Grid Soil Sampling for Precision and Profit

Site specific management of plant nutrients for crop production begins with an inventory of soil test levels in a field. Fertilizer recommendations are based on the expected response to addition of fertilizers as a function of soil test levels. Therefore, the accuracy of site specific fertilizer applications depends on how accurately the nutrient status of soils is mapped. Mapping accuracy usually increases as fields are divided and sampled as smaller areas

Coherent strong-field control of multiple states by a single chirped femtosecond laser pulse

We present a joint experimental and theoretical study on strong-field photo-ionization of sodium atoms using chirped femtosecond laser pulses. By tuning the chirp parameter, selectivity among the population in the highly excited states 5p, 6p, 7p and 5f, 6f is achieved. Different excitation pathways enabling control are identified by simultaneous ionization and measurement of photoelectron angular distributions employing the velocity map imaging technique. Free electron wave packets at an energy of around 1 eV are observed. These photoelectrons originate from two channels. The predominant 2+1+1 Resonance Enhanced Multi-Photon Ionization (REMPI) proceeds via the strongly driven two-photon transition $4s\leftarrow\leftarrow3s$, and subsequent ionization from the states 5p, 6p and 7p whereas the second pathway involves 3+1 REMPI via the states 5f and 6f. In addition, electron wave packets from two-photon ionization of the non-resonant transiently populated state 3p are observed close to the ionization threshold. A mainly qualitative five-state model for the predominant excitation channel is studied theoretically to provide insights into the physical mechanisms at play. Our analysis shows that by tuning the chirp parameter the dynamics is effectively controlled by dynamic Stark-shifts and level crossings. In particular, we show that under the experimental conditions the passage through an uncommon three-state "bow-tie" level crossing allows the preparation of coherent superposition states

Interference in the resonance fluorescence of two incoherently coupled transitions

The fluorescence light emitted by a 4-level system in $J=1/2$ to $J=1/2$ configuration driven by a monochromatic laser field and in an external magnetic field is studied. We show that the spectrum of resonance fluorescence emitted on the $\pi$ transitions shows a signature of spontaneously generated interference effects. The degree of interference in the fluorescence spectrum can be controlled by means of the external magnetic field, provided that the Land\'e g-factors of the excited and the ground state doublet are different. For a suitably chosen magnetic field strength, the relative weight of the Rayleigh line can be completely suppressed, even for low intensities of the coherent driving field. The incoherent fluorescence spectrum emitted on the $\pi$ transitions exhibits a very narrow peak whose width and weight depends on the magnetic field strength. We demonstrate that the spectrum of resonance fluorescence emitted on the $\sigma$ transitions show an indirect signature of interference. A measurement of the relative peak heights in the spectrum from the $\sigma$ transitions allows to determine the branching ratio of the spontaneous decay of each excited state into the $\sigma$ channel

Frag4Lead Growing crystallographic fragment hits by catalog using fragment guided template docking

In recent years, crystallographic fragment screening has matured into an almost routine experiment at several modern synchrotron sites. The hits of the screening experiment, i.e. small molecules or fragments binding to the target protein, are revealed along with their 3D structural information. Therefore, they can serve as useful starting points for further structure based hit to lead development. However, the progression of fragment hits to tool compounds or even leads is often hampered by a lack of chemical feasibility. As an attractive alternative, compound analogs that embed the fragment hit structurally may be obtained from commercial catalogs. Here, a workflow is reported based on filtering and assessing such potential follow up compounds by template docking. This means that the crystallographic binding pose was integrated into the docking calculations as a central starting parameter. Subsequently, the candidates are scored on their interactions within the binding pocket. In an initial proof of concept study using five starting fragments known to bind to the aspartic protease endothiapepsin, 28 follow up compounds were selected using the designed workflow and their binding was assessed by crystallography. Ten of these compounds bound to the active site and five of them showed significantly increased affinity in isothermal titration calorimetry of up to single digit micromolar affinity. Taken together, this strategy is capable of efficiently evolving the initial fragment hits without major synthesis efforts and with full control by X ray crystallograph

Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial

Objective: Assess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents. Methods: In this phase 3, multicentre, placebo-controlled trial, 312 adults with active PsA were randomised (stratified by site, weight (≤100 kg/>100 kg), methotrexate use) to ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. At week 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape (placebo→45 mg, 45 mg→90 mg, 90 mg→90 mg). The primary endpoint was ≥20% improvement in American College of Rheumatology (ACR20) criteria at week 24. Secondary endpoints included week 24 Health Assessment Questionnaire-Disability Index (HAQ-DI) improvement, ACR50, ACR70 and ≥75% improvement in Psoriasis Area and Severity Index (PASI75). Efficacy was assessed in all patients, anti-TNF-naïve (n=132) patients and anti-TNF-experienced (n=180) patients. Results: More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 (p<0.001). Significant treatment differences were observed for week 24 HAQ-DI improvement (p<0.001), ACR50 (p≤0.05) and PASI75 (p<0.001); all benefits were sustained through week 52. Among patients previously treated with ≥1 TNF inhibitor, sustained ustekinumab efficacy was also observed (week 24 combined vs placebo: ACR20 35.6% vs 14.5%, PASI75 47.1% vs 2.0%, median HAQ-DI change −0.13 vs 0.0; week 52 ustekinumab-treated: ACR20 38.9%, PASI75 43.4%, median HAQ-DI change −0.13). No unexpected adverse events were observed through week 60. Conclusions: The interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients

Binding adaptation of GS 441524 diversifies macro domains and downregulate SARS CoV 2 de MARylation capacity

Viral infection in cells triggers a cascade of molecular defense mechanisms to maintain host cell homoeostasis. One of these mechanisms is ADP ribosylation, a fundamental post translational modification PTM characterized by the addition of ADP ribose ADPr on substrates. Poly ADP ribose polymerases PARPs are implicated in this process and they perform ADP ribosylation on host and pathogen proteins. Some viral families contain structural motifs that can reverse this PTM. These motifs known as macro domains MDs are evolutionarily conserved protein domains found in all kingdoms of life. They are divided in different classes with the viral belonging to Macro D type class because of their properties to recognize and revert the ADP ribosylation. Viral MDs are potential pharmaceutical targets, capable to counteract host immune response. Sequence and structural homology between viral and human MDs are an impediment for the development of new active compounds against their function. Remdesivir, is a drug administrated in viral infections inhibiting viral replication through RNA dependent RNA polymerase RdRp . Herein, GS 441524, the active metabolite of the remdesivir, is tested as a hydrolase inhibitor for several viral MDs and for its binding to human homologs found in PARPs. This study presents biochemical and biophysical studies, which indicate that GS 441524 selectively modifies SARS CoV 2 MD de MARylation activity, while it does not interact with hPARP14 MD2 and hPARP15 MD2. The structural investigation of MD GS 441524 complexes, using solution NMR and X ray crystallography, discloses the impact of certain amino acids in ADPr binding cavity suggesting that F360 and its adjacent residues tune the selective binding of the inhibitor to SARS CoV 2 M

Epistatic Module Detection for Case-Control Studies: A Bayesian Model with a Gibbs Sampling Strategy

The detection of epistatic interactive effects of multiple genetic variants on the susceptibility of human complex diseases is a great challenge in genome-wide association studies (GWAS). Although methods have been proposed to identify such interactions, the lack of an explicit definition of epistatic effects, together with computational difficulties, makes the development of new methods indispensable. In this paper, we introduce epistatic modules to describe epistatic interactive effects of multiple loci on diseases. On the basis of this notion, we put forward a Bayesian marker partition model to explain observed case-control data, and we develop a Gibbs sampling strategy to facilitate the detection of epistatic modules. Comparisons of the proposed approach with three existing methods on seven simulated disease models demonstrate the superior performance of our approach. When applied to a genome-wide case-control data set for Age-related Macular Degeneration (AMD), the proposed approach successfully identifies two known susceptible loci and suggests that a combination of two other loci—one in the gene SGCD and the other in SCAPER—is associated with the disease. Further functional analysis supports the speculation that the interaction of these two genetic variants may be responsible for the susceptibility of AMD. When applied to a genome-wide case-control data set for Parkinson's disease, the proposed method identifies seven suspicious loci that may contribute independently to the disease

Catalytic cleavage of HEAT and subsequent covalent binding of the tetralone moiety by the SARS-CoV-2 main protease

Here we present the crystal structure of SARS-CoV-2 main protease (Mpro) covalently bound to 2-methyl-1-tetralone. This complex was obtained by co-crystallization of Mpro with HEAT (2-(((4-hydroxyphenethyl)amino)methyl)-3,4-dihydronaphthalen-1(2H)-one) in the framework of a large X-ray crystallographic screening project of Mpro against a drug repurposing library, consisting of 5632 approved drugs or compounds in clinical phase trials. Further investigations showed that HEAT is cleaved by Mpro in an E1cB-like reaction mechanism into 2-methylene-1-tetralone and tyramine. The catalytic Cys145 subsequently binds covalently in a Michael addition to the methylene carbon atom of 2-methylene-1-tetralone. According to this postulated model HEAT is acting in a pro-drug-like fashion. It is metabolized by Mpro, followed by covalent binding of one metabolite to the active site. The structure of the covalent adduct elucidated in this study opens up a new path for developing non-peptidic inhibitors