Structural Basis for Binding of Allosteric Drug Leads in the Adenosine A1 Receptor

This work is licensed under a Creative Commons Attribution 4.0 International License.Despite intense interest in designing positive allosteric modulators (PAMs) as selective drugs of the adenosine A1 receptor (A1AR), structural binding modes of the receptor PAMs remain unknown. Using the first X-ray structure of the A1AR, we have performed all-atom simulations using a robust Gaussian accelerated molecular dynamics (GaMD) technique to determine binding modes of the A1AR allosteric drug leads. Two prototypical PAMs, PD81723 and VCP171, were selected. Each PAM was initially placed at least 20 Å away from the receptor. Extensive GaMD simulations using the AMBER and NAMD simulation packages at different acceleration levels captured spontaneous binding of PAMs to the A1AR. The simulations allowed us to identify low-energy binding modes of the PAMs at an allosteric site formed by the receptor extracellular loop 2 (ECL2), which are highly consistent with mutagenesis experimental data. Furthermore, the PAMs stabilized agonist binding in the receptor. In the absence of PAMs at the ECL2 allosteric site, the agonist sampled a significantly larger conformational space and even dissociated from the A1AR alone. In summary, the GaMD simulations elucidated structural binding modes of the PAMs and provided important insights into allostery in the A1AR, which will greatly facilitate the receptor structure-based drug design.Extreme Science and Engineering Discovery Environment award TG-MCB170129National Energy Research Scientific Computing Center project M2874American Heart Association (Award 17SDG33370094)College of Liberal Arts and Sciences at the University of KansasNHMRC Senior Principal Research FellowAustralian Heart Foundation Future Leader Fello

How Might Recharge Change Under Projected Climate Change in the Western U.S.?

Although groundwater is a major water resource in the western U.S., little research has been done on the impacts of climate change on groundwater storage and recharge in the West. Here we assess the impact of projected changes in climate on groundwater recharge in the near (2021–2050) and far (2071–2100) future across the western U.S. Variable Infiltration Capacity model was run with RCP 6.0 forcing from 11 global climate models and “subsurface runoff” output was considered as recharge. Recharge is expected to decrease in the West (−5.8 ± 14.3%) and Southwest (−4.0 ± 6.7%) regions in the near future and in the South region (−9.5 ± 24.3%) in the far future. The Northern Rockies region is expected to get more recharge in the near (+5.3 ± 9.2%) and far (+11.8 ± 12.3%) future. Overall, southern portions of the western U.S. are expected to get less recharge in the future and northern portions will get more. Climate change interacts with land surface properties to affect the amount of recharge that occurs in the future. Effects on recharge due to change in vegetation response from projected changes in climate and CO2 concentration, though important, are not considered in this study.Key PointsClimate change interacts with land surface properties to affect the amount of recharge that occurs in the futureSouthern portions of the western U.S. are expected to get less and northern portions more recharge in the futureThe large variability in projected recharge across the GCMs is associated with variability in projected precipitationPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/139906/1/grl56569.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/139906/2/grl56569_am.pd

Crystal structures and Hirshfeld surface analyses of methyl 4-{2,2-di­chloro-1-[(E)-phenyl­diazen­yl]eth­enyl}benzoate, methyl 4-{2,2-di­chloro-1-[(E)-(4-methyl­phen­yl)diazen­yl]ethen­yl}benzoate and methyl 4-{2,2-di­chloro-1-[(E)-(3,4-di­methyl­phen­yl)diazen­yl]ethen­yl}benzoate

The crystal structures and Hirshfeld surface analyses of three similar azo compounds are reported. Methyl 4-{2,2-dichloro-1-[(E)-phenyldiazenyl]ethenyl}benzoate, C16H12Cl2N2O2, (I), and methyl 4-{2,2-dichloro-1-[(E)-(4-methylphenyl)diazenyl]ethenyl}benzoate, C17H14Cl2N2O2, (II), crystallize in the space group P21/c with Z = 4, and methyl 4-{2,2-dichloro-1-[(E)-(3,4-dimethylphenyl)diazenyl]ethenyl}benzoate, C18H16Cl2N2O2, (III), in the space group P\overline{1} with Z = 2. In the crystal of (I), molecules are linked by C—H⋯N hydrogen bonds, forming chains with C(6) motifs parallel to the b axis. Short intermolecular Cl⋯O contacts of 2.8421 (16) Å and weak van der Waals interactions between these chains stabilize the crystal structure. In (II), molecules are linked by C—H⋯O hydrogen bonds and C—Cl⋯π interactions, forming layers parallel to (010). Weak van der Waals interactions between these layers

Hail injury in large cardamom (Amomum subulatum Roxb.) at high altitudes of Sikkim

Hail injury as an abiotic stress factor affecting large cardamom (Amomum subulatum) in Sikkim during February-May and its implications are described. Hail damage to foliage appeared as bruising, shredding or physical mangling and on the pseudostem as open, ragged-edged wounds. In addition to direct damage caused by hails the wounds also served as infection court for fungal pathogens. Since hail occurred at flowering stage (February-May) of large cardamom, it resulted in physical damage of floral parts too and thus affected the yield. &nbsp

Effectiveness of interventions to promote healthy diet in primary care: systematic review and meta-analysis of randomised controlled trials

Background A diet rich in fruit, vegetables and dietary fibre and low in fat is associated with reduced risk of chronic disease. This review aimed to estimate the effectiveness of interventions to promote healthy diet for primary prevention among participants attending primary care.<p></p> Methods A systematic review of trials using individual or cluster randomisation of interventions delivered in primary care to promote dietary change over 12 months in healthy participants free from chronic disease or defined high risk states. Outcomes were change in fruit and vegetable intake, consumption of total fat and fibre and changes in serum cholesterol concentration.<p></p> Results Ten studies were included with 12,414 participants. The design and delivery of interventions were diverse with respect to grounding in behavioural theory and intervention intensity. A meta-analysis of three studies showed an increase in fruit consumption of 0.25 (0.01 to 0.49) servings per day, with an increase in vegetable consumption of 0.25 (0.06 to 0.44) serving per day. A further three studies that reported on fruit and vegetable consumption together showed a pooled increment of 0.50 (0.13 to 0.87) servings per day. The pooled effect on consumption of dietary fibre, from four studies, was estimated to be 1.97 (0.43 to 3.52) gm fibre per day. Data from five studies showed a mean decrease in total fat intake of 5.2% of total energy (1.5 to 8.8%). Data from three studies showed a mean decrease in serum cholesterol of 0.10 (-0.19 to 0.00) mmol/L.<p></p> Conclusion Presently-reported interventions to promote healthy diet for primary prevention in primary care, which illustrate a diverse range of intervention methods, may yield small beneficial changes in consumption of fruit, vegetables, fibre and fat over 12 months. The present results do not exclude the possibility that more effective intervention strategies might be developed.<p></p&gt

Ethnobotany in the Nepal Himalaya

<p>Abstract</p> <p>Background</p> <p>Indigenous knowledge has become recognized worldwide not only because of its intrinsic value but also because it has a potential instrumental value to science and conservation. In Nepal, the indigenous knowledge of useful and medicinal plants has roots in the remote past.</p> <p>Methods</p> <p>The present study reviews the indigenous knowledge and use of plant resources of the Nepal Himalayas along the altitudinal and longitudinal gradient. A total of 264 studies focusing on ethnobotany, ethnomedicine and diversity of medicinal and aromatic plants, carried out between 1979 and 2006 were consulted for the present analysis. In order to cross check and verify the data, seven districts of west Nepal were visited in four field campaigns.</p> <p>Results</p> <p>In contrast to an average of 21–28% ethnobotanically/ethnomedicinally important plants reported for Nepal, the present study found that up to about 55% of the flora of the study region had medicinal value. This indicates a vast amount of undocumented knowledge about important plant species that needs to be explored and documented. The richness of medicinal plants decreased with increasing altitude but the percentage of plants used as medicine steadily increased with increasing altitude. This was due to preferences given to herbal remedies in high altitude areas and a combination of having no alternative choices, poverty and trust in the effectiveness of folklore herbal remedies.</p> <p>Conclusion</p> <p>Indigenous knowledge systems are culturally valued and scientifically important. Strengthening the wise use and conservation of indigenous knowledge of useful plants may benefit and improve the living standard of poor people.</p

Measurement of the underground atmospheric muon charge ratio using the MINOS Near Detector

The magnetized MINOS Near Detector, at a depth of 225 mwe, is used to measure the atmospheric muon charge ratio. The ratio of observed positive to negative atmospheric muon rates, using 301 days of data, is measured to be 1.266±0.001(stat)_(-0.014)^(+0.015)(syst). This measurement is consistent with previous results from other shallow underground detectors and is 0.108±0.019(stat+syst) lower than the measurement at the functionally identical MINOS Far Detector at a depth of 2070 mwe. This increase in charge ratio as a function of depth is consistent with an increase in the fraction of muons arising from kaon decay for increasing muon surface energie

Elliptic flow of electrons from heavy-flavor hadron decays in Au+Au collisions at sNN=\sqrt{s_{\rm NN}} = 200, 62.4, and 39 GeV

We present measurements of elliptic flow ($v_2$) of electrons from the decays of heavy-flavor hadrons ($e_{HF}$) by the STAR experiment. For Au+Au collisions at $\sqrt{s_{\rm NN}} =$ 200 GeV we report $v_2$, for transverse momentum ($p_T$) between 0.2 and 7 GeV/c using three methods: the event plane method ($v_{2}${EP}), two-particle correlations ($v_2${2}), and four-particle correlations ($v_2${4}). For Au+Au collisions at $\sqrt{s_{\rm NN}}$ = 62.4 and 39 GeV we report $v_2${2} for $p_T< 2$ GeV/c. $v_2${2} and $v_2${4} are non-zero at low and intermediate $p_T$ at 200 GeV, and $v_2${2} is consistent with zero at low $p_T$ at other energies. The $v_2${2} at the two lower beam energies is systematically lower than at $\sqrt{s_{\rm NN}} =$ 200 GeV for $p_T < 1$ GeV/c. This difference may suggest that charm quarks interact less strongly with the surrounding nuclear matter at those two lower energies compared to $\sqrt{s_{\rm NN}} = 200$ GeV.Comment: Version accepted by PR

Isolation of Flow and Nonflow Correlations by Two- and Four-Particle Cumulant Measurements of Azimuthal Harmonics in sNN=\sqrt{s_{_{\rm NN}}} = 200 GeV Au+Au Collisions

A data-driven method was applied to measurements of Au+Au collisions at $\sqrt{s_{_{\rm NN}}} =$ 200 GeV made with the STAR detector at RHIC to isolate pseudorapidity distance $\Delta\eta$-dependent and $\Delta\eta$-independent correlations by using two- and four-particle azimuthal cumulant measurements. We identified a component of the correlation that is $\Delta\eta$-independent, which is likely dominated by anisotropic flow and flow fluctuations. It was also found to be independent of $\eta$ within the measured range of pseudorapidity $|\eta|<1$. The relative flow fluctuation was found to be $34\% \pm 2\% (stat.) \pm 3\% (sys.)$ for particles of transverse momentum $p_{T}$ less than $2$ GeV/$c$. The $\Delta\eta$-dependent part may be attributed to nonflow correlations, and is found to be $5\% \pm 2\% (sys.)$ relative to the flow of the measured second harmonic cumulant at $|\Delta\eta| > 0.7$

Observation of charge asymmetry dependence of pion elliptic flow and the possible chiral magnetic wave in heavy-ion collisions

We present measurements of $\pi^-$ and $\pi^+$ elliptic flow, $v_2$, at midrapidity in Au+Au collisions at $\sqrt{s_{_{\rm NN}}} =$ 200, 62.4, 39, 27, 19.6, 11.5 and 7.7 GeV, as a function of event-by-event charge asymmetry, $A_{ch}$, based on data from the STAR experiment at RHIC. We find that $\pi^-$ ($\pi^+$) elliptic flow linearly increases (decreases) with charge asymmetry for most centrality bins at $\sqrt{s_{_{\rm NN}}} = \text{27 GeV}$ and higher. At $\sqrt{s_{_{\rm NN}}} = \text{200 GeV}$, the slope of the difference of $v_2$ between $\pi^-$ and $\pi^+$ as a function of $A_{ch}$ exhibits a centrality dependence, which is qualitatively similar to calculations that incorporate a chiral magnetic wave effect. Similar centrality dependence is also observed at lower energies.Comment: 6 pages, 4 figure