Efficacy of dual intracerebroventricular and intravitreal gene therapy in sheep prompts the first clinical trial to treat CLN5 Batten disease.

Mutations in the gene cause the fatal, pediatric, neurodegenerative disease CLN5 neuronal ceroid lipofuscinosis. Affected children suffer progressive neuronal loss, visual failure and premature death. Presently there is no treatment.

Long-term safety and dose escalation of intracerebroventricular CLN5 gene therapy in sheep supports clinical translation for CLN5 Batten disease.

CLN5 neuronal ceroid lipofuscinosis (NCL, Batten disease) is a rare, inherited fatal neurodegenerative disorder caused by mutations in the gene. The disease is characterised by progressive neuronal loss, blindness, and premature death. There is no cure.

Reproductive performance of a cohort of Standardbred mares under a commercial breeding system.

Background: Despite being a large commercial breeding industry, there is little published data on the reproductive success of Standardbred mares.

Objectives: To quantify the reproductive performance of Standardbred mares under artificial breeding systems in a commercial setting and determine the incidence of early embryonic and other pre-partum losses.

Study Design: Retrospective cohort study.

Characterization of neuropathology in ovine CLN5 and CLN6 neuronal ceroid lipofuscinoses (Batten disease).

Sheep with naturally occurring CLN5 and CLN6 forms of neuronal ceroid lipofuscinoses (Batten disease) share the key clinical features of the human disease and represent an ideal model system in which the clinical efficacy of gene therapies is developed and test. However, it was first important to characterize the neuropathological changes that occur with disease progression in affected sheep. This study compared neurodegeneration, neuroinflammation, and lysosomal storage accumulation in CLN5 affected Borderdale, CLN6 affected South Hampshire, and Merino sheep brains from birth to end-stage disease at ≤24 months of age.

Urine and fecal excretion patterns of dairy cows divergent for milk urea nitrogen breeding values consuming either a plantain or ryegrass diet.

Environmental degradation has been attributed to inefficient nitrogen utilization from pastoral dairy production systems. This degradation has especially been associated with the urine patch, which has been identified as a key component of nitrate leaching to waterways. However, a lack of information exists regarding the pattern of urination events and individual urination characteristics across the day, which would help inform strategic management decisions.

Nitrogen Balance of Dairy Cows Divergent for Milk Urea Nitrogen Breeding Values Consuming Either Plantain or Perennial Ryegrass.

Inefficient nitrogen (N) use from pastoral dairy production systems has resulted in environmental degradation, as a result of excessive concentrations of urinary N excretion leaching into waterways and NO emissions from urination events into the atmosphere. The objectives of this study were to measure and evaluate the total N balance of lactating dairy cows selected for milk urea N concentration breeding values (MUNBVs) consuming either a 100% perennial ryegrass ( L.) or 100% plantain ( L.

SAR11 Cells Rely on Enzyme Multifunctionality To Metabolize a Range of Polyamine Compounds.

In the ocean surface layer and cell culture, the polyamine transport protein PotD of SAR11 bacteria is often one of the most abundant proteins detected. Polyamines are organic cations at seawater pH produced by all living organisms and are thought to be an important component of dissolved organic matter (DOM) produced in planktonic ecosystems. We hypothesized that SAR11 cells uptake and metabolize multiple polyamines and use them as sources of carbon and nitrogen.

Electroretinography data from ovine models of CLN5 and CLN6 neuronal ceroid lipofuscinoses.

This article presents datasets associated with the research article entitled "Intravitreal gene therapy protects against retinal dysfunction and degeneration in sheep with CLN5 Batten disease" (Murray et al., [1]). The neuronal ceroid lipofuscinoses (NCL; Batten disease) are a group of fatal inherited diseases caused by mutations in a number of genes that lead to degenerative and fatal encephalopathies in children.

Plantain () reduces the environmental impact of farmed red deer ().

The objective of this study was to evaluate the effect of plantain ( L.) on water dynamics and balance, as well as nitrogen (N) excretion by red deer ( L.) as a potential forage tool to reduce negative environmental impacts.

Grazing dairy cows with low milk urea nitrogen breeding values excrete less urinary urea nitrogen.

There is an increasing pressure on temperate pastoral dairy production systems to reduce environmental impacts, coming from the inefficient use of N by cows in the form of excessive urinary N excretion and subsequent N leaching to the waterways and NO emissions to the atmosphere, these impacts have spurred research into various mitigation strategies, which have so far overlooked animal-based solutions. The objectives of this study were first, to investigate the relationship between MUN breeding values (MUNBV) and urinary urea N (UUN) concentrations and total excretion in grazing dairy cows; and secondly, to evaluate such a potential relationship in the context of different sward compositions and stage of lactation. Forty-eight multiparous, lactating Holstein-Friesian dairy cows genetically divergent for MUNBV were strip-grazed on either a ryegrass-white clover (24 cows) or ryegrass, white clover and plantain sward (24 cows), during both early and late lactation.

An Appraisal of Methods for Measuring Welfare of Grazing Ruminants.

Although disturbances in body function of animals can be measured to determine whether a state of stress may exist, there is growing interest in finding ways to assess their emotional status as an indicator of good or bad welfare status. Generally it is easier to determine poor states of well-being than positive ones. For grazing ruminants some indicators of well-being include absence of illness, good growth and productivity, and longevity.

Computed tomography provides enhanced techniques for longitudinal monitoring of progressive intracranial volume loss associated with regional neurodegeneration in ovine neuronal ceroid lipofuscinoses.

Introduction: The neuronal ceroid lipofuscinoses (NCLs; Batten disease) are a group of fatal neurodegenerative lysosomal storage diseases of children caused by various mutations in a range of genes. Forms associated with mutations in two of these, CLN5 and CLN6, are being investigated in well-established sheep models. Brain atrophy leading to psychomotor degeneration is among the defining features, as is regional progressive ossification of the inner cranium.

Longitudinal In Vivo Monitoring of the CNS Demonstrates the Efficacy of Gene Therapy in a Sheep Model of CLN5 Batten Disease.

Neuronal ceroid lipofuscinoses (NCLs; Batten disease) are neurodegenerative lysosomal storage diseases predominantly affecting children. Single administration of brain-directed lentiviral or recombinant single-stranded adeno-associated virus 9 (ssAAV9) vectors expressing ovine CLN5 into six pre-clinically affected sheep with a naturally occurring CLN5 NCL resulted in long-term disease attenuation. Treatment efficacy was demonstrated by non-invasive longitudinal in vivo monitoring developed to align with assessments used in human medicine.

Molecular forms of C-type natriuretic peptide in cerebrospinal fluid and plasma reflect differential processing in brain and pituitary tissues.

C-type natriuretic peptide (CNP) is a paracrine growth factor widely expressed within tissues of the central nervous system. Consistent with this is the high concentration of CNP in cerebrospinal fluid (CSF), exceeding levels in the systemic circulation. CNP abundance is high in hypothalamus and especially enriched in pituitary tissue where - in contrast to hypothalamus - processing to CNP-22 is minimal.

Dexamethasone increases production of C-type natriuretic peptide in the sheep brain.

Although C-type natriuretic peptide (CNP) has high abundance in brain tissues and cerebrospinal fluid (CSF), the source and possible factors regulating its secretion within the central nervous system (CNS) are unknown. Here we report the dynamic effects of a single IV bolus of dexamethasone or saline solution on plasma, CSF, CNS and pituitary tissue content of CNP products in adult sheep, along with changes in CNP gene expression in selected tissues. Both CNP and NTproCNP (the amino-terminal product of proCNP) in plasma and CSF showed dose-responsive increases lasting 12-16 h after dexamethasone, whereas other natriuretic peptides were unaffected.

Nutrient restriction in early ovine pregnancy stimulates C-type natriuretic peptide production.

C-type natriuretic peptide (CNP), a paracrine growth factor promoting vasodilation and angiogenesis, is upregulated in human and ovine pregnancy in response to vascular stress or nutrient restriction (NR) in late gestation. Postulating that maternal plasma CNP products are increased by modest NR (50% of metabolisable energy requirement) early in pregnancy, and further enhanced by litter size, we studied serial changes of maternal plasma CNP in pregnant ewes receiving a normal (NC, n=12) or restricted (NR, n=13) diet from Day 30 to Day 93 or 94 of gestation. Liveweight of NR ewes was 10kg less than that of NC ewes at slaughter.

Expression of regulatory neuropeptides in the hypothalamus of red deer (Cervus elaphus) reveals anomalous relationships in the seasonal control of appetite and reproduction.

Red deer are seasonal with respect to reproduction and food intake, so we tested the hypothesis that their brains would show seasonal changes in numbers of cells containing hypothalamic neuropeptides that regulate these functions. We examined the brains of male and female deer in non-breeding and breeding seasons to quantify the production of kisspeptin, gonadotropin inhibitory hormone (GnIH), neuropeptide Y (NPY) and γ-melanocyte stimulating hormone (γ-MSH - an index of pro-opiomelanocortin production), using immunohistochemistry. These neuropeptides are likely to be involved in the regulation of reproductive function and appetite.

Sustained increases in plasma C-type natriuretic peptides fail to increase concentrations in cerebrospinal fluid: Evidence from pregnant sheep.

C-type natriuretic peptide (CNP) is a paracrine growth factor with high abundance in CNS tissues and cerebrospinal fluid (CSF). Consistent with findings of CNP transcripts in the cerebral microvasculature and hypothalamus, CNP increases the permeability of the blood-brain barrier and reduces food intake when administered intracerebroventricularly in rodents. Whether high concentrations of CNP in plasma can affect CSF levels is unknown.

Modification of a method for cannulation of the cisterna magna in sheep to enable chronic collection of cerebrospinal fluid.

A method is described for chronic cannulation of the cisterna magna to enable repeated sampling of cerebrospinal fluid from conscious, ambulatory sheep by means of a flexible vinyl tube. Ease of sampling and duration of cannula patency are similar to those obtained with rigid, metal cannulae, but this modified method minimizes the degree of surgical intervention, and possible trauma, occurring during placement of the cannula.

Comparison of analytical and predictive methods for water, protein, fat, sugar, and gross energy in marine mammal milk.

Mammalian milks may differ greatly in composition from cow milk, and these differences may affect the performance of analytical methods. High-fat, high-protein milks with a preponderance of oligosaccharides, such as those produced by many marine mammals, present a particular challenge. We compared the performance of several methods against reference procedures using Weddell seal (Leptonychotes weddellii) milk of highly varied composition (by reference methods: 27-63% water, 24-62% fat, 8-12% crude protein, 0.

Differential response of C-type natriuretic peptide to estrogen and dexamethasone in adult bone.

C-type natriuretic peptide (CNP) is crucial in promoting endochondral bone growth in mammals including humans but whether this paracrine hormone participates in maintaining bone integrity in the mature skeleton is unknown. Accordingly we studied changes in plasma and bone tissue CNP in anoestrus adult ewes receiving short term anabolic (estrogen) or catabolic (dexamethasone) treatment for 7days. CNP and the aminoterminal fragment of the CNP prohormone (NTproCNP) were measured in plasma and extracts of cancellous bone excised from vertebral, iliac, tibial and marrow tissues.

Milk composition in the Weddell seal Leptonychotes weddellii: evidence for a functional role of milk carbohydrates in pinnipeds.

We propose that secretion of milk sugar has important consequences for the metabolic economies of lactating phocid seals and their pups. Milk was collected from 21 Weddell seals Leptonychotes weddellii in McMurdo Sound, Antarctica, and assayed by standard methods. Milk composition changed over the course of lactation, but at mid- to late lactation (16-40 d postpartum), Weddell seal milk composition was relatively constant at 33.

Caloric restriction, but not caloric loading, affects circulating fetal and maternal C-type natriuretic peptide concentrations in late ovine gestation.

The factors regulating the greatly elevated concentrations of maternal plasma C-type natriuretic peptide (CNP) forms in ruminant pregnancy are largely unknown, but nutrient status is likely to be important. Previous work has shown that increases in maternal plasma CNP, sourced from the placenta, occur in response to caloric restriction in late gestation. Whether oversupply of nutrients also regulates CNP secretion in pregnancy has not been studied.

The trophoblast binucleate cell is the source of maternal circulating C-type natriuretic peptide during ovine pregnancy.

Maternal plasma concentrations of C-type natriuretic peptide (CNP) and a co-secreted bioinactive amino-terminal fragment (NTproCNP) are elevated during ovine pregnancy. Although the uteroplacental unit has been implicated as a likely source of CNP, the relative contributions of specific uterine and placental tissues, and identity of the cellular site/s of production remain unknown. Therefore, we measured CNP and NTproCNP in intercaruncular uterine tissue and maternal (caruncle) and fetal (cotyledon) placental tissues throughout gestation.

Effect of nutrition on plasma C-type natriuretic peptide forms in adult sheep: evidence for enhanced C-type natriuretic peptide degradation during caloric restriction.

Previous studies in lambs and children show that the plasma concentration of amino terminal pro-C-type natriuretic peptide (NTproCNP), a stable product of proCNP, is strongly correlated with skeletal growth and markers of bone formation. Consistent with these findings, CNP expression is sensitive to nutritional status and is reduced by caloric restriction (CR) in both the fetus and the postnatal lamb. However, the effect of nutritional status on CNP in the adult, once linear growth is complete, is unknown.