Identification of tetrahydrocarbazoles as novel multifactorial drug candidates for treatment of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder and the most frequent cause of dementia. To date, there are only a few approved drugs for AD, which show little or no effect on disease progression. Impaired intracellular calcium homeostasis is believed to occur early in the cascade of events leading to AD. Here, we examined the possibility of normalizing the disrupted calcium homeostasis in the endoplasmic reticulum (ER) store as an innovative approach for AD drug discovery. High-throughput screening of a small-molecule compound library led to the identification of tetrahydrocarbazoles, a novel multifactorial class of compounds that can normalize the impaired ER calcium homeostasis. We found that the tetrahydrocarbazole lead structure, first, dampens the enhanced calcium release from ER in HEK293 cells expressing familial Alzheimer's disease (FAD)-linked presenilin 1 mutations. Second, the lead structure also improves mitochondrial function, measured by increased mitochondrial membrane potential. Third, the same lead structure also attenuates the production of amyloid-beta (A beta) peptides by decreasing the cleavage of amyloid precursor protein (APP) by beta-secretase, without notably affecting alpha- and gamma-secretase cleavage activities. Considering the beneficial effects of tetrahydrocarbazoles addressing three key pathological aspects of AD, these compounds hold promise for the development of potentially effective AD drug candidates

Water balance creates a threshold in soil pH at the global scale

Soil pH regulates the capacity of soils to store and supply nutrients, and thus contributes substantially to controlling productivity in terrestrial ecosystems. However, soil pH is not an independent regulator of soil fertility-rather, it is ultimately controlled by environmental forcing. In particular, small changes in water balance cause a steep transition from alkaline to acid soils across natural climate gradients. Although the processes governing this threshold in soil pH are well understood, the threshold has not been quantified at the global scale, where the influence of climate may be confounded by the effects of topography and mineralogy. Here we evaluate the global relationship between water balance and soil pH by extracting a spatially random sample (n = 20,000) from an extensive compilation of 60,291 soil pH measurements. We show that there is an abrupt transition from alkaline to acid soil pH that occurs at the point where mean annual precipitation begins to exceed mean annual potential evapotranspiration. We evaluate deviations from this global pattern, showing that they may result from seasonality, climate history, erosion and mineralogy. These results demonstrate that climate creates a nonlinear pattern in soil solution chemistry at the global scale; they also reveal conditions under which soils maintain pH out of equilibrium with modern climate

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field

Methane oxidation in freely and poorly drained grassland soils and effects of cattle urine application.

A sink for atmospheric methane (CH4) is microbial oxidation in soils. We report CH4 oxidation rates in freely and poorly drained soils on an intensively managed dairy farm. Following cattle urine application to half the plots (650 kg of nitrogen [N] ha(-1)) 31 chamber measurements were made over 100 d during autumn and winter. In the control plots, the freely and poorly drained soils' integrated CH4 oxidation rates averaged 1.8+/-0.2 and 0.6+/-0.1 kg CH4 ha(-1) yr(-1), respectively. In the poorly drained soil, the highest CH4 oxidation rates occurred when water-filled pore space (WFPS)<56% and CH4 oxidation rate declined by ninefold to near zero as WFPS increased from 56 to 68%. Urine application induced the freely and poorly drained soils' CH4 oxidation rates to decline for up to 2 mo by 0.7+/-0.2 and 0.4+/-0.1 kg CH4 ha(-1) yr(-1), respectively. The two soils' responses were thus not significantly different. After urine application, soil pore space CH4 concentration profiles suggested a simultaneous inhibition of bacteria that were CH4 oxidizers and stimulation of CH4 producers

Determining nitrous oxide emissions from subsurface measurements in grazed pasture: A field trial of alternative technology

Beneath pasture grazed by farmed animals, the soils nitrogen (N), oxygen, and temperature regimes can be unevenly distributed in time and space. It is difficult to capture spatial and temporal variation of N2O using conventional emission measurement technology based on gas samples taken in chambers that briefly cover a small area of the soils surface. We report the results from field deployment of alternative, non-intrusive N2O emission measurement technology that uses subsurface measurements incorporating the soil processes controlling the net N2O production and gas diffusion rates. During 100 autumn and winter days after dairy cattle urine was applied (650 kg N/ha) to freely and poorly drained pastoral soils near Hamilton, New Zealand (37.8° S, 175.3° E), N2O emissions were determined. The measured values ranged from 0.024 to 1.55 and 0.048 to 3.33 mg N2O-N/m2.h for the freely and poorly drained soils, respectively. Over the 100 days, it was estimated that 0.4 and 1.3% of the applied N was directly emitted to the atmosphere as N2O from the freely and poorly drained soils, respectivel

Soil carbon stock beneath an established irrigated pasture grazed by dairy cattle

Soils were sampled at intervals to 0.8 m depth on an irrigated dairy farm in the Canterbury region of New Zealand and a nearby (control) area with unimproved grasses which was not known to have been irrigated, fertilised or grazed by farmed animals. Eleven years earlier, the dairy farm had been converted from an unirrigated sheep farm. For each depth interval, we measured the bulk density and organic carbon (C) concentration. By volumetric calculations to depth 0.3 m, the irrigated site’s mean soil C stock was 28% greater than the control (10.0 ± 0.3 kg C m⁻² [±standard error] vs 7.8 ± 0.6 kg C m⁻²), a statistically significant difference (P < 0.05). In contrast, by volumetric calculations to depth 0.8 m and on an equivalent soil mass basis, the corresponding differences were not statistically significant (13.0 ± 0.4 vs 12.9 ± 0.2 kg C m⁻² and 11.6 ± 0.4 vs 12.9 ± 0.2 kg C m⁻² respectively). Although C stock change was inferred by sampling soils on irrigated and control sites, these results suggested changes can depend on the sampling depth and calculation basis

Determining the nitrous oxide transfer velocity and emission factor of an agricultural drain

There have been few studies examining indirect nitrous oxide (N₂O) emissions (E N₂O ) associated with nitrogen (N) leaching from agricultural soils. For agricultural drainage water, N₂O equals the water’s E N₂O concentration in excess of the atmospheric value multiplied by the N₂O transfer velocity (V N₂O ). Using this equation, tracers and chamber methods, E N₂O and V N₂O were measured from an agricultural drain. Estimates of V N₂O were made by measuring water speed and depth using the relationship developed by O’Connor and Dobbins [1958. Mechanisms of reaeration in natural streams. Transactions of the American Society of Civil Engineers. 123:641–684]. The measurements and estimates were not significantly different and V N₂O averaged 5 m d⁻¹ . Alternatively, for the method developed by the Intergovernmental Panel on Climate Change, E N₂O equals the mass of N flowing in the water multiplied by an emission factor (EF). By additional measurements of the drain’s width, the water’s flow rate and nitrate (NO₃⁻) concentration, the estimated EF was 1.2 × 10⁻⁴ kg N₂O kg⁻¹ NO₃⁻ − N

Nitrous oxide emissions from in situ deposition of ¹⁵N-labeled ryegrass litter in a pasture soil

During pasture grazing, freshly harvested herbage (litterfall) is dropped onto soils from the mouths of dairy cattle, potentially inducing nitrous oxide (N₂O) emissions. Although the Intergovernmental Panel on Climate Change (IPCC) recommends accounting for N₂O emissions from arable crop residues in national inventories, emissions from the litterfall of grazed pasture systems are not recognized. The objective of this study was to investigate the potential of litterfall to contribute to N₂O emissions in a field study located on a pasture site in Canterbury, New Zealand (43°38.50' S, 172°27.17' E). We applied ¹⁵N-labeled perennial ryegrass (Lolium perenne L.) to the surface of a pastoral soil (Temuka clay loam) and, for up to 139 d thereafter, quantified the contribution of herbage decomposition to N₂O production and soil N dynamics. Litterfall contributed to the ¹⁵N enrichment of soil NO₃-N and N₂O-N pools. After 49 d, ¹⁵N recovery as N₂O equated to 0.93% of the surface-applied litter ¹⁵N, with 38 to 75% of the cumulative N₂O flux occurring within 4 to 10 d of treatment application. Emissions of N₂O likely resulted from ammonification followed by a coupling of nitrification and denitrification during litter decomposition on the soil surface. The emission factor of the litter deposited in situ was 1.2 ± 0.2%, which is not substantially greater than the IPCC default emission factor value of 1% for crop residues. Further in situ studies using different pasture species and litterfall rates are required to understand the microbial processes responsible for litter-induced N₂O emissions