Novel Type II Fatty Acid Biosynthesis (FAS II) Inhibitors as Multistage Antimalarial Agents

Malaria is a potentially fatal disease caused by Plasmodium parasites and poses a major medical risk in large parts of the world. The development of new, affordable antimalarial drugs is of vital importance as there are increasing reports of resistance to the currently available therapeutics. In addition, most of the current drugs used for chemoprophylaxis merely act on parasites already replicating in the blood. At this point, a patient might already be suffering from the symptoms associated with the disease and could additionally be infectious to an Anopheles mosquito. These insects act as a vector, subsequently spreading the disease to other humans. In order to cure not only malaria but prevent transmission as well, a drug must target both the blood‐ and pre‐erythrocytic liver stages of the parasite. P. falciparum (Pf) enoyl acyl carrier protein (ACP) reductase (ENR) is a key enzyme of plasmodial type II fatty acid biosynthesis (FAS II). It has been shown to be essential for liver‐stage development of Plasmodium berghei and is therefore qualified as a target for true causal chemoprophylaxis. Using virtual screening based on two crystal structures of PfENR, we identified a structurally novel class of FAS inhibitors. Subsequent chemical optimization yielded two compounds that are effective against multiple stages of the malaria parasite. These two most promising derivatives were found to inhibit blood‐stage parasite growth with IC₅₀ values of 1.7 and 3.0 μM and lead to a more prominent developmental attenuation of liver‐stage parasites than the gold‐standard drug, primaquine.     

Effects of Added Phosphates on Lipid Stability During Salt Curing and Rehydration of Cod (Gadus morhua)

Effects of added phosphates on retardation of lipid oxidation of salted cod during processing, storage and after rehydration were investigated. Lipid hydrolysis progress and development of color, primary and secondary lipid oxidation products and fluorescence intensities were determined. Added phosphates significantly retarded lipid hydrolysis and lipid oxidation progress, resulting in lower free fatty acid , lipid hydroperoxides (PV), thiobarbituric acid-reactive substances (TBARS) as well as fluorescence intensities (δF _or and δF _aq). Significant correlation between the lipid oxidation products (PV, TBARS, δF _or and δF _aq) and yellow/brownish discoloration (b* value) of salted cod was observed. Principal component analysis showed that TBARS, b* value and δF _or were the strongest indicators of lipid oxidation during salting and storage.     

Probing the Role of Backbone Hydrogen Bonding in a Critical β Sheet of the Extracellular Domain of a Cys‐Loop Receptor

Probing the sheet : The network of hydrogen bonds formed in the outer β sheet of the nicotinic acetylcholine receptor (nAChR; see figure) is fairly robust and tolerates single amide‐to‐ester mutations throughout. However, eliminating two proximal hydrogen bonds completely destroys receptor function; this adds further support to gating models that ascribe important roles to these β strands of the nAChR extracellular domain.

     

Agronomic performance of high oleic,low linolenic soybean in Tennessee

Soybean oil hydrogenation alters the linolenic acid molecule to prevent the oil from becoming rancid, however, health reports have indicated trans-fat caused by hydrogenation, is not generally regarded as safe. Typical soybeans contain approximately 80 g kg⁻¹ to 120 g kg⁻¹ linolenic acid and 240 g kg⁻¹ of oleic acid. In an effort to accommodate the need for high-quality oil, the United Soybean Board introduced an industry standard for a high oleic acid greater than 750 g kg⁻¹ and linolenic acid less than 30 g kg⁻¹ oil. By combing mutations in the soybean plant at four loci, FAD2-1A and FAD2-1B, oleate desaturase genes and FAD3A and FAD3C, linoleate desaturase genes, and seed oil will not require hydrogenation to prevent oxidation and produce high-quality oil. In 2017 and 2018, a study comparing four near-isogenic lines across multiple Tennessee locations was performed to identify agronomic traits associated with mutations in FAD3A and FAD3C loci, while holding FAD2-1A and FAD2-1B constant in the mutant (high oleic) state. Soybean lines were assessed for yield and oil quality based on mutations at FAD2-1 and FAD3 loci. Variations of wild-type and mutant genotypes were compared at FAD3A and FAD3C loci. Analysis using a generalized linear mixed model in SAS 9.4, indicated no yield drag or other negative agronomic traits associated with the high oleic and low linolenic acid genotype. All four mutations of fad2-1A, fad2-1B, fad3A, and fad3C were determined as necessary to produce a soybean with the new industry standard (>750 g kg⁻¹ oleic and <30 g kg⁻¹ linolenic acid) in a maturity group-IV-Late cultivar for Tennessee growers.     

Kidney Injury Caused by Preeclamptic Pregnancy Recovers Postpartum in a Transgenic Rat Model

Preeclampsia (PE) is characterized by the onset of hypertension (≥140/90 mmHg) and presence of proteinuria (>300 mg/L/24 h urine) or other maternal organ dysfunctions. During human PE, renal injuries have been observed. Some studies suggest that women with PE diagnosis have an increased risk to develop renal diseases later in life. However, in human studies PE as a single cause of this development cannot be investigated. Here, we aimed to investigate the effect of PE on postpartum renal damage in an established transgenic PE rat model. Female rats harboring the human-angiotensinogen gene develop a preeclamptic phenotype after mating with male rats harboring the human-renin gene, but are normotensive before and after pregnancy. During pregnancy PE rats developed mild tubular and glomerular changes assessed by histologic analysis, increased gene expression of renal damage markers such as kidney injury marker 1 and connective-tissue growth factor, and albuminuria compared to female wild-type rats (WT). However, four weeks postpartum, most PE-related renal pathologies were absent, including albuminuria and elevated biomarker expression. Only mild enlargement of the glomerular tuft could be detected. Overall, the glomerular and tubular function were affected during pregnancy in the transgenic PE rat. However, almost all these pathologies observed during PE recovered postpartum.     

High resolution spatiotemporal patterns of flow at the landscape scale in montane non-perennial streams

Intermittent and ephemeral streams in dryland environments support diverse assemblages of aquatic and terrestrial life. Understanding when and where water flows provide insights into the availability of water, its response to external controlling factors, and potential sensitivity to climate change and a host of human activities. Knowledge regarding the timing of drying/wetting cycles can also be useful to map critical habitats for species and ecosystems that rely on these temporary water sources. However, identifying the locations and monitoring the timing of streamflow and channel sediment moisture remains a challenging endeavor. In this paper, we analyzed daily conductivity from 37 sensors distributed along 10 streams across an arid mountain front in Arizona (United States) to assess spatiotemporal patterns in flow permanence, defined as the timing and extent of water in streams. Conductivity sensors provide information on surface flow and sediment moisture, supporting a stream classification based on seasonal flow dynamics. Our results provide insight into flow responses to seasonal rainfall, highlighting stream reaches very reactive to rainfall versus those demonstrating more stable streamflow. The strength of stream responses to precipitation are explored in the context of surficial geology. In summary, conductivity data can be used to map potential stream habitat for water-dependent species in both space and time, while also providing the basis upon which sensitivity to ongoing climate change can be evaluated.     

Multi‐Material Tissue Engineering Scaffold with Hierarchical Pore Architecture

Multi‐material polymer scaffolds with multiscale pore architectures are characterized and tested with vascular and heart cells as part of a platform for replacing damaged heart muscle. Vascular and muscle scaffolds are constructed from a new material, poly(limonene thioether) (PLT32i), which meets the design criteria of slow biodegradability, elastomeric mechanical properties, and facile processing. The vascular–parenchymal interface is a poly(glycerol sebacate) (PGS) porous membrane that meets different criteria of rapid biodegradability, high oxygen permeance, and high porosity. A hierarchical architecture of primary (macroscale) and secondary (microscale) pores is created by casting the PLT32i prepolymer onto sintered spheres of poly(methyl methacrylate) (PMMA) within precisely patterned molds followed by photocuring, de‐molding, and leaching out the PMMA. Prefabricated polymer templates are cellularized, assembled, and perfused in order to engineer spatially organized, contractile heart tissue. Structural and functional analyses show that the primary pores guide heart cell alignment and enable robust perfusion while the secondary pores increase heart cell retention and reduce polymer volume fraction.     

On the Path to Homeownership: Money,Family Composition and Low-income Households

In Norway, as in many other countries, homeownership is encouraged politically, and a majority of the households become homeowners at some stage in their life cycle. Many households move house when circumstances change, and it is often at this point that they also make their tenure choice. This paper employs a bivariate probit framework to model the transition rate from renting into homeownership. Using a sample of initial renters, subsequent tenure choice is analysed jointly with the stay-move decision. A particularly important question in this context is whether low-income households face differential constraints on entering owner occupation that could be addressed by policy change. The empirical model includes financial characteristics, household characteristics and changes in household characteristics as explanatory variables. Changes in household composition are particularly important in explaining variations in both tenure choice and mobility. Hence, the common practice of estimating housing market behaviour using a panel of intact households potentially obfuscates important determinants of that behaviour. The paper proceeds by using the equivalent of a Chow test to show that a hypothesis of equal coefficients in samples of low- and high-income households is firmly rejected. Thus low-income households do behave differently. Short-term variations in income appear to have little effect on people's capacity to enter owner occupation. However, low-income households are more dependent on past savings for successful entry. This suggests a rather different policy approach if owner occupation is to be expanded.     

Brain potentials implicate temporal lobe abnormalities in criminal psychopaths.

Psychopathy is associated with abnormalities in attention and orienting. However, few studies have examined the neural systems underlying these processes. To address this issue, the authors recorded event-related potentials (ERPs) while 80 incarcerated men, classified as psychopathic or nonpsychopathic via the Hare Psychopathy Checklist-Revised (R. D. Hare, 1991, 2003), completed an auditory oddball task. Consistent with hypotheses, processing of targets elicited larger frontocentral negativities (N550) in psychopaths than in nonpsychopaths. Psychopaths also showed an enlarged N2 and reduced P3 during target detection. Similar ERP modulations have been reported in patients with amygdala and temporal lobe damage. The data are interpreted as supporting the hypothesis that psychopathy may be related to dysfunction of the paralimbic system--a system that includes parts of the temporal and frontal lobes. (PsycINFO Database Record (c) 2010 APA, all rights reserved)