Exploring management and environment effects on edge-of-field phosphorus losses with linear mixed models.

Evaluating how weather, farm management, and soil conditions impact phosphorus (P) loss from agricultural sites is essential for improving our waterways in agricultural watersheds. In this study, rainfall characteristics, manure application timing, tillage, surface condition, and soil test phosphorus (STP) were analyzed to determine their effects on total phosphorus (TP) and dissolved phosphorus (DP) loss using 125 site-years of runoff data collected by the University of Wisconsin Discovery Farms and Discovery Farms Minnesota. Three linear mixed models (LMMs) were then used to evaluate the influence of those factors on TP and DP losses: (1) a model that included all runoff events, (2) manured sites only, and (3) precipitation events only.

Lipophilic bisphosphonates reduced cyst burden and ameliorated hyperactivity of mice chronically infected with .

The current treatments for toxoplasmosis are only active against fast-growing tachyzoites, present in acute infections, with little effect on slow-growing bradyzoites within tissue cysts, present in latent chronic infections. The mitochondrion of is essential for its survival, and one of the major anti-parasitic drugs, atovaquone, inhibits the mitochondrial electron transport chain at the coenzyme Q:cytochrome c oxidoreductase site. Coenzyme Q (also known as ubiquinone [UQ]) consists of a quinone head and a lipophilic, isoprenoid tail that anchors UQ to membranes.

The Tuberculosis Drug Candidate SQ109 and Its Analogs Have Multistage Activity against .

Toward repositioning the antitubercular clinical candidate SQ109 as an antimalarial, analogs were investigated for structure-activity relationships for activity against asexual blood stages of the human malaria parasite pathogenic forms, as well as transmissible, sexual stage gametocytes. We show that equipotent activity (IC) in the 100-300 nM range could be attained for both asexual and sexual stages, with the activity of most compounds retained against a multidrug-resistant strain. The multistage activity profile relies on high lipophilicity ascribed to the adamantane headgroup, and antiplasmodial activity is critically dependent on the diamine linker.

Who dies from venous thromboembolism after hospitalisation for other reasons in England?: a national retrospective cohort study.

Objectives: Venous thromboembolism (VTE) is a major cause of morbidity and mortality globally, with hospital-associated thrombosis (HAT) accounting for at least half of VTE. We set out to understand more about deaths from HAT in England, to focus improvement efforts where they are needed most.

Design: A retrospective cohort combining death certification and hospital activity data to identify people with an inpatient or day case hospitalisation where no VTE diagnosis was recorded, and who died from VTE in a hospital or within 90 days of discharge, between April 2017 and March 2020.

The importance of accounting method and sampling depth to estimate changes in soil carbon stocks.

Background: As interest in the voluntary soil carbon market surges, carbon registries have been developing new soil carbon measurement, reporting, and verification (MRV) protocols. These protocols are inconsistent in their approaches to measuring soil organic carbon (SOC). Two areas of concern include the type of SOC stock accounting method (fixed-depth (FD) vs.

A double-blind comparison of morphological and collagen fingerprinting (ZooMS) methods of skeletal identifications from Paleolithic contexts.

Modeling the subsistence strategies of prehistoric groups depends on the accuracy of the faunal identifications that provide the basis for these models. However, our knowledge remains limited about the reproducibility of published taxonomic identifications and how they accurately reflect the range of species deposited in the archaeological record. This study compares taxonomic identifications at three Paleolithic sites (Saint-Césaire and Le Piage in France, Crvena Stijena in Montenegro) characterized by high levels of fragmentation.

Phosphoantigens glue butyrophilin 3A1 and 2A1 to activate Vγ9Vδ2 T cells.

In both cancer and infections, diseased cells are presented to human Vγ9Vδ2 T cells through an 'inside out' signalling process whereby structurally diverse phosphoantigen (pAg) molecules are sensed by the intracellular domain of butyrophilin BTN3A1. Here we show how-in both humans and alpaca-multiple pAgs function as 'molecular glues' to promote heteromeric association between the intracellular domains of BTN3A1 and the structurally similar butyrophilin BTN2A1. X-ray crystallography studies visualized that engagement of BTN3A1 with pAgs forms a composite interface for direct binding to BTN2A1, with various pAg molecules each positioned at the centre of the interface and gluing the butyrophilins with distinct affinities.

Investigation into the Mechanism of Action of the Tuberculosis Drug Candidate SQ109 and Its Metabolites and Analogues in Mycobacteria.

We tested a series of SQ109 analogues against and , in addition to determining their uncoupling activity. We then investigated potential protein targets, involved in quinone and cell wall biosynthesis, using "rescue" experiments. There was little effect of menaquinone on growth inhibition by SQ109, but there were large increases in the IC of SQ109 and its analogues (up to 20×) on addition of undecaprenyl phosphate (Up), a homologue of the mycobacterial decaprenyl (C) diphosphate.

Distinct Energy-Coupling Factor Transporter Subunits Enable Flavin Acquisition and Extracytosolic Trafficking for Extracellular Electron Transfer in Listeria monocytogenes.

A variety of electron transfer mechanisms link bacterial cytosolic electron pools with functionally diverse redox activities in the cell envelope and extracellular space. In Listeria monocytogenes, the ApbE-like enzyme FmnB catalyzes extracytosolic protein flavinylation, covalently linking a flavin cofactor to proteins that transfer electrons to extracellular acceptors. L.

Synthesis and Testing of Analogs of the Tuberculosis Drug Candidate SQ109 against Bacteria and Protozoa: Identification of Lead Compounds against and Malaria Parasites.

SQ109 is a tuberculosis drug candidate that has high potency against and is thought to function at least in part by blocking cell wall biosynthesis by inhibiting the MmpL3 transporter. It also has activity against bacteria and protozoan parasites that lack MmpL3, where it can act as an uncoupler, targeting lipid membranes and Ca homeostasis. Here, we synthesized 18 analogs of SQ109 and tested them against , , , , and , as well as against the protozoan parasites , , , , and .

The Heptaprenyl Diphosphate Synthase (Coq1) Is the Target of a Lipophilic Bisphosphonate That Protects Mice against Toxoplasma gondii Infection.

Prenyldiphosphate synthases catalyze the reaction of allylic diphosphates with one or more isopentenyl diphosphate molecules to form compounds such as farnesyl diphosphate, used in, e.g., sterol biosynthesis and protein prenylation, as well as longer "polyprenyl" diphosphates, used in ubiquinone and menaquinone biosynthesis.

A Structural and Bioinformatics Investigation of a Fungal Squalene Synthase and Comparisons with Other Membrane Proteins.

There is interest in the development of drugs to treat fungal infections due to the increasing threat of drug resistance, and here, we report the first crystallographic structure of the catalytic domain of a fungal squalene synthase (SQS), SQS (AfSQS), a potential drug target, together with a bioinformatics study of fungal, human, and protozoal SQSs. Our X-ray results show strong structural similarities between the catalytic domains in these proteins, but, remarkably, using bioinformatics, we find that there is also a large, highly polar helix in the fungal proteins that connects the catalytic and membrane-anchoring transmembrane domains. This polar helix is absent in squalene synthases from all other lifeforms.

In Vivo Efficacy of SQ109 against , spp. and and In Vitro Activity of SQ109 Metabolites.

SQ109 is an anti-tubercular drug candidate that has completed Phase IIb/III clinical trials for tuberculosis and has also been shown to exhibit potent in vitro efficacy against protozoan parasites including and spp. However, its in vivo efficacy against protozoa has not been reported. Here, we evaluated the activity of SQ109 in mouse models of spp.

Crediting agricultural soil carbon sequestration.

Regional consistency is necessary for carbon credit integrity.

Differential Effect of Light and Dark Period Sleep Fragmentation on Composition of Gut Microbiome and Inflammation in Mice.

Bi-directional interactions amongst the gut microbiota, immune system, and brain function are thought to be critical mediators of health and disease. The role sleep plays in mediating these interactions is not known. We assessed the effects of sleep fragmentation (SF) on the microbiota-gut-brain axis.

Mycobacterial membrane protein Large 3-like-family proteins in bacteria, protozoa, fungi, plants, and animals: A bioinformatics and structural investigation.

Lipid transporters play an important role in most if not all organisms, ranging from bacteria to humans. For example, in Mycobacterium tuberculosis, the trehalose monomycolate transporter MmpL3 is involved in cell wall biosynthesis, while in humans, cholesterol transporters are involved in normal cell function as well as in disease. Here, using structural and bioinformatics information, we propose that there are proteins that also contain "MmpL3-like" (MMPL) transmembrane (TM) domains in many protozoa, including Trypanosoma cruzi, as well as in the bacterium Staphylococcus aureus, where the fatty acid transporter FarE has the same set of "active-site" residues as those found in the mycobacterial MmpL3s, and in T.

Structure, Detection, and Antibacterial Activity of Metabolites of SQ109, an Anti-Infective Drug Candidate.

SQ109 is a drug candidate for the treatment of tuberculosis (TB). It is thought to target primarily the protein MmpL3 in , but it also inhibits the growth of some other bacteria. SQ109 is metabolized by the liver, and it has been proposed that some of its metabolites might be responsible for its activity against TB.

Immuno-antibiotics: targeting microbial metabolic pathways sensed by unconventional T cells.

Human Vγ9/Vδ2 T cells, mucosal-associated invariant T (MAIT) cells, and other unconventional T cells are specialised in detecting microbial metabolic pathway intermediates that are absent in humans. The recognition by such semi-invariant innate-like T cells of compounds like ()-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), the penultimate metabolite in the MEP isoprenoid biosynthesis pathway, and intermediates of the riboflavin biosynthesis pathway and their metabolites allows the immune system to rapidly sense pathogen-associated molecular patterns that are shared by a wide range of micro-organisms. Given the essential nature of these metabolic pathways for microbial viability, they have emerged as promising targets for the development of novel antibiotics.

Positive long-term impacts of restoration on soils in an experimental urban forest.

As urbanization increases worldwide, investments in nature-based solutions that aim to mitigate urban stressors and counter the impacts of global climate change are also on the rise. Tree planting on degraded urban lands-or afforestation-is one form of nature-based solution that has been increasingly implemented in cities around the world. The benefits of afforestation are, however, contingent on the capacity of soils to support the growth of planted trees, which poses a challenge in some urban settings where unfavorable soil conditions limit tree performance.

Discovery of Prenyltransferase Inhibitors with and Antibacterial Activity.

-prenyltransferases such as undecaprenyl diphosphate synthase (UPPS) and decaprenyl diphosphate synthase (DPPS) are essential enzymes in bacteria and are involved in cell wall biosynthesis. UPPS and DPPS are absent in the human genome, so they are of interest as targets for antibiotic development. Here, we screened a library of 750 compounds from National Cancer Institute Diversity Set V for the inhibition of DPPS and found 17 hits, and then ICs were determined using dose-response curves.