Robust Species Distribution Mapping of Crop Mixtures Using Color Images and Convolutional Neural Networks.

Crop mixtures are often beneficial in crop rotations to enhance resource utilization and yield stability. While targeted management, dependent on the local species composition, has the potential to increase the crop value, it comes at a higher expense in terms of field surveys. As fine-grained species distribution mapping of within-field variation is typically unfeasible, the potential of targeted management remains an open research area. In this work, we propose a new method for determining the biomass species composition from high resolution color images using a DeepLabv3+ based convolutional neural network. Data collection has been performed at four separate experimental plot trial sites over three growing seasons. The method is thoroughly evaluated by predicting the biomass composition of different grass clover mixtures using only an image of the canopy. With a relative biomass clover content prediction of R2 = 0.91, we present new state-of-the-art results across the largely varying sites. Combining the algorithm with an all terrain vehicle (ATV)-mounted image acquisition system, we demonstrate a feasible method for robust coverage and species distribution mapping of 225 ha of mixed crops at a median capacity of 17 ha per hour at 173 images per hectare.

The role of orthodontics in the repair of gingival recessions.

INTRODUCTION: The goal of this research was to assess the impact of orthodontic root movement on gingival recessions. METHODS: Twelve consecutive adult patients with a mandibular incisor presenting buccal or lingual gingival recession and with the root positioned outside the alveolar bone were enrolled. The roots were moved toward the center of the alveolar process with a goal oriented segmented appliance. The following variables were measured at baseline and after orthodontic treatment: (1) recession depth, (2) recession width, and (3) recession area. In addition, pocket probing depth, keratinized tissue height, and changes in Miller's classification were registered. RESULTS: The depth, width, and area of the gingival recessions were reduced in all patients without increased pocket probing depth. On average, the recession depth decreased with 23%, the width with 38%, and the recession area with 63% of the baseline value. All patients improved in Miller's classification from Class III and IV to Class I or II. CONCLUSIONS: Orthodontic correction of the root toward the center of the alveolar envelope consistently reduced gingival recessions. The changes in Miller's classification indicated improved prognosis for full root coverage with mucogingival surgery.

A small molecule activator of Nav 1.1 channels increases fast-spiking interneuron excitability and GABAergic transmission in vitro and has anti-convulsive effects in vivo.

Nav 1.1 (SCN1A) channels primarily located in gamma-aminobutyric acid (GABA)ergic fast-spiking interneurons are pivotal for action potential generation and propagation in these neurons. Inappropriate function of fast-spiking interneurons, leading to disinhibition of pyramidal cells and network desynchronization, correlates with decreased cognitive capability. Further, reduced functionality of Nav 1.1 channels is linked to various diseases in the central nervous system. There is, at present, however no subtype selective pharmacological activators of Nav 1.1 channels available for studying pharmacological modulation of interneuron function. In the current study, we identified a small molecule Nav 1.1 activator, 3-amino-5-(4-methoxyphenyl)thiophene-2-carboxamide, named AA43279, and provided an in vitro to in vivo characterization of the compound. In HEK-293 cells expressing human Nav 1.1 channels, AA43279 increased the Nav 1.1-mediated current in a concentration-dependent manner mainly by impairing the fast inactivation kinetics of the channels. In rat hippocampal brain slices, AA43279 increased the firing activity of parvalbumin-expressing, fast-spiking GABAergic interneurons and increased the spontaneous inhibitory post-synaptic currents (sIPSCs) recorded from pyramidal neurons. When tested in vivo, AA43279 had anti-convulsive properties in the maximal electroshock seizure threshold test. AA43279 was tested for off-target effects on 72 different proteins, including Nav 1.2, Nav 1.4, Nav 1.5, Nav 1.6 and Nav 1.7 and exhibited reasonable selectivity. Taken together, AA43279 might constitute a valuable tool compound for revealing biological functions of Nav 1.1 channels.

Designing and Testing a UAV Mapping System for Agricultural Field Surveying.

A Light Detection and Ranging (LiDAR) sensor mounted on an Unmanned Aerial Vehicle (UAV) can map the overflown environment in point clouds. Mapped canopy heights allow for the estimation of crop biomass in agriculture. The work presented in this paper contributes to sensory UAV setup design for mapping and textual analysis of agricultural fields. LiDAR data are combined with data from Global Navigation Satellite System (GNSS) and Inertial Measurement Unit (IMU) sensors to conduct environment mapping for point clouds. The proposed method facilitates LiDAR recordings in an experimental winter wheat field. Crop height estimates ranging from 0.35-0.58 m are correlated to the applied nitrogen treatments of 0-300 kg N ha . The LiDAR point clouds are recorded, mapped, and analysed using the functionalities of the Robot Operating System (ROS) and the Point Cloud Library (PCL). Crop volume estimation is based on a voxel grid with a spatial resolution of 0.04 × 0.04 × 0.001 m. Two different flight patterns are evaluated at an altitude of 6 m to determine the impacts of the mapped LiDAR measurements on crop volume estimations.

FieldSAFE: Dataset for Obstacle Detection in Agriculture.

In this paper, we present a multi-modal dataset for obstacle detection in agriculture. The dataset comprises approximately 2 h of raw sensor data from a tractor-mounted sensor system in a grass mowing scenario in Denmark, October 2016. Sensing modalities include stereo camera, thermal camera, web camera, 360 ∘ camera, LiDAR and radar, while precise localization is available from fused IMU and GNSS. Both static and moving obstacles are present, including humans, mannequin dolls, rocks, barrels, buildings, vehicles and vegetation. All obstacles have ground truth object labels and geographic coordinates.

Dicotyledon Weed Quantification Algorithm for Selective Herbicide Application in Maize Crops.

The stricter legislation within the European Union for the regulation of herbicides that are prone to leaching causes a greater economic burden on the agricultural industry through taxation. Owing to the increased economic burden, research in reducing herbicide usage has been prompted. High-resolution images from digital cameras support the studying of plant characteristics. These images can also be utilized to analyze shape and texture characteristics for weed identification. Instead of detecting weed patches, weed density can be estimated at a sub-patch level, through which even the identification of a single plant is possible. The aim of this study is to adapt the monocot and dicot coverage ratio vision (MoDiCoVi) algorithm to estimate dicotyledon leaf cover, perform grid spraying in real time, and present initial results in terms of potential herbicide savings in maize. The authors designed and executed an automated, large-scale field trial supported by the Armadillo autonomous tool carrier robot. The field trial consisted of 299 maize plots. Half of the plots (parcels) were planned with additional seeded weeds; the other half were planned with naturally occurring weeds. The in-situ evaluation showed that, compared to conventional broadcast spraying, the proposed method can reduce herbicide usage by 65% without measurable loss in biological effect.

Discovery and optimization of Lu AF58801, a novel, selective and brain penetrant positive allosteric modulator of alpha-7 nicotinic acetylcholine receptors: attenuation of subchronic phencyclidine (PCP)-induced cognitive deficits in rats following oral administration.

In this Letter, we describe a chemical lead optimization campaign starting from a novel, weak α7 nicotinic acetylcholine receptor positive allosteric modulator (PAM) hit from a HTS screen. Exploration of the structure-activity relationships for α7 PAM potency, intrinsic hepatic clearance, the structure-property relationships for lipophilicity, and thermodynamic solubility, led to the identification of Lu AF58801: a potent, orally available, brain penetrant PAM of the α7 nicotinic acetylcholine receptor, showing efficacy in a novel object recognition task in rats treated subchronically with phencyclidine (PCP).

Is there a role for the no observed adverse effect level in safety pharmacology?

In nonclinical toxicology the highest dose or exposure without test article-related adverse effects, known as the No Observed Adverse Effect Level (NOAEL), is a variable that may be determined. In safety pharmacology the vast majority of the endpoints measured are quantitative numeric functional endpoints such as changes in heart rate, blood pressure or respiratory frequency, endpoints that are usually not assessed using a defined framework of adversity. Therefore, we asked the question: is there a role for the NOAEL in safety pharmacology? To help answer this question, we conducted a survey via the Safety Pharmacology Society. We found that within safety pharmacology there is no formal definition of adversity and no guidance on defining NOAEL. We also found, perhaps unsurprisingly, there is no agreed rubric for using a NOAEL in safety pharmacology and we learned that the NOAEL is not a requirement in order to progress a new investigational drug through the regulatory process. Thus, a summary label such as NOAEL lacks nuance and disregards context in relation to the nature and the severity of the safety pharmacology findings. Consequently, defining 'adversity' and determining a NOAEL in safety pharmacology studies are not recommended since the range of functional endpoints investigated do not conform to a binary 'toxic/non-toxic' rubric. Focusing on describing test article-related effects on safety pharmacology endpoints, using reasoned arguments as part of an integrated risk assessment, will ensure that the clinical pharmacologists and regulatory bodies see a clear description of relevant findings at each dose or exposure level.

Ion currents of cardiomyocytes in different regions of the Göttingen minipig heart.

INTRODUCTION: The Göttingen minipig is a promising model for pharmacological safety assessment and for translational research in cardiology. We have examined the main ion currents in cardiomyocytes of the minipig heart. METHODS: Cardiac cells were isolated from different cardiac regions (endo-, mid- and epicardial left ventricle and right ventricle) from Göttingen minipigs and examined using the whole cell patch clamp technique combined with pharmacological interventions. RESULTS: The inward rectifier (IK1), the delayed rectifier (IK), with the rapid and slow components, (IKr, IKs) and the L-type Ca2+ channel (ICa,L) were identified in the different regions of the heart, whereas the Ca2+-independent transient outward current (Ito1) was observed in only a few cells. IK1 was similar in the cardiac regions with a slightly lower value in the epicardial cells. IKs was smaller in epi- and endo-cardial regions. DISCUSSION: The equivalents of the main human cardiac ion currents are present in the minipig cardiomyocytes with the exception of the Ca2+-independent Ito1. The study provides further evidence that the minipig is a valid model for investigating cardiovascular pharmacology.

Novel selective PDE type 1 inhibitors cause vasodilatation and lower blood pressure in rats.

BACKGROUND AND PURPOSE: The PDE enzymes (PDE1-11) hydrolyse and thus inactivate cyclic nucleotides and are important in the regulation of the cardiovascular system. Here,we have investigated the effects on the cardiovascular system, of two novel selective PDE1 inhibitors, Lu AF41228 and Lu AF58027. EXPERIMENTAL APPROACH: We used rat mesenteric small arteries (internal diameters of 200-300 µm), RT-PCR and measured isometric wall tension. Effects of Lu AF41228 and Lu AF58027 on heart rate and BP were assessed in both anaesthetized and conscious male rats. KEY RESULTS: Nanomolar concentrations of Lu AF41228 and Lu AF58027 inhibited PDE1A, PDE1B and PDE1C enzyme activity, while micromolar concentrations were required to observe inhibitory effects at other PDEs. RT-PCR revealed expression of PDE1A, PDE1B and PDE1C in rat brain, heart and aorta, but only PDE1A and PDE1B in mesenteric arteries. In rat isolated mesenteric arteries contracted with phenylephrine or U46619, Lu AF41228 and Lu AF58027 induced concentration-dependent relaxations which were markedly reduced by inhibitors of guanylate cyclase, ODQ, and adenylate cyclase, SQ22536, and in preparations without endothelium. In anaesthetized rats, Lu AF41228 and Lu AF58027 dose-dependently lowered mean BP and increased heart rate. In conscious rats with telemetric pressure transducers, repeated dosing with Lu AF41228 lowered mean arterial BP 10-15 mmHg and increased heart rate. CONCLUSIONS AND IMPLICATIONS: These novel PDE1 inhibitors induce vasodilation and lower BP, suggesting a potential use of these vasodilators in the treatment of hypertension and vasospasm.

Exploratory toxicology as an integrated part of drug discovery. Part I: Why and how.

Toxicity and clinical safety have major impact on drug development success. Moving toxicological studies into earlier phases of the R&D chain prevents drug candidates with a safety risk from entering clinical development. However, to identify candidates without such risk, safety has to be designed actively. Therefore, we argue that toxicology should be fully integrated into the discovery process. We describe our strategy, including safety assessment of novel targets, selection of chemical series without inherent liabilities, designing out risk factors and profiling of candidates, and we discuss considerations regarding what to screen for. We aim to provide timely go/no-go decisions (fail early) and direction to the discovery teams, by steering away from safety risk (showing what will not fail).

Exploratory toxicology as an integrated part of drug discovery. Part II: Screening strategies.

In an effort to reduce toxicity-related attrition, different strategies have been implemented throughout the pharmaceutical industry. Previously (in Part I), we have outlined our 'integrated toxicology' strategy, which aims to provide timely go/no-go decisions (fail early) but also to show a direction to the drug discovery teams (showing what will not fail). In this review (Part II of the series) we describe our compound testing strategies with respect to cardiovascular safety, hepatotoxicity, genotoxicity, immunotoxicity and exploratory in vivo toxicity. We discuss the in vitro, ex vivo and in vivo assays and models we employ to assess safety risks and optimize compound series during the drug discovery process, including their predictivity and the decisions they generate.

G-protein-coupled inward rectifier potassium current contributes to ventricular repolarization.

AIMS: The purpose of this study was to investigate the functional role of G-protein-coupled inward rectifier potassium (GIRK) channels in the cardiac ventricle. METHODS AND RESULTS: Immunofluorescence experiments demonstrated that GIRK4 was localized in outer sarcolemmas and t-tubules in GIRK1 knockout (KO) mice, whereas GIRK4 labelling was not detected in GIRK4 KO mice. GIRK4 was localized in intercalated discs in rat ventricle, whereas it was expressed in intercalated discs and outer sarcolemmas in rat atrium. GIRK4 was localized in t-tubules and intercalated discs in human ventricular endocardium and epicardium, but absent in mid-myocardium. Electrophysiological recordings in rat ventricular tissue ex vivo showed that the adenosine A1 receptor agonist N6-cyclopentyladenosine (CPA) and acetylcholine (ACh) shortened action potential duration (APD), and that the APD shortening was reversed by either the GIRK channel blocker tertiapin-Q, the adenosine A1 receptor antagonist DPCPX or by the muscarinic M2 receptor antagonist AF-DX 116. Tertiapin-Q prolonged APD in the absence of the exogenous receptor activation. Furthermore, CPA and ACh decreased the effective refractory period and the effect was reversed by either tertiapin-Q, DPCPX or AF-DX 116. Receptor activation also hyperpolarized the resting membrane potential, an effect that was reversed by tertiapin-Q. In contrast, tertiapin-Q depolarized the resting membrane potential in the absence of the exogenous receptor activation. CONCLUSION: Confocal microscopy shows that among species GIRK4 is differentially localized in the cardiac ventricle, and that it is heterogeneously expressed across human ventricular wall. Electrophysiological recordings reveal that GIRK current may contribute significantly to ventricular repolarization and thereby to cardiac electrical stability.

An evaluation of insertion sites for mini-implants: a micro - CT study of human autopsy material.

OBJECTIVE: (1) To report the thickness of the cortical bone in insertion sites commonly used for orthodontic mini-implants, (2) to assess the impact of a change in insertion angle on primary cortical bone-to-implant contact, and (3) to evaluate the risk of maxillary sinus perforation. MATERIALS AND METHODS: At autopsy, 27 human samples containing three to five adjacent teeth were excised and scanned using a table-top micro-computed tomography system. Bone thickness measurements were taken at 45° and 90° to the long the axis of the adjacent teeth, simulating a mini-implant insertion at the mid-root level. RESULTS: In the maxilla, the overall mean cortical thickness at 90° was 0.7 mm buccally in the lateral region, 1.0 mm buccally in the anterior region, and 1.3 mm palatally. In the mandible, the mean cortical thickness was 0.7 mm buccally and 1.8 mm lingually in the anterior region; 1.9 mm buccally and 2.6 mm lingually in the lateral region. Changing the insertion angle from 90° to 45° increased the cortical bone-to-implant contact by an average of 47%. Perpendicular insertion at the mid-root level only rarely interfered with the sinus, whereas apically inclined insertion increased the risk of sinus perforation. CONCLUSIONS: Buccally and palatally in the maxilla and buccally in the anterior mandible, the thickness of the alveolar cortical bone is often less than 1 mm. In contrast, the alveolar cortical bone is frequently thicker than 2 mm laterally in the mandible. Changing the insertion angle to 45° will generally enhance implant stability but increase the risk of perforation to the maxillary sinus.

Keeping the rhythm -- pro-arrhythmic investigations in isolated Göttingen minipig hearts.

INTRODUCTION: Cardiac arrhythmia is a potentially lethal condition. A better prediction and mechanistic understanding of human cardiac arrhythmia is dependent on the development of good animal models. Minipigs are increasingly being used in cardiovascular research and we hypothesize that Langendorff-perfused minipig hearts could serve as a novel model of pro-arrhythmia. METHODS: We studied arrhythmic biomarkers and overt arrhythmia using sharp electrode recordings and Langendorff-perfusion of minipig and dog hearts. Hearts were subjected to pharmacological blockade of repolarizing currents, chemical and surgical AV-block, and programmed electrical stimulation. RESULTS: Minipigs have significantly longer cardiac action potentials and QT intervals than dogs at comparable cycle lengths. In addition, minipigs were relatively resistant to arrhythmias in a variety of settings and arrhythmias were only observed in response to programmed electrical S1-S2 stimulation after surgical AV-ablation and combined I(Kr) and I(Ks) blockade. Accordingly, the short term variability of the action potential remained very low in minipigs. In addition, the electro-mechanical window (EMw) remained positive in both dog and minipig experiments, although the EMw approached negative values in dogs during I(Ks) blockade and ß-adrenergic stimulation. Isoprenaline- or pacing-induced changes in frequency resulted in paradoxical transient effects on repolarization. DISCUSSION: The evidence presented indicates that Langendorff-perfused Göttingen minipig hearts are resistant to the development of arrhythmias in experimental settings known to be pro-arrhythmic in other species including dogs. A possible mechanistic explanation could be the long electrical systole compared to dogs, combined with a short vulnerable window, recorded in minipig hearts. We also find that EMw recordings from Langendorff perfused hearts are less sensitive to I(Ks) blockade than what has been reported from in vivo experiments, most likely due to the mechanical properties of the recording apparatus.

Characterization of cardiac repolarization in the Göttingen minipig.

INTRODUCTION: The minipig represents an attractive experimental animal within cardiovascular research due to its extensive similarities to the human heart in terms of anatomy and physiology. Although minipigs have been used for cardiovascular research for decades no thorough characterization of the minipig cardiac electrophysiology has been performed. Therefore, we have for the first time characterized the minipig cardiac repolarization in a series of experiments ranging from mRNA quantification to in vivo studies. METHODS: Göttingen minipigs were used throughout the study. Cardiac mRNA quantification was performed using quantitative PCR methods. For ex vivo experiments, hearts were excised using cardioplegic procedures and Langendorff and microelectrode action potential recordings were performed. Effects of temperature in vivo were recorded in anesthetized animals. RESULTS: On the mRNA level the expression profile of major cardiac ion channel proteins in both atria and ventricle was very similar to what has been reported for humans. In both intact isolated heart and isolated endocardial strips the I(Kr) blocker dofetilide increased action potential duration (APD). The I(Ks) blocker HMR1556 increased APD and triangulation only when I(Kr) was blocked with dofetilide. In the presence of I(Kr) and I(Ks) blockade a reduction of [K+](e) resulted in a marked increase in APD(90) in isolated hearts. I(K1) blockade with Ba²+ increased APD in whole heart and isolated endocardium. In isolated endocardium, ß-adrenergic stimulation with isoprenaline resulted in an increase in APD and potential amplitude but a decrease in triangulation. There was a rate-dependent decrease in APD in both whole heart and isolated endocardium. In vivo and ex vivo investigations revealed a negative correlation between temperature and duration of cardiac repolarization. DISCUSSION: Our results point toward the minipig being a promising species for cardiac safety research.