatin A (1a) was reported to inhibit nitric oxide production in LPS-stimulated murine macrophage RAW 264.7 cells. In the current study, solid-phase total synthesis of stylissatin A was performed by using a safety-catch linker and yielded the peptide with a trans-Phe(7) -Pro(6) linkage, whereas the natural product is the cis rotamer at this position as evidenced by a marked difference in NMR chemical shifts. In order to preclude the possibility of 1b being an epimer of the natural product, we repeated the synthesis using d-allo-Ile in place of l-Ile and a different site for macrocyclization. The resulting product (d-allo-Ile(2) )-stylissatin A (1c) was also found to have the trans-Phe(7) -Pro(6) peptide conformations like rotamer 1b. Applying the second route to the synthesis of stylissatin A itself, we obtained stylissatin A natural rotamer 1a accompanied by rotamer 1b as the major product. Rotamers 1a, 1b, and the epimer 1c were separable by HPLC, and 1a was found to match the natural product in structure and biological activity. Six related analogs 2-7 of stylissatin A were synthesized on Wang resin and characterized by spectral analysis. The natural product (1a), the rotamer (1b), and (d-allo-Ile(2) )-stylissatin A (1c) exhibited significant inhibition of NO(.) . Further investigations were focused on 1b, which also inhibited proliferation of T-cells and inflammatory cytokine IL-2 production. The analogs 2-7 weakly inhibited NO(.) production, but strongly inhibited IL-2 cytokine production compared with synthetic peptide 1b. All analogs inhibited the proliferation of T-cells, with analog 7 having the strongest effect. In the analogs, the Pro(6) residue was replaced by Glu/Ala, and the SAR indicates that the nature of this residue plays a role in the biological function of these peptides. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.