We present a detailed report on sterile neutrino oscillation and 235Uν¯e energy spectrum measurement results from the PROSPECT experiment at the highly enriched High Flux Isotope Reactor (HFIR) at ...Oak Ridge National Laboratory. In 96 calendar days of data taken at an average baseline distance of 7.9 m from the center of the 85 MW HFIR core, the PROSPECT detector has observed more than 50,000 interactions of νe produced in beta decays of 235U fission products. New limits on the oscillation of ν¯e to light sterile neutrinos have been set by comparing the detected energy spectra of ten reactor-detector baselines between 6.7 and 9.2 meters. Measured differences in energy spectra between baselines show no statistically significant indication of ν¯e to sterile neutrino oscillation and disfavor the reactor antineutrino anomaly best-fit point at the 2.5σ confidence level. The reported 235U ν¯e energy spectrum measurement shows excellent agreement with energy spectrum models generated via conversion of the measured 235U beta spectrum, with a χ2/d.o.f. of 31/31. PROSPECT is able to disfavor at 2.4σ confidence level the hypothesis that 235U ν¯e are solely responsible for spectrum discrepancies between model and data obtained at commercial reactor cores. A data-model deviation in PROSPECT similar to that observed by commercial core experiments is preferred with respect to no observed deviation, at a 2.2σ confidence level.
Understanding what causes weather‐related stresses that lead to crop failures is a critical step toward stabilizing global food production. While there are many sources of weather‐related stresses, ...the 30–60 days of Madden‐Julian Oscillation (MJO) is the dominant source of subseasonal climate variability in the tropics, making it a potential—but as of yet unexplored—source of crop yield anomalies. Here crop models and observational yield statistics are used to assess whether the MJO affects maize yields. We find that the influence of the MJO is widespread; it can increase or reduce maize yields throughout the tropics. In dry, hot environments the MJO can reduce maize yields by reducing precipitation, decreasing soil moisture, and increasing extreme heat, while in wetter, cooler environments—where water stress is less common—MJO‐forced decreases in rainfall bring increases in solar radiation that benefits maize yields. These results provide a pathway to develop actionable early warnings using subseasonal forecasts.
Key Points
The MJO affects maize yields in regions throughout the tropics and subtropics
In dry hot environments the MJO contributes to crop failures by reducing precipitation, decreasing soil moisture, and increasing heat stress
In sufficiently wet environments MJO‐induced decreases in rainfall reduces cloud cover, increases solar radiation, and benefits crop yields
Bistable 2rotaxanes display controllable switching properties in solution, on surfaces, and in devices. These phenomena are based on the electrochemically and electrically driven mechanical shuttling ...motion of the ring-shaped component, cyclobis(paraquat-p-phenylene) (CBPQT4+), between a monopyrrolotetrathiafulvalene (mpTTF) unit and a 1,5-dioxynaphthalene (DNP) unit located along a dumbbell component. The most stable state of the rotaxane (CBPQT4+@mpTTF) is that in which the CBPQT4+ ring encircles the mpTTF unit, but a second less favored metastable co-conformation with the CBPQT4+ ring surrounding the DNP (CBPQT4+@DNP) can be formed experimentally. For both co-conformations of an amphiphilic bistable 2rotaxane, we report here the structure and surface pressure−area isotherm of a Langmuir monolayer (LM) on a water subphase as a function of the area per molecule. These results from atomistic molecular dynamics (MD) studies are validated by comparing with experiments based on similar amphiphilic rotaxanes. For both co-conformations, we found that as the area per molecule increases the thickness of the LM decreases while the molecular tilt increases. Both co-conformations led to similar LM thicknesses at the same packing area. From the simulated LM systems, we calculated the electron density profiles of the monolayer as a function of area per molecule, which show good agreement with experimental analyses from synchrotron X-ray reflectivity measurements of related systems. Decomposing the overall electron density profiles into component contributions, we found distinct differences in molecular packing in the film depending upon the co-conformation. Thus we find that the necessity of allowing the tetracationic ring to become solvated by water leads to differences in the structures for the two co-conformations in the LM. At the same packing area, the value of the overall tilt angle does not seem to be sensitive to whether the CBPQT4+ ring is encircling the mpTTF or the DNP unit. However, the conformation of the dumbbell does depend on the location of the CBPQT4+ ring, which is reflected in the segmental tilt angles of the mpTTF and DNP units. Using the Kirkwood−Buff formula in conjunction with MD calculations, we find the surface pressure−area isotherms for each co-conformation in which the CBPQT4+@mpTTF form has smaller surface tension and therefore larger surface pressure than the CBPQT4+@DNP at the same packing area, differences that decreases with increasing area per molecule, which is verified experimentally.
Thermochronologic results from zircon fission track and (U‐Th)/He data collected across the Patagonian batholith, basement and thrust belt of the southern Patagonian Andes between 51°S and 53°S ...resolves new spatiotemporal patterns of Paleogene rock cooling that allows us to reconstruct deformational and erosional events along‐ and across‐strike. Our study applies a novel modeling strategy, the Path Family Approach, to filter geologically plausible thermal solutions from inverse modeling results for rocks in this study according to a sample's structural and tectonic context. Our results identify minimal cooling and interpreted exhumation of batholith rocks throughout the Paleogene. However, in the western domain we identify synchronous cooling of Jurassic volcaniclastic rocks in the thrust belt both along‐ and across‐strike between 50 and 35 Ma, which we interpret as a period of out‐of‐sequence deformation that coincides with the start of a distinct period of orogenesis in the Fuegian Andes (54°S). This finding may suggest that the southern Patagonian Andes and Fuegian Andes evolved as a connected orogenic system along the bend of the Patagonian orocline. In the central domain, modeled cooling of thermally reset Cretaceous basinal strata from 60 to 50 Ma corresponds to a well‐recognized erosional unconformity in the adjacent Cenozoic foreland depocenter, indicating that contemporaneous exhumation occurred beyond the margins of the basin. Although not diagnostic, exhumation within the orogenic belt, beyond the Cenozoic foreland basin, provides a new regional context to interpret the cause of this regional erosion event. Collectively these results inform the Paleogene tectonic evolution of the orogen.
Key Points
Thermochronology data support orogenesis in the southern Patagonian Andes (51°–53°S) from 50 to 35 Ma
Results of our study require Eocene contractional deformation along the bend of the Patagonian orocline
Exhumation driving the Paleogene foreland basin unconformity extended beyond the basin boundary
G protein-coupled receptors (GPCRs) mediate our sense of vision, smell, taste, and pain. They are also involved in cell recognition and communication processes, and hence have emerged as a prominent ...superfamily for drug targets. Unfortunately, the atomic-level structure is available for only one GPCR (bovine rhodopsin), making it difficult to use structure-based methods to design drugs and mutation experiments. We have recently developed first principles methods (MembStruk and HierDock) for predicting structure of GPCRs, and for predicting the ligand binding sites and relative binding affinities. Comparing to the one case with structural data, bovine rhodopsin, we find good accuracy in both the structure of the protein and of the bound ligand. We report here the application of MembStruk and HierDock to β1-adrenergic receptor, endothelial differential gene 6, mouse and rat 17 olfactory receptors, and human sweet receptor. We find that the predicted structure of β1-adrenergic receptor leads to a binding site for epinephrine that agrees well with the mutation experiments. Similarly the predicted binding sites and affinities for endothelial differential gene 6, mouse and rat I7 olfactory receptors, and human sweet receptor are consistent with the available experimental data. These predicted structures and binding sites allow the design of mutation experiments to validate and improve the structure and function prediction methods. As these structures are validated they can be used as targets for the design of new receptor-selective antagonists or agonists for GPCRs.
Dopamine neurotransmitter and its receptors play a critical role in the cell signaling process responsible for information transfer in neurons functioning in the nervous system. Development of ...improved therapeutics for such disorders as Parkinson's disease and schizophrenia would be significantly enhanced with the availability of the 3D structure for the dopamine receptors and of the binding site for dopamine and other agonists and antagonists. We report here the 3D structure of the long isoform of the human D2 dopamine receptor, predicted from primary sequence using first-principles theoretical and computational techniques (i.e., we did not use bioinformatic or experimental 3D structural information in predicting structures). The predicted 3D structure is validated by comparison of the predicted binding site and the relative binding affinities of dopamine, three known dopamine agonists (antiparkinsonian), and seven known antagonists (antipsychotic) in the D2 receptor to experimentally determined values. These structures correctly predict the critical residues for binding dopamine and several antagonists, identified by mutation studies, and give relative binding affinities that correlate well with experiments. The predicted binding site for dopamine and agonists is located between transmembrane (TM) helices 3, 4, 5, and 6, whereas the best antagonists bind to a site involving TM helices 2, 3, 4, 6, and 7 with minimal contacts to TM helix 5. We identify characteristic differences between the binding sites of agonists and antagonists.
The prevailing paradigm for G protein-coupled receptors is that each receptor is narrowly tuned to its ligand and closely related agonists. An outstanding problem is whether this paradigm applies to ...olfactory receptor (ORs), which is the largest gene family in the genome, in which each of 1,000 different G protein-coupled receptors is believed to interact with a range of different odor molecules from the many thousands that comprise "odor space." Insights into how these interactions occur are essential for understanding the sense of smell. Key questions are: (i) Is there a binding pocket? (ii) Which amino acid residues in the binding pocket contribute to peak affinities? (iii) How do affinities change with changes in agonist structure? To approach these questions, we have combined single-cell PCR results Malnic, B., Hirono, J., Sato, T. & Buck, L. B. (1999) Cell 96, 713-723 and well-established molecular dynamics methods to model the structure of a specific OR (OR S25) and its interactions with 24 odor compounds. This receptor structure not only points to a likely odor-binding site but also independently predicts the two compounds that experimentally best activate OR S25. The results provide a mechanistic model for olfactory transduction at the molecular level and show how the basic G protein-coupled receptor template is adapted for encoding the enormous odor space. This combined approach can significantly enhance the identification of ligands for the many members of the OR family and also may shed light on other protein families that exhibit broad specificities, such as chemokine receptors and P450 oxidases.
Nitrate uptake is essential for various bacterial processes and combines with nitrite export to form the usual initial steps of denitrification, a process that reduces nitrate to dinitrogen gas. ...Although many bacterial species contain NarK-like transporters that are proposed to function as either nitrate/proton symporters or nitrate/nitrite antiporters based on sequence homology, these transporters remain, in general, poorly characterized. Several bacteria appear to contain a transporter that is a fusion of two NarK-like proteins, although the significance of this arrangement remains elusive. We demonstrate that NarK from Paracoccus denitrificans is expressed as a fusion of two NarK-like transporters. NarK1 and NarK2 are separately capable of supporting anaerobic denitrifying growth but with growth defects that are partially mitigated by coexpression of the two domains. NarK1 appears to be a nitrate/proton symporter with high affinity for nitrate and NarK2 a nitrate/nitrite antiporter with lower affinity for nitrate. Each transporter requires two conserved arginine residues for activity. A transporter consisting of inactivated NarK1 fused to active NarK2 has a dramatically increased affinity for nitrate compared with NarK2 alone, implying a functional interaction between the two domains. A potential model for nitrate and nitrite transport in P. denitrificans is proposed.
Glucocorticoids are proposed to act as intermediary factors that transcribe the developmental programming sequelae of maternal nutrient restriction (NR). Periconceptional under-nutrition of sheep ...markedly activates fetal hypothalamic–pituitary–adrenal (HPA) axis activity leading to preterm birth, while transient undernutrition during late gestation in sheep programs adult HPA axis function. To date, no study has examined resting or stimulated HPA axis function in young adult offspring following a periconceptional nutritional challenge. In the present study, 20 ewes were either periconceptionally undernourished (50% metabolisable energy requirements from days 1 to 30 gestation; NR, n = 8) or fed to control levels (100% requirement; controls, n = 12) to term (147 days gestation). Ewes were blood sampled remotely at 2 and 30 days using automated blood sampling equipment. Thereafter, offspring (controls, n = 6/6 males/females; NR, n = 4/4 males/females) were reared to 1 year of age and on separate days received either an i.v. corticotrophin-releasing hormone (CRH; 0.5 μg/kg) and vasopressin (AVP; 0.1 μg/kg) challenge or a synthetic ACTH i.v. bolus (Synacthen; 1.25 μg/kg), and blood samples were taken (manually and remotely) at appropriate intervals for measurement of plasma ACTH and cortisol accordingly. Resting plasma cortisol, assessed remotely, was similar in ewes during undernutrition (control 18.3 ± 1.4 vs NR 23.4 ± 1.9 nmol/l) and in offspring at 4 months of age (control male 17.6 ± 2.9; control female 17.2 ± 0.4, NR male 16.5 ± 3.1, NR female 21.7 ± 4.0 nmol/l). At 12 months of age, however, resting plasma cortisol was significantly increased in NR females (control male 28.0 ± 1.5, control female 32.9 ± 9, NR male 32 ± 7, NR female 53 ± 10 nmol/l, F 5.7, P = 0.02) despite no difference in plasma ACTH concentration. There was an interaction between nutritional group and gender for both the pituitary and adrenal responses to CRH and AVP, i.e. for controls, females exhibited increased plasma ACTH or cortisol relative to males but for NR this trend was either not present or reversed. The adrenocortical response to synthetic ACTH was gender-dependent only, being greater in female offspring. Combined CRH and AVP provoked a transient hypertension and marked bradycardia in all animals, irrespective of dietary group or gender and could be effectively reproduced by an AVP bolus alone. In conclusion, the present study has shown that periconceptional undernutrition of sheep has only a minor influence on HPA axis function in their young adult offspring when considered alongside the effect of gender per se.
G-protein-coupled receptors (GPCRs) are involved in cell communication processes and with mediating such senses as vision, smell, taste, and pain. They constitute a prominent superfamily of drug ...targets, but an atomic-level structure is available for only one GPCR, bovine rhodopsin, making it difficult to use structure-based methods to design receptor-specific drugs. We have developed the MembStruk first principles computational method for predicting the three-dimensional structure of GPCRs. In this article we validate the MembStruk procedure by comparing its predictions with the high-resolution crystal structure of bovine rhodopsin. The crystal structure of bovine rhodopsin has the second extracellular (EC-II) loop closed over the transmembrane regions by making a disulfide linkage between Cys-110 and Cys-187, but we speculate that opening this loop may play a role in the activation process of the receptor through the cysteine linkage with helix 3. Consequently we predicted two structures for bovine rhodopsin from the primary sequence (with no input from the crystal structure)—one with the EC-II loop closed as in the crystal structure, and the other with the EC-II loop open. The MembStruk-predicted structure of bovine rhodopsin with the closed EC-II loop deviates from the crystal by 2.84
Å coordinate root mean-square (CRMS) in the transmembrane region main-chain atoms. The predicted three-dimensional structures for other GPCRs can be validated only by predicting binding sites and energies for various ligands. For such predictions we developed the HierDock first principles computational method. We validate HierDock by predicting the binding site of 11-
cis-retinal in the crystal structure of bovine rhodopsin. Scanning the whole protein without using any prior knowledge of the binding site, we find that the best scoring conformation in rhodopsin is 1.1
Å CRMS from the crystal structure for the ligand atoms. This predicted conformation has the carbonyl O only 2.82
Å from the N of Lys-296. Making this Schiff base bond and minimizing leads to a final conformation only 0.62
Å CRMS from the crystal structure. We also used HierDock to predict the binding site of 11-
cis-retinal in the MembStruk-predicted structure of bovine rhodopsin (closed loop). Scanning the whole protein structure leads to a structure in which the carbonyl O is only 2.85
Å from the N of Lys-296. Making this Schiff base bond and minimizing leads to a final conformation only 2.92
Å CRMS from the crystal structure. The good agreement of the ab initio-predicted protein structures and ligand binding site with experiment validates the use of the MembStruk and HierDock first principles’ methods. Since these methods are generic and applicable to any GPCR, they should be useful in predicting the structures of other GPCRs and the binding site of ligands to these proteins.