Chronic ethanol alters adrenergic receptor gene expression and produces cognitive deficits in male mice.

Hyperkateifia and stress-induced alcohol cravings drive relapse in individuals with alcohol use disorder (AUD). The brain stress signal norepinephrine (also known as noradrenaline) tightly controls cognitive and affective behavior and was thought to be broadly dysregulated with AUD. The locus coeruleus (LC) is a major source of forebrain norepinephrine, and it was recently discovered that the LC sends distinct projections to addiction-associated regions suggesting that alcohol-induced noradrenergic changes may be more brain region-specific than originally thought. Here we investigated whether ethanol dependence alters adrenergic receptor gene expression in the medial prefrontal cortex (mPFC) and central amgydala (CeA), as these regions mediate the cognitive impairment and negative affective state of ethanol withdrawal. We exposed male C57BL/6J mice to the chronic intermittent ethanol vapor-2 bottle choice paradigm (CIE-2BC) to induce ethanol dependence, and assessed reference memory, anxiety-like behavior and adrenergic receptor transcript levels during 3-6 days of withdrawal. Dependence bidirectionally altered mouse brain α1 and ß receptor mRNA levels, potentially leading to reduced mPFC adrenergic signaling and enhanced noradrenergic influence over the CeA. These brain region-specific gene expression changes were accompanied by long-term retention deficits and a shift in search strategy in a modified Barnes maze task, as well as greater spontaneous digging behavior and hyponeophagia. Current clinical studies are evaluating adrenergic compounds as a treatment for AUD-associated hyperkatefia, and our findings can contribute to the refinement of these therapies by increasing understanding of the specific neural systems and symptoms that may be targeted.

Chronic ethanol induces a pro-inflammatory switch in interleukin-1ß regulation of GABAergic signaling in the medial prefrontal cortex of male mice.

Neuroimmune pathways regulate brain function to influence complex behavior and play a role in several neuropsychiatric diseases, including alcohol use disorder (AUD). In particular, the interleukin-1 (IL-1) system has emerged as a key regulator of the brain's response to ethanol (alcohol). Here we investigated the mechanisms underlying ethanol-induced neuroadaptation of IL-1ß signaling at GABAergic synapses in the prelimbic region of the medial prefrontal cortex (mPFC), an area responsible for integrating contextual information to mediate conflicting motivational drives. We exposed C57BL/6J male mice to the chronic intermittent ethanol vapor-2 bottle choice paradigm (CIE-2BC) to induce ethanol dependence, and conducted ex vivo electrophysiology and molecular analyses. We found that the IL-1 system regulates basal mPFC function through its actions at inhibitory synapses on prelimbic layer 2/3 pyramidal neurons. IL-1ß can selectively recruit either neuroprotective (PI3K/Akt) or pro-inflammatory (MyD88/p38 MAPK) mechanisms to produce opposing synaptic effects. In ethanol naïve conditions, there was a strong PI3K/Akt bias leading to a disinhibition of pyramidal neurons. Ethanol dependence produced opposite IL-1 effects - enhanced local inhibition via a switch in IL-1ß signaling to the canonical pro-inflammatory MyD88 pathway. Ethanol dependence also increased cellular IL-1ß in the mPFC, while decreasing expression of downstream effectors (Akt, p38 MAPK). Thus, IL-1ß may represent a key neural substrate in ethanol-induced cortical dysfunction. As the IL-1 receptor antagonist (kineret) is already FDA-approved for other diseases, this work underscores the high therapeutic potential of IL-1 signaling/neuroimmune-based treatments for AUD.

Electronic Nicotine Vapor Exposure Produces Differential Changes in Central Amygdala Neuronal Activity, Thermoregulation and Locomotor Behavior in Male Mice.

Nicotine is an addictive substance historically consumed through smoking and more recently through the use of electronic vapor devices. The increasing prevalence and popularity of vaping prompts the need for preclinical rodent models of nicotine vapor exposure and an improved understanding of the impact of vaping on specific brain regions, bodily functions, and behaviors. We used a rodent model of electronic nicotine vapor exposure to examine the cellular and behavioral consequences of acute and repeated vapor exposure. Adult male C57BL/6J mice were exposed to a single 3-h session (acute exposure) or five daily sessions (repeated exposure) of intermittent vapes of 120 mg/ml nicotine in propylene glycol:vegetable glycerol (PG/VG) or PG/VG control. Acute and repeated nicotine vapor exposure did not alter body weight, and both exposure paradigms produced pharmacologically significant serum nicotine and cotinine levels in the 120 mg/ml nicotine group compared with PG/VG controls. Acute exposure to electronic nicotine vapor increased central amygdala (CeA) activity in individual neuronal firing and in expression of the molecular activity marker, cFos. The changes in neuronal activity following acute exposure were not observed following repeated exposure. Acute and repeated nicotine vapor exposure decreased core body temperature, however acute exposure decreased locomotion while repeated exposure increased locomotion. Collectively, these studies provide validation of a mouse model of nicotine vapor exposure and important evidence for how exposure to electronic nicotine vapor produces differential effects on CeA neuronal activity and on specific body functions and behaviors like thermoregulation and locomotion.

Association between fear of hypoglycemia and physical activity in youth with type 1 diabetes: The SEARCH for diabetes in youth study.

BACKGROUND: Youth with type 1 diabetes (T1D) are encouraged to participate in physical activity (PA). Studies have identified fear of hypoglycemia (FOH) as a barrier to participating in PA. OBJECTIVES: To examine (a) PA patterns in youth with T1D by age group and (b) the relationship between both parental and youth FOH and youth PA. METHODS: A cross-sectional analysis from the SEARCH cohort study visit of youth ages 10 to 17 years with T1D (n = 1129) was conducted. Linear regression models estimated the association between self-reported number of days of vigorous PA (VPA) and moderate PA (MPA) and both youth- and parent-reported FOH. Multivariable models were adjusted for age, sex, race, duration of T1D, HbA1c, use of continuous glucose monitoring (CGM), recent severe hypoglycemia, primary insulin regimen, and BMI. RESULTS: Participants were 52% female, had mean (sd) age 14.4 (4.2) years, diabetes duration 7.5 years (1.8), HbA1c 9.2% (1.7). Older youth were less likely to engage in VPA (P < .01), or sports teams (P < .01), but more likely to engage in MPA (P < .01). Higher youth FOH (behavior subscale) was associated with increased levels of VPA (ß (se) 0.30 (0.11), P = .01) but not significantly associated with MPA (P = .06). There was no statistically significant association between parental FOH and youth PA. CONCLUSIONS: In SEARCH participants with T1D, VPA, and team sports participation declined with age, while MPA increased. We observed that higher scores on the youth FOH behavioral subscale were associated with increased VPA levels, suggesting that FOH may be less of a barrier to PA than previously thought.

Genotype by environment interaction in response to cold stress in a composite beef cattle breed.

Extreme weather conditions such as cold stress influence the productivity and survivability of beef cattle raised on pasture. The objective of this study was to identify and evaluate the extent of the impact of genotype by environment interaction due to cold stress on birth weight (BW) and weaning weight (WW) in a composite beef cattle population. The effect of cold stress was modelled as the accumulation of total cold load (TCL) calculated using the Comprehensive Climate Index units, considering three TCL classes defined based on temperature: less than -5°C (TCL5), -15°C (TCL15) and -25°C (TCL25). A total of 4221 and 4217 records for BW and WW, respectively, were used from a composite beef cattle population (50% Red Angus, 25% Charolais and 25% Tarentaise) between 2002 and 2015. For both BW and WW, a univariate model (ignoring cold stress) and a reaction norm model were implemented. As cold load increased, the direct heritability slightly increased in both BW and WW for TCL5 class; however, this heritability remained consistent across the cold load of TCL25 class. In contrast, the maternal heritability of BW was constant with cold load increase in all TCL classes, although a slight increase of maternal heritability was observed for TCL5 and TCL15. The direct and maternal genetic correlation for BW and maternal genetic correlation for WW across different cold loads between all TCL classes were high (r > 0.99), whereas the lowest direct genetic correlations observed for WW were 0.88 for TCL5 and 0.85 for TCL15. The Spearman rank correlation between the estimated breeding value of top bulls (n = 79) using univariate and reaction norm models across TCL classes showed some re-ranking in direct and maternal effects for both BW and WW particularly for TCL5 and TCL15. In general, cold stress did not have a big impact on direct and maternal genetic effects of BW and WW.

Effect of low and moderate dose FEIBA to reverse major bleeding in patients on direct oral anticoagulants.

OBJECTIVE: Management of acute, major or life threatening bleeding in the presence of direct acting oral anticoagulants (DOAC) is unclear. In the absence of a specific antidote, or in situations where there is a need for adjunctive therapy, the ideal prothrombin complex concentrate and dose is unclear. The goal of our study was to evaluate the outcomes of our reduced dosing strategy with FEIBA in patients experiencing a DOAC-related bleeding event. DESIGN: Retrospective analysis of patients treated with FEIBA for a DOAC-related bleeding event. SETTING: Academic medical center PATIENTS: Consecutive patients between May 2011 and April 2017 receiving FEIBA for a DOAC-related bleed INTERVENTIONS: None MEASUREMENTS & MAIN RESULTS: Of the 64 patients included in this analysis, 38 patients received low dose FEIBA (mean 10.0 ±â€¯3.6 units/kg) and 26 received moderate dose (mean 24.3 ±â€¯2.1 units/kg) FEIBA; an additional dose was requested in 6 patients. Six dabigatran patients received idarucizumab. 30 day event rates included 5 thromboembolic events (8%) and 9 (14%) patients expired. Follow-up CT-imaging for ICH, endoscopy/colonoscopy, or interventional radiology exams did not reveal any clinically concerning active bleeding or hematoma expansion except in 2 ICH patients with slight expansion between imaging sessions. CONCLUSIONS: Low (<20 units/kg) to moderate (20-30 units/kg) doses of FEIBA, with the option for a repeat dose, may be an effective management strategy for obtaining hemostasis in DOAC-related major bleeding events.

Effects of anterior compartment fasciotomy on intramuscular compartment pressure in patients with chronic exertional compartment syndrome.

BACKGROUND: Patients with chronic exertional compartment syndrome (CECS) have pain during exercise that usually subsides at rest. Diagnosis is usually confirmed by measurement of intramuscular compartment pressure (IMCP) following exclusion of other possible causes. Management usually requires fasciotomy but reported outcomes vary widely. There is little evidence of the effectiveness of fasciotomy on IMCP. Testing is rarely repeated postoperatively and reported follow-up is poor. Improved diagnostic criteria based on preselection and IMCP levels during dynamic exercise testing have recently been reported. OBJECTIVES: (1) To compare IMCP in three groups, one with classical symptoms and no treatment and the other with symptoms of CECS who have been treated with fasciotomy and an asymptomatic control group. (2) Establish if differences in IMCP in these groups as a result of fasciotomy relate to functional and symptomatic improvement. METHODS: Twenty subjects with symptoms of CECS of the anterior compartment, 20 asymptomatic controls and 20 patients who had undergone fasciotomy for CECS were compared. All other possible diagnoses were excluded using rigorous inclusion criteria and MRI. Dynamic IMCP was measured using an electronic catheter wire before, during and after participants exercised on a treadmill during a standardised 15 min exercise challenge. Statistical analysis included t-tests and analysis of variance. RESULTS: Fasciotomy results in reduced IMCP at all time points during a standardised exercise protocol compared with preoperative cases. In subjects responding to fasciotomy, there is a significant reduction in IMCP below that of preoperative groups (P<0.001). Postoperative responders to fasciotomy have no significant differences in IMCP from asymptomatic controls (P=0.182). CONCLUSION: Fasciotomy reduces IMCP in all patients. Larger studies are required to confirm that the reduction in IMCP accounts for differences in functional outcomes and pain reductions seen in postoperative patients with CECS.

Barefoot plantar pressure measurement in Chronic Exertional Compartment Syndrome.

BACKGROUND: Patients with Chronic Exertional Compartment Syndrome (CECS) have exercise-limiting pain that subsides at rest. Diagnosis is confirmed by intramuscular compartment pressure (IMCP) measurement. Accompanying CECS, subjective changes to gait (foot slap) are frequently reported by patients. This has not previously been investigated. The aim of this study was to investigate differences in barefoot plantar pressure (BFPP) between CECS cases and asymptomatic controls prior to the onset of painful symptoms. METHODS: 40 male military volunteers, 20 with symptoms of CECS and 20 asymptomatic controls were studied. Alternative diagnoses were excluded with rigorous inclusion criteria, magnetic resonance imaging and dynamic IMCP measurement. BFPP was measured during walking and marching. Data were analysed for: Stance Time (ST); foot progression angle (FPA); centre of force; plantarflexion rate after heel strike (IFFC-time); the distribution of pressure under the heel; and, the ratio between inner and outer metatarsal loading. Correlation coefficients of each variable with speed and leg length were calculated followed by ANCOVA or t-test. Receiver operating characteristic (ROC) curves were constructed for IFFC-time. RESULTS: Caseshad shorter ST and IFFC-times than controls. FPA was inversely related to walking speed (WS) in controls only. The area under the ROC curve for IFFC-time ranged from 0.746 (95%CI: 0.636-0.87) to 0.773 (95%CI: 0.671-0.875) representing 'fair predictive validity'. CONCLUSION: Patients with CECS have an increased speed of ankle plantarflexion after heel strike that precedes the onset of painful symptoms likely resulting from a mechanical disadvantage of Tibialis Anterior. These findings provide further insight into the pathophysiology of CECS and support further investigation of this non-invasive diagnostic. The predictive value of IFFC-time in the diagnosis of CECS is comparable to post-exercise IMCP but falls short of dynamic IMCP measured during painful symptoms.

Binder-free Sn-Si heterostructure films for high capacity Li-ion batteries.

This study fabricated and demonstrated a functional, stable electrode structure for a high capacity Li-ion battery (LIB) anode. Effective performance is assessed in terms of reversible lithiation for a significant number of charge-discharge cycles to 80% of initial capacity. The materials selected for this study are silicon and tin and are co-deposited using an advanced manufacturing technique (plasma-enhanced chemical vapour deposition), shown to be a scalable process that can facilitate film growth on 3D substrates. Uniform and hybrid crystalline-amorphous Si nanowire (SiNW) growth is achieved via a vapour-liquid-solid mechanism using a Sn metal catalyst. SiNWs of less than 300 nm diameter are known to be less susceptible to fracture and when grown this way have direct electrical conductivity to the current collector, with sufficient room for expansion. Electrochemical characterisation shows stable cycling at capacities of 1400 mA h g-1 (>4 × the capacity limit of graphite). This hybrid system demonstrates promising electrochemical performance, can be grown at large scale and has also been successfully grown on flexible carbon paper current collectors. These findings will have impact on the development of flexible batteries and wearable energy storage.

A Upf3b-mutant mouse model with behavioral and neurogenesis defects.

Nonsense-mediated RNA decay (NMD) is a highly conserved and selective RNA degradation pathway that acts on RNAs terminating their reading frames in specific contexts. NMD is regulated in a tissue-specific and developmentally controlled manner, raising the possibility that it influences developmental events. Indeed, loss or depletion of NMD factors have been shown to disrupt developmental events in organisms spanning the phylogenetic scale. In humans, mutations in the NMD factor gene, UPF3B, cause intellectual disability (ID) and are strongly associated with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD) and schizophrenia (SCZ). Here, we report the generation and characterization of mice harboring a null Upf3b allele. These Upf3b-null mice exhibit deficits in fear-conditioned learning, but not spatial learning. Upf3b-null mice also have a profound defect in prepulse inhibition (PPI), a measure of sensorimotor gating commonly deficient in individuals with SCZ and other brain disorders. Consistent with both their PPI and learning defects, cortical pyramidal neurons from Upf3b-null mice display deficient dendritic spine maturation in vivo. In addition, neural stem cells from Upf3b-null mice have impaired ability to undergo differentiation and require prolonged culture to give rise to functional neurons with electrical activity. RNA sequencing (RNAseq) analysis of the frontal cortex identified UPF3B-regulated RNAs, including direct NMD target transcripts encoding proteins with known functions in neural differentiation, maturation and disease. We suggest Upf3b-null mice serve as a novel model system to decipher cellular and molecular defects underlying ID and neurodevelopmental disorders.

Genomic prediction of continuous and binary fertility traits of females in a composite beef cattle breed.

Reproduction efficiency is a major factor in the profitability of the beef cattle industry. Genomic selection (GS) is a promising tool that may improve the predictive accuracy and genetic gain of fertility traits. There is a wide range of traits used to measure fertility in dairy and beef cattle including continuous (days open), discrete (pregnancy status), and count (number of inseminations) responses. In this study, a joint analysis of age of puberty (AOP), age at first calving (AOC), and the heifer pregnancy status (HPS) was performed. Data used in this study consisted of records from 1,365 Composite Gene Combination (CGC; 50% Red Angus, 25% Charolais, 25% Tarentaise) first parity females born between 2002 and 2011. The pedigree file included 5,374 animals. A total of 3,902 animals were genotyped with different density SNP chips (3K to 50K SNP). Animals genotyped with low-density arrays were imputed to higher density (BovineSNP50 BeadChip) using FImpute. Data were analyzed using univariate and multivariate classical quantitative models (pedigree based) and univariate genomic approaches. For the latter, 3 different Bayesian methods (BayesA, BayesB, and BayesCπ) were implemented and compared. Estimates of heritabilities using univariate and multivariate analyses based on pedigree relationships ranged between 0.03 (for AOC) to 0.2 (AOP). Heritability of pregnancy status was 0.15 and 0.09 using the univariate and multivariate analyses, respectively. Genetic correlation between pregnancy status and the other 2 traits was low being 0.08 with age at puberty and -0.10 with age at first calving. Heritability estimates were slightly higher using genomic rather than average additive relationships. The accuracy of genomic prediction was similar across the 3 Bayesian methods with higher accuracies for age of puberty than the age at first calving likely due to the higher heritability of the former. The prediction of the binary pregnancy status measured using the area under the curve increased by 27% to 29% compared to a random classifier. Due to the small size of the data, all estimates have large posterior standard deviations and results should be interpreted with caution.

Developmental and reproductive characteristics of beef heifers classified by pubertal status at time of first breeding.

Data collected for 10 or more years at the West Central Research and Extension Center, North Platte, NE ( = 1,104); the Gudmundsen Sandhills Laboratory, Whitman, NE ( = 1,333); and the USDA, ARS, Fort Keogh Livestock and Range Research Laboratory, Miles City, MT ( = 1,176) were retrospectively analyzed to evaluate growth and reproductive performance of beef heifers classified by pubertal status before first breeding. Concentrations of progesterone in serum from 2 blood samples collected 9 to 11 d apart before the breeding season classified heifers as pubertal (progesterone ≥ 1.0 ng/mL in 1 or both samples) or nonpubertal (progesterone < 1.0 ng/mL in both samples). Average date of birth was earlier ( < 0.06) and proportion born in the first 21 d of the calving season was 10 to 20 percentage points greater for heifers that were pubertal at the start of breeding compared with heifers not pubertal by the start of breeding. Heifers that were pubertal by the start of breeding were 7 to 10 kg heavier ( < 0.01) and 1 cm taller ( < 0.01) at weaning than heifers not pubertal by the start of breeding. Differences in BW persisted through the start of breeding to pregnancy diagnosis. Heifers that achieved puberty by the start of breeding had greater ( < 0.05) feed intake and G:F during postweaning development and had greater ( < 0.01) LM area and fat thickness over the LM at approximately 1 yr of age compared with heifers not pubertal by the start of breeding. Heifers that achieved puberty before the start of breeding had greater ( < 0.01) ADG from birth to weaning but slower ( < 0.10) rates of gain from the start of breeding through pregnancy diagnosis. Pregnancy rate was greater ( < 0.01) for heifers that were pubertal at the start of breeding. In heifers that became pregnant, those that were pubertal before the start of breeding calved earlier ( < 0.01), with a greater ( < 0.01) percentage calving in the first 21 d of calving than heifers not pubertal at the start of breeding. Calves from heifers that achieved puberty before the start of breeding were heavier at weaning ( < 0.01) than calves from heifers that had not achieved puberty by the start of breeding. In summary, heifers that failed to achieve puberty by the start of breeding were less desirable for several traits evaluated. Based on these results, implementing feeding strategies to increase the proportion of heifers that achieve puberty before first breeding could result in propagation of undesirable characteristics.

Water temperature impacts water consumption by range cattle in winter.

Water consumption and DMI have been found to be positively correlated, and both may interact with ingestion of cold water or grazed frozen forage due to transitory reductions in the temperature of ruminal contents. The hypothesis underpinning the study explores the potential that cows provided warm drinking water would have increased in situ NDF and OM disappearances and a more stable rumen temperature, drink more water, and lose less BW during the winter. This hypothesis was tested in 3 experiments. In Exp. 1, ruminal extrusa (93.1% DM, 90.2% OM, 81.1% NDF [DM], and 4.9% CP [DM]) were randomly allocated to 1 of 5 in vitro incubation temperatures. In 2 independent trials, temperatures evaluated were 39, 37, or 35°C (trial 1) and 39, 33, or 31°C (trial 2). In Exp. 2, 4 pregnant rumen cannulated cows grazing in January were fitted with Kahne (KB1000) temperature continuous recording boluses for 22 d. Two grazed in a paddock provided cold water (8.2°C) and 2 in a paddock provided warm water (31.1°C). Two in situ trials were conducted placing 6 in situ bags containing 2 g of winter range ruminal extrusa in each of the 4 ruminally cannulated cows and incubating bags for 72 h for measurement of NDF disappearance. In Exp. 3, 6 paddocks ( = 3/water treatment) were grazed by 10 to 13 pregnant crossbred Angus cows from December through February across 3 yr from 2009 to 2012. Water intake per paddock was measured daily and ambient temperature was recorded. Motion-activated cameras were used to determine the time of day water was consumed and the number of cow appearances at water. In Exp. 1, rate and total gas production ( < 0.05) and NDF disappearance ( < 0.001) at 48 h was reduced by each incubation temperature below 39°C. In Exp. 2, ruminal temperature for cows supplied with warm water dropped below 38°C 1.5% of the time whereas ruminal temperature for cows provided cold water dropped below 38°C 9.4% of the time ( < 0.01). Drinking water temperature did not alter in situ OM or NDF disappearance. In Exp. 3, cows with access to warm water consumed 30% ( < 0.05) more water than cows provided cold water. In this study, there were energetic costs to range cows proportional to consumption of water at temperatures less than body temperature. The magnitude of these costs were found to be less than the heat increment because no improvement to BW gain, BCS change, or calf birth weight were found for cows consuming warmed water.

Identifying errors in dust models from data assimilation.

Airborne mineral dust is an important component of the Earth system and is increasingly predicted prognostically in weather and climate models. The recent development of data assimilation for remotely sensed aerosol optical depths (AODs) into models offers a new opportunity to better understand the characteristics and sources of model error. Here we examine assimilation increments from Moderate Resolution Imaging Spectroradiometer AODs over northern Africa in the Met Office global forecast model. The model underpredicts (overpredicts) dust in light (strong) winds, consistent with (submesoscale) mesoscale processes lifting dust in reality but being missed by the model. Dust is overpredicted in the Sahara and underpredicted in the Sahel. Using observations of lighting and rain, we show that haboobs (cold pool outflows from moist convection) are an important dust source in reality but are badly handled by the model's convection scheme. The approach shows promise to serve as a useful framework for future model development.

TRIENNIAL REPRODUCTION SYMPOSIUM: Beef heifer development and lifetime productivity in rangeland-based production systems.

Nutritional and environmental factors have been shown to cause epigenetic changes that influence characteristics of the offspring throughout life. In livestock, small differences in nutrition during gestation may alter lifetime production efficiency of offspring. Therefore, the potential for fetal programing should be considered when determining supplemental feeding strategies during gestation. For example, female offspring born to cows grazing dormant winter pasture supplemented with 1.1 kg/d of alfalfa hay during the last third of gestation were 10 kg heavier and had greater BCS at 5 yr of age than those from dams supplemented with 1.8 kg/d of alfalfa hay. These differences were beneficial for maintaining reproductive performance in offspring managed with fewer harvested feed inputs. Evaluation of female offspring from cows wintered on either low-quality or high-quality pasture for 30 to 45 d during the fifth to sixth month of gestation indicated a trend for longer duration of productivity in daughters from cows wintered on improved pasture. In recent studies comparing offspring from cows with or without protein supplementation while grazing dormant winter range during late gestation, heifers from protein-supplemented dams had greater BW at weaning. This BW increase persisted throughout pregnancy and to subsequent calving, and pregnancy rates were greater in heifers from protein-supplemented dams. Heifers from protein-supplemented dams had lower G:F compared with heifers from unsupplemented dams. Therefore, in utero exposure to nutritionally limited environments (nonsupplemented dams) may promote greater feed efficiency in the heifer offspring later in life. Nutrition during postweaning development may also affect lifetime productivity. Heifers developed on low-quality native range with RUP supplementation had greater retention beyond 3 yr of age than cohorts developed in a feedlot with higher quality feed and greater ADG. Collectively, these examples show nutritional management strategies used during gestation and development may influence lifetime productivity.

Evaluation of TLR4 Inhibitor, T5342126, in Modulation of Ethanol-Drinking Behavior in Alcohol-Dependent Mice.

AIMS: Several lines of evidence support a critical role of TLR4 in the neuroimmune responses associated with alcohol disorders and propose inhibitors of TLR4 signaling as potential treatments for alcoholism. In this work, we investigated the effect of T5342126 compound, a selective TLR4 inhibitor, on excessive drinking and microglial activation associated with ethanol dependence. METHODS: We used 2BC-CIE (two-bottle choice-chronic ethanol intermittent vapor exposure) paradigm to induce ethanol dependence in mice. After induction of the ethanol dependence, we injected T5342126 (i.p., 57 mg/kg) for 14 days while monitoring ethanol intake by 2BC (limited access to ethanol) method. RESULTS: T5342126 decreased ethanol drinking in both ethanol-dependent and non-dependent mice but T5342126 showed also dose-dependent non-specific effects represented by decreased animal locomotor activity, saccharine intake, and body core temperature. Six days after the last ethanol-drinking session, we examined the immunohistochemical staining of Iba-1 (ionized calcium-binding adapter molecule 1), a microglial activation marker, in the central nucleus of the amygdala (CeA) and dentate gyrus (DG) of the hippocampus. Notably, T5342126 reduced Iba-1 density in the CeA of both ethanol-dependent and non-dependent mice injected with T5342126. There were no significant differences in the DG Iba-1 density among the treatment groups. CONCLUSIONS: Collectively, our data suggest that T5342126, via blocking TLR4 activation, contributes to the reduction of ethanol drinking and ethanol-induced neuroimmune responses. However, the non-specific effects of T5342126 may play a significant role in the T5342126 effects on ethanol drinking and thus, may limit its therapeutic potential for treatment of alcohol dependence. SHORT SUMMARY: T5342126, an experimental TLR4 inhibitor, is effective in reducing ethanol drinking and inhibiting the activation and proliferation of microglia in both ethanol-dependent and non-dependent mice. However, T5342126's use as a potential candidate for the treatment of alcohol addiction may be limited due to its non-specific effects.

11ß-hydroxysteroid dehydrogenase inhibition as a new potential therapeutic target for alcohol abuse.

The identification of new and more effective treatments for alcohol abuse remains a priority. Alcohol intake activates glucocorticoids, which have a key role in alcohol's reinforcing properties. Glucocorticoid effects are modulated in part by the activity of 11ß-hydroxysteroid dehydrogenases (11ß-HSD) acting as pre-receptors. Here, we tested the effects on alcohol intake of the 11ß-HSD inhibitor carbenoxolone (CBX, 18ß-glycyrrhetinic acid 3ß-O-hemisuccinate), which has been extensively used in the clinic for the treatment of gastritis and peptic ulcer and is active on both 11ß-HSD1 and 11ß-HSD2 isoforms. We observed that CBX reduces both baseline and excessive drinking in rats and mice. The CBX diastereomer 18α-glycyrrhetinic acid 3ß-O-hemisuccinate (αCBX), which we found to be selective for 11ß-HSD2, was also effective in reducing alcohol drinking in mice. Thus, 11ß-HSD inhibitors may be a promising new class of candidate alcohol abuse medications, and existing 11ß-HSD inhibitor drugs may be potentially re-purposed for alcohol abuse treatment.

BEEF SPECIES SYMPOSIUM: Can we build the cowherd by increasing longevity of females?

Increasing longevity of beef cows by decreasing the proportion culled due to reproductive failure provides an efficient process to rebuild a cow herd and can reduce number of replacements needed to sustain a constant herd size. Rate of reproductive failure varies due to cow age, where failure in cows 2 to 4 yr of age is often greater than in cows 5 to 7 yr of age. In addition, BW of cow and calf at weaning increase as cows advance from 2 to 5 yr of age. The cumulative effect of increasing retention of young cows is improved production efficiency through decreased replacement rate and changing age structure of the herd resulting in a greater proportion of cows at maximal production potential for calf BW at weaning and cow BW at time of culling. Calculations from cow age-specific culling and BW data from commercial and research herds indicated that reducing replacement rate from 18% to 14% resulted in a 23% increase in calf BW weaned and a 2% increase in cull cow BW per pregnant replacement heifer going into the herd. Although improving longevity increases production efficiency, genetic advancement in sustained reproductive function is challenging, as it is the sequential culmination of the annual repetition of numerous discrete physiological processes, each ending in a qualitative response. Successful completion of one process is prerequisite to evaluating subsequent processes. These physiological processes are subject to nutritional threshold requirements that may vary due to genetic potential for other production traits such as milk, growth, and mature size resulting in genetic-by-nutrition interactions. This is in contrast to most traits for which EPD exist, where genetic-by-environment interactions are not considered to be significant. Extensive research concerning impact of limited nutrition on reproduction has led to recommendations that heifers and cows be fed to a threshold BW or BCS to ensure reproductive success; a process that masks nutritional interactions that might otherwise result in reproductive failure. This management approach minimizes selection for animals capable of sustained reproductive function under limited nutritional environments. Rearing and managing cows under nutritionally limited environments may lead to adaptations that result in relatively high levels of reproductive success under lower input levels. Such adaptation may improve chances for longer retention in their offspring in nutrient-limited environments.

Sources of variability in livestock water quality over 5 years in the Northern Great Plains.

Concentrated dissolved minerals in naturally occurring water accessible to livestock grazing semiarid landscapes can negatively influence animal productivity and well-being. Twelve indicators of water quality (Ca, Cl, Fe, F, Mg, Mn, Na, nitrate N, pH, SO4, total dissolved solids [TDS], and temperature) were measured at 45 livestock water sites over 5 yr from 2009 through 2013 at the 22,257-ha USDA-ARS Fort Keogh Livestock and Range Research Laboratory (Miles City, MT) to estimate variation. Water was sampled from 4 sources: 1) flowing surface water, 2) groundwater, 3) reservoirs, and 4) springs. The sampled area was classified by 3 cardinal compass bearings (locations): 1) north, 2) southeast, and 3) southwest of the Yellowstone River. Samples were collected twice yearly in 2 seasons, May (wet) and September (dry). Year, location, source, and season and their interactions were analyzed as a 5 × 3 × 4 × 2 factorial arrangement of treatments. A location × year interaction (P < 0.04) was found for Mg, Na, SO4, and TDS. The southwest location had the greatest concentrations in 2012 of Na, SO4, and TDS. A source × year interaction (P < 0.02) was found for Ca, Fe, F, Mg, Mn, Na, SO4, TDS, and temperature. Iron, Mg, and Mn had the greatest concentrations in flowing surface water in 2012. Greater and then lower precipitation in 2011 followed by below-average precipitation in 2012 was associated with elevated mineral concentrations in sources in the southwest location and flowing surface water sources demonstrating sources of water quality variability within time and space at the study site. Average concentrations of Ca, Cl, Mg, and nitrate N and pH levels across sources and locations did not exceed the upper maximum intake level for beef cattle. In contrast, concentrations of F, Fe, Na, SO4, and TDS at times exceeded the upper maximum level for beef cattle, indicating these minerals may negatively impact range beef cattle performance.