Poor water-solubility is a common characteristic of drug candidates in pharmaceutical development pipelines today. Various processes have been developed to increase the solubility, dissolution rate ...and bioavailability of these active ingredients belonging to BCS II and IV classifications. Over the last decade, nano-crystal delivery forms and amorphous solid dispersions have become well established in commercially available products and industry literature. This article is a comparative analysis of these two methodologies primarily for orally delivered medicaments. The thermodynamic and kinetic theories relative to these technologies are presented along with marketed product evaluations and a survey of commercial relevant scientific literature.
Fermentation of pasture grasses and grains in the rumen of dairy cows and other ruminants produces methane as a by-product, wasting energy and contributing to the atmospheric load of greenhouse ...gasses. Many feeding trials in farmed ruminants have tested the impact of dietary components on feed efficiency, productivity and methane yield (MeY). Such diets remodel the rumen microbiome, altering bacterial, archaeal, fungal and protozoan populations, with an altered fermentation outcome. In dairy cows, some dietary grains can reduce enteric methane production. This is especially true of wheat, in comparison to corn or barley. Using a feeding trial of cows fed rolled wheat, corn or barley grain, in combination with hay and canola, we identified wheat-associated changes in the ruminal microbiome. Ruminal methane production, pH and VFA concentration data together with 16S rRNA gene amplicon sequences were used to compare ruminal bacterial and archaeal populations across diets. Differential abundance analysis of clustered sequences (OTU) identified members of the bacterial families Lachnospiraceae, Acidaminococcaceae, Eubacteriaceae, Prevotellaceae, Selenomonadaceae, Anaerovoracaceae and Fibrobacteraceae having a strong preference for growth in wheat-fed cows. Within the methanogenic archaea, (at >99% 16S rRNA sequence identity) the growth of Methanobrevibacter millerae was favoured by the non-wheat diets, while Methanobrevibacter olleyae was unaffected. From the wheat-preferring bacteria, correlation analysis found OTU strongly linked to reduced MeY, reduced pH and raised propionic acid levels. OTU from the genera Shuttleworthia and Prevotella_7 and especially Selenomonadaceae had high anti-methane correlations. An OTU likely representing (100% sequence identity) the fumarate-reducing, hydrogen-utilising, rumen bacterium Mitsuokella jalaludinii, had an especially high negative correlation coefficient (-0.83) versus MeY and moderate correlation (-0.6) with rumen pH, strongly suggesting much of the MeY suppression is due to reduced hydrogen availablity. Other OTU, representing as yet unknown species from the Selenomonadaceae family and the genera Prevotella_7, Fibrobacter and Syntrophococcus also had high to moderate negative MeY correlations, but low correlation with pH. These latter likely represent bacterial species able to reduce MeY without causing greater ruminal acidity, making them excellent candidates, provided they can be isolated, for development as anti-methane probiotics.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dairy products are a key source of valuable proteins and fats for many millions of people worldwide. Dairy cattle are highly susceptible to heat-stress induced decline in milk production, and as the ...frequency and duration of heat-stress events increases, the long term security of nutrition from dairy products is threatened. Identification of dairy cattle more tolerant of heat stress conditions would be an important progression towards breeding better adapted dairy herds to future climates. Breeding for heat tolerance could be accelerated with genomic selection, using genome wide DNA markers that predict tolerance to heat stress. Here we demonstrate the value of genomic predictions for heat tolerance in cohorts of Holstein cows predicted to be heat tolerant and heat susceptible using controlled-climate chambers simulating a moderate heatwave event. Not only was the heat challenge stimulated decline in milk production less in cows genomically predicted to be heat-tolerant, physiological indicators such as rectal and intra-vaginal temperatures had reduced increases over the 4 day heat challenge. This demonstrates that genomic selection for heat tolerance in dairy cattle is a step towards securing a valuable source of nutrition and improving animal welfare facing a future with predicted increases in heat stress events.
The secretion of recombinant disulfide-bond containing proteins into the periplasm of Gram-negative bacterial hosts, such as E. coli, has many advantages that can facilitate product isolation, ...quality and activity. However, the secretion machinery of E. coli has a limited capacity and can become overloaded, leading to cytoplasmic retention of product; which can negatively impact cell viability and biomass accumulation. Fine control over recombinant gene expression offers the potential to avoid this overload by matching expression levels to the host secretion capacity.
Here we report the application of the RiboTite gene expression control system to achieve this by finely controlling cellular expression levels. The level of control afforded by this system allows cell viability to be maintained, permitting production of high-quality, active product with enhanced volumetric titres.
The methods and systems reported expand the tools available for the production of disulfide-bond containing proteins, including antibody fragments, in bacterial hosts.
The methods for estimating methane emissions from cattle as used in the Australian national inventory are based on older data that have now been superseded by a large amount of more recent data. ...Recent data suggested that the current inventory emissions estimates can be improved. To address this issue, a total of 1034 individual animal records of daily methane production (MP) was used to reassess the relationship between MP and each of dry matter intake (DMI) and gross energy intake (GEI). Data were restricted to trials conducted in the past 10 years using open-circuit respiration chambers, with cattle fed forage-based diets (forage >70%). Results from diets considered to inhibit methanogenesis were omitted from the dataset. Records were obtained from dairy cattle fed temperate forages (220 records), beef cattle fed temperate forages (680 records) and beef cattle fed tropical forages (133 records). Relationships were very similar for all three production categories and single relationships for MP on a DMI or GEI basis were proposed for national inventory purposes. These relationships were MP (g/day) = 20.7 (±0.28) × DMI (kg/day) (R2 = 0.92, P < 0.001) and MP (MJ/day) = 0.063 (±0.008) × GEI (MJ/day) (R2 = 0.93, P < 0.001). If the revised MP (g/day) approach is used to calculate Australia’s national inventory, it will reduce estimates of emissions of forage-fed cattle by 24%. Assuming a global warming potential of 25 for methane, this represents a 12.6 Mt CO2-e reduction in calculated annual emissions from Australian cattle.
BT75, a boron-containing retinoid, is a novel retinoic acid receptor (RAR)α agonist synthesized by our group. Previous studies indicated that activation of retinoic acid (RA) signaling may attenuate ...progression of Alzheimer’s disease (AD). Presently, we aimed to examine the anti-inflammatory effect of BT75 and explore the possible mechanism using cultured cells and an AD mouse model. Pretreatment with BT75 (1–25 µM) suppressed the release of nitric oxide (NO) and IL-1β in the culture medium of mouse microglial SIM-A9 cells activated by LPS. BMS195614, an RARα antagonist, partially blocked the inhibition of NO production by BT75. Moreover, BT75 attenuated phospho-Akt and phospho-NF-κB p65 expression augmented by LPS. In addition, BT75 elevated arginase 1, IL-10, and CD206, and inhibited inducible nitric oxide synthase (iNOS) and IL-6 formation in LPS-treated SIM-A9 cells, suggesting the promotion of M1–M2 microglial phenotypic polarization. C57BL/6 mice were injected intracerebroventricularly (icv) with streptozotocin (STZ) (3 mg/kg) to provide an AD-like mouse model. BT75 (5 mg/kg) or the vehicle was intraperitoneally (ip) injected to icv-STZ mice once a day for 3 weeks. Immunohistochemical analyses indicated that GFAP-positive cells and rod or amoeboid-like Iba1-positive cells, which increased in the hippocampal fimbria of icv-STZ mice, were reduced by BT75 treatment. Western blot results showed that BT75 decreased levels of neuronal nitric oxide synthase (nNOS), GFAP, and phosphorylated Tau, and increased levels of synaptophysin in the hippocampus of icv-STZ mice. BT75 may attenuate neuroinflammation by affecting the Akt/NF-κB pathway and microglial M1–M2 polarization in LPS-stimulated SIM-A9 cells. BT75 also reduced AD-like pathology including glial activation in the icv-STZ mice. Thus, BT75 may be a promising anti-inflammatory and neuroprotective agent worthy of further AD studies.
Selecting for lower methane (CH4) emitting animals is one of the best approaches to reduce CH4 given that genetic progress is permanent and cumulative over generations. As genetic selection requires ...a large number of animals with records and few countries actively record CH4, combining data from different countries could help to expedite accurate genetic parameters for CH4 traits and build a future genomic reference population. Additionally, if we want to include CH4 in the breeding goal, it is important to know the genetic correlations of CH4 traits with other economically important traits. Therefore, the aim of this study was first to estimate genetic parameters of 7 suggested methane traits, as well as genetic correlations between methane traits and production, maintenance, and efficiency traits using a multicountry database. The second aim was to estimate genetic correlations within parities and stages of lactation for CH4. The third aim was to evaluate the expected response of economically important traits by including CH4 traits in the breeding goal. A total of 15,320 methane production (MeP, g/d) records from 2,990 cows belonging to 4 countries (Canada, Australia, Switzerland, and Denmark) were analyzed. Records on dry matter intake (DMI), body weight (BW), body condition score, and milk yield (MY) were also available. Additional traits such as methane yield (MeY; g/kg DMI), methane intensity (MeI; g/kg energy-corrected milk), a genetic standardized methane production, and 3 definitions of residual methane production (g/d), residual feed intake, metabolic BW (MBW), BW change, and energy-corrected milk were calculated. The estimated heritability of MeP was 0.21, whereas heritability estimates for MeY and MeI were 0.30 and 0.38, and for the residual methane traits heritability ranged from 0.13 to 0.16. Genetic correlations between different methane traits were moderate to high (0.41 to 0.97). Genetic correlations between MeP and economically important traits ranged from 0.29 (MY) to 0.65 (BW and MBW), being 0.41 for DMI. Selection index calculations showed that residual methane had the most potential for inclusion in the breeding goal when compared with MeP, MeY, and MeI, as residual methane allows for selection of low methane emitting animals without compromising other economically important traits. Inclusion of residual feed intake in the breeding goal could further reduce methane, as the correlation with residual methane is moderate and elicits a favorable correlated response. Adding a negative economic value for methane could facilitate a substantial reduction in methane emissions while maintaining an increase in milk production.
Wheat is the most common concentrate fed to dairy cows in Australia, but few studies have examined the effects of wheat feeding on enteric methane emissions, and no studies have compared the relative ...potencies of wheat, corn, and barley for their effects on enteric methane production. In this 35-d experiment, 32 Holstein dairy cows were offered 1 of 4 diets: a corn diet (CRN) of 10.0 kg of dry matter (DM)/d of single-rolled corn grain, 1.8 kg of DM/d of canola meal, 0.2 kg of DM/d of minerals, and 11.0 kg of DM/d of chopped alfalfa hay; a wheat diet (WHT) similar to the CRN diet but with the corn replaced by single-rolled wheat; a barley diet (SRB) similar to the CRN diet but with the corn replaced by single-rolled barley; and a barley diet (DRB) similar to the CRN diet but with the corn replaced by double-rolled barley. Individual cow feed intakes, milk yields, and milk compositions were measured daily but reported for the last 5 d of the experiment. During the last 5 d of the experiment, individual cow methane emissions were measured using the SF6 tracer technique for all cows, and ruminal fluid pH was continuously measured by intraruminal sensors for 3 cows in each treatment group. The average DM intake of cows offered the CRN, WHT, SRB, and DRB diets was 22.2, 21.1, 22.6, and 22.6 kg/d. The mean energy-corrected milk of cows fed the WHT diet was less than that of cows fed the other diets. This occurred because the milk fat percentage of cows fed the WHT diet was significantly less than that of cows fed the other diets. The mean methane emissions and methane yields of cows fed the WHT diet were also significantly less than those of cows fed the other diets. Indeed, the CRN, SRB, and DRB diets were associated with 49, 73, and 78% greater methane emissions, respectively, compared with the emissions from the WHT diet. Methane yield was found to be most strongly related to the minimum daily ruminal fluid pH. This study showed that although the inclusion of wheat in the diet of dairy cows could be an effective strategy for substantially reducing their methane emissions, it also reduced their milk fat percentage and production of milk fat and energy-corrected milk.
Developmental exposure to ethanol is a leading cause of cognitive, emotional and behavioral problems, with fetal alcohol spectrum disorder (FASD) affecting more than 1:100 children. Recently, ...comorbid sleep deficits have been highlighted in these disorders, with sleep repair a potential therapeutic target. Animal models of FASD have shown non-REM (NREM) sleep fragmentation and slow-wave oscillation impairments that predict cognitive performance. Here we use a mouse model of perinatal ethanol exposure to explore whether reduced sleep pressure may contribute to impaired NREM sleep, and compare the function of a brain network reported to be impacted by insomnia-the Salience network-in developmental ethanol-exposed mice with sleep-deprived, saline controls. Mice were exposed to ethanol or saline on postnatal day 7 (P7) and allowed to mature to adulthood for testing. At P90, telemetered cortical recordings were made for assessment of NREM sleep in home cage before and after 4 h of sleep deprivation to assess basal NREM sleep and homeostatic NREM sleep response. To assess Salience network functional connectivity, mice were exposed to the 4 h sleep deprivation period or left alone, then immediately sacrificed for immunohistochemical analysis of c-Fos expression. The results show that developmental ethanol severely impairs both normal rebound NREM sleep and sleep deprivation induced increases in slow-wave activity, consistent with reduced sleep pressure. Furthermore, the Salience network connectome in rested, ethanol-exposed mice was most similar to that of sleep-deprived, saline control mice, suggesting a sleep deprivation-like state of Salience network function after developmental ethanol even without sleep deprivation.
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