Predicted genetic burden and frequency of phenotype-associated variants in the horse.

Disease-causing variants have been identified for less than 20% of suspected equine genetic diseases. Whole genome sequencing (WGS) allows rapid identification of rare disease causal variants. However, interpreting the clinical variant consequence is confounded by the number of predicted deleterious variants that healthy individuals carry (predicted genetic burden). Estimation of the predicted genetic burden and baseline frequencies of known deleterious or phenotype associated variants within and across the major horse breeds have not been performed. We used WGS of 605 horses across 48 breeds to identify 32,818,945 variants, demonstrate a high predicted genetic burden (median 730 variants/horse, interquartile range: 613-829), show breed differences in predicted genetic burden across 12 target breeds, and estimate the high frequencies of some previously reported disease variants. This large-scale variant catalog for a major and highly athletic domestic animal species will enhance its ability to serve as a model for human phenotypes and improves our ability to discover the bases for important equine phenotypes.

Skeletal muscle reprogramming enhances reinnervation after peripheral nerve injury.

Peripheral Nerve Injuries (PNI) affect more than 20 million Americans and severely impact quality of life by causing long-term disability. The onset of PNI is characterized by nerve degeneration distal to the nerve injury resulting in long periods of skeletal muscle denervation. During this period, muscle fibers atrophy and frequently become incapable of "accepting" innervation because of the slow speed of axon regeneration post injury. We hypothesize that reprogramming the skeletal muscle to an embryonic-like state may preserve its reinnervation capability following PNI. To this end, we generated a mouse model in which NANOG, a pluripotency-associated transcription factor can be expressed locally upon delivery of doxycycline (Dox) in a polymeric vehicle. NANOG expression in the muscle upregulated the percentage of Pax7+ nuclei and expression of eMYHC along with other genes that are involved in muscle development. In a sciatic nerve transection model, NANOG expression led to upregulation of key genes associated with myogenesis, neurogenesis and neuromuscular junction (NMJ) formation, and downregulation of key muscle atrophy genes. Further, NANOG mice demonstrated extensive overlap between synaptic vesicles and NMJ acetylcholine receptors (AChRs) indicating restored innervation. Indeed, NANOG mice showed greater improvement in motor function as compared to wild-type (WT) animals, as evidenced by improved toe-spread reflex, EMG responses and isometric force production. In conclusion, we demonstrate that reprogramming the muscle can be an effective strategy to improve reinnervation and functional outcomes after PNI.

Pineal Gland from the Cell Culture to Animal Models: A Review.

This review demonstrates current literature on pineal gland physiology, pathology, and animal model experiments to concisely explore future needs in research development with respect to pineal gland function and neuro-regenerative properties. The pineal gland plays an integral role in sleep and recovery by promoting physiologic circadian rhythms via production and release of melatonin. Yet, the current literature shows that the pineal gland has neuroprotective effects that modulate both peripheral and central nerve injuries through several direct and indirect mechanisms, such as angiogenesis and induction of growth factors and anti-inflammatory mediators. Animal models have also shown correlations between pineal gland function and metabolic homeostasis. Studies have shown that a functional pineal gland is essential in preventing and slowing the progression of certain diseases such as diabetes, osteoporosis, vertebral osteoarthritis, and neurodegenerative processes. Lastly, the array of cell culturing methods and animal models that can be used to further develop the study of pineal gland function and nervous system injury were reviewed.

Genetic Variation and the Distribution of Variant Types in the Horse.

Genetic variation is a key contributor to health and disease. Understanding the link between an individual's genotype and the corresponding phenotype is a major goal of medical genetics. Whole genome sequencing (WGS) within and across populations enables highly efficient variant discovery and elucidation of the molecular nature of virtually all genetic variation. Here, we report the largest catalog of genetic variation for the horse, a species of importance as a model for human athletic and performance related traits, using WGS of 534 horses. We show the extent of agreement between two commonly used variant callers. In data from ten target breeds that represent major breed clusters in the domestic horse, we demonstrate the distribution of variants, their allele frequencies across breeds, and identify variants that are unique to a single breed. We investigate variants with no homozygotes that may be potential embryonic lethal variants, as well as variants present in all individuals that likely represent regions of the genome with errors, poor annotation or where the reference genome carries a variant. Finally, we show regions of the genome that have higher or lower levels of genetic variation compared to the genome average. This catalog can be used for variant prioritization for important equine diseases and traits, and to provide key information about regions of the genome where the assembly and/or annotation need to be improved.

Immunotherapy with engineered bacteria by targeting the STING pathway for anti-tumor immunity.

Synthetic biology is a powerful tool to create therapeutics which can be rationally designed to enable unique and combinatorial functionalities. Here we utilize non-pathogenic E coli Nissle as a versatile platform for the development of a living biotherapeutic for the treatment of cancer. The engineered bacterial strain, referred to as SYNB1891, targets STING-activation to phagocytic antigen-presenting cells (APCs) in the tumor and activates complementary innate immune pathways. SYNB1891 treatment results in efficacious antitumor immunity with the formation of immunological memory in murine tumor models and robust activation of human APCs. SYNB1891 is designed to meet manufacturability and regulatory requirements with built in biocontainment features which do not compromise its efficacy. This work provides a roadmap for the development of future therapeutics and demonstrates the transformative potential of synthetic biology for the treatment of human disease when drug development criteria are incorporated into the design process for a living medicine.

So Close and Yet So Irritating: Negative Relations and Implications for Well-being by Age and Closeness.

OBJECTIVES: Negative social relationships are associated with poor health, chronic illness, and mortality. Yet, we know little about the dynamics of negative aspects of relationships within individual's closest relationships over time, how those experiences vary by age, and the implications of those relationships for well-being. METHOD: A total of 592 participants (ages 25-97; M = 57.5; 63.3% women) from the Social Relations Study completed monthly web surveys for up to 12 months. Each month they reported negative relationship quality with their three closest network members and multiple dimensions of well-being (positive affect, negative affect, self-rated health, and sleep quality). RESULTS: Multilevel models revealed older individuals reported less negativity in their relationships than younger people, but fewer age differences in the closest tie. Greater negative relationship quality predicted poor well-being (i.e., greater negative affect, sleep problems). Links between negative relations and well-being were less strong among older individuals; especially in the closest ties. DISCUSSION: Results were partially consistent with the strength and vulnerability integration (SAVI) model, which proposes fewer age-related improvements in emotion regulation when individuals are unable to avoid tensions. Despite feeling just as negative as younger individuals, older individuals may be more resilient to tensions in their closest relationships.

Direct Intracellular Signaling by the Carboxy terminus of NMDA Receptor GluN2 Subunits Regulates Dendritic Morphology in Hippocampal CA1 Pyramidal Neurons.

N-methyl-d-aspartate receptors (NMDARs) are glutamatergic receptors that take part in excitatory synaptic transmission and drive functional and structural neuronal plasticity, including activity-dependent changes in dendritic morphology. Forebrain NMDARs contribute to neuronal plasticity in at least two ways: through calcium-mediated processes or via direct intracellular postsynaptic signaling. Both properties are regulated by the GluN2 subunits. However, the separate contributions of these properties to the regulation of dendritic morphology are unknown. We created transgenic mice that express chimeric GluN2 subunits and examined the impact on pyramidal cell dendritic morphology in hippocampal region CA1. Golgi-Cox impregnation and transgenic expression of green fluorescent protein were employed to visualize dendritic arbors. In adult mice with a predominantly native GluN2A background, overexpression of the GluN2B carboxy terminus increased the total path of the dendritic arbor without affecting branch number or tortuosity. Overexpressing the amino terminus and transmembrane domains of GluN2B had little effect. It may be inferred from these results that NMDAR-dependent intracellular signaling regulates dendritic morphology of hippocampal pyramidal cells more so than calcium conductance dynamics. The findings add to the understanding of NMDAR-mediated signaling in hippocampal neurons and support re-investigation of the molecular underpinnings of NMDAR involvement in postnatal dendrite maturation.

Caring for an individual with mild cognitive impairment: a qualitative perspective of health-related quality of life from caregivers.

OBJECTIVES: Little is known regarding the effect that caring for an individual with Mild Cognitive Impairment (MCI) has on health-related quality of life (HRQOL). We sought to identify the most important aspects of HRQOL related to caring for an individual with MCI. METHODS: Six focus groups were conducted with caregivers of individuals with MCI (n = 32). Qualitative frequency analysis was used to analyze the data. RESULTS: Findings indicated that caregivers most frequently discussed social health, including changes in social roles and an increased need for social support (51.2% of the total discussion). This was followed by mental health concerns (37.9%) centering on anger/frustration, and a need for patience in the caregiving role, as well as caregiver-specific anxiety. Other topics included physical health (10.0%; including the impact that stress and burden have on medical heath), and caregivers' cognitive health (0.9%; including memory problems in relation to caregiver strain, sleep disruption, and cognitive fatigue). CONCLUSIONS: Findings illustrate the multiple domains of HRQOL that are affected in individuals providing care for someone with MCI. Moreover, the findings highlight the need for extending support services to MCI caregivers, a group that is typically not offered support services due to the 'less severe' nature of an MCI diagnosis.

Defining the limitations of transcutaneous bilirubin measurement in late preterm newborns.

OBJECTIVE: The objective of this study is to determine the impact of postnatal age on the bias between transcutaneous (TcB) and total serum bilirubin (TSB), and evaluate a TcB screening protocol. STUDY DESIGN: Preterm and term infants had paired TcB and TSB performed on days 1 to 3 of life; a subset of preterm infants had measurements on days 4 to 7. Sensitivity and specificity of TcB (plotted on an age-specific TSB nomogram) for prediction of high-intermediate (HIR) or high-risk TSB were calculated. RESULTS: Median TcB bias was 2.6 and 2.5 mg dl-1 for term and preterm infants in the first 3 days of life, respectively. However, median bias was 2.2 mg dl-1 for preterm infants at 4 to 7 days of life. TcB in preterm infants predicted HIR or high-risk TSB with 94% sensitivity and 56% specificity. CONCLUSION: TcB screening protocols developed for term infants can be used for late preterm infants in the first 3 days of life.

The effect of by-product inclusion level on milk production, nutrient digestibility and excretion, and rumen fermentation parameters in lactating dairy cows offered a pasture-based diet.

The objective of this study was to investigate the effects of replacing barley and soybean meal with increasing levels of by-products on production, digestive, and metabolic parameters in early-mid lactation dairy cows offered perennial ryegrass-based pasture. Forty-eight (32 multiparous and 16 primiparous) dairy cows that were 64 ± 24 d in milk were assigned to 1 of 4 pasture-based dietary treatments (n = 12) in a randomized block design experiment that ran for 70 d. Treatments consisted of a perennial ryegrass-based pasture and 1 of 4 supplementary concentrates: BP35, BP55, BP75, and BP95 containing 35, 55, 75, and 95% by-products, respectively, in the concentrate on a dry matter basis. The by-products used were soyhulls, dried distillers grains, and palm kernel extract in equal proportions. Barley and soybean meal were replaced as by-product inclusion level increased. In this study, intakes of pasture dry matter (15.7 kg) and total dry matter (21.1 kg) were not affected by treatment. Similarly, milk production parameters (milk yield, milk composition, somatic cell count, and urea) were not different between treatments. Unsaturated fatty acids were lower in the milk of cows offered BP35 and BP55 compared with those offered BP75 and BP95. Concentrations of ß-hydroxybutyrate, nonesterified fatty acids, and other blood metabolites were within normal range and did not differ between treatments, and cow body condition score and body weight were also not different. Equally, N was unaffected by diet. Blood urea N was lower in the BP75 group compared with BP35. This study demonstrated that barley and soybean meal can be replaced with soyhulls, dried distillers grains, and palm kernel extract without affecting milk production, digestive, or metabolic parameters in dairy cows offered a pasture-based diet.

The impact of water use fees on dispatching and water requirements for water-cooled power plants in Texas.

We utilize a unit commitment and dispatch model to estimate how water use fees on power generators would affect dispatching and water requirements by the power sector in the Electric Reliability Council of Texas' (ERCOT) electric grid. Fees ranging from 10 to 1000 USD per acre-foot were separately applied to water withdrawals and consumption. Fees were chosen to be comparable in cost to a range of water supply projects proposed in the Texas Water Development Board's State Water Plan to meet demand through 2050. We found that these fees can reduce water withdrawals and consumption for cooling thermoelectric power plants in ERCOT by as much as 75% and 23%, respectively. To achieve these water savings, wholesale electricity generation costs might increase as much as 120% based on 2011 fuel costs and generation characteristics. We estimate that water saved through these fees is not as cost-effective as conventional long-term water supply projects. However, the electric grid offers short-term flexibility that conventional water supply projects do not. Furthermore, this manuscript discusses conditions under which the grid could be effective at "supplying" water, particularly during emergency drought conditions, by changing its operational conditions.

Impact of untreated portal vein thrombosis on pre and post liver transplant outcomes in cirrhosis.

BACKGROUND AND AIMS: Most portal vein thromboses (PVT) in cirrhotics are discovered incidentally. While case series demonstrate improved portal vein patency with anti-coagulation, there is little information on impact of PVT on morbidity and mortality. This study aimed to compare morbidity and mortality in cirrhotics with untreated PVT with those without PVT. MATERIAL AND METHODS: Cirrhotics evaluated for orthotopic liver transplant in a single large transplant center were prospectively followed. Subjects had contrast CT or MRI at initial evaluation and serial imaging every 6 months until transplantation, removal from the list or death. Univariate and multivariate Cox regression analysis were used to assess associations between new PVT and factors of interest. RESULTS: Of the 290 prospectively followed cirrhotics who met inclusion criteria, PVT was detected in 70 (24.1%)-47 had PVT at the time of initial evaluation and 23 developed one during the pre-transplant study period. A third of the patients with PVT had re-canalization or spontaneous resolution of thrombus while awaiting transplantation. There was no difference in the pre or posttransplant mortality between cirrhotics with and without PVT. CONCLUSION: Cirrhotics with untreated PVT fared equally well as those without PVT before and after transplantation. Further studies with larger numbers of patients are needed to determine if anticoagulation therapy truly improves outcomes in cirrhotics with portal vein thrombosis.

Implementation of an electronic data monitoring system decreases the rate of hyperoxic episodes in premature neonates.

OBJECTIVE: To determine whether an electronic data surveillance system, or Data Sniffer (DS), could reduce the rate of hyperoxic episodes (HEs) among premature neonates being managed by a standardized respiratory treatment protocol (RTP). STUDY DESIGN: A total of 86 infants born at <29 weeks of gestation were included in the study. The rates of HEs were compared among four epochs (E) as follows: E1: no RTP, no DS; E2:with RTP, no DS; E3: with RTP, with DS; E4: with RTP, no DS. RESULT: After implementing the RTP in E2, the rate of HEs was 44% lower than that of E1. Activating the DS in E3 further reduced HEs by 26%, whereas its deactivation in E4 resulted in a rebound in HEs to baseline rates; P<0.0001 for each comparison. CONCLUSION: The implementation of an electronic data monitoring system was associated with less frequent episodes of hyperoxia among premature neonates.

Energy return on investment for algal biofuel production coupled with wastewater treatment.

This study presents a second-order energy return on investment analysis to evaluate the mutual benefits of combining an advanced wastewater treatment plant (WWTP) (with biological nutrient removal) with algal biofuel production. With conventional, independently operated systems, algae production requires significant material inputs, which require energy directly and indirectly, and the WWTP requires significant energy inputs for treatment of the waste streams. The second-order energy return on investment values for independent operation of the WWTP and the algal biofuels production facility were determined to be 0.37 and 0.42, respectively. By combining the two, energy inputs can be reduced significantly. Consequently, the integrated system can outperform the isolated system, yielding a second-order energy return on investment of 1.44. Combining these systems transforms two energy sinks to a collective (second-order) energy source. However, these results do not include capital, labor, and other required expenses, suggesting that profitable deployment will be challenging.

Randomised clinical trial: the safety and efficacy of long-acting octreotide in patients with portal hypertension.

BACKGROUND: It remains unclear whether a long-acting preparation of octreotide (Sandostatin LAR) can be safely used for portal hypertension in patients with compensated cirrhosis. AIM: To determine the safety and efficacy of LAR among patients with Child Pugh Class A or B cirrhosis and small oesophageal varices. METHODS: A randomised, double-blind, placebo-controlled study was conducted in 39 patients with cirrhosis and small oesophageal varices. Safety was based on frequency and severity of adverse events. Efficacy was determined by hepatic vein pressure gradient (HVPG) measured at baseline and day 84 following administration of LAR 10 mg (n = 15), 30 mg (n = 10) or saline (n = 14). Fasting and postprandial portal blood flow (PBF), superior mesenteric artery pulsatility index (SMA-PI), glucagon and octreotide levels were measured. An intention-to-treat analysis was performed. RESULTS: Four patients in the LAR 30 group (40%) withdrew from the study due to serious adverse events. No patient in the LAR 10 or control group had serious adverse events. There was no statistically significant decrease between HVPG at day 84 and baseline with LAR 30 mg (11.8 ± 2.3 mmHg vs. 14.1 ± 3.2), LAR 10 mg (15.3 ± 4.8 mmHg vs. 15.1 ± 3.8), or saline (13.3 ± 3.8 mmHg vs. 15.1 ± 4.3) (P = 0.26). Neither PBF, SMA-PI nor plasma glucagon levels were significantly decreased from baseline (P = 0.56). CONCLUSIONS: The absence of significant haemodynamic benefit, as well as the high frequency of severe adverse events associated with use of LAR, do not support the use of this agent in the treatment of portal hypertension.

Stability and change in the intergenerational family: a convoy approach.

There have been fundamental changes in the intergenerational family, and yet families continue to be an important part of people's lives. We use the convoy model to describe the factors that influence supportive relations within intergenerational families, beginning with a description of the changing structure of the intergenerational family. We next outline support exchanges, detailing how personal characteristics, especially gender, race, age and socio-economic status, and situational characteristics, in particular family structure and intergenerational context, influence support exchanges. Instrumental and emotional family exchanges are described, with special attention to the unique circumstances of care-giving in intergenerational families. We also examine the importance of recognising differences in the quality of intergenerational relations, again noting the influence of personal and situational characteristics. Variations in support quality, e.g. positive, negative and ambivalent, and its influence on wellbeing are discussed. As families and individuals change, differences emerge at the individual, family and societal levels. We consider the implications of changes and stability in intergenerational relations and make recommendations about how best to envisage and plan future intergenerational family support. Societies with fewer resources as well as individuals and families with diverse individual histories must be innovative and creative in meeting the needs of older people as well as those of all family members.

Water intensity of transportation.

As the need for alternative transportation fuels increases, it is important to understand the many effects of introducing fuels based upon feedstocks other than petroleum. Water intensity in "gallons of water per mile traveled" is one method to measure these effects on the consumer level. In this paper we investigate the water intensity for light duty vehicle (LDV) travel using selected fuels based upon petroleum, natural gas, unconventional fossil fuels, hydrogen, electricity, and two biofuels (ethanol from corn and biodiesel from soy). Fuels more directly derived from fossil fuels are less water intensive than those derived either indirectly from fossil fuels (e.g., through electricity generation) or directly from biomass. The lowest water consumptive (<0.15 gal H20/mile) and withdrawal (<1 gal H2O/mile) rates are for LDVs using conventional petroleum-based gasoline and diesel, nonirrigated biofuels, hydrogen derived from methane or electrolysis via nonthermal renewable electricity, and electricity derived from nonthermal renewable sources. LDVs running on electricity and hydrogen derived from the aggregate U.S. grid (heavily based upon fossil fuel and nuclear steam-electric power generation) withdraw 5-20 times and consume nearly 2-5 times more water than by using petroleum gasoline. The water intensities (gal H20/mile) of LDVs operating on biofuels derived from crops irrigated in the United States at average rates is 28 and 36 for corn ethanol (E85) for consumption and withdrawal, respectively. For soy-derived biodiesel the average consumption and withdrawal rates are 8 and 10 gal H2O/mile.

The water intensity of the plugged-in automotive economy.

Converting light-duty vehicles from full gasoline power to electric power, by using either hybrid electric vehicles or fully electric power vehicles, is likely to increase demand for water resources. In the United States in 2005, drivers of 234 million cars, lighttrucks, and SUVs drove approximately 2.7 trillion miles and consumed over 380 million gallons of gasoline per day. We compare figures from literature and government surveys to calculate the water usage, consumption, and withdrawal, in the United States during petroleum refining and electricity generation. In displacing gasoline miles with electric miles, approximately 2-3 [corrected] times more water is consumed (0.24 [corrected] versus 0.07--0.14 gallons/mile) and over 12 [corrected] times more water is withdrawn (7.8 [corrected] versus 0.6 gallons/mile) primarily due to increased water cooling of thermoelectric power plants to accommodate increased electricity generation. Overall, we conclude that the impact on water resources from a widespread shift to grid-based transportation would be substantial enough to warrant consideration for relevant public policy decision-making. That is not to say that the negative impacts on water resources make such a shift undesirable, but rather this increase in water usage presents a significant potential impact on regional water resources and should be considered when planning for a plugged-in automotive economy.

Nonlinear frequency-dependent attenuation in sandy sediments.

This paper summarizes evidence of a nonlinear frequency dependence of attenuation for compressional waves in shallow-water waveguides with sandy sediment bottoms. Sediment attenuation is found consistent with alpha(f) = alpha(f(o)) x (f/f(o))n, n approximately 1.8 +/- 0.2 at frequencies less than 1 kHz in agreement with the theoretical expectation, (n = 2), of Biot [J. Acoust. Soc. Am. 28(2), 168-178, 1956]. For frequencies less than 10 kHz, the sediment layers, within meters of the water-sediment interface, appear to play a role in the attenuation that strongly depends on the power law. The accurate calculation of sound transmission in a shallow-water waveguide requires the depth-dependent sound speed, density, and frequency-dependent attenuation.