Mutant Cx30-A88V mice exhibit hydrocephaly and sex-dependent behavioral abnormalities, implicating a functional role for Cx30 in the brain.

Connexin 30 (Cx30; also known as Gjb6 when referring to the mouse gene) is expressed in ependymal cells of the brain ventricles, in leptomeningeal cells and in astrocytes rich in connexin 43 (Cx43), leading us to question whether patients harboring GJB6 mutations exhibit any brain anomalies. Here, we used mice harboring the human disease-associated A88V Cx30 mutation to address this gap in knowledge. Brain Cx30 levels were lower in male and female Cx30A88V/A88V mice compared with Cx30A88V/+ and Cx30+/+ mice, whereas Cx43 levels were lower only in female Cx30 mutant mice. Characterization of brain morphology revealed a disrupted ependymal cell layer, significant hydrocephalus and enlarged ventricles in 3- to 6-month-old adult male and female Cx30A88V/A88V mice compared with Cx30A88V/+ or Cx30+/+ sex-matched littermate mice. To determine the functional significance of these molecular and morphological changes, we investigated a number of behavioral activities in these mice. Interestingly, only female Cx30A88V/A88V mice exhibited abnormal behavior compared with all other groups. Cx30A88V/A88V female mice demonstrated increased locomotor and exploratory activity in both the open field and the elevated plus maze. They also exhibited dramatically reduced ability to learn the location of the escape platform during Morris water maze training, although they were able to swim as well as other genotypes. Our findings suggest that the homozygous A88V mutation in Cx30 causes major morphological changes in the brain of aging mice, possibly attributable to an abnormal ependymal cell layer. Remarkably, these changes had a more pronounced consequence for cognitive function in female mice, which is likely to be linked to the dysregulation of both Cx30 and Cx43 levels in the brain.

2D Oligosilyl Metal-Organic Frameworks as Multi-state Switchable Materials.

We report the synthesis of a set of 2D metal-organic frameworks (MOFs) constructed with organosilicon-based linkers. These oligosilyl MOFs feature linear Sin Me2n (C6 H4 CO2 H)2 ligands (lin-Sin , n=2, 4) connected by Cu paddlewheels. The stacking arrangement of the 2D sheets is dictated by van der Waals interactions and is tunable by solvent exchange, leading to reversible structural transformations between many crystalline and amorphous phases.

Stereocontrolled Syntheses of Functionalized cis- and trans-Siladecalins.

We report the synthesis of both diastereomers of an all-silicon analog of decalin. Carbocyclic decalin is a ubiquitous bicyclic structural motif. The siladecalin synthesis provides materials functionalized with either Si-Ph or Si-H groups, versatile entry points for further chemical diversification. The synthesis of silicon-stereogenic silanes is significantly less precedented than the synthesis of asymmetric carbon centers, and strategies for control of relative stereochemistry in oligosilanes are hardly described. This study offers insights of potential generality, such as the epimerization of the cis-isomer to the thermodynamically downhill trans-isomer via a hypothesized pentavalent intermediate. Decalin is a classic example in the conformational analysis of organic ring systems, and the carbocyclic diastereomers have highly divergent conformational profiles. Like the carbocycle, we observe different conformational properties in cis- and trans-siladecalins with consequences for NMR spectroscopy, optical properties, and vibrational spectroscopy. This study showcases the utility of targeted synthesis for preparing complex and functionalized polycyclic silanes.

The connexin 30 A88V mutant reduces cochlear gap junction expression and confers long-term protection against hearing loss.

Mutations in the genes that encode the gap junction proteins connexin 26 (Cx26, encoded by GJB2) and Cx30 (GJB6) are the leading cause of hereditary hearing loss. That said, the Cx30 p.Ala88Val (A88V) mutant causes Clouston syndrome, but not hearing loss. Here, we report that the Cx30-A88V mutant, despite being toxic to inner ear-derived HEI-OC1 cells, conferred remarkable long-term protection against age-related high frequency hearing loss in Cx30A88V/A88V mice. During early development, there were no overt structural differences in the cochlea between genotypes, including a normal complement of hair cells; however, the supporting cell Cx30 gap junction plaques in mutant mice were reduced in size. In adulthood, Cx30A88V/A88V mutant mice had a reduction of cochlear Cx30 mRNA and protein, yet a full complement of hair cells. Conversely, the age-related high frequency hearing loss in Cx30+/+ and Cx30+/A88V mice was due to extensive loss of outer hair cells. Our data suggest that the Cx30-A88V mutant confers long-term hearing protection and prevention of hair cell death, possibly via a feedback mechanism that leads to the reduction of total Cx30 gap junction expression in the cochlea.

Correction to: Disease-linked connexin26 S17F promotes volar skin abnormalities and mild wound healing defects in mice.

Correction to: NPG Asia Materials (2018) https://doi.org/10.1038/s41427-018-0014-9 published online on 16 April 2018.

Directional Building Blocks Determine Linear and Cyclic Silicon Architectures.

Silicon nanomaterials combine earth abundance and biodegradability with exceptional electronic properties. Strategic synthesis promises access to novel architectures with well-defined surface structure, size, and shape. Herein, we describe a five-step synthesis of functional macrocyclic polysilanes. Comparison of the materials isolated from isomeric building blocks provides evidence that building block directionality controls the shape of the resulting nanomaterial. Infrared (IR) and 1H and 29Si NMR spectroscopies, coupled to computational data, provide evidence of a well-defined Si-H and Si-Me terminated structure. The intrinsic porosity and the polarization arising from the hydridic character of the Si-H bond suggest applications in lithium-ion batteries, which are supported by quantum chemical calculations.

Cooperative Noncovalent Interactions Induce Ion Pair Separation in Diphenylsilanides.

This crystallographic and computational study describes an unusual potassium silanide structure. A contact ion pair is expected in the solid state between potassium and silicon, yet the potassium cation binds an aromatic ring and the anionic silanide interacts with CH bonds on neighboring crown ether molecules. These structure-bonding phenomena are attributed to strong soft-soft interactions.

Disease-linked connexin26 S17F promotes volar skin abnormalities and mild wound healing defects in mice.

Several mutant mice have been generated to model connexin (Cx)-linked skin diseases; however, the role of connexins in skin maintenance and during wound healing remains to be fully elucidated. Here we generated a novel, viable, and fertile mouse (Cx26CK14-S17F/+) with the keratitis-ichthyosis-deafness mutant (Cx26S17F) driven by the cytokeratin 14 promoter. This mutant mouse mirrors several Cx26-linked human skin pathologies suggesting that the etiology of Cx26-linked skin disease indeed stems from epidermal expression of the Cx26 mutant. Cx26CK14-S17F/+ foot pad epidermis formed severe palmoplantar keratoderma, which expressed elevated levels of Cx26 and filaggrin. Primary keratinocytes isolated from Cx26CK14-S17F/+ neonates exhibited reduced gap junctional intercellular communication and migration. Furthermore, Cx26CK14-S17F/+ mouse skin wound closure was normal but repaired epidermis appeared hyperplastic with elevated expression of cytokeratin 6. Taken together, we suggest that the Cx26S17F mutant disturbs keratinocyte differentiation and epidermal remodeling following wound closure. We further posit that Cx26 contributes to epidermal homeostasis by regulating keratinocyte differentiation, and that mice harboring a disease-linked Cx26 mutant display epidermal abnormalities yet retain most wound healing properties.

Induction of cell death and gain-of-function properties of connexin26 mutants predict severity of skin disorders and hearing loss.

Connexin26 (Cx26) is a gap junction protein that oligomerizes in the cell to form hexameric transmembrane channels called connexons. Cell surface connexons dock between adjacent cells to allow for gap junctional intercellular communication. Numerous autosomal dominant mutations in the Cx26-encoding GJB2 gene lead to many skin disorders and sensorineural hearing loss. Although some insights have been gained into the pathogenesis of these diseases, it is not fully understood how distinct GJB2 mutations result in hearing loss alone or in skin pathologies with comorbid hearing loss. Here we investigated five autosomal dominant Cx26 mutants (N14K, D50N, N54K, M163V, and S183F) linked to various syndromic or nonsyndromic diseases to uncover the molecular mechanisms underpinning these disease links. We demonstrated that when gap junction-deficient HeLa cells expressed the N14K and D50N mutants, they undergo cell death. The N54K mutant was retained primarily within intracellular compartments and displayed dominant or transdominant properties on wild-type Cx26 and coexpressed Cx30 and Cx43. The S183F mutant formed some gap junction plaques but was largely retained within the cell and exhibited only a mild transdominant reduction in gap junction communication when co-expressed with Cx30. The M163V mutant, which causes only hearing loss, exhibited impaired gap junction function and showed no transdominant interactions. These findings suggest that Cx26 mutants that promote cell death or exert transdominant effects on other connexins in keratinocytes will lead to skin diseases and hearing loss, whereas mutants having reduced channel function but exhibiting no aberrant effects on coexpressed connexins cause only hearing loss. Moreover, cell death-inducing GJB2 mutations lead to more severe syndromic disease.

Synthesis of a Fragment of Crystalline Silicon: Poly(Cyclosilane).

We report a strategic synthesis of poly(cyclosilane), a well-defined polymer inspired by crystalline silicon. The synthetic strategy relies on the design of a functionalized cyclohexasilane monomer for transition-metal-promoted dehydrocoupling polymerization. Our approach takes advantage of the dual function of the phenylsilyl group, which serves a crucial role both in the synthesis of a novel α,ω-oligosilanyl dianion and as a latent electrophile. We show that the cyclohexasilane monomer prefers a chair conformation. The monomer design ensures enhanced reactivity in transition-metal-promoted dehydrocoupling polymerization relative to secondary silanes, such as methylphenylsilane. Comprehensive NMR spectroscopy yields a detailed picture of the polymer end-group structure and microstructure. Poly(cyclosilane) has red-shifted optical absorbance relative to the monomer. We synthesize a σ-π hybrid donor-acceptor polymer by catalytic hydrosilylation.