Macroscopic behavior of bidisperse suspensions of noncolloidal particles in yield stress fluids

We study both experimentally and theoretically the rheological behavior of isotropic bidisperse suspensions of noncolloidal particles in yield stress fluids. We focus on materials in which noncolloidal particles interact with the suspending fluid only through hydrodynamical interactions. We observe that both the elastic modulus and yield stress of bidisperse suspensions are lower than those of monodisperse suspensions of same solid volume fraction. Moreover, we show that the dimensionless yield stress of such suspensions is linked to their dimensionless elastic modulus and to their solid volume fraction through the simple equation of Chateau et al.[J. rheol. 52, 489-506 (2008)]. We also show that the effect of the particle size heterogeneity can be described by means of a packing model developed to estimate random loose packing of assemblies of dry particles. All these observations finally allow us to propose simple closed form estimates for both the elastic modulus and the yield stress of bidisperse suspensions: while the elastic modulus is a function of the reduced volume fraction $\phi/\phi_m$ only, where $\phi_m$ is the estimated random loose packing, the yield stress is a function of both the volume fraction $\phi$ and the reduced volume fraction

Rates of predation on mammals by gombe chimpanzees, 1972–1975

Rates of chimpanzee predation on mammals are calculated using data on 75 kills recorded during focal observation in Gombe National Park, Tanzania, from January 1972 to April 1975. The chimpanzees were members of two study communities (Kanyawara, or Northern, and Kahama, or Southern, community), and were observed as focal individuals for 14,583 hr by more than 30 researchers and field assistants working in pairs. The rate of predation by females was too low to allow reasonable estimates. For males, the mean rate of killing during the study period was 0.31 kills per male per 100 hr ( N =17 males), or 4.65 kills per 100 hr in the two communities. In contrast to results from Mahale Mountains, there was no difference in predation rate between wet and dry seasons. However, predation rates varied over time, increasing by four times between the first three and last four seasons of the sample period. In an average year the 15 adult and subadult male chimpanzees are calculated to have killed 204 prey per year in an area of 16 km 2 , varying between 99 and 420 prey per year in periods of low and high predation rate. Red colobus were the most frequent prey, followed by bushpig and bushbuck. Predation rates varied greatly on different prey species, and were not related to either the proportion of time spent within 200 m of male chimpanzees, or to their population densities. In relation to encounter rates and population density, baboons, blue monkeys, and redtail monkeys were killed at a fraction of the rate of red colobus monkeys, which suffered severe mortality from chimpanzee predation. Predation on bushpig and bushbuck also appears to have been high in relation to population density. The amount of food provided by predation is estimated to have averaged 600 kg per year for chimpanzees in the two communities (totalling 14–17 adult or subadult males, 18–20 adult of subadult females, and about 19 infants or juveniles). This suggests that adult males consumed around 25 kg of meat per year, although any average figure undoubtedly masks considerable individual variation. Present data suggest that chimpanzees in Gombe and Tai National Park, Ivory Coast, prey on mammals at rates higher than other populations.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41607/1/10329_2006_Article_BF02380938.pd

Accelerating functional gene discovery in osteoarthritis

Osteoarthritis causes debilitating pain and disability, resulting in a considerable socioeconomic burden, yet no drugs are available that prevent disease onset or progression. Here, we develop, validate and use rapid-throughput imaging techniques to identify abnormal joint phenotypes in randomly selected mutant mice generated by the International Knockout Mouse Consortium. We identify 14 genes with functional involvement in osteoarthritis pathogenesis, including the homeobox gene Pitx1, and functionally characterize 6 candidate human osteoarthritis genes in mouse models. We demonstrate sensitivity of the methods by identifying age-related degenerative joint damage in wild-type mice. Finally, we phenotype previously generated mutant mice with an osteoarthritis-associated polymorphism in the Dio2 gene by CRISPR/Cas9 genome editing and demonstrate a protective role in disease onset with public health implications. We hope this expanding resource of mutant mice will accelerate functional gene discovery in osteoarthritis and offer drug discovery opportunities for this common, incapacitating chronic disease

Sex differences in behavioral and neurochemical effects of gonadectomy and aromatase inhibition in rats

Aromatase inhibitors, which are widely used for the treatment of estrogen-dependent cancers, have been associated with psychiatric side effects ranging from mania to depression. In the present study, we investigated sex differences in the behavioral and neurochemical effects of aromatase inhibition on male and female, sham-operated or gonadectomized adult rats. Three weeks after surgery, rats received chronic treatment with the aromatase inhibitor letrozole or vehicle and were then subjected to the open field test, which assesses general activity. Half of the subjects were subsequently exposed to the stressful procedure of the forced swim test (FST), which is also a test of antidepressant activity. Aromatase activity was analyzed in the hypothalamus and testosterone and corticosterone were assayed in the blood serum of all rats. The hippocampus and prefrontal cortex (PFC) were analyzed for monoamine (noradrenaline, dopamine and serotonin), as well as amino acid (GABA, glutamate, glycine, taurine, alanine and histidine) levels. The observed decrease in hypothalamic aromatase activity confirmed the efficacy of letrozole treatment in both sexes. Moreover, letrozole enhanced testosterone levels in sham-operated females. In the open field test, females were overall more active and explorative than males and gonadectomy eliminated this sex difference. In the FST, females exhibited overall higher immobility than males and gonadectomy further enhanced this passive behavior in both sexes. However, sustained aromatase inhibition had no effect on open field and FST behaviors. Head shakes during FST, which were fewer in females than in males, were reduced by castration in males and by letrozole treatment in ovariectomized females, suggesting a role of testosterone and extra-gonadal estrogens in the expression of this behavior. Sustained aromatase inhibition also decreased noradrenaline and the dopaminergic turnover rates [DOPAC/DA, HVA/DA] in the hippocampus and PFC of male and female rats, irrespectively of gonadectomy. Moreover, letrozole treatment enhanced the serotonergic turnover [5HIAA/5HT] rate in the hippocampus of males and females, irrespectively of gonadectomy. Amino acid levels were not influenced by letrozole, but sex differences were demonstrated with higher levels in the PFC of females vs. males. Present findings suggest that the neuropsychiatric effects of aromatase inhibition can be attributed to the inhibition of extragonadal estrogen synthesis, presumably in the brain, and could be further associated with serotonergic and catecholaminergic changes in brain regions involved in mood and cognition. Importantly, present data could be linked with the neurobiology of affective side-effects in post-menopausal women receiving aromatase inhibitors. © 2017 Elsevier Lt

Sex differences in behavioral and neurochemical effects of gonadectomy and aromatase inhibition in rats

Aromatase inhibitors, which are widely used for the treatment of estrogen-dependent cancers, have been as- sociated with psychiatric side effects ranging from mania to depression. In the present study, we investigated sex differences in the behavioral and neurochemical effects of aromatase inhibition on male and female, sham- operated or gonadectomized adult rats. Three weeks after surgery, rats received chronic treatment with the aromatase inhibitor letrozole or vehicle and were then subjected to the open field test, which assesses general activity. Half of the subjects were subsequently exposed to the stressful procedure of the forced swim test (FST), which is also a test of antidepressant activity. Aromatase activity was analyzed in the hypothalamus and tes- tosterone and corticosterone were assayed in the blood serum of all rats. The hippocampus and prefrontal cortex (PFC) were analyzed for monoamine (noradrenaline, dopamine and serotonin), as well as amino acid (GABA, glutamate, glycine, taurine, alanine and histidine) levels. The observed decrease in hypothalamic aromatase activity confirmed the efficacy of letrozole treatment in both sexes. Moreover, letrozole enhanced testosterone levels in sham-operated females. In the open field test, females were overall more active and explorative than males and gonadectomy eliminated this sex difference. In the FST, females exhibited overall higher immobility than males and gonadectomy further enhanced this passive behavior in both sexes. However, sustained ar- omatase inhibition had no effect on open field and FST behaviors. Head shakes during FST, which were fewer in females than in males, were reduced by castration in males and by letrozole treatment in ovariectomized fe- males, suggesting a role of testosterone and extra-gonadal estrogens in the expression of this behavior. Sustained aromatase inhibition also decreased noradrenaline and the dopaminergic turnover rates [DOPAC/DA, HVA/DA] in the hippocampus and PFC of male and female rats, irrespectively of gonadectomy. Moreover, letrozole treatment enhanced the serotonergic turnover [5HIAA/5HT] rate in the hippocampus of males and females, irrespectively of gonadectomy. Amino acid levels were not influenced by letrozole, but sex differences were demonstrated with higher levels in the PFC of females vs. males. Present findings suggest that the neu- ropsychiatric effects of aromatase inhibition can be attributed to the inhibition of extragonadal estrogen synthesis, presumably in the brain, and could be further associated with serotonergic and catecholaminergic changes in brain regions involved in mood and cognition. Importantly, present data could be linked with the neurobiology of affective side-effects in post-menopausal women receiving aromatase inhibitors

Intracerebral Gene Therapy in Four Children with Sanfilippo B Syndrome: 5.5-Year Follow-Up Results

We report the safety (primary endpoint) and efficacy (secondary endpoint) of a novel intracerebral gene therapy at 5.5 years of follow-up in children with Sanfilippo B. An uncontrolled, phase 1/2 clinical trial was performed in four patients aged 20, 26, 30, and 53 months. Treatment consisted of 16 intracerebral and cerebellar deposits of a recombinant adeno-associated viral vector encoding human α-N-acetylglucosaminidase (rAAV2/5-hNAGLU) plus immunosuppression. An intermediate report at 30 months was previously published. Thirty treatment-emergent adverse events were reported between 30 and 66 months after surgery, including three classified as severe with no serious drug reactions. At 5.5 years, NAGLU activity was persistently detected in the lumbar cerebrospinal fluid (18% of unaffected control level). Circulating T cells reacting against NAGLU peptides were present, indicating a lack of acquired tolerance. Patients 2, 3, and 4 showed progressive brain atrophy and neurocognitive evolution that did not differ from untreated Sanfilippo A/B children. Patient 1, enrolled at 20 months of age, had a milder disease with normal brain imaging and a significantly better cognitive outcome than the three other patients and untreated patients, although not equivalent to normal children. After 5.5 years, the primary endpoint of this study was achieved with a good safety profile of the proposed treatment. We have also observed sustained enzyme production in the brain and absence of immunological tolerance. Cognitive benefit was not confirmed in the three oldest patients. Milder disease in the youngest patient supports further investigations of adeno-associated vector-mediated intracerebral gene therapy in Sanfilippo B