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Contains fulltext : 251572.pdf (Publisher’s version ) (Closed access) We assessed genotype-phenotype correlations among the visual, auditory, and olfactory phenotypes of 127 participants with Usher syndrome (USH2) (n =80) or nonsyndromic autosomal recessive retinitis pigmentosa (ARRP) (n = 47) due to USH2A variants, using clinical data and molecular diagnostics from the Rate of Progression in USH2A Related Retinal Degeneration (RUSH2A) study. USH2A truncating alleles were associated with USH2 and had a dose-dependent effect on hearing loss severity with no effect on visual loss severity within the USH2 subgroup. A group of missense alleles in an interfibronectin domain appeared to be hypomorphic in ARRP. These alleles were associated with later age of onset, larger visual field area, better sensitivity thresholds, and better electroretinographic responses. No effect of genotype on the severity of olfactory deficits was observed. This study unveils a unique, tissue-specific USH2A allelic hierarchy with important prognostic implications for patient counseling and treatment trial endpoints. These findings may inform clinical care or research approaches in others with allelic disorders or pleiotropic phenotypes.

Tuning the coefficients of thermal expansion (CTE) of polymeric materials through a combination of zinc cyanide and ionic liquid.

Pleural and tracheal injuries remain significant problems, and an easy to use, effective pleural or tracheal sealant would be a significant advance. The major challenges are requirements for adherence, high strength and elasticity, dynamic durability, appropriate biodegradability, and lack of cell or systemic toxicity. We designed and evaluated two sealant materials comprised respectively of alginate methacrylate and of gelatin methacryloyl, each functionalized by conjugation with dopamine HCl. Both compounds are cross-linked into easily applied as pre-formed hydrogel patches or as in situ hydrogels formed at the wound site utilizing FDA-approved photo-initiators and oxidants. Material testing demonstrates appropriate adhesiveness, tensile strength, burst pressure, and elasticity with no significant cell toxicity in vitro assessments. Air-leak was absent after sealant application to experimentally-induced injuries in ex-vivo rat lung and tracheal models and in ex vivo pig lungs. Sustained repair of experimentally-induced pleural injury was observed for up to one month in vivo rat models and for up to 2 weeks in vivo rat tracheal injury models without obvious air leak or obvious toxicities. The alginate-based sealant worked best in a pre-formed hydrogel patch whereas the gelatin-based sealant worked best in an in situ formed hydrogel at the wound site thus providing two potential approaches. These studies provide a platform for further pre-clinical and potential clinical investigations. Statement of significance Pneumothorax and pleural effusions resulting from trauma and a range of lung diseases and critical illnesses can result in lung collapse that can be immediately life-threatening or result in chronic leaking (bronchopleural fistula) that is currently difficult to manage. This leads to significantly increased morbidity, mortality, hospital stays, health care costs, and other complications. We have developed sealants originating from alginate and gelatin biomaterials, each functionalized by methacryloylation and by dopamine conjugation to have desired mechanical characteristics for use in pleural and tracheal injuries. The sealants are easily applied, non-cytotoxic, and perform well in vitro and in vivo model systems of lung and tracheal injuries. These initial proof of concept investigations provide a platform for further studies.

Despite the availability of numerous neat polymers, polymer composites offer a wide range of advantages over traditional materials such as metals, ceramics, and neat polymers [...]

Background Rare Eye Diseases (RED) are the leading cause of visual impairment and blindness for children and young adults in Europe. This heterogeneous group of conditions includes over 900 disorders ranging from relatively prevalent disorders such as retinitis pigmentosa to very rare entities such as developmental eye anomalies. A significant number of patients with RED have an underlying genetic etiology. One of the aims of the European Reference Network for Rare Eye Diseases (ERN–EYE) is to facilitate improvement in diagnosis of RED in European member states. Main body Technological advances have allowed genetic and genomic testing for RED. The outcome of genetic testing allows better understanding of the condition and allows reproductive and therapeutic options. The increase of the number of clinical trials for RED has provided urgency for genetic testing in RED. A survey of countries participating in ERN-EYE demonstrated that the majority are able to access some forms of genomic testing. However, there is significant variability, particularly regarding testing as part of clinical service. Some countries have a well-delineated rare disease pathway and have a national plan for rare diseases combined or not with a national plan for genomics in medicine. In other countries, there is a well-established organization of genetic centres that offer reimbursed genomic testing of RED and other rare diseases. Clinicians often rely upon research-funded laboratories or private companies. Notably, some member states rely on cross-border testing by way of an academic research project. Consequently, many clinicians are either unable to access testing or are confronted with long turnaround times. Overall, while the cost of sequencing has dropped, the cumulative cost of a genomic testing service for populations remains considerable. Importantly, the majority of countries reported healthcare budgets that limit testing. Short conclusion Despite technological advances, critical gaps in genomic testing remain in Europe, especially in smaller countries where no formal genomic testing pathways exist. Even within larger countries, the existing arrangements are insufficient to meet the demand and to ensure access. ERN-EYE promotes access to genetic testing in RED and emphasizes the clinical need and relevance of genetic testing in RED.

Purpose: Determining the role of DYNC2H1 variants in nonsyndromic inherited retinal disease (IRD).\ud \ud Methods: Genome and exome sequencing were performed for five unrelated cases of IRD with no identified variant. In vitro assays were developed to validate the variants identified (fibroblast assay, induced pluripotent stem cell [iPSC] derived retinal organoids, and a dynein motility assay).\ud \ud Results: Four novel DYNC2H1 variants (V1, g.103327020_103327021dup; V2, g.103055779A>T; V3, g.103112272C>G; V4, g.103070104A>C) and one previously reported variant (V5, g.103339363T>G) were identified. In proband 1 (V1/V2), V1 was predicted to introduce a premature termination codon (PTC), whereas V2 disrupted the exon 41 splice donor site causing incomplete skipping of exon 41. V1 and V2 impaired dynein-2 motility in vitro and perturbed IFT88 distribution within cilia. V3, homozygous in probands 2–4, is predicted to cause a PTC in a retina-predominant transcript. Analysis of retinal organoids showed that this new transcript expression increased with organoid differentiation. V4, a novel missense variant, was in trans with V5, previously associated with Jeune asphyxiating thoracic dystrophy (JATD).\ud \ud Conclusion: The DYNC2H1 variants discussed herein were either hypomorphic or affecting a retina-predominant transcript and caused nonsyndromic IRD. Dynein variants, specifically DYNC2H1 variants are reported as a cause of non syndromic IRD.

The strain hardening behavior of polymers has important roles in processing such as foaming, film formation, and fiber spinning. The most common method to enhance strain hardening is to introduce a long-chain branching structure on the backbone of a linear polymer, but this method is costly and challenging to tailor the behavior. We hypothesized that in situ shrinking fibers can increase the strain hardening of linear polymers, and the degree can be efficiently controlled. In this study, we show that heat-activated shrinking fibers compounded in linear polypropylene enhance strain hardening and foamability. Moreover, changing processing conditions, such as temperature, can amplify the degree of enhancement. Rheological measurements and physical foaming tests are shown to support our hypothesis.

Biodegradable plastics are thought to be the possible directions in managing plastic pollutions. Unfortunately, they are not recycled in most countries since they are designed to decompose even though recycling is a more pragmatic method than landfill or incineration. Thus, it is more constructive to develop methods to recycle biodegradable plastics or to develop biodegradable yet recyclable plastics. In this study, we used cutlery with a composite of poly(lactic acid) (PLA) and talc. The possibility to recycle it to make foams was studied even though it will have lowered mechanical strength from the recycling process as it is less significant for this product. Tensile properties of solid PLA and foams showed no significant decrease in the strength up to three processes of compression molding and foaming. We performed shear rheometry to determine the thermal stability and dependences of the complex viscosity on frequency and temperature. The magnitude of the complex viscosity dramatically increased with decreasing frequency and such an upturn increased with temperature, but time-temperature superposition was valid at high temperatures. The extensional rheometry showed no strain hardening, but physical foaming using supercritical carbon dioxide (CO2) could still occur, and the operating conditions to obtain various foamed structures were determined. We also compared the effects of one-directional against three-dimensional expansion. Overall, the concentration of CO2 in PLA and crystallinity of the foams are the two key variables to describe the bulkiness of foams. Surprisingly, the lower the CO2 concentration, the bulkier the foams at any sorption temperature and pressure.

Gases or supercritical fluids (SCF) are widely used in polymer science and engineering, as their dissolution into polymeric materials will alter their inherent thermal properties; including melting and crystallization temperatures (Tm and Tc). One possible method to determine these temperatures, at elevated pressures, is to use a high-pressure differential scanning calorimeter (HP-DSC). However, the elevated pressures used in HP-DSC may result in signal instabilities, limiting the testing window for these pressures. This study presents a novel testing system using dielectric measurements to determine the effects of dissolved gas/SCF on the Tm and Tc of polymers. We have developed an instrument to determine the dielectric properties of both polymer/gas and polymer/SCF mixtures, at elevated pressures and temperatures. Using the change in the measured dielectric constant or loss, Tm and Tc were determined. The effects of hydrostatic pressure and plasticization due to dissolved carbon dioxide (CO2) and Helium (He) on the Tm and Tc of high density polyethylene (HDPE) are presented and discussed. Both Tm and Tc increase with pressure and decrease due to plasticization, i.e., pressure and plasticization are competing variables. The dissolution of He, having a low solubility into HDPE, reveals that pressure is the dominant effect. In contrast, the dissolution of CO2, having a high solubility into HDPE, shows that plasticization is predominant.

Zero shear viscosity data of an amorphous polycarbonate (PC) were obtained by pressure-sweep tests at seven pressures from 1 to 700 bar, at 160, 180, 200, 220, and 240 °C above the glass transition temperature T g . Independent shifts of the logarithmic zero shear viscosity and of the pressure were performed in order to build an empirical master curve at the reference temperature T 0 = 240 °C. On the basis of a Vogel-type model, analytical expressions which fit the empirical logarithmic zero shear viscosity and the pressure shift factors were obtained. Additionally, a general equation of the zero shear viscosity as a function of pressure at any reference temperature was deduced. It is shown that the temperature dependence of the zero shear viscosity follows the Williams-Landel-Ferry (WLF) equation, with a pressure dependence parameter B(P) = B(0) $$ \left(1-4.4\times {10}^{-4}\frac{1}{\mathrm{bar}}P\right) $$ , B(0) = 02.87 from which it is obtained that the pressure dependence of fractional free volume of PC at the glass transition temperature is f(T g , P) = 0.022 B(P).

Purpose: To characterize a series of 7 patients with cone-rod dystrophy (CORD) and amelogenesis imperfecta (AI) owing to confirmed mutations in CNNM4, first described as “Jalili Syndrome.” Design: Retrospective observational case series. Methods: Seven patients from 6 families with Jalili Syndrome were identified at 3 tertiary referral centers. We systematically reviewed their available medical records, spectral-domain optical coherence tomography (SD-OCT), fundus autofluorescence imaging (FAF), color fundus photography, and electrophysiological assessments. Results: The mean age at presentation was 6.7 years (range 3-16 years), with 6 male and 1 female patient. CNNM4 mutations were identified in all patients. The mean Snellen best-corrected visual acuity (BCVA) at presentation was 20/246 (range 20/98 to 20/399) in the right eye and 20/252 (range 20/98 to 20/480) in the left. Nystagmus was observed in all 7 patients, and photophobia was present in 6. Funduscopic findings at presentation were variable, ranging from only mild disc pallor to retinal vascular attenuation and macular atrophy. Multimodal imaging demonstrated disease progression in all 7 patients over time. Electroretinography uniformly revealed progressive cone-rod dysfunction. Conclusions: Jalili Syndrome is a rare CORD associated with AI. We have further characterized its ocular phenotype, including describing SD-OCT, FAF, and electrophysiological features; and report several novel disease-causing sequence variants. Moreover, this study presents novel longitudinal data demonstrating structural and functional progression over time, allowing better informed advice on prognosis.

Allogeneic lung transplant is limited both by the shortage of available donor lungs and by the lack of suitable long-term lung assist devices to bridge patients to lung transplantation. Avian lungs have different structure and mechanics resulting in more efficient gas exchange than mammalian lungs. Decellularized avian lungs, recellularized with human lung cells, could therefore provide a powerful novel gas exchange unit for potential use in pulmonary therapeutics. To initially assess this in both small and large avian lung models, chicken (Gallus gallus domesticus) and emu (Dromaius novaehollandiae) lungs were decellularized using modifications of a detergent-based protocol, previously utilized with mammalian lungs. Light and electron microscopy, vascular and airway resistance, quantitation and gel analyses of residual DNA, and immunohistochemical and mass spectrometric analyses of remaining extracellular matrix (ECM) proteins demonstrated maintenance of lung structure, minimal residual DNA, and retention of major ECM proteins in the decellularized scaffolds. Seeding with human bronchial epithelial cells, human pulmonary vascular endothelial cells, human mesenchymal stromal cells, and human lung fibroblasts demonstrated initial cell attachment on decellularized avian lungs and growth over a 7-day period. These initial studies demonstrate that decellularized avian lungs may be a feasible approach for generating functional lung tissue for clinical therapeutics.

Strain hardening has important roles in understanding material structures and polymer processing methods, such as foaming, film forming, and fiber extruding. A common method to improve strain hardening behavior is to chemically branch polymer structures, which is costly, thus preventing users from controlling the degree of behavior. A smart microfiber blending technology, however, would allow cost-efficient tuning of the degree of strain hardening. In this study, we investigated the effects of compounding polymers with microfibers for both shear and extensional rheological behaviors and characteristics and thus for the final foam morphologies formed by batch physical foaming with carbon dioxide. Extensional rheometry showed that compounding of in situ shrinking microfibers significantly enhanced strain hardening compared to compounding of nonshrinking microfibers. Shear rheometry with linear viscoelastic data showed a greater increase in both the loss and storage modulus in composites with shrinking microfibers than in those with nonshrinking microfibers at low frequencies. The batch physical foaming results demonstrated a greater increase in the cell population density and expansion ratio with in situ shrinking microfibers than with nonshrinking microfibers. The enhancement due to the shrinkage of compounded microfibers decreasing with temperature implies that the strain hardening can be tailored by changing processing conditions.

Two tube-based molecular models, the hierarchical 3.0 model and the branch-on-branch model were evaluated for their abilities to predict the behavior of a series of polydisperse, H-shaped, 1,4-polybutadienes. The samples had been synthesized using a novel technique designed to suppress the generation of high molar mass by-products. While size exclusion chromatography data indicated that the samples were monodisperse, low molar mass by-products were later revealed by temperature gradient interaction chromatography. Viscoelastic data were obtained at temperatures ranging from −75 °C to 25 °C, and the samples were found to be thermorheologically simple. Sensitivity and uncertainty analyses revealed that among the model parameters, the value of plateau modulus has the strongest effect on model predictions. As molecular models improve, it will become ever more essential to evaluate them using accurate data on materials whose microstructures have been reliably established. This is especially important for materials that are structurally polydisperse.

The structural details of a set of highly entangled H-shaped polybutadienes (PBDs) prepared by anionic polymerization were examined in detail by three reputable laboratories using size exclusion chromatography (SEC) and temperature gradient interaction chromatography (TGIC). While SEC data indicated that samples having the desired structures (i.e., nearly monodisperse H-shaped polymer) had been produced, additional SEC data from other laboratories showed that the samples were structurally more complex than originally thought. TGIC data revealed that while the samples did not contain high molecular weight byproducts, they did contain low molecular weight byproducts. To discern these structural details of the branched PBDs, small amounts of sample were fractionated by TGIC. By combining knowledge of the polymerization process with the TGIC data of fractionated samples, it was possible to work out the detailed compositions of the samples and the branching structures of each component.

We studied polymer-polymer interfacial slip in bilayer films of highly immiscible (interaction parameter, χ≅0.1) polyethylene and fluoropolymer from medium to higher shear stresses (10–200 kPa) using both visualization and stress reduction. We found good agreement between results from the two methods as well as with previous studies using multilayers by Lee et al. [J. Rheol. 53, 893–915 (2009)] and visualization of flow in a transparent capillary by Migler et al. [J. Rheol. 45, 565–581 (2001)]. We observed two power-law regions: Vslip∝τ6.2 with a transition to Vslip∝τ1.8 at 50 kPa. This is in contrast to the theory of Brochard-Wyart and de Gennes [C. R. Acad. Sci., Ser. II: Mec., Phys., Chim., Sci. Terre Univers 317, 13–17 (1993)], which predicts a transition from infinite slope to a slope of one at a critical stress.

Several samples of a recently developed olefin multiblock copolymer were studied by means of rheology, differential scanning calorimetry (DSC) and small-angle X-ray scattering (SAXS). The synthesis involves a chain shuttling agent (CSA) that switches the growing chain between two catalysts, one that favors the incorporation of an α-olefin comonomer and one that suppresses incorporation. The data were used to determine the effect of octene comonomer content and CSA level on rheological behavior and the occurrence of mesophase separation transition (MST) in the melt. To distinguish between crystallization and MST, we made calorimetry scans and measured the density and rheological properties over a range of temperatures. Small angle X-ray scattering analysis of a sample that had undergone planar extensional flow revealed strong alignment of lamellar mesodomains, which maintained their alignment after annealing. This result confirmed the hypothesis based on rheological evidence that a lamellar mesophase is pr...