Assessment of the onset of action of afoxolaner against existing adult flea (Ctenocephalides felis) infestations on dogs

AbstractThe speed of kill of afoxolaner against experimental infestations by Ctenocephalides felis was evaluated after oral administration of afoxolaner in a soft chew (NEXGARD®) at a dose to achieve 2.5mg/kg bodyweight. Forty beagles were allocated to two treatment groups. Dogs in Treatment Group 1 were untreated controls. Dogs in Treatment Group 2 were treated on Day-0 with afoxolaner, according to their pre-treatment bodyweight. All dogs were infested with approximately 100 C. felis on Day-1. Live fleas were counted upon removal at 5 time points after treatment (i.e., 2, 4, 8, 12 and 24h after treatment). For each time point, counts were performed on 4 dogs from each of the treated and the untreated groups. Early curative flea killing efficacy was evaluated with respect to the untreated control group. The afoxolaner treated group had significantly fewer fleas than the untreated control group at 8, 12, and 24h (p<0.001). The percent efficacies of orally administered afoxolaner were 15.0%, 87.8%, 99.5%, 100.0%, and 100.0% at 2, 4, 8, 12, and 24h, respectively. In this study, afoxolaner began killing fleas by 2h after treatment with increasing efficacy at subsequent time points and had >99.5% efficacy at 8, 12, and 24h after treatment demonstrating an early onset of action

Streamlining screening of emotional function in Veterans with traumatic brain injury

ObjectivesThis study examined how depression, anxiety, and sleep items from the Neurobehavioral Symptom Inventory (NSI) predict results from longer inventories.MethodThis was a retrospective review from 484, predominantly male (96.1%) Veterans, mean age 29.7 years, who underwent brief neuropsychological screening during a comprehensive, multidisciplinary evaluation for mild traumatic brain injury (TBI). Participants completed the NSI, insomnia severity index (ISI), and hospital anxiety and depression scale (HADS).Results: Overall,97.1% who endorsed “severe”/“very severe” anxiety on the NSI had significant anxiety on the HADS; 85% reporting “severe”/“very severe” depression on the NSI, had significant depression on the HADS; and 97.7% reporting “severe”/“very severe” sleep problems on the NSI, had significant sleep difficulties on the ISI.ConclusionClose correspondence between “severe”/“very severe” symptoms on the NSI and lengthier checklists suggests additional checklists may be eliminated and individuals can be referred for mental health treatment. NSI reports of “mild”/“moderate” require further screening.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/144598/1/jclp22595_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/144598/2/jclp22595.pd

High-precision determination of transition amplitudes of principal transitions in Cs from van der Waals coefficient C_6

A method for determination of atomic dipole matrix elements of principal transitions from the value of dispersion coefficient C_6 of molecular potentials correlating to two ground-state atoms is proposed. The method is illustrated on atomic Cs using C_6 deduced from high-resolution Feshbach spectroscopy. The following reduced matrix elements are determined < 6S_{1/2} || D || 6P_{1/2} > =4.5028(60) |e| a0 and =6.3373(84) |e| a0 (a0= 0.529177 \times 10^{-8} cm.) These matrix elements are consistent with the results of the most accurate direct lifetime measurements and have a similar uncertainty. It is argued that the uncertainty can be considerably reduced as the coefficient C_6 is constrained further.Comment: 4 pages; 3 fig

Quantum computation with trapped polar molecules

We propose a novel physical realization of a quantum computer. The qubits are electric dipole moments of ultracold diatomic molecules, oriented along or against an external electric field. Individual molecules are held in a 1-D trap array, with an electric field gradient allowing spectroscopic addressing of each site. Bits are coupled via the electric dipole-dipole interaction. Using technologies similar to those already demonstrated, this design can plausibly lead to a quantum computer with $\gtrsim 10^4$ qubits, which can perform $\sim 10^5$ CNOT gates in the anticipated decoherence time of $\sim 5$ s.Comment: 4 pages, RevTeX 4, 2 figures. Edited for length and converted to RevTeX, but no substantial changes from earlier pdf versio

A constitutively active and uninhibitable caspase-3 zymogen efficiently induces apoptosis

The caspase-3 zymogen has essentially zero activity until it is cleaved by initiator caspases during apoptosis. However, a mutation of V266E in the dimer interface activates the protease in the absence of chain cleavage. We show that low concentrations of the pseudo-activated procaspase-3 kill mammalian cells rapidly and, importantly, this protein is not cleaved nor is it inhibited efficiently by the endogenous regulator XIAP (X-linked inhibitor of apoptosis). The 1.63 Å (1 Å = 0.1 nm) structure of the variant demonstrates that the mutation is accommodated at the dimer interface to generate an enzyme with substantially the same activity and specificity as wild-type caspase-3. Structural modelling predicts that the interface mutation prevents the intersubunit linker from binding in the dimer interface, allowing the active sites to form in the procaspase in the absence of cleavage. The direct activation of procaspase-3 through a conformational switch rather than by chain cleavage may lead to novel therapeutic strategies for inducing cell death

Fingerprinting the Substrate Specificity of M1 and M17 Aminopeptidases of Human Malaria, Plasmodium falciparum

Plasmodium falciparum, the causative agent of human malaria, expresses two aminopeptidases, PfM1AAP and PfM17LAP, critical to generating a free amino acid pool used by the intraerythrocytic stage of the parasite for proteins synthesis, growth and development. These exopeptidases are potential targets for the development of a new class of anti-malaria drugs.To define the substrate specificity of recombinant forms of these two malaria aminopeptidases we used a new library consisting of 61 fluorogenic substrates derived both from natural and unnatural amino acids. We obtained a detailed substrate fingerprint for recombinant forms of the enzymes revealing that PfM1AAP exhibits a very broad substrate tolerance, capable of efficiently hydrolyzing neutral and basic amino acids, while PfM17LAP has narrower substrate specificity and preferentially cleaves bulky, hydrophobic amino acids. The substrate library was also exploited to profile the activity of the native aminopeptidases in soluble cell lysates of P. falciparum malaria.This data showed that PfM1AAP and PfM17LAP are responsible for majority of the aminopeptidase activity in these extracts. These studies provide specific substrate and mechanistic information important for understanding the function of these aminopeptidases and could be exploited in the design of new inhibitors to specifically target these for anti-malaria treatment

Hematology and serum biochemistry values of free-ranging Iberian wolves (Canis lupus) trapped by leg-hold snares

Hematology and serum biochemistry are important tools in assessing the health and physiological status of wildlife populations. Nevertheless, studies on free-ranging wolves (Canis lupus) are scarce, and no reference values are available neither for Iberian wolves nor for wolves captured with leghold snares. We report 37 hematology and serum biochemistry variables obtained from 26 free-ranging Iberian wolves captured with leg-hold snares between 2007 and 2014, including variables previously not reported in the literature. The values obtained are similar to the published reference intervals for Scandinavian wolves captured by darting from a helicopter, except for higher values for mean corpuscular hemoglobin concentration (MCHC), red blood cell distribution width (RDW), leukocyte count, creatinine kinase (CK), ?-globulins, and total bilirubin (TBIL) and lower values for alkaline phosphatase (ALP). We propose that differences in leukocyte count, CK, and TBIL are related to the method of capture, while differences in RDW, MCHC, ALP, and ?-globulins could reflect physiological adaptations to environmental conditions, sampling, or pre-analytical artifacts. Lymphocyte count was lower and neutrophil/lymphocyte ratio was significantly higher in older, reproductive females, while ALP and phosphorus were higher in juvenile wolves. For the first time, we describe hematology and serum biochemistry values of free-ranging Iberian wolves captured with leg-hold snares. The data reported here is the first published reference for wolves captured with similar methods and for monitoring Iberian wolves populations’ physiological and health status.We thank Nuria Fandos and Carla Ferreira, rangers from Xunta de Galicia and Parque Nacional de los Picos de Europa, and volunteers who helped during the trapping sessions. The wolves were captured under projects financed by Associacao de Conservacao do Habitat do Lobo Iberico (ACHLI) in Portugal and by Picos de Europa National Park, Ministerio de Agricultura, Alimentacion y Medio Ambiente, and Xunta de Galicia in Spain. Sara Roque benefited from grant SFRH/BD/12291/2003 from Fundacao para a Ciencia e a Tecnologia. Jose V. Lopez-Bao was supported by a postdoctoral contract from the Spanish Ministry of Economy and Competitiveness. This is the paper no. 5 from the Iberian Wolf Research Team

The modulating effect of education on semantic interference during healthy aging

Aging has traditionally been related to impairments in name retrieval. These impairments have usually been explained by a phonological transmission deficit hypothesis or by an inhibitory deficit hypothesis. This decline can, however, be modulated by the educational level of the sample. This study analyzed the possible role of these approaches in explaining both object and face naming impairments during aging. Older adults with low and high educational level and young adults with high educational level were asked to repeatedly name objects or famous people using the semantic-blocking paradigm. We compared naming when exemplars were presented in a semantically homogeneous or in a semantically heterogeneous context. Results revealed significantly slower rates of both face and object naming in the homogeneous context (i.e., semantic interference), with a stronger effect for face naming. Interestingly, the group of older adults with a lower educational level showed an increased semantic interference effect during face naming. These findings suggest the joint work of the two mechanisms proposed to explain age-related naming difficulties, i.e., the inhibitory deficit and the transmission deficit hypothesis. Therefore, the stronger vulnerability to semantic interference in the lower educated older adult sample would possibly point to a failure in the inhibitory mechanisms in charge of interference resolution, as proposed by the inhibitory deficit hypothesis. In addition, the fact that this interference effect was mainly restricted to face naming and not to object naming would be consistent with the increased age-related difficulties during proper name retrieval, as suggested by the transmission deficit hypothesis.This research was supported by grants PSI2013-46033-P to A.M., PSI2015-65502-C2-1-P to M.T.B., PCIN-2015-165-C02-01 to D.P., PSI2017-89324-C2-1-P to DP from the Spanish Ministry of Economy and Competitiveness (http://www.mineco.gob.es/)