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

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

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

Intracerebral Administration of Adeno-Associated Viral Vector Serotype rh.10 Carrying Human SGSH and SUMF1 cDNAs in Children with Mucopolysaccharidosis Type IIIA Disease: Results of a Phase I/II Trial.

Mucopolysaccharidosis type IIIA is a severe degenerative disease caused by an autosomal recessive defect of a gene encoding a lysosomal heparan-N-sulfamidase, the N-sulfoglycosamine sulfohydrolase (SGSH), the catalytic site of which is activated by a sulfatase-modifying factor (SUMF1). Four children (Patients 1-3, aged between 5.5 and 6 years; Patient 4 aged 2 years 8 months) received intracerebral injections of an adeno-associated viral vector serotype rh.10-SGSH-IRES-SUMF1 vector in a phase I/II clinical trial. All children were able to walk, but their cognitive abilities were abnormal and had declined (Patients 1-3). Patients 1-3 presented with brain atrophy. The therapeutic vector was delivered in a frameless stereotaxic device, at a dose of 7.2x10(11) viral genomes/patient simultaneously via 12 needles as deposits of 60l over a period of 2hr. The vector was delivered bilaterally to the white matter anterior, medial, and posterior to the basal ganglia. Immunosuppressive treatment (mycophenolate mofetil and tacrolimus) was initiated 15 days before surgery and maintained for 8 weeks (mycophenolate mofetil) or throughout follow-up (tacrolimus, with progressive dose reduction) to prevent elimination of transduced cells. Safety data collected from inclusion, during the neurosurgery period and over the year of follow-up, showed good tolerance, absence of adverse events related to the injected product, no increase in the number of infectious events, and no biological sign of toxicity related to immunosuppressive drugs. Efficacy analysis was necessarily preliminary in this phase I/II trial on four children, in the absence of validated surrogate markers. Brain atrophy evaluated by magnetic resonance imaging seemed to be stable in Patients 1 and 3 but tended to increase in Patients 2 and 4. Neuropsychological evaluations suggested a possible although moderate improvement in behavior, attention, and sleep in Patients 1-3. The youngest patient was the most likely to display neurocognitive benefit

Crystal chemistry and selected physical properties of inorganic fluorides and oxide-fluorides

importance in the development of many new technologies, andare impacting various key points of modern life, that is, energyproduction and storage, microelectronics and photonics,catalysis, automotive, building, etc. Many research fields andapplications are indeed concerned by a better knowledge of therelationships occurring between the structure of suchcompounds and some pertinent physical properties. ThisReview deals with the structural chemistry of solid-stateinorganic fluorides and oxide-fluorides, mostly transitionmetal-based, including rare-earth elements. Such a Review hasnot been published for a long time.1 Articles that recentlyappeared on inorganic fluorinated compounds were mostlyfocused on material science characteristics: morphology, surfacefunctionalization, nanostructuration of the materials andapplications, rather than on the description of characteristicstructural features.2−5 Detailed reviews focused on rare earthbasedinorganic fluorides have also appeared some yearsago..