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Releasing sterile or incompatible male insects is a proven method of population management in agricultural systems with the potential to revolutionize mosquito control. Through a collaborative venture with the “Debug” Verily Life Sciences team, we assessed the incompatible insect technique (IIT) with the mosquito vector Aedes aegypti in northern Australia in a replicated treatment control field trial. Backcrossing a US strain of Ae. aegypti carrying Wolbachia wAlbB from Aedes albopictus with a local strain, we generated a wAlbB2-F4 strain incompatible with both the wild-type (no Wolbachia) and wMel-Wolbachia Ae. aegypti now extant in North Queensland. The wAlbB2-F4 strain was manually mass reared with males separated from females using Verily sex-sorting technologies to obtain no detectable female contamination in the field. With community consent, we delivered a total of three million IIT males into three isolated landscapes of over 200 houses each, releasing ∼50 males per house three times a week over 20 wk. Detecting initial overflooding ratios of between 5:1 and 10:1, strong population declines well beyond 80% were detected across all treatment landscapes when compared to controls. Monitoring through the following season to observe the ongoing effect saw one treatment landscape devoid of adult Ae. aegypti early in the season. A second landscape showed reduced adults, and the third recovered fully. These encouraging results in suppressing both wild-type and wMel-Ae. aegypti confirms the utility of bidirectional incompatibility in the field setting, show the IIT to be robust, and indicate that the removal of this arbovirus vector from human-occupied landscapes may be achievable.

A grazing trial was conducted in Mississippi during 2016 and 2017 to compare pasture, animal, and economic performance of three perennial, warm‐season grass systems. Grass treatments included: (i) Argentine bahiagrass (Paspalum notatum Fluegge; BAH); (ii) KY Ecotype big bluestem (Andropogon gerardii Vitman; BBS); and (iii), KY Ecotype indiangrass [Sorghastrum nutans (L.) Nash], big bluestem and little bluestem [Schizachyrium scoparium (Michx.) Nash; MIX]. Paddocks were continuously stocked using weaned beef (Bos taurus) steers across three grazing intervals (I, II, and III) during late spring and summer. Pasture measurements included forage mass (FM) and nutritive value. Greatest FM was observed during grazing interval II in 2016 (931.70 kg ha–1). Nutritive values declined as the season progressed. The BAH had greater CP and TDN, and lower ADF and NDF concentrations than BBS and MIX in 2016. Differences were not as discernable in 2017. Greatest ADG were observed for BBS interval I in 2017 (1.34 kg d–1), MIX interval I 2017 (1.21 kg d–1), and BBS interval I 2016 (1.19 kg d–1). Beef yield per hectare (GAIN) was greatest for interval I across both years (464.78 kg ha–1). By species, GAIN was greatest for BBS in interval I (451.32 kg ha–1). For economic analysis, BBS had the lowest total annual pasture cost (US$142.65 ha–1), and had the greatest NET returns for 2016 ($268.96 ha–1) and 2017 ($249.98 ha–1). Implementing native warm‐season grasses (NWSG) in stocker cattle systems for early‐season grazing can be productive in Mississippi.

Purpose We developed a mouse model that enables non-invasive assessment of changes in β cell mass. Procedures We generated a transgenic mouse expressing luciferase under control of the mouse insulin I promoter [mouse insulin promoter-luciferase-Vanderbilt University (MIP-Luc-VU)] and characterized this model in mice with increased or decreased β cell mass and after islet transplantation. Results Streptozotocin-induced, diabetic MIP-Luc-VU mice had a progressive decline in bioluminescence that correlated with a decrease in β cell mass. MIP-Luc-VU animals fed a high-fat diet displayed a progressive increase in bioluminescence that reflected an increase in β cell mass. MIP-Luc-VU islets transplanted beneath the renal capsule or into the liver emitted bioluminescence proportional to the number of islets transplanted and could be imaged for more than a year. Conclusions Bioluminescence in the MIP-Luc-VU mouse model is proportional to β cell mass in the setting of increased and decreased β cell mass and after transplantation.

Livestock economics encompasses the dynamics and linkages of the complex livestock production industry. This dissertation focuses on three topics that relate to this field and offer insights and recommendations to market participants at differing stages along the production chain. The first chapter analyzes the Rainfall Index Annual Forage pilot program and its ability to provide risk coverage for annual forage producers. Annual forage is used by cattle producers to provide winter grazing in and around Oklahoma. This article utilizes unique data from a long-term study of annual ryegrass production with rainfall recorded at the site to determine whether or not the use of rainfall indices provides adequate coverage for annual forage growers. The second chapter focuses on an issue near the other end of the production chain where beef is sold to consumers. Today, the U.S. produces more beef from fewer cattle due to the ability to get more meat from each animal. While the benefits of this increase in efficiency are well documented, unintended adverse consequences have been less well understood. This article aims to identify and quantify one of these adverse effects. With larger cattle have come larger steaks. Using data from a nationwide survey, this article estimates consumer willingness to pay for beef steak dimensions to draw insights into the consumer welfare changes that have resulted from increasing steak sizes. The third chapter focuses on the behavior of commodity prices, including grains which are important for livestock feed and cattle prices. Changing underlying means are inherent in commodity prices and can create biased estimates if not correctly specified when performing unit root tests. Prominent financial models include terms for both mean reversion and unit roots but assume that mean reversion occurs gradually over time. Other models require the researcher to determine if prices are either mean-reverting or follow a unit root process. We discuss the models commonly used for commodity prices and how their assumptions align with how commodity spot and futures prices actually behave. We argue for using panel unit root tests for futures prices. Each of these chapters has implications for the livestock industry.

We developed a mouse model that enables non-invasive assessment of changes in β cell mass. We generated a transgenic mouse expressing luciferase under control of the mouse insulin I promoter [mouse insulin promoter-luciferase-Vanderbilt University (MIP-Luc-VU)] and characterized this model in mice with increased or decreased β cell mass and after islet transplantation. Streptozotocin-induced, diabetic MIP-Luc-VU mice had a progressive decline in bioluminescence that correlated with a decrease in β cell mass. MIP-Luc-VU animals fed a high-fat diet displayed a progressive increase in bioluminescence that reflected an increase in β cell mass. MIP-Luc-VU islets transplanted beneath the renal capsule or into the liver emitted bioluminescence proportional to the number of islets transplanted and could be imaged for more than a year. Bioluminescence in the MIP-Luc-VU mouse model is proportional to β cell mass in the setting of increased and decreased β cell mass and after transplantation.[PUBLICATION ABSTRACT]

Voltage-gated sodium (Na v ) channels initiate action potentials in most neurons, including primary afferent nerve fibres of the pain pathway. Local anaesthetics block pain through non-specific actions at all Na v channels, but the discovery of selective modulators would facilitate the analysis of individual subtypes of these channels and their contributions to chemical, mechanical, or thermal pain. Here we identify and characterize spider ( Heteroscodra maculata ) toxins that selectively activate the Na v 1.1 subtype, the role of which in nociception and pain has not been elucidated. We use these probes to show that Na v 1.1-expressing fibres are modality-specific nociceptors: their activation elicits robust pain behaviours without neurogenic inflammation and produces profound hypersensitivity to mechanical, but not thermal, stimuli. In the gut, high-threshold mechanosensitive fibres also express Na v 1.1 and show enhanced toxin sensitivity in a mouse model of irritable bowel syndrome. Together, these findings establish an unexpected role for Na v 1.1 channels in regulating the excitability of sensory nerve fibres that mediate mechanical pain. Two spider toxins are shown to target the Na v 1.1 subtype of sodium channel specifically, shedding light on the role of these channels in mechanical pain signalling. Na v 1.1 channels mediate mechanical pain Mutations affecting several Na v 1 subtype voltage-gated sodium channels have been shown to be associated with insensitivity to pain or persistent pain syndromes. Na v 1.1 is expressed by somatosensory neurons, but no direct link has been established between this subtype and nociception. Further studies have been hampered by a paucity of pharmacological agents that discriminate between the closely related members of the Na v 1 family. Now David Julius and colleagues have identified two spider toxins specifically targeting Na v 1.1, and use them to show that this channel is key to the specific transduction of mechanical but not thermal pain by myelinated Aδ sensory fibres. Previous genetic studies of Na v 1.1 indicate that such selective agents may open therapeutic avenues in disorders associated with the central nervous system, such as epilepsy, autism and Alzheimer disease. The involvement of Na v 1.1 channels in mediating mechanical pain reported here was unexpected.

Calcium/calmodulin-stimulated protein kinase II (CaMKII) is a multi-functional kinase that controls a range of cellular functions, including proliferation, differentiation and apoptosis. The biological properties of CaMKII are regulated by multi-site phosphorylation. However, the role that CaMKII phosphorylation plays in cancer cell metastasis has not been examined. We demonstrate herein that CaMKII expression and phosphorylation at T286 is increased in breast cancer when compared to normal breast tissue, and that increased CAMK2 mRNA is associated with poor breast cancer patient prognosis (worse overall and distant metastasis free survival). Additionally, we show that overexpression of WT, T286D and T286V forms of CaMKII in MDA-MB-231 and MCF-7 breast cancer cells increases invasion, migration and anchorage independent growth, and that overexpression of the T286D phosphomimic leads to a further increase in the invasive, migratory and anchorage independent growth capacity of these cells. Pharmacological inhibition of CaMKII decreases MDA-MB-231 migration and invasion. Furthermore, we demonstrate that overexpression of T286D, but not WT or T286V-CaMKII, leads to phosphorylation of FAK, STAT5a, and Akt. These results demonstrate a novel function for phosphorylation of CaMKII at T286 in the control of breast cancer metastasis, offering a promising target for the development of therapeutics to prevent breast cancer metastasis.

Assessments for spatial working memory (SWM) in pet dogs that can detect age-related cognitive deficits in a single session may aid in diagnosing canine dementia and may facilitate translational research on Alzheimer’s disease in humans. Adaptive testing procedures are widely used in single-session assessments for humans with diverse cognitive abilities. In this study, we designed and deployed two up-down staircase assessments for SWM in which 26 pet dogs were required to recall the location of a treat hidden behind one of two identical boxes following delays of variable length. In the first experiment, performance tended to decline with age but few dogs completed the test (n = 10). However, all of the dogs that participated in the second experiment (n = 24) completed the assessment and provided reliable evidence of learning and retaining the task. Delay length and age significantly predicted performance supporting the validity of this assessment. The relationships between age and performance were described by inverted U-shaped functions as both old and young dogs displayed deficits in weighted cumulative-scores and trial-by-trial performance. Thus, SWM in pet dogs may develop until midlife and decline thereafter. Exploratory analyses of non-mnemonic fixation strategies, sustained engagement, inhibitory control, and potential improvements for future SWM assessments which adopt this paradigm are also discussed.

Voltage-gated sodium (Na V ) channels are essential for the transmission of pain signals in humans making them prime targets for the development of new analgesics. Spider venoms are a rich source of peptide modulators useful to study ion channel structure and function. Here we describe β/δ-TRTX-Pre1a, a 35-residue tarantula peptide that selectively interacts with neuronal Na V channels inhibiting peak current of hNa V 1.1, rNa V 1.2, hNa V 1.6, and hNa V 1.7 while concurrently inhibiting fast inactivation of hNa V 1.1 and rNa V 1.3. The DII and DIV S3-S4 loops of Na V channel voltage sensors are important for the interaction of Pre1a with Na V channels but cannot account for its unique subtype selectivity. Through analysis of the binding regions we ascertained that the variability of the S1-S2 loops between Na V channels contributes substantially to the selectivity profile observed for Pre1a, particularly with regards to fast inactivation. A serine residue on the DIV S2 helix was found to be sufficient to explain Pre1a’s potent and selective inhibitory effect on the fast inactivation process of Na V 1.1 and 1.3. This work highlights that interactions with both S1-S2 and S3-S4 of Na V channels may be necessary for functional modulation, and that targeting the diverse S1-S2 region within voltage-sensing domains provides an avenue to develop subtype selective tools.

Voltage-gated sodium (Na.sub.v) channels initiate action potentials in most neurons, including primary afferent nerve fibres of the pain pathway. Local anaesthetics block pain through non-specific actions at all Na.sub.v channels, but the discovery of selective modulators would facilitate the analysis of individual subtypes of these channels and their contributions to chemical, mechanical, or thermal pain. Here we identify and characterize spider (Heteroscodra maculata) toxins that selectively activate the Na.sub.v1.1 subtype, the role of which in nociception and pain has not been elucidated. We use these probes to show that Na.sub.v1.1-expressing fibres are modality-specific nociceptors: their activation elicits robust pain behaviours without neurogenic inflammation and produces profound hypersensitivity to mechanical, but not thermal, stimuli. In the gut, high-threshold mechanosensitive fibres also express Na.sub.v1.1 and show enhanced toxin sensitivity in a mouse model of irritable bowel syndrome. Together, these findings establish an unexpected role for Na.sub.v1.1 channels in regulating the excitability of sensory nerve fibres that mediate mechanical pain.