Plant availability of nutrients recovered as solids from human urine tested in climate chamber on Triticum aestivum L

Recovered nutrients by freezing-thawing from human urine in combination with struvite precipitation and nitrogen adsorption on zeolite and activated carbon have been tested in pot trials with wheat, Triticum aestivum L., in a climate chamber during 21 days. A simple test design using sand as substrate was chosen to give a first, general evaluation of the nutrient (P and N) availability from these sources. Dry weight, plant growth morphology, total-P and total-N were analysed. The tests show a slow-release of nutrients (P and N) from struvite and from N-adsorbents. The nitrogen in all treatments was in the deficiency range for optimum yield for wheat. Higher pH than usual for soil tests contributed to the difficulties in plant uptake, especially in the pots with only struvite (with highest MgO addition) as nutrient source.     

Development of potent, orally active 1-substituted-3,4-dihydro-2-quinolone glycogen phosphorylase inhibitors

A series of substituted 3,4-dihydro-2-quinolone glycogen phosphorylase inhibitors, which have potential as antidiabetic agents, is described. Initial members of the series showed good enzyme inhibitory potency but poor physical properties. Optimisation of the 1-substituent led to 2,3-dihydroxypropyl compounds which showed good in vitro potency and improved physical properties, together with good DMPK profiles and acute in vivo efficacy in a rat model. X-ray crystallographic data are presented, showing an unexpected variety of binding orientations at the dimer interface site.     

Radiolabeled divalent peptidomimetic vitronectin receptor antagonists as potential tumor radiotherapeutic and imaging agents

The integrin receptor alphavbeta3 is overexpressed on the endothelial cells of growing tumors and on some tumor cells themselves. A radiolabeled alphavbeta3 antagonists belonging to the quinolin-4-one class of peptidomimetics (TA138) was previously shown to exhibit high affinity for integrin alphavbeta3 and high selectivity versus other integrin receptors. 111In-TA138 exhibited high tumor uptake in the c-neu Oncomouse mammary adenocarcinoma model and produced excellent scintigraphic images. This study describes the synthesis of eight divalent versions of TA138 and their evaluation as potential tumor radiotherapeutic agents. The two main variables in this study were the length of the spacer bridging the biotargeting moieties and the total negative charge of the molecules imparted by the cysteic acid pharmacokinetic modifiers. Receptor affinity was evaluated in a panel of integrin receptor affinity assays, and biodistribution studies using the 111In-labeled derivatives were carried out in the c-neu Oncomouse model. All divalent agents maintained the high receptor affinity and selectivity of TA138, and six of the eight 111In derivatives exhibited blood clearance that was faster than 111In-TA138 at 24 h postinjection (PI). All divalent agents exhibited tumor uptake and retention at 24 h PI that was higher than 111In-TA138. Tumor/organ ratios were improved for most of the divalent agents at 24 h PI in critical nontarget organs marrow, kidney, and liver, with the agents having intermediate-length spacers (29-43 A) showing the largest improvement. As an example, 111In-15 showed tumor uptake of 14.3% ID/g at 24 h PI and tumor/organ ratios as follows: marrow, 3.24; kidney, 7.29; liver, 8.51. A comparison of therapeutic indices for 90Y-TA138 and 177Lu-15 indicate an improved therapeutic index for the divalent agent. The implications for radiotherapeutic applications and the mechanism of this multivalent effect are discussed.     

Effect of mechanomyography as a biofeedback method to enhance muscle relaxation and performance

The purpose of the study was to examine the potential for using the mechanomyographic (MMG) signal as a biofeedback method to enhance muscular relaxation and to improve performance during forearm flexion repetitions to fatigue. Twelve adult (mean +/- SD; age: 22.0 +/- 1.1 years) moderately trained subjects (weight: 82.3 +/- 29.2 kg; height: 165.7 +/- 49.0 cm) were instructed to relax the biceps brachii muscle using MMG biofeedback (BIO) provided by viewing a computer screen graphically displaying the MMG signal and then without using MMG biofeedback (NOBIO). Electromyographic (EMG) and MMG signals were detected midway over the biceps brachii during the relaxation protocol. In subsequent visits to the laboratory, subjects performed as many repetitions as possible at 85% of 1 repetition maximum with BIO and NOBIO using the seated preacher curl exercise. Two-way (biofeedback x gender) mixed factorial analyses of variance revealed significantly (p < 0.05) lower MMG (mean +/- SEM; BIO = 0.6 +/- 0.1 mV; NOBIO = 1.1 +/- 0.2 mV) and EMG amplitudes (BIO = 6.6 +/- 0.6 microV; NOBIO = 9.4 +/- 1.4 microV) for BIO when subjects were instructed to relax the biceps brachii muscle. There was no significant difference in the number of forearm flexion repetitions performed for BIO (mean +/- SD; 7.9 +/- 0.4 reps) vs. NOBIO (8.1 +/- 0.6 reps). The results of the present study revealed that using MMG as a biofeedback technique can enhance the development of muscle relaxation, but is not useful in delaying fatigue during forearm flexion repetitions. Our results may have been influenced by a relatively short training phase designed to teach subjects to use the MMG signal as a biofeedback method. Future studies are needed to determine whether MMG biofeedback can be used for other purposes. If MMG is found to be useful as a biofeedback method, it has some distinct practical advantages over EMG that the strength and conditioning athlete and professional may find appealing.     

Targeted agri‐environment schemes significantly improve the population size of common farmland bumblebee species

Changes in agricultural practice across Europe and North America have been associated with range contractions and local extinction of bumblebees (Bombus spp.). A number of agri‐environment schemes have been implemented to halt and reverse these declines, predominantly revolving around the provision of additional forage plants. Although it has been demonstrated that these schemes can attract substantial numbers of foraging bumblebees, it remains unclear to what extent they actually increase bumblebee populations. We used standardized transect walks and molecular techniques to compare the size of bumblebee populations between Higher Level Stewardship (HLS) farms implementing pollinator‐friendly schemes and Entry Level Stewardship (ELS) control farms. Bumblebee abundance on the transect walks was significantly higher on HLS farms than ELS farms. Molecular analysis suggested maximum foraging ranges of 566 m for Bombus hortorum, 714 m for B. lapidarius, 363 m for B. pascuorum and 799 m for B. terrestris. Substantial differences in maximum foraging range were found within bumblebee species between farm types. Accounting for foraging range differences, B. hortorum (47 vs 13 nests/km²) and B. lapidarius (45 vs 22 nests/km²) were found to nest at significantly greater densities on HLS farms than ELS farms. There were no significant differences between farm type for B. terrestris (88 vs 38 nests/km²) and B. pascuorum (32 vs 39 nests/km²). Across all bumblebee species, HLS management had a significantly positive effect on bumblebee nest density. These results show that targeted agri‐environment schemes that increase the availability of suitable forage can significantly increase the size of wild bumblebee populations.     

Improving Phenotypic Prediction by Combining Genetic and Epigenetic Associations

We tested whether DNA-methylation profiles account for inter-individual variation in body mass index (BMI) and height and whether they predict these phenotypes over and above genetic factors. Genetic predictors were derived from published summary results from the largest genome-wide association studies on BMI (n ∼ 350,000) and height (n ∼ 250,000) to date. We derived methylation predictors by estimating probe-trait effects in discovery samples and tested them in external samples. Methylation profiles associated with BMI in older individuals from the Lothian Birth Cohorts (LBCs, n = 1,366) explained 4.9% of the variation in BMI in Dutch adults from the LifeLines DEEP study (n = 750) but did not account for any BMI variation in adolescents from the Brisbane Systems Genetic Study (BSGS, n = 403). Methylation profiles based on the Dutch sample explained 4.9% and 3.6% of the variation in BMI in the LBCs and BSGS, respectively. Methylation profiles predicted BMI independently of genetic profiles in an additive manner: 7%, 8%, and 14% of variance of BMI in the LBCs were explained by the methylation predictor, the genetic predictor, and a model containing both, respectively. The corresponding percentages for LifeLines DEEP were 5%, 9%, and 13%, respectively, suggesting that the methylation profiles represent environmental effects. The differential effects of the BMI methylation profiles by age support previous observations of age modulation of genetic contributions. In contrast, methylation profiles accounted for almost no variation in height, consistent with a mainly genetic contribution to inter-individual variation. The BMI results suggest that combining genetic and epigenetic information might have greater utility for complex-trait prediction.     

Differential Sensitivities of Fast- and Slow-Cycling Cancer Cells to Inosine Monophosphate Dehydrogenase 2 Inhibition by Mycophenolic Acid

As uncontrolled cell proliferation requires nucleotide biosynthesis, inhibiting enzymes that mediate nucleotide biosynthesis constitutes a rational approach to the management of oncological diseases. In practice, however, results of this strategy are mixed and thus elucidation of the mechanisms by which cancer cells evade the effect of nucleotide biosynthesis restriction is urgently needed. Here we explored the notion that intrinsic differences in cancer cell cycle velocity are important in the resistance toward inhibition of inosine monophosphate dehydrogenase (IMPDH) by mycophenolic acid (MPA). In short-term experiments, MPA treatment of fast-growing cancer cells effectively elicited G0/G1 arrest and provoked apoptosis, thus inhibiting cell proliferation and colony formation. Forced expression of a mutated IMPDH2, lacking a binding site for MPA but retaining enzymatic activity, resulted in complete resistance of cancer cells to MPA. In nude mice subcutaneously engrafted with HeLa cells, MPA moderately delayed tumor formation by inhibiting cell proliferation and inducing apoptosis. Importantly, we developed a lentiviral vector–based Tet-on label-retaining system that enables to identify, isolate and functionally characterize slow-cycling or so-called label-retaining cells (LRCs) in vitro and in vivo. We surprisingly found the presence of LRCs in fast-growing tumors. LRCs were superior in colony formation, tumor initiation and resistance to MPA as compared with fast-cycling cells. Thus, the slow-cycling compartment of cancer seems predominantly responsible for resistance to MPA.     

Chronic mTOR inhibition in mice with rapamycin alters T,B, myeloid,and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

The mammalian (mechanistic) target of rapamycin (mTOR) regulates critical immune processes that remain incompletely defined. Interest in mTOR inhibitor drugs is heightened by recent demonstrations that the mTOR inhibitor rapamycin extends lifespan and healthspan in mice. Rapamycin or related analogues (rapalogues) also mitigate age‐related debilities including increasing antigen‐specific immunity, improving vaccine responses in elderly humans, and treating cancers and autoimmunity, suggesting important new clinical applications. Nonetheless, immune toxicity concerns for long‐term mTOR inhibition, particularly immunosuppression, persist. Although mTOR is pivotal to fundamental, important immune pathways, little is reported on immune effects of mTOR inhibition in lifespan or healthspan extension, or with chronic mTOR inhibitor use. We comprehensively analyzed immune effects of rapamycin as used in lifespan extension studies. Gene expression profiling found many and novel changes in genes affecting differentiation, function, homeostasis, exhaustion, cell death, and inflammation in distinct T‐ and B‐lymphocyte and myeloid cell subpopulations. Immune functions relevant to aging and inflammation, and to cancer and infections, and innate lymphoid cell effects were validated in vitro and in vivo. Rapamycin markedly prolonged lifespan and healthspan in cancer‐ and infection‐prone mice supporting disease mitigation as a mechanism for mTOR suppression‐mediated longevity extension. It modestly altered gut metagenomes, and some metagenomic effects were linked to immune outcomes. Our data show novel mTOR inhibitor immune effects meriting further studies in relation to longevity and healthspan extension.     

Estimating biogeochemical and biotic interactions between a stream channel and a created riparian wetland: A medium-scale physical model

Straightened channels and altered and drained adjacent riparian wetlands have adversely impacted streams and rivers throughout the US Midwest. This research investigated the biological connection and water quality of a 0.07 ha diversion wetland and adjacent stream at the Olentangy River Wetland Research Park in central Ohio. Before the flowthrough conditions were established, we demonstrated with mark and recapture techniques that the wetland already was a biorefuge for fish under extreme conditions; two species (Centrarchidae) captured in the stream before a total drawdown of the stream were found in the wetland a year later. In addition, water at the bottom remained at around 4 °C over the winter likely due to groundwater input, which possibly provided a warmer shelter for fish. Stream water quality of the lower section, downstream of the wetland outlet, generally improved with hydrologic pulsing in spring after flow-through reconnection due to the trapping of nutrients in the wetland. Mean removal per flood pulse for nitrate-nitrite, total nitrogen (TN), soluble reactive phosphorus (SRP), total phosphorus (TP) were 1.81 g-N m⁻² per pulse, 1.02 g-N m⁻² per pulse, 0.014 g-P m⁻² per pulse, and 0.004 g-P m⁻² per pulse, respectively. The wetland exported 2.8 g-C m⁻² per pulse of organic carbon. A greater attenuation of NO₃⁻ and TP occurred in the marshy outlet channel section of the wetland than the open water section. The diversion wetland successfully removed nitrate and phosphorus during storm pulses in spring. Similar designs should be applied to other locations to examine their function under different climatic and hydrological conditions.