Co-located ecological data for exploring top- and subsoil carbon dynamics across grassland-woodland contrasts.

Soil organic carbon (SOC) is a soil health indicator and understanding dynamics changing SOC stocks will help achieving net zero goals. Here we present four datasets featuring 11,750 data points covering co-located aboveground and below-ground metrics for exploring ecosystem SOC dynamics. Five sites across England with an established land use contrast, grassland and woodland next to each other, were rigorously sampled for aboveground (n = 109), surface (n = 33 soil water release curves), topsoil, and subsoil metrics. Commonly measured soil metrics were analysed in five soil increments for 0-1 metre (n = 4550). Less commonly measured soil metrics which were assumed to change across the soil profile were measured on a subset of samples only (n = 3762). Additionally, we developed a simple method for soil organic matter fractionation using density fractionation which is part of the less common metrics. Finally, soil metrics which may impact SOC dynamics, but with less confidence as to their importance across the soil profile were only measured on topsoil (~5-15 cm = mineral soil) and subsoil (below 50 cm) samples (n = 2567).

Sex, Endothelial Cell Functions, and Peripheral Artery Disease.

Peripheral artery disease (PAD) is caused by blocked arteries due to atherosclerosis and/or thrombosis which reduce blood flow to the lower limbs. It results in major morbidity, including ischemic limb, claudication, and amputation, with patients also suffering a heightened risk of heart attack, stroke, and death. Recent studies suggest women have a higher prevalence of PAD than men, and with worse outcomes after intervention. In addition to a potential unconscious bias faced by women with PAD in the health system, with underdiagnosis, and lower rates of guideline-based therapy, fundamental biological differences between men and women may be important. In this review, we highlight sexual dimorphisms in endothelial cell functions and how they may impact PAD pathophysiology in women. Understanding sex-specific mechanisms in PAD is essential for the development of new therapies and personalized care for patients with PAD.

Structure-Guided Design and Synthesis of a Pyridazinone Series of Trypanosoma cruzi Proteasome Inhibitors.

There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, a preclinical candidate for visceral leishmaniasis which acted through inhibition of the Leishmania proteasome. A related analogue, active against Trypanosoma cruzi, showed suboptimal efficacy in an animal model of Chagas disease, so alternative proteasome inhibitors were investigated. Screening a library of phenotypically active analogues against the T. cruzi proteasome identified an active, selective pyridazinone, the development of which is described herein. We obtained a cryo-EM co-structure of proteasome and a key inhibitor and used this to drive optimization of the compounds. Alongside this, optimization of the absorption, distribution, metabolism, and excretion (ADME) properties afforded a suitable compound for mouse efficacy studies. The outcome of these studies is discussed, alongside future plans to further understand the series and its potential to deliver a new treatment for Chagas disease.

Development of soil health benchmarks for managed and semi-natural landscapes.

Efforts to improve soil health require that target values of key soil properties are established. No agreed targets exist but providing population data as benchmarks is a useful step to standardise soil health comparison between landscapes. We exploited nationally representative topsoil (0-15 cm) measurements to derive soil health benchmarks for managed and semi-natural environments across Great Britain. In total, 4587 soil organic matter (SOM), 3860 pH, 2908 bulk density (BD), and 465 earthworm abundance (EA) datapoints were used. As soil properties are sensitive to site-specific characteristics, data were stratified by habitat, soil type, and mean annual precipitation, with benchmarks defined as the middle 80 % of values in each distribution - yielding 135 benchmarks. BD and pH decreased with land management intensity (agriculture > semi-natural grasslands > woodlands > heathlands > wetlands), and vice versa for SOM and EA. Normalising benchmark ranges by medians revealed soil health indicator benchmark widths increased in the order: pH < BD < SOM < EA, while width increased with decreasing land management intensity. Arable and horticulture and improved grassland exhibited narrow benchmarks for SOM, pH and BD, yet the widest EA benchmark, suggesting additional drivers impact EA patterns. Upland wetlands had the widest BD benchmarks, important when determining carbon stocks. East Anglia currently possesses the largest proportions of atypical soils, including below typical SOM (19.2 %), above typical BD (17.4 %) and pH (39.1 %), and the smallest proportions of above typical SOM (2.4 %), and below typical BD (5.8 %) and pH (2.3 %). This is found even after land use, soil type and rainfall have been considered, underscoring how urgently soil health should be addressed here. Our benchmarking framework allows landowners to compare where their measured soil health indicators fall within expected ranges and is applicable to other biomes, national and multinational contexts.

A hidden problem: peripheral artery disease in women.

Peripheral artery disease (PAD) has a huge social and economic burden and is an important contributor to the global health burden. Sex differences in PAD are apparent, with recent data suggesting equal if not greater prevalence in women, and women having worse clinical outcomes. Why this occurs is not clear. To identify underlying reasons for gender inequalities in PAD, we executed a deeper exploration through a social constructive perspective. A scoping review was conducted using the World Health Organization model for analysis of gender-related needs in healthcare. Complex interacting factors, including biological, clinical, and societal variables, were reviewed to highlight gender-related inequities in the diagnosis, treatment, and management of PAD. Current gaps in knowledge were identified and insights into future directions aimed at improving these inequalities were discussed. Our findings highlight the multi-level complexities that need to be considered for strategies to improve gender-related needs in PAD healthcare.

Agricultural practices drive elevated rates of topsoil decline across Kenya, but terracing and reduced tillage can reverse this.

As agricultural land area increases to feed an expanding global population, soil erosion will likely accelerate, generating unsustainable losses of soil and nutrients. This is critical for Kenya where cropland expansion and nutrient loading from runoff and erosion is contributing to eutrophication of freshwater ecosystems and desertification. We used the Revised Universal Soil Loss Equation (RUSLE) to predict soil erosion rates under present land cover and potential natural vegetation nationally across Kenya. Simulating natural vegetation conditions allows the degree to which erosion rates are elevated under current land use practices to be determined. This methodology exploits new digital soil maps and two vegetation cover maps to model topsoil (top 20 cm) erosion rates, lifespans (the mass of topsoil divided by erosion rate), and lateral nutrient fluxes (nutrient concentration times erosion rate) under both scenarios. We estimated the mean soil erosion rate under current land cover at ~5.5 t ha-1 yr-1, ~3 times the rate estimated for natural vegetation cover (~1.8 t ha-1 yr-1), and equivalent to ~320 Mt yr-1 of topsoil lost nationwide. Under present erosion rates, ~8.8 Mt, ~315 Kt, and ~ 110 Kt of soil organic carbon, nitrogen and phosphorous are lost from soil every year, respectively. Further, 5.3 % of topsoils (~3.1 Mha), including at >25 % of croplands, have short lifespans (<100 years). Additional scenarios were tested that assume combinations of terracing and reduced tillage practices were adopted on croplands to mitigate erosion. Establishing bench terraces with zoned tillage could reduce soil losses by ≥75 %; up to 87.1 t ha-1 yr-1. These reductions are comparable to converting croplands to natural vegetation, demonstrating most agricultural soils can be conserved successfully. Extensive long-term monitoring of croplands with terraces and reduced tillage established is required to verify the efficacy of these agricultural support practices as indicated by our modelling.

Factors associated with successful median arcuate ligament release in an international, multi-institutional cohort.

OBJECTIVE: Prior research on median arcuate ligament syndrome has been limited to institutional case series, making the optimal approach to median arcuate ligament release (MALR) and resulting outcomes unclear. In the present study, we compared the outcomes of different approaches to MALR and determined the predictors of long-term treatment failure. METHODS: The Vascular Low Frequency Disease Consortium is an international, multi-institutional research consortium. Data on open, laparoscopic, and robotic MALR performed from 2000 to 2020 were gathered. The primary outcome was treatment failure, defined as no improvement in median arcuate ligament syndrome symptoms after MALR or symptom recurrence between MALR and the last clinical follow-up. RESULTS: For 516 patients treated at 24 institutions, open, laparoscopic, and robotic MALR had been performed in 227 (44.0%), 235 (45.5%), and 54 (10.5%) patients, respectively. Perioperative complications (ileus, cardiac, and wound complications; readmissions; unplanned procedures) occurred in 19.2% (open, 30.0%; laparoscopic, 8.9%; robotic, 18.5%; P < .001). The median follow-up was 1.59 years (interquartile range, 0.38-4.35 years). For the 488 patients with follow-up data available, 287 (58.8%) had had full relief, 119 (24.4%) had had partial relief, and 82 (16.8%) had derived no benefit from MALR. The 1- and 3-year freedom from treatment failure for the overall cohort was 63.8% (95% confidence interval [CI], 59.0%-68.3%) and 51.9% (95% CI, 46.1%-57.3%), respectively. The factors associated with an increased hazard of treatment failure on multivariable analysis included robotic MALR (hazard ratio [HR], 1.73; 95% CI, 1.16-2.59; P = .007), a history of gastroparesis (HR, 1.83; 95% CI, 1.09-3.09; P = .023), abdominal cancer (HR, 10.3; 95% CI, 3.06-34.6; P < .001), dysphagia and/or odynophagia (HR, 2.44; 95% CI, 1.27-4.69; P = .008), no relief from a celiac plexus block (HR, 2.18; 95% CI, 1.00-4.72; P = .049), and an increasing number of preoperative pain locations (HR, 1.12 per location; 95% CI, 1.00-1.25; P = .042). The factors associated with a lower hazard included increasing age (HR, 0.99 per increasing year; 95% CI, 0.98-1.0; P = .012) and an increasing number of preoperative diagnostic gastrointestinal studies (HR, 0.84 per study; 95% CI, 0.74-0.96; P = .012) Open and laparoscopic MALR resulted in similar long-term freedom from treatment failure. No radiographic parameters were associated with differences in treatment failure. CONCLUSIONS: No difference was found in long-term failure after open vs laparoscopic MALR; however, open release was associated with higher perioperative morbidity. These results support the use of a preoperative celiac plexus block to aid in patient selection. Operative candidates for MALR should be counseled regarding the factors associated with treatment failure and the relatively high overall rate of treatment failure.

Endothelial cell dysfunction: Implications for the pathogenesis of peripheral artery disease.

Peripheral artery disease (PAD) is caused by occluded or narrowed arteries that reduce blood flow to the lower limbs. The treatment focuses on lifestyle changes, management of modifiable risk factors and vascular surgery. In this review we focus on how Endothelial Cell (EC) dysfunction contributes to PAD pathophysiology and describe the largely untapped potential of correcting endothelial dysfunction. Moreover, we describe current treatments and clinical trials which improve EC dysfunction and offer insights into where future research efforts could be made. Endothelial dysfunction could represent a target for PAD therapy.

Lysyl-tRNA synthetase, a target for urgently needed M. tuberculosis drugs.

Tuberculosis is a major global cause of both mortality and financial burden mainly in low and middle-income countries. Given the significant and ongoing rise of drug-resistant strains of Mycobacterium tuberculosis within the clinical setting, there is an urgent need for the development of new, safe and effective treatments. Here the development of a drug-like series based on a fused dihydropyrrolidino-pyrimidine scaffold is described. The series has been developed against M. tuberculosis lysyl-tRNA synthetase (LysRS) and cellular studies support this mechanism of action. DDD02049209, the lead compound, is efficacious in mouse models of acute and chronic tuberculosis and has suitable physicochemical, pharmacokinetic properties and an in vitro safety profile that supports further development. Importantly, preliminary analysis using clinical resistant strains shows no pre-existing clinical resistance towards this scaffold.

Global meta-analysis of soil hydraulic properties on the same soils with differing land use.

Global land use change has resulted in more pasture and cropland, largely at the expense of woodlands, over the last 300 years. How this change affects soil hydraulic function with regard to feedbacks to the hydrological cycle is unclear for earth system modelling (ESM). Pedotransfer functions (PTFs) used to predict soil hydraulic conductivity (K) take no account of land use. Here, we synthesize >800 measurements from around the globe from sites that measured near-saturated soil hydraulic conductivity, or infiltration, at the soil surface, on the same soil type at each location, but with differing land use, woodland (W), grassland (G) and cropland (C). We found that texture based PTFs predict K reasonably well for cropland giving unbiased results, but increasingly underestimate K in grassland and woodland. In native woodland and grassland differences in K can usually be accounted for by differences in bulk density. However, heavy grazing K responses can be much lower indicating compaction likely reduces connectivity. We show that the K response ratios (RR) between land uses vary with cropland (C/W = 0.45 [W/C = 2.2]) and grassland (G/W = 0.63 [W/G = 1.6]) having about half the K of woodland.

Toolkit of Approaches To Support Target-Focused Drug Discovery for Plasmodium falciparum Lysyl tRNA Synthetase.

There is a pressing need for new medicines to prevent and treat malaria. Most antimalarial drug discovery is reliant upon phenotypic screening. However, with the development of improved target validation strategies, target-focused approaches are now being utilized. Here, we describe the development of a toolkit to support the therapeutic exploitation of a promising target, lysyl tRNA synthetase (PfKRS). The toolkit includes resistant mutants to probe resistance mechanisms and on-target engagement for specific chemotypes; a hybrid KRS protein capable of producing crystals suitable for ligand soaking, thus providing high-resolution structural information to guide compound optimization; chemical probes to facilitate pulldown studies aimed at revealing the full range of specifically interacting proteins and thermal proteome profiling (TPP); as well as streamlined isothermal TPP methods to provide unbiased confirmation of on-target engagement within a biologically relevant milieu. This combination of tools and methodologies acts as a template for the development of future target-enabling packages.

GloSEM: High-resolution global estimates of present and future soil displacement in croplands by water erosion.

Healthy soil is the foundation underpinning global agriculture and food security. Soil erosion is currently the most serious threat to soil health, leading to yield decline, ecosystem degradation and economic impacts. Here, we provide high-resolution (ca. 100 × 100 m) global estimates of soil displacement by water erosion obtained using the Revised-Universal-Soil-Loss-Equation-based Global Soil Erosion Modelling (GloSEM) platform under present (2019) and future (2070) climate scenarios (i.e. Shared Socioeconomic Pathway [SSP]1-Representative Concentration Pathway [RCP]2.6, SSP2-RCP4.5 and SSP5-RCP8.5). GloSEM is the first global modelling platform to take into account regional farming systems, the mitigation effects of conservation agriculture (CA), and climate change projections. We provide a set of data, maps and descriptive statistics to support researchers and decision-makers in exploring the extent and geography of soil erosion, identifying probable hotspots, and exploring (with stakeholders) appropriate actions for mitigating impacts. In this regard, we have also provided an Excel spreadsheet that can provide useful insights into the potential mitigating effects of present and future alternative CA scenarios at the country level.

The function and phylogeny of eye movements.

Good vision requires images on the retina to be reasonably stable. However, motion of objects in the world, or motion of the eyes in space, can cause images to slip across the retina. If images move across the retina too fast or are too far from the area of greatest sensitivity, vision becomes degraded. Thus, the oculomotor systems serve vision by stabilizing images on the retina despite object or body movements. Control of eye movements is divided among several systems. Failure of these systems lead to specific clinical disorders.

The behavior of motoneurons.

Eye movements occur when motor neurons (cranial nerves III, IV and VI) discharge and cause contractions of the extraocular muscles. Movements of the eye are influenced by several main factors: the force generated in each muscle, the inertia of the globe, the viscous and elastic properties of the muscles, and the viscoelasticity of the suspensory orbital tissues (all of which constitute the oculomotor plant). Overall, the response of the plant is sluggish, so the innervation to the muscles must have a specific time-course of activation. Otherwise, the movements of the eye would be too slow and would lead to smearing of images across the retina. Differential equations are derived that describe the activity in motoneurons and the response of the plant.

Basic framework of the vestibulo-ocular reflex.

Direct and indirect pathways mediating the vestibulo-ocular reflexes, considering contributions made by the vestibular commissure, cerebellum, and vestibular efferent neurons are reviewed. This background leads to a detailed treatment of three-dimensional aspects of the vestibulo-ocular reflex, comparing the planes of the labyrinthine semicircular canals with the pulling directions of the extraocular muscles. By applying matrix algebra and rotational vectors, Robinson provides insights into the comparative anatomy of the vestibular system in different species, how central circuits process raw vestibular signals in three dimensions, and how the directions of eye movement caused by brainstem and cerebellar lesions can be explained.

Oculomotor signals.

Drawing on electrophysiological data, and assuming that each neuronal population has similar discharge properties, Robinson proposes a series of differential equations to describe the activity of key populations of neurons that contribute to the control of eye movements. Rotations of the eyes are related to the activity of ocular motoneurons. Equations describe the vestibular, visual and saccadic inputs to the motoneurons. The quantitative properties of component neurons in the saccadic and vestibular systems are derived. Consideration is also given to the neural signals underlying combined eye-head movements, and the problems posed by neural noise. These simple differential equations are used in later chapters to build neuromimetic, mathematical models of the vestibular-optokinetic, saccadic, and pursuit systems.

Signal processing in the vestibulo-ocular reflex.

In this chapter, Robinson develops models to account for the neural control of the vestibulo-ocular reflex in response to horizontal and vertical head rotations. By combining knowledge of the discharge properties of the several subpopulations of neurons that contribute to vestibular eye movements with their known anatomical connections, these models seek to explain how specific signals are combined to enable the ocular motoneurons to program vestibular eye movements that compensate for head perturbations. Details such as the integration of raw vestibular signals, differences in the neuronal processing for vertical versus horizontal reflexes, and the role of individual pathways such as the medial longitudinal fasciculus are discussed.

Plasticity and repair of the vestibulo-ocular reflex.

It is self-evident, once one thinks about it, that the vestibulo-ocular reflex must have caretaker systems that keep it operating correctly over the span of a lifetime. When a movement is not correct (e.g., in position, speed, direction) it is said to be dysmetric. For the vestibulo-ocular reflex (VOR), if eye velocity is not equal and opposite to head velocity within reasonable limits, one has vestibulo-ocular dysmetria. Consequently, the function of the caretaker systems is to eliminate vestibulo-ocular dysmetria. These systems are first required to act just after birth when the gain of the reflex is usually not normal, and must be initially calibrated; and then maintained as the animal grows older; and then in adult life an important function of the caretaker systems is the compensation required after damage. The mechanisms of this caretaker system and ensuring motor learning is the focus of this chapter.

The behavior of the optokinetic system.

Optokinetic responses in several species are compared, describing differences in afoveate and foveate animals, and the effects of visual testing conditions, including directions of stimulus motion. Smooth pursuit contributes to responses to full-field visual motion in foveate species; in the latter, measurement of optokinetic after-nystagmus in darkness allows investigation of the optokinetic system. The concept of optokinetic-vestibular symbiosis and velocity storage are discussed, pertinent electrophysiological studies (such as vestibular nucleus neurons that respond to both optokinetic and vestibular stimuli) are reviewed and a model is developed. The different purposes and properties of optokinetic responses (to maintain clear vision during self-rotation) and smooth pursuit (to visually track a moving target) are clarified.