Risk factors associated with exposure to bovine respiratory disease pathogens during the peri-weaning period in dairy bull calves

peer-reviewedBackground Bovine respiratory disease (BRD) remains among the leading causes of death of cattle internationally. The objective of this study was to identify risk factors associated with exposure to BRD pathogens during the peri-weaning period (day (d)-14 to d 14 relative to weaning at 0) in dairy bull calves using serological responses to these pathogens as surrogate markers of exposure. Clinically normal Holstein-Friesian and Jersey breed bull calves (n = 72) were group housed in 4 pens using a factorial design with calves of different breeds and planes of nutrition in each pen. Intrinsic, management and clinical data were collected during the pre-weaning (d − 56 to d − 14) period. Calves were gradually weaned over 14 days (d − 14 to d 0). Serological analysis for antibodies against key BRD pathogens (BRSV, BPI3V, BHV-1, BHV-4, BCoV, BVDV and H. somni) was undertaken at d − 14 and d 14. Linear regression models (for BVDV, BPI3V, BHV-1, BHV-4, BCoV and H. somni) and a single mixed effect random variable model (for BRSV) were used to identify risk factors for changes in antibody levels to these pathogens. Results BRSV was the only pathogen which demonstrated clustering by pen. Jersey calves experienced significantly lower changes in BVDV S/P than Holstein-Friesian calves. Animals with a high maximum respiratory score (≥8) recorded significant increases in H. somni S/P during the peri-weaning period when compared to those with respiratory scores of ≤3. Haptoglobin levels of between 1.32 and 1.60 mg/ml at d − 14 were significantly associated with decreases in BHV-1 S/N during the peri-weaning period. Higher BVDV S/P ratios at d − 14 were significantly correlated with increased changes in serological responses to BHV-4 over the peri-weaning period. Conclusions Haptoglobin may have potential as a predictor of exposure to BHV-1. BRSV would appear to play a more significant role at the ‘group’ rather than ‘individual animal’ level. The significant associations between the pre-weaning levels of antibodies to certain BRD pathogens and changes in the levels of antibodies to the various pathogens during the peri-weaning period may reflect a cohort of possibly genetically linked ‘better responders’ among the study population

Dog breeds and conformations predisposed to osteosarcoma in the UK: a VetCompass study

Background: Osteosarcoma is a malignant bone neoplasia that has high welfare consequences for affected dogs. Awareness of breed and canine conformational risk factors for osteosarcoma can assist with earlier diagnosis and improved clinical management. Study of osteosarcoma in dogs also offers translational value for humans. Anonymised clinical data within VetCompass on dogs under primary veterinary care in the UK were searched for osteosarcoma cases. Descriptive statistics reported overall and breed-specific prevalence. Risk factor analysis used multivariable logistic regression modelling. Results: From 905,552 study dogs, 331 osteosarcoma cases were confirmed yielding a one-year period prevalence of 0.037% (95% CI: 0.033-0.041). Breeds with the highest annual prevalence were the Scottish Deerhound (3.28%, 95% CI 0.90-8.18), Leonberger (1.48%, 95% CI 0.41- 3.75), Great Dane (0.87%, 95% CI 0.43- 1.55) and Rottweiler (0.84%, 95% CI 0.64-1.07). The median age at diagnosis was 9.64 years (IQR: 7.97-11.41). Following multivariable modelling, 11 breeds showed increased odds of osteosarcoma compared with crossbred dogs. Breeds with the highest odds included Scottish Deerhound (OR 118.40, 95% CI 41.12-340.95), Leonberger (OR 55.79, 95% CI 19.68-158.15), Great Dane (OR 34.24, 95% CI 17.81-65.83) and Rottweiler (OR 26.67, 95% CI 18.57-38.29). Compared with breeds with mesocephalic skull conformation, breeds with dolichocephalic skull conformation (OR 2.72, 95% CI 2.06-3.58) had increased odds while breeds with brachycephalic skull conformation showed reduced odds (OR 0.50, 95% CI 0.32-0.80). Chondrodystrophic breeds had 0.10 times the odds (95% CI 0.06-0.15) compared with non-chondrodystrophic breeds. Increasing adult bodyweight was associated with increasing odds of osteosarcoma. Conclusions: The current study cements the concept that breed, bodyweight and longer leg or longer skull length are all strong risk factors for osteosarcoma in dogs. With this awareness, veterinarians can update their clinical suspicion and judgement, breeders can select towards lower-risk animals, and researchers can robustly define more useful study populations for fundamental and translational bioscience

Dynamics of barred galaxies: effects of disk height

We study dynamics of bars in models of disk galaxies embeded in realistic dark matter halos. We find that disk thickness plays an important, if not dominant, role in the evolution and structure of the bars. We also make extensive numerical tests of different N-body codes used to study bar dynamics. Models with thick disks typically used in this type of modeling (height-to-length ratio hz/Rd=0.2) produce slowly rotating, and very long, bars. In contrast, more realistic thin disks with the same parameters as in our Galaxy (hz/Rd= 0.1) produce bars with normal length Rbar approx R_d, which rotate quickly with the ratio of the corotation radius to the bar radius 1.2-1.4 compatible with observations. Bars in these models do not show a tendency to slow down, and may lose as little as 2-3 percent of their angular momentum due to dynamical friction with the dark matter over cosmological time. We attribute the differences between the models to a combined effect of high phase-space density and smaller Jeans mass in the thin disk models, which result in the formation of a dense central bulge. Special attention is paid to numerical effects such as the accuracy of orbital integration, force and mass resolution. Using three N-body codes -- Gadget, ART, and Pkdgrav -- we find that numerical effects are very important and, if not carefully treated, may produce incorrect and misleading results. Once the simulations are performed with sufficiently small time-steps and with adequate force and mass resolution, all the codes produce nearly the same results: we do not find any systematic deviations between the results obtained with TREE codes (Gadget and Pkdgrav) and with the Adaptive-Mesh-Refinement (ART) code.Comment: 15 pages, 14 plots, submitted to MNRA

Cmr1/WDR76 defines a nuclear genotoxic stress body linking genome integrity and protein quality control

DNA replication stress is a source of genomic instability. Here we identify ​changed mutation rate 1 (​Cmr1) as a factor involved in the response to DNA replication stress in Saccharomyces cerevisiae and show that ​Cmr1—together with ​Mrc1/​Claspin, ​Pph3, the chaperonin containing ​TCP1 (CCT) and 25 other proteins—define a novel intranuclear quality control compartment (INQ) that sequesters misfolded, ubiquitylated and sumoylated proteins in response to genotoxic stress. The diversity of proteins that localize to INQ indicates that other biological processes such as cell cycle progression, chromatin and mitotic spindle organization may also be regulated through INQ. Similar to ​Cmr1, its human orthologue ​WDR76 responds to proteasome inhibition and DNA damage by relocalizing to nuclear foci and physically associating with CCT, suggesting an evolutionarily conserved biological function. We propose that ​Cmr1/​WDR76 plays a role in the recovery from genotoxic stress through regulation of the turnover of sumoylated and phosphorylated proteins

M2 pyruvate kinase provides a mechanism for nutrient sensing and regulation of cell proliferation

We show that the M2 isoform of pyruvate kinase (M2PYK) exists in equilibrium between monomers and tetramers regulated by allosteric binding of naturally occurring small-molecule metabolites. Phenylalanine stabilizes an inactive T-state tetrameric conformer and inhibits M2PYK with an IC(50) value of 0.24 mM, whereas thyroid hormone (triiodo-l-thyronine, T3) stabilizes an inactive monomeric form of M2PYK with an IC(50) of 78 nM. The allosteric activator fructose-1,6-bisphosphate [F16BP, AC(50) (concentration that gives 50% activation) of 7 μM] shifts the equilibrium to the tetrameric active R-state, which has a similar activity to that of the constitutively fully active isoform M1PYK. Proliferation assays using HCT-116 cells showed that addition of inhibitors phenylalanine and T3 both increased cell proliferation, whereas addition of the activator F16BP reduced proliferation. F16BP abrogates the inhibitory effect of both phenylalanine and T3, highlighting a dominant role of M2PYK allosteric activation in the regulation of cancer proliferation. X-ray structures show constitutively fully active M1PYK and F16BP-bound M2PYK in an R-state conformation with a lysine at the dimer-interface acting as a peg in a hole, locking the active tetramer conformation. Binding of phenylalanine in an allosteric pocket induces a 13° rotation of the protomers, destroying the peg-in-hole R-state interface. This distinct T-state tetramer is stabilized by flipped out Trp/Arg side chains that stack across the dimer interface. X-ray structures and biophysical binding data of M2PYK complexes explain how, at a molecular level, fluctuations in concentrations of amino acids, thyroid hormone, and glucose metabolites switch M2PYK on and off to provide the cell with a nutrient sensing and growth signaling mechanism

Early NFΚB activation is inhibited during focal cerebral ischemia in interleukin-1Β-converting enzyme deficient mice

Our previous study demonstrated that the inhibition of interleukin-1Β (IL-1Β) reduces ischemic brain injury; however, the molecular mechanism of the action of IL-1 in cerebral ischemia is unclear. We are investigating currently the role of NFΚB during focal cerebral ischemia, using mutant mice deficient in the interleukin-1 converting enzyme gene (ICE KO) in a middle cerebral artery occlusion (MCAO) model. Adult male ICE KO and wild-type mice ( n = 120) underwent up to 24 hr of permanent MCAO. Cytoplasmic phospho-NFΚB/p65 expression in ischemic brain was examined using Western blot analysis and immunohistochemistry. NFΚB DNA-binding activity was detected using electrophoretic mobility shift assay (EMSA). Furthermore, ICAM-1 expression was examined in both the ICE KO and wild-type mice (WT). Western blot analysis and immunostaining showed that the level of cytosolic phosphorylated NFΚB/p65 increased after 2 and 4 hr of MCAO in WT mice; however, NFΚB/p65 was significantly reduced after MCAO in the ICE KO mice ( P < 0.05). EMSA showed that NFΚB DNA-binding activity increased after MCAO in WT mice; but this effect was reduced in the ICE KO mice. The number of ICAM-1-positive vessels in the ischemic hemisphere was greatly attenuated in the ICE KO mice ( P < 0.05), which paralleled the results of immunohistochemistry. Our results demonstrate that NFΚB phosphorylation is reduced in ICE KO mice, suggesting that ICE or IL-1 are involved in early NFΚB phosphorylation. Because cerebral ischemia induced infarction is significantly reduced in ICE KO mice, we conclude that early NFΚB phosphorylation plays a disruptive role in the ischemic process. © 2003 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/34868/1/10654_ftp.pd

Mathematical Structures of Space-Time

At first we introduce the space-time manifold and we compare some aspects of Riemannian and Lorentzian geometry such as the distance function and the relations between topology and curvature. We then define spinor structures in general relativity, and the conditions for their existence are discussed. The causality conditions are studied through an analysis of strong causality, stable causality and global hyperbolicity. In looking at the asymptotic structure of space-time, we focus on the asymptotic symmetry group of Bondi, Metzner and Sachs, and the b-boundary construction of Schmidt. The Hamiltonian structure of space-time is also analyzed, with emphasis on Ashtekar's spinorial variables. Finally, the question of a rigorous theory of singularities in space-times with torsion is addressed, describing in detail recent work by the author. We define geodesics as curves whose tangent vector moves by parallel transport. This is different from what other authors do, because their definition of geodesics only involves the Christoffel symbols, though studying theories with torsion. We then prove how to extend Hawking's singularity theorem without causality assumptions to the space-time of the ECSK theory. This is achieved studying the generalized Raychaudhuri equation in the ECSK theory, the conditions for the existence of conjugate points and properties of maximal timelike geodesics. Our result can also be interpreted as a no-singularity theorem if the torsion tensor does not obey some additional conditions. Thus, it seems that the occurrence of singularities in closed cosmological models based on the ECSK theory is less generic than in general relativity. Our work should be compared with important previous papers. There are some relevant differences, because we rely on a different definition ofComment: 63 pages, plain-tex, published in Fortschritte der Physik, volume 40, pages 1-30, year 199

When Should We Treat Galaxies as Isolated?

Traditionally, secular evolution is defined as evolution of systems where the internal growth of structure and instabilities dominates the growth via external drivers (e.g. accretion/mergers). Most study has focused on 'isolated' galaxies, where seed asymmetries may represent realistic cosmological substructure, but subsequent evolution ignores galaxy growth. Large-scale modes in the disk then grow on a timescale of order a disk rotation period (0.1-1 Gyr). If, however, galaxies evolve cosmologically on a shorter timescale, then it may not be appropriate to consider them 'isolated.' We outline simple scalings to ask whether the timescale for secular evolution is shorter than the timescale for cosmological accretion and mergers. This is the case in a narrow, but important range of perturbation amplitudes corresponding to substructure or mode/bar fractional amplitudes 0.01-0.1, a range of interest for observed strong bars and pseudobulges. At smaller amplitudes <<0.1, systems are not isolated: typical disks will grow by accretion at a comparable level over even a single dynamical time. At larger amplitudes >>0.1, the evolution is no longer secular; direct gravitational evolution of the seed swamps the internal disk response. We derive criteria for when disks can be well-approximated as 'isolated' as a function of mass, redshift, and disk stability. The relevant parameter space shrinks at higher mass, higher disk stability, and higher-z as accretion rates increase. Cosmological rates of galaxy evolution also define a maximum bar/mode lifetime of practical interest, of ~0.1/H(z). Longer-lived modes will de-couple from their drivers (if driven) and encounter cosmological effects.Comment: 10 pages, 7 figures, accepted to MNRAS. A routine to provide merger rates discussed herein is available at http://www.cfa.harvard.edu/~phopkins/Site/mergercalc.htm

The role of inflammation in epilepsy.

Epilepsy is the third most common chronic brain disorder, and is characterized by an enduring predisposition to generate seizures. Despite progress in pharmacological and surgical treatments of epilepsy, relatively little is known about the processes leading to the generation of individual seizures, and about the mechanisms whereby a healthy brain is rendered epileptic. These gaps in our knowledge hamper the development of better preventive treatments and cures for the approximately 30% of epilepsy cases that prove resistant to current therapies. Here, we focus on the rapidly growing body of evidence that supports the involvement of inflammatory mediators-released by brain cells and peripheral immune cells-in both the origin of individual seizures and the epileptogenic process. We first describe aspects of brain inflammation and immunity, before exploring the evidence from clinical and experimental studies for a relationship between inflammation and epilepsy. Subsequently, we discuss how seizures cause inflammation, and whether such inflammation, in turn, influences the occurrence and severity of seizures, and seizure-related neuronal death. Further insight into the complex role of inflammation in the generation and exacerbation of epilepsy should yield new molecular targets for the design of antiepileptic drugs, which might not only inhibit the symptoms of this disorder, but also prevent or abrogate disease pathogenesis