Inadequate feed consumption reduces intestinal barrier function in both ruminants and monogastrics. Objectives were to characterize how progressive feed restriction (FR) affects inflammation, ...metabolism, and intestinal morphology, and to investigate if glucagon-like peptide 2 (GLP2) administration influences the aforementioned responses. Twenty-eight Holstein cows (157 ± 9 d in milk) were enrolled in 2 experimental periods. Period 1 5 d of ad libitum (AL) feed intake served as baseline for period 2 (5 d), during which cows received 1 of 6 treatments: (1) 100% of AL feed intake (AL100; n = 3), (2) 80% of AL feed intake (n = 5), (3) 60% of AL feed intake (n = 5), (4) 40% of AL feed intake (AL40; n = 5), (5) 40% of AL feed intake + GLP2 administration (AL40G; 75 µg/kg of BW s.c. 2×/d; n = 5), or (6) 20% of AL feed intake (n = 5). As the magnitude of FR increased, body weight and milk yield decreased linearly. Blood urea nitrogen and insulin decreased, whereas nonesterified fatty acids and liver triglyceride content increased linearly with progressive FR. Circulating endotoxin, lipopolysaccharide binding protein, haptoglobin, serum amyloid A, and lymphocytes increased or tended to increase linearly with advancing FR. Circulating haptoglobin decreased (76%) and serum amyloid A tended to decrease (57%) in AL40G relative to AL40 cows. Cows in AL100, AL40, and AL40G treatments were euthanized to evaluate intestinal histology. Jejunum villus width, crypt depth, and goblet cell area, as well as ileum villus height, crypt depth, and goblet cell area, were reduced (36, 14, 52, 22, 28, and 25%, respectively) in AL40 cows compared with AL100 controls. Ileum cellular proliferation tended to be decreased (14%) in AL40 versus AL100 cows. Relative to AL40, AL40G cows had improved jejunum and ileum morphology, including increased villus height (46 and 51%), villus height to crypt depth ratio (38 and 35%), mucosal surface area (30 and 27%), cellular proliferation (43 and 36%), and goblet cell area (59 and 41%). Colon goblet cell area was also increased (48%) in AL40G relative to AL40 cows. In summary, progressive FR increased circulating markers of inflammation, which we speculate is due to increased intestinal permeability as demonstrated by changes in intestinal architecture. Furthermore, GLP2 improved intestinal morphology and ameliorated circulating markers of inflammation. Consequently, FR is a viable model to study consequences of intestinal barrier dysfunction and administering GLP2 appears to be an effective mitigation strategy to improve gut health.
The impact of factors such as density dependence, food availability and weather are known to be important for predicting population change in a wide range of species. However, a challenge in ecology ...is understanding the contributory and interactive role of these drivers on populations. This is necessary to design effective conservation and management strategies. Using data from long‐term studies of five hazel dormouse Muscardinus avellanarius populations in Europe, we tested the relationship between population density and weather and their impact on demographic rates. We used an integrated population modelling approach, estimating age‐specific overwinter survival, annual population growth and fecundity rates. We found strong negative effects of population density, precipitation and winter temperature on population growth rates. This suggests that warmer and wetter weather negatively affects dormouse survival for both adults and juveniles, but we found subtle differences in these effects between age classes. We also identified an interaction between weather measures and population density on age‐specific survival, possibly as a result of weather impacts during hibernation. Although we found low winter temperature was positively associated with population growth, we found evidence consistent with density dependence. We discuss our results in the context of woodland habitat conservation management.
The impact of factors such as density dependence and food availability are known to be important for predicting population change in a wide range of species, whilst climate variation is also known to impact on the dynamics of populations. We found a strong negative effect of density dependence, precipitation, and winter temperature variation on population growth rates in the hazel dormouse Muscardinus avellanarius. We also found an interaction effect between climatic conditions and density on age‐specific survival, which may result in reduction of the hibernation season and decreasing length and frequency of hibernation bouts. We suggest that management of woodland resources, such as food availability, could be used to mitigate stressors experienced by hibernating woodland species.
The effect of feeding ractopamine hydrochloride (RAC) on growth performance, carcass and pork quality, and blood acid-base and catecholamine responses to handling and transport in finishing pigs was ...evaluated using a randomized complete block design to compare 2 RAC levels (0 vs. 10 mg/kg). Crossbred pigs ( = 144) were housed in single-sex pens (barrow or gilt) of 3 with 24 pens/RAC level. The study was carried out for a 28-d period from 104.0 ± 5.99 to 136.7 ± 6.44 kg BW. At the end of the growth study, pigs were subjected to handling and transport procedures that involved an initial aggressive handling procedure (pigs moved 50 m with 8 shocks from an electric prod) followed by a 30-min transport on a standard livestock trailer at a floor space of 0.46 m/pig followed by a final gentle handling procedure (pigs moved 100 m using sort boards and slap paddles). A blood sample was taken and rectal temperature was measured 2 h before (baseline) and immediately after the final handling procedure (final). Barrows ( = 72) were harvested and carcass and pork quality were measured. Feeding RAC increased ( ≤ 0.05) ADG (19.6%), ADFI (4.2%), and G:F (14.8%). The increase in plasma epinephrine levels from baseline to final was greater ( ≤ 0.05) for pigs fed RAC; there was a trend ( ≤ 0.10) for pigs fed RAC to have greater final blood lactate and to show a greater change from baseline to final in blood bicarbonate, partial pressure of and total carbon dioxide, and oxygen saturation levels. However, there were no differences between treatments for changes from baseline to final in rectal temperature, blood pH and lactate, and plasma norepinephrine levels. The incidence of physical indicators of stress and of nonambulatory, noninjured pigs during the handling and transport procedures was similar for the 0 and 10 mg/kg RAC levels. Final farm BW was 4.1 kg heavier, carcass yield was 1.4 percentage units greater, and LM area was 5.18 cm greater for pigs fed RAC compared to the control ( ≤ 0.05). Minolta a* and b* values were lower ( ≤ 0.05) and ultimate pH (0.05 units) and Warner-Bratzler shear force (0.43 kg) were greater ( ≤ 0.05) for pigs fed 10 compared to 0 mg/kg RAC. These results confirm the substantial improvement from feeding 10 mg/kg RAC in growth performance and carcass yield and suggest relatively limited effects on pork quality and on responses to the handling and transport procedures used in this study.
This experiment consisted of the following treatment-breed groups: 1) White crossbred gilts, 2) White crossbred gilts treated with progesterone (200 mg/d in corn oil given on d 2 and 3 after estrus), ...and 3) Chinese Meishan gilts. Pregnant and nonpregnant gilts (n = 3 to 6) from each treatment-breed combination were assigned to be slaughtered on d 10, 11, 12, 13, and 15. At slaughter each uterine horn was flushed with 20 mL of minimal essential medium. Uterine flushings were assayed for total protein, acid phosphatase, uteroferrin, retinol-binding protein, and oxytocin. Uterine flush total protein was increased by progesterone treatment, was unaffected by pregnancy status, and was less in Meishans. Similar patterns were found for retinol binding protein and uteroferrin, except that uteroferrin was greater in pregnant than in nonpregnant gilts. Oxytocin was greater in pregnant than in nonpregnant gilts, was not influenced by progesterone treatment, and was similar in Meishan and in White crossbred gilts. These results indicate that the conceptus does not influence secretion of either total protein or retinol binding protein during pregnancy and that the onset of secretion of these uterine proteins may be controlled by progesterone. The presence of the conceptus is associated with increased uteroferrin and oxytocin production. The decreased secretion of uterine proteins in Meishan gilts may partially explain the slower embryonic development that has been reported for this breed.
As shifts in the epidemiology of β-lactamase-mediated resistance continue, carbapenem-resistant
(CRE) and carbapenem-resistant
(CRPA) are the most urgent threats. Although approved β-lactam ...(BL)-β-lactamase inhibitor (BLI) combinations address widespread serine β-lactamases (SBLs), such as CTX-M-15, none provide broad coverage against either clinically important serine-β-lactamases (KPC, OXA-48) or clinically important metallo-β-lactamases (MBLs; e.g., NDM-1). VNRX-5133 (taniborbactam) is a new cyclic boronate BLI that is in clinical development combined with cefepime for the treatment of infections caused by β-lactamase-producing CRE and CRPA. Taniborbactam is the first BLI with direct inhibitory activity against Ambler class A, B, C, and D enzymes. From biochemical and structural analyses, taniborbactam exploits substrate mimicry while employing distinct mechanisms to inhibit both SBLs and MBLs. It is a reversible covalent inhibitor of SBLs with slow dissociation and a prolonged active-site residence time (half-life, 30 to 105 min), while in MBLs, it behaves as a competitive inhibitor, with inhibitor constant (
) values ranging from 0.019 to 0.081 μM. Inhibition is achieved by mimicking the transition state structure and exploiting interactions with highly conserved active-site residues. In microbiological testing, taniborbactam restored cefepime activity in 33/34 engineered
strains overproducing individual enzymes covering Ambler classes A, B, C, and D, providing up to a 1,024-fold shift in the MIC. Addition of taniborbactam restored the antibacterial activity of cefepime against all 102
clinical isolates tested and 38/41
clinical isolates tested with MIC
s of 1 and 4 μg/ml, respectively, representing ≥256- and ≥32-fold improvements, respectively, in antibacterial activity over that of cefepime alone. The data demonstrate the potent, broad-spectrum rescue of cefepime activity by taniborbactam against clinical isolates of CRE and CRPA.
A major resistance mechanism in Gram-negative bacteria is the production of β-lactamase enzymes. Originally recognized for their ability to hydrolyze penicillins, emergent β-lactamases can now confer ...resistance to other β-lactam drugs, including both cephalosporins and carbapenems. The emergence and global spread of β-lactamase-producing multi-drug-resistant “superbugs” has caused increased alarm within the medical community due to the high mortality rate associated with these difficult-to-treat bacterial infections. To address this unmet medical need, we initiated an iterative program combining medicinal chemistry, structural biology, biochemical testing, and microbiological profiling to identify broad-spectrum inhibitors of both serine- and metallo-β-lactamase enzymes. Lead optimization, beginning with narrower-spectrum, weakly active compounds, provided 20 (VNRX-5133, taniborbactam), a boronic-acid-containing pan-spectrum β-lactamase inhibitor. In vitro and in vivo studies demonstrated that 20 restored the activity of β-lactam antibiotics against carbapenem-resistant Pseudomonas aeruginosa and carbapenem-resistant Enterobacteriaceae. Taniborbactam is the first pan-spectrum β-lactamase inhibitor to enter clinical development.
Retinol-binding protein (RBP) is a major secretory product of the porcine conceptus. Using an oligonucleotide probe corresponding to a highly conserved region of all known mammalian RBP, we have ...isolated an apparently full-length cDNA clone for porcine conceptus RBP from a cDNA library constructed from pig conceptuses collected between days 13-17 of pregnancy. The cDNA was 937 base-pairs in length and coded for a protein whose inferred amino-terminal sequence was identical to that reported for both porcine conceptus RBP and porcine serum RBP. Its length was consistent with the size (approximately 1 kilobase) of the RBP message in porcine conceptuses. Porcine conceptus RBP and human serum RBP share 91% amino acid sequence identity. The inferred differences in sequence were evenly distributed throughout the length of the polypeptide. RBP mRNA was detectable within the trophoblast of day 11 porcine conceptuses by in situ hybridization with a 618-basepair 35S-labeled probe corresponding to the 3' end of porcine RBP. Silver grain density was distributed relatively uniformly over the trophoblast and the inner cell mass. Western blot analysis of conceptus culture medium demonstrated that the conceptuses of cattle (on day 19) and sheep (on day 15) as well as pigs secrete RBP during early pregnancy. Secretion of large quantities of RBP by the trophoblast of preimplantation pig conceptuses suggests important roles for vitamin A and RBP near the time of conceptus elongation.
The porcine uterus synthesizes a proteinase inhibitor (Mr 14,000) under the influence of progesterone that is relatively specific for plasmin and trypsin, but that also has weak affinity for ...chymotrypsin. Several isoforms of this uterine plasmin/trypsin inhibitor were purified by a procedure whose final two steps involved affinity chromatography on immobilized chymotrypsin and cation exchange chromatography. Amino-terminal sequencing showed that at least three of the isoforms were closely related. An oligonucleotide probe based on the protein sequence was used to identify a cDNA that contained an open reading frame coding for a mature protein (Mr 10,295) of 93 amino acids. The inhibitor had a well defined, but unique, Kunitz domain of 64 residues at its amino terminus that shared 67% sequence identity to bovine pancreatic trypsin inhibitor. Its P1 residue was arginine rather than lysine. Northern analysis showed the presence of a single mRNA species (700 bases) that in adult female pigs appeared to be confined to the uterus. During pregnancy, UPTI mRNA expression was high until Day 30 and decreased significantly thereafter. By contrast, uteroferrin, mRNA reached maximal concentrations in late pregnancy. These data are consistent with an earlier hypothesis that the inhibitor serves to neutralize the activities of one or more serine proteinases generated by the proliferating trophoblast during the formation of the noninvasive placenta of the pig
Changes in plasma and follicular fluid concentrations of inhibin were examined in sows after weaning at 28-32 days post partum. From 0 to 48 h after weaning, inhibin concentrations were 200-300 times ...higher in follicular fluid from small (less than 4 mm) and medium-large (greater than or equal to 4 mm) follicles than in ovarian venous plasma. Inhibin concentrations increased in follicular fluid from medium-large follicles at 24 and 48 h after weaning; concentrations in ovarian venous plasma were positively correlated with the number of medium-large follicles (r = 0.40) and with ovarian venous plasma concentrations of oestradiol (r = 0.61). Blood samples were collected for 30 days from sows (n = 6) that exhibited oestrus within 5 days after weaning and from sows (n = 5) that remained anoestrous for 11 days after weaning. Plasma inhibin concentrations rose in oestrous and anoestrous sows by 12 h and continued to rise for 60 h after weaning. Plasma inhibin concentrations rose further and were higher at 3.5-4.5 days after weaning in oestrous sows than in sows that remained anoestrous. After oestrus, plasma inhibin concentrations declined. At weaning, plasma concentrations of follicle-stimulating hormone (FSH) were higher in sows that subsequently exhibited oestrus than in sows that remained anoestrous. After weaning, plasma concentrations of FSH declined in both groups, reached a nadir at 2.5 days, and increased gradually in anoestrous sows; oestrous sows exhibited an FSH surge at oestrus. Plasma FSH returned to preweaning concentrations in both groups of sows at Days 7-8.
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