Simulated and Experimental Research of Multi-Band Acoustic Metamaterial with a Single Resonant Structure.

We present a multi-band acoustic metamaterial (AMM) with a single structural unit of a nested split hollow sphere (NSHS). The transmissions of the NSHS-AMM from the simulation and experiment revealed two dips which were attributed to local coupling resonance. Using the retrieval method from the experimental data, we calculated the effective modulus of the NSHS-AMM and found it to be negative near the bands of the two dips. The AMM with a negative modulus can be easily tuned due to the coupling effect in the NSHS. The two dips can be simultaneously tuned by changing the diameter and the direction angle of the split holes of the interior and exterior split hollow sphere (SHS) in the NSHS. We designed a three-nested SHS-AMM with a negative modulus in three bands. Given the obvious local coupling resonance in the NSHS, such NSHS-AMMs may provide a viable path for the design of broadband AMMs or acoustic metasurfaces.

Mutual Inductance and Coupling Effects in Acoustic Resonant Unit Cells.

We present an acoustic metamaterial (AMM) consisting of a dumbbell-shaped split hollow sphere (DSSHS). Transmission results of experiments and simulations both presented a transmitted dip at the resonant frequency of AMM, which demonstrated its negative modulus property. As the two split holes in the DSSHS had strong coupling effects for the acoustic medium in the local region, the dip could be simply manipulated by tuning the distance between the split holes. When the distance was large enough, the mutual inductance tended to disappear, and a weak interaction existed in the structure. According to the property of weak interaction, a multiband AMM and a broadband AMM with a negative modulus could be achieved by arraying DSSHS clusters with different distances. Furthermore, mutual inductance and coupling in DSSHS reinforced the local resonance, and this kind of cell could be used to design the acoustic metasurface to abnormally control the refractive waves.

High-Efficiency and Wide-Angle Versatile Polarization Controller Based on Metagratings.

Metamaterials with their customized properties enable us to efficiently manipulate the polarization states of electromagnetic waves with flexible approaches, which is of great significance in various realms. However, most current metamaterial-based polarization controllers can only realize single function, which has extremely hindered the expansion of their applications. Here, we experimentally demonstrate highly efficient and multifunctional polarization conversion effects using metagrating by integrating single-structure metallic meta-atoms into the dielectric gratings. Benefiting from the combined advantages of the gratings and the metamaterials, the considered metagrating can operate in transmission and reflection modes simultaneously, acting as a high-performance and wide-angle quarter-wave or half-wave plate with distinct functions in different frequency bands. This metagrating structure is scalable to other frequency ranges and may provide opportunities to design compact multifunctional optical polarization control devices.

Tunable Acoustic Metasurface with High-Q Spectrum Splitting.

We propose a tunable acoustic metasurface using a nested structure as the microunit, which is constituted by two distinct resonators. Thanks to the coupling resonance for the microunit and by simply adjusting the rotation angle of the inner split cavity, this nested structure provides nearly 2π phase shift. The full-wave simulations demonstrate that the constructed metasurface can be tuned to reflect incident sound waves to different directions in the operation frequency region with a very narrow bandwidth, which is a key functionality for many applications such as filtering and imaging. Meanwhile, the reflected sound waves out of the operation frequency region always remain unchanged. As a result, a high Q-factor spectrum splitting can be realised. The presented metasurface is of importance to develop many metamaterial-based devices, such as tunable acoustic cloaks and acoustic switching devices.

Inducing drop to bubble transformation via resonance in ultrasound.

Bubble formation plays an important role in industries concerned with mineral flotation, food, cosmetics, and materials, which requires additional energy to produce the liquid-gas interfaces. A naturally observed fact is, owing to the effect of surface tension, a bubble film tends to retract to reduce its surface area. Here we show a "reverse" phenomenon whereby a drop is transformed into a bubble using acoustic levitation via acoustic resonance. Once the volume of the cavity encapsulated by the buckled film reaches a critical value V*, resonance occurs and an abrupt inflation is triggered, leading to the formation of a closed bubble. Experiments and simulations both reveal that V* decreases with increasing acoustic frequency, which agrees well with acoustic resonance theory. The results afford enlightening insights into acoustic resonance and highlight its role in manipulating buckled fluid-fluid interfaces, providing a reference for fabricating unique core-shell-like materials.

Broadband angle- and permittivity-insensitive nondispersive optical activity based on planar chiral metamaterials.

Because of the strong inherent resonances, the giant optical activity obtained via chiral metamaterials generally suffers from high dispersion, which has been a big stumbling block to broadband applications. In this paper, we propose a type of planar chiral metamaterial consisting of interconnected metal helix slat structures with four-fold symmetry, which exhibits nonresonant Drude-like response and can therefore avoid the highly dispersive optical activity resulting from resonances. It shows that the well-designed chiral metamaterial can achieve nondispersive and pure optical activity with high transmittance in a broadband frequency range. And the optical activity of multi-layer chiral metamaterials is proportional to the layer numbers of single-layer chiral metamaterial. Most remarkably, the broadband behaviors of nondispersive optical activity and high transmission are insensitive to the incident angles of electromagnetic waves and permittivity of dielectric substrate, thereby enabling more flexibility in polarization manipulation.

Madelung-like deformity in pseudohypoparathyroidism type 1b.

CONTEXT: Pseudohypoparathyroidism (PHP) types 1a and 1b are distinguished by clinical, biochemical, and molecular features. We report extended kindred with PHP 1b in which many affected members also had growth plate defects, including brachydactyly and a Madelung-like deformity. DESIGN: Analyses included clinical examination, assessment of mineral metabolism, thyroid function, skeletal radiography, and analysis of the GNAS and STX16 genes. SETTING: Patients were studied in an academic medical center. RESULTS: We studied 37 members of a family in which PHP 1b occurred in 23 individuals. Ten of 17 affected patients who were examined had brachydactyly E, including two subjects with Madelung-like defects. Five of 16 subjects had subclinical hypothyroidism; no subject showed sc ossification or short stature. None of the unaffected members had brachydactyly or an elevated serum level of PTH or TSH. Levels of immunoactive erythrocyte Gα(s) were normal in two affected subjects tested. Linkage analysis indicated linkage between PTH resistance and the GNAS gene locus; however, no mutations were identified in GNAS exons 1-13. Methylation analysis of genomic DNA from affected subjects showed loss of maternal epigenotype in exon 1A with normal methylation of the differentially methylated regions for XLGαs and NESP55, and PCR demonstrated heterozygosity for a 3.0-kb deletion in the STX16 gene. CONCLUSION: The segregation of brachydactyly with PHP 1b in this family indicates that an imprinting defect in GNAS can lead to growth plate defects, including brachydactyly and Madelung deformity. These features suggest that GNAS signaling plays a more extensive role in chondrocyte maturation than previously thought.

A novel loss-of-function mutation, Gln459Arg, of the calcium-sensing receptor gene associated with apparent autosomal recessive inheritance of familial hypocalciuric hypercalcemia.

CONTEXT: Mutations that inactivate one allele of the gene encoding the calcium sensing receptor (CaSR) cause autosomal dominant familial hypocalciuric hypercalcemia (FHH), whereas homozygous mutations cause neonatal severe hyperparathyroidism. OBJECTIVE: We describe the identification and biochemical characterization of a novel CASR gene mutation that caused apparent autosomal recessive FHH in an extended consanguineous kindred. DESIGN: The study design involved direct sequence analysis of the CaSR gene, clinical and biochemical analyses of patients, and in vitro immunobiochemical studies of the mutant CaSR. RESULTS: A novel inactivating mutation (Q459R) was identified in exon 4 of both alleles of the CASR in the proband, who presented with asymptomatic hypercalcemia and hypocalciuria at age 2 yr. The proband's parents were heterozygous for the Q459R mutation consistent with autosomal recessive inheritance of FHH. Among 13 family members that were studied, eight subjects were heterozygous for the Q459R mutation and five had normal genotypes. All heterozygous subjects were asymptomatic and normocalcemic apart from one subject who was mildly hypercalcemic. The Q459R mutant CaSR was normally expressed at the cell membrane but retained only 30-50% of the calcium-dependent activity of the wild-type CaSR. CONCLUSION: We identified a novel loss-of-function Q459R mutation in the CASR gene that exhibits mildly reduced sensitivity to calcium and that is associated with apparent autosomal recessive transmission of FHH. This study demonstrates the importance of genetic testing in FHH to distinguish between de novo and inherited mutations of the CASR gene and assist in management decisions.

Analysis of the GCM2 gene in isolated hypoparathyroidism: a molecular and biochemical study.

CONTEXT: Hypoparathyroidism is characterized by hypocalcemia, hyperphosphatemia, and absent or markedly reduced serum levels of intact PTH. The transcription factor GCM2 is critical for the development of parathyroid glands in mice and humans. OBJECTIVE: We sought to determine the prevalence of GCM2 gene mutations in patients with familial or sporadic forms of isolated hypoparathyroidism (IH). DESIGN AND SETTING: We used PCR to analyze the promoter, the exons, and flanking intronic sequences in 10 IH families with 17 affected members and in 10 patients with sporadic IH. Wild-type and mutant GCM2 proteins were expressed in HEK293 cells and characterized. RESULTS: We identified nine single nucleotide changes, three in the 5' untranslated region and six in exon 5, that led to nonsynonymous changes in the GCM2 protein (G203S, I227V, Y282D, N315D, Q330L, and M354V). Variant GCM2 proteins had normal size, nuclear localization, and transactivational function when expressed in HEK293 cells. Similar analyses of two previously described GCM2 missense mutations, R47L and G63S, revealed decreased nuclear expression and markedly reduced (5-20% of normal) transactivational activity. The variant alleles did not segregate with inheritance of IH, and many of the single nucleotide substitutions were present in DNA from unrelated normal subjects, suggesting that these base changes were polymorphisms. CONCLUSION: Our study describes nine single nucleotide changes in the GCM2 gene that represent polymorphisms. Although GCM2 mutations appear to be an uncommon cause of IH, the wide variety of GCM2 polymorphisms suggests that variant alleles may have a role in determining parathyroid function.

A highly sensitive polymerase chain reaction method detects activating mutations of the GNAS gene in peripheral blood cells in McCune-Albright syndrome or isolated fibrous dysplasia.

BACKGROUND: The somatic nature of mutations in the GNAS gene in McCune-Albright syndrome and isolated fibrous dysplasia makes their identification difficult. Conventional methods for the detection of mosaic mutations of GNAS have required polymerase chain reaction analysis of genomic DNA from affected tissues or multiple rounds of tandem polymerase chain reaction and endonuclease digestion to enrich for mutant alleles in genomic deoxyribonucleic acid (DNA) from other tissues. Peptide nucleic acid (PNA) primers specifically block synthesis from the nonmutant or wild-type allele. We therefore used PNA-clamping to detect low copy numbers of mutant GNAS alleles in DNA from peripheral blood cells from patients with McCune-Albright syndrome and fibrous dysplasia. METHODS: We applied the PNA-clamping method to the analysis of genomic DNA from peripheral blood cells of thirteen patients with McCune-Albright syndrome and three patients with isolated fibrous dysplasia. Polymerase chain reaction was performed in the presence and absence of PNA, and the polymerase chain reaction products were sequenced. In the absence of PNA, a strong 325 base-pair polymerase chain reaction band was generated from all samples; in the presence of PNA, there was an approximately 50% to 90% reduction in the intensity of this polymerase chain reaction product. RESULTS: In the absence of PNA, direct sequencing of the polymerase chain reaction products demonstrated R201 mutations in GNAS alleles of three of the thirteen patients with McCune-Albright syndrome and none of the three patients with fibrous dysplasia. In contrast, in the presence of PNA, R201 mutations were detected in eleven of the thirteen patients with McCune-Albright syndrome and in all three of the patients with fibrous dysplasia. In mixing experiments involving the use of wild-type and mutant DNA samples, we were able to determine the presence of a mutant GNAS allele in the equivalent of one cell in 1000 to 5000 cells. CONCLUSIONS: Inclusion of a specific PNA primer in the polymerase chain reaction for GNAS exon 8 allows the selective amplification of low numbers of mutant alleles, and it permits detection of activating mutations in genomic DNA from peripheral blood cells in patients with McCune-Albright syndrome and fibrous dysplasia.

Reduction in Gsalpha induces osteogenic differentiation in human mesenchymal stem cells.

We hypothesized that a decrease in Gsalpha expression occurs with osteogenic differentiation and that when Gsalpha expression was decreased by antisense oligonucleotides or direct inhibition of protein kinase A there was a concomitant increase in Runx2/Cbfa1. We also investigated the mechanism involved in the change in Runx2/Cbfa1 levels and whether the expression of other genes known to be involved in bone formation was altered. There was a decrease in Gsalpha expression with osteogenic differentiation and antisense oligonucleotides, and protein kinase A inhibition led to increased expression and DNA binding of the osteoblast-specific Runx2/Cbfa1. Additionally, with decreased Gsalpha expression or protein kinase A inhibition, Runx2/Cbfa1 protein was serine phosphorylated and ubiquitinated less. Microarray analysis, after the addition of antisense Gsalpha, showed a more than 10-fold increase in collagen Type I Alpha 2 mRNA (a target of Runx2/Cbfa1). These data show that reduced expression of Gsalpha can induce an osteoblast-like phenotype. The results also indicate a potential pathophysiologic role in patients with heterozygous inactivating mutations in GNAS1, the gene for the alpha chain (Gsalpha) of the heterotrimeric G protein, present in three disorders with ectopic intramembranous bone: Albright's hereditary osteodystrophy, progressive osseous heteroplasia, and osteoma cutis.

Expression of GCMB by intrathymic parathyroid hormone-secreting adenomas indicates their parathyroid cell origin.

GCMA and GCMB are related transcription factors that are critically important for embryological development of the placenta and parathyroid glands, respectively. Mice in which parathyroid glands have been surgically removed or fail to develop due to genetic loss of GCMB show continued production of PTH from a subset of thymic cells that express GCMA. In this study we examined whether human thymus produces PTH and/or GCMA and whether intrathymic PTH-secreting adenomas express GCMA or GCMB to determine the embryological origin of the secretory cells. By contrast to mouse thymus, analysis of 22 samples of human thymus tissue by RT-PCR and/or immunohistochemistry failed to demonstrate the expression of either PTH or GCMA. RT-PCR analysis of 16 intrathymic adenomas from patients with surgically cured primary hyperparathyroidism showed that these tumors expressed PTH and GCMB and not GCMA. We conclude that the normal human thymus does not express GCMA or PTH, and therefore, in contrast to the mouse, the human thymus is not a source of PTH production. Finally, intrathymic PTH-secreting adenomas express the parathyroid-specific GCMB gene, which suggests that these tumors were derived from parathyroid cells that migrated errantly during embryogenesis.

Discordance between genetic and epigenetic defects in pseudohypoparathyroidism type 1b revealed by inconsistent loss of maternal imprinting at GNAS1.

Although the molecular basis of pseudohypoparathyroidism type 1b (PHP type 1b) remains unknown, a defect in imprinting at the GNAS1 locus has been suggested by the consistent finding of paternal-specific patterns of DNA methylation on maternally inherited GNAS1 alleles. To characterize the relationship between the genetic and epigenetic defects in PHP type 1b, we analyzed allelic expression and methylation of CpG islands within exon 1A of GNAS1 in patients with sporadic PHP type 1b and in affected and unaffected individuals from five multigenerational kindreds with PHP type 1b. All subjects with resistance to parathyroid hormone (PTH) showed loss of methylation of the exon 1A region on the maternal GNAS1 allele and/or biallelic expression of exon 1A-containing transcripts, consistent with an imprinting defect. Paternal transmission of the disease-associated haplotype was associated with normal patterns of GNAS1 methylation and PTH responsiveness. We found that affected and unaffected siblings in one kindred had inherited the same GNAS1 allele from their affected mother, evidence for dissociation between the genetic and epigenetic GNAS1 defects. The absence of the epigenetic defect in subjects who have inherited a defective maternal GNAS1 allele suggests that the genetic mutation may be incompletely penetrant, and it indicates that the epigenetic defect, not the genetic mutation, leads to renal resistance to PTH in PHP type 1b.