This paper provides a detailed overview of developments in transducer materials technology relating to their current and future applications in micro-scale devices. Recent advances in piezoelectric, magnetostrictive and shape-memory alloy systems are discussed and emerging transducer materials such as magnetic nanoparticles, expandable micro-spheres and conductive polymers are introduced. Materials properties, transducer mechanisms and end applications are described and the potential for integration of the materials with ancillary systems components is viewed as an essential consideration. The review concludes with a short discussion of structural polymers that are extending the range of micro-fabrication techniques available to designers and production engineers beyond the limitations of silicon fabrication technology.
Baraitser-Winter, Fryns-Aftimos and cerebrofrontofacial syndrome types 1 and 3 have recently been associated with heterozygous gain-of-function mutations in one of the two ubiquitous cytoplasmic actin-encoding genes ACTB and ACTG1 that encode b-and c-actins. We present detailed phenotypic descriptions and neuroimaging on 36 patients analyzed by our group and six cases from the literature with a molecularly proven actinopathy (9 ACTG1 and 33 ACTB). The major clinical anomalies are striking dysmorphic facial features with hypertelorism, broad nose with large tip and prominent root, congenital non-myopathic ptosis, ridged metopic suture and arched eyebrows. Iris or retinal coloboma is present in many cases, as is sensorineural deafness. Cleft lip and palate, hallux duplex, congenital heart defects and renal tract anomalies are seen in some cases. Microcephaly may develop with time. Nearly all patients with ACTG1 mutations, and around 60% of those with ACTB mutations have some degree of pachygyria with anteroposterior severity gradient, rarely lissencephaly or neuronal heterotopia. Reduction of shoulder girdle muscle bulk and progressive joint stiffness is common. Early muscular involvement, occasionally with congenital arthrogryposis, may be present. Progressive, severe dystonia was seen in one family. Intellectual disability and epilepsy are variable in severity and largely correlate with CNS anomalies. One patient developed acute lymphocytic leukemia, and another a cutaneous lymphoma, indicating that actinopathies may be cancerpredisposing disorders. Considering the multifaceted role of actins in cell physiology, we hypothesize that some clinical manifestations may be partially mutation specific. Baraitser-Winter cerebrofrontofacial syndrome is our suggested designation for this clinical entity.
Signaling output of bone morphogenetic proteins (BMPs) is determined by two sets of opposing interactions, one with heterotetrameric complexes of cell surface receptors, the other with secreted antagonists that act as ligand traps. We identified two mutations (N445K,T) in patients with multiple synostosis syndrome (SYM1) in the BMP–related ligand GDF5. Functional studies of both mutants in chicken micromass culture demonstrated a gain of function caused by a resistance to the BMP–inhibitor NOGGIN and an altered signaling effect. Residue N445, situated within overlapping receptor and antagonist interfaces, is highly conserved among the BMP family with the exception of BMP9 and BMP10, in which it is substituted with lysine. Like the mutant GDF5, both BMPs are insensitive to NOGGIN and show a high chondrogenic activity. Ectopic expression of BMP9 or the GDF5 mutants resulted in massive induction of cartilage in an in vivo chick model presumably by bypassing the feedback inhibition imposed by endogenous NOGGIN. Swapping residues at the mutation site alone was not sufficient to render Bmp9 NOG-sensitive; however, successive introduction of two additional substitutions imparted high to total sensitivity on customized variants of Bmp9. In conclusion, we show a new mechanism for abnormal joint development that interferes with a naturally occurring regulatory mechanism of BMP signaling.
Craniofrontonasal syndrome (CFNS) is an X-linked disorder characterized by a more severe manifestation in heterozygous females than in hemizygous males. Heterozygous females have craniofrontonasal dysplasia (CFND) and occasionally extracranial manifestations including midline defects and skeletal abnormalities, whereas hemizygous males show no or only mild features such as hypertelorism and rarely show cleft lip or palate. Mutations in the EFNB1 gene in Xq12 are responsible for familial and sporadic CFNS. The EFNB1 gene encodes ephrin-B1, a transmembrane ligand that also exhibits receptor-like effects. We performed mutation analysis in nine unrelated families and 29 sporadic patients with CFNS. DNA sequencing revealed mutations in 33 (86.8%) cases including 26 distinct novel mutations. A recurrent nonsense mutation, c.196C>T/R66X, was detected in one family and four sporadic patients. The majority of mutations (26/33) were located in exons 2 and 3 of the EFNB1 gene encoding the extracellular ephrin domain. The mutation spectrum includes frameshift, nonsense, missense, and splice site mutations, with a predominance of frameshift and nonsense mutations resulting in premature truncation codons. For the first time we describe mutations in exons 4 and 5 of EFNB1. Of particular interest are the frameshift mutations located in the last 25 codons of EFNB1 encoding the carboxyterminal end of ephrin-B1. They result in an extension by 44 residues. These mutations disrupt the intracellular binding sites for Grb4 and PDZ-effector proteins involved in reverse signaling. We conclude that the major causes of familial as well as sporadic CFNS are loss of function mutations in the EFNB1 gene that comprise premature termination or abrogate receptor-ligand interaction, oligomerization, and ephrin-B1 reverse signaling.
Using magnetic particles with sizes in the nanometer range in biomedical magnetic separation has gained much interest recently due to their higher surface area to particle volume and lower sedimentation rates. In this paper, we report our both theoretical and experimental investigation of the motion of magnetic particles in a magnetic field gradient with particle sizes from 425 nm down to 50 nm. In the experimental measurements, we monitor the absorbance change of the sample volume as the particle concentration varies over time. We also implement a Brownian dynamics algorithm to investigate the influence of particle interactions during the separation and compare it to the experimental results for validation. The simulation agrees well with the measurements for particle sizes around 425 nm. Some discrepancies remain for smaller particle sizes, which may indicate that additional factors also influence the separation for the smaller size range. We observe that the separation process includes the formation of chainlike particle aggregates due to the magnetic dipole-dipole interactions between particles when subjected to an external magnetic field. We can also see that the hydrodynamic interaction between these chains contributes to reducing the separation time. In conclusion, we show that the formation of these particle aggregates, and to a less extent the hydrodynamic interactions between them contributes to significantly enhancing the particle separation process.
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