Redox-responsive branched-bottlebrush polymers for \u3ci\u3ein vivo\u3c/i\u3e MRI and fluorescence imaging

Stimuli-responsive multimodality imaging agents have broad potential in medical diagnostics. Herein, we report the development of a new class of branched-bottlebrush polymer dual-modality organic radical contrast agents—ORCAFluors—for combined magnetic resonance and near-infrared fluorescence imaging in vivo. These nitroxide radical-based nanostructures have longitudinal and transverse relaxation times that are on par with commonly used heavy-metal-based magnetic resonance imaging (MRI) contrast agents. Furthermore, these materials display a unique compensatory redox response: fluorescence is partially quenched by surrounding nitroxides in the native state; exposure to ascorbate or ascorbate/glutathione leads to nitroxide reduction and a concomitant 2- to 3.5-fold increase in fluorescence emission. This behaviour enables correlation of MRI contrast, fluorescence intensity and spin concentration with tissues known to possess high concentrations of ascorbate in mice. Our in vitro and in vivo results, along with our modular synthetic approach, make ORCAFluors a promising new platform for multimodality molecular imaging

Proximity-induced quasi-one-dimensional superconducting quantum anomalous Hall state: a promising scalable top-down approach towards localized Majorana modes

In this work, ~100 nm wide quantum anomalous Hall insulator (QAHI) nanoribbons are etched from a two-dimensional QAHI film. One part of the nanoribbon is covered with superconducting Nb, while the other part is connected to an Au lead via two-dimensional QAHI regions. Andreev reflection spectroscopy measurements were performed, and multiple in-gap conductance peaks were observed in three different devices. In the presence of an increasing magnetic field perpendicular to the QAHI film, the multiple in-gap peak structure evolves into a single zero-bias conductance peak (ZBCP). Theoretical simulations suggest that the measurements are consistent with the scenario that the increasing magnetic field drives the nanoribbons from a multi-channel occupied regime to a single channel occupied regime, and that the ZBCP may be induced by zero energy Majorana modes as previously predicted [24]. Although further experiments are needed to clarify the nature of the ZBCP, we provide initial evidence that quasi-1D QAHI nanoribbon/superconductor heterostructures are new and promising platforms for realizing zero-energy Majorana modes

Hearing loss prevalence and years lived with disability, 1990–2019: findings from the Global Burden of Disease Study 2019

Background Hearing loss affects access to spoken language, which can affect cognition and development, and can negatively affect social wellbeing. We present updated estimates from the Global Burden of Disease (GBD) study on the prevalence of hearing loss in 2019, as well as the condition's associated disability. Methods We did systematic reviews of population-representative surveys on hearing loss prevalence from 1990 to 2019. We fitted nested meta-regression models for severity-specific prevalence, accounting for hearing aid coverage, cause, and the presence of tinnitus. We also forecasted the prevalence of hearing loss until 2050. Findings An estimated 1·57 billion (95% uncertainty interval 1·51–1·64) people globally had hearing loss in 2019, accounting for one in five people (20·3% [19·5–21·1]). Of these, 403·3 million (357·3–449·5) people had hearing loss that was moderate or higher in severity after adjusting for hearing aid use, and 430·4 million (381·7–479·6) without adjustment. The largest number of people with moderate-to-complete hearing loss resided in the Western Pacific region (127·1 million people [112·3–142·6]). Of all people with a hearing impairment, 62·1% (60·2–63·9) were older than 50 years. The Healthcare Access and Quality (HAQ) Index explained 65·8% of the variation in national age-standardised rates of years lived with disability, because countries with a low HAQ Index had higher rates of years lived with disability. By 2050, a projected 2·45 billion (2·35–2·56) people will have hearing loss, a 56·1% (47·3–65·2) increase from 2019, despite stable age-standardised prevalence. Interpretation As populations age, the number of people with hearing loss will increase. Interventions such as childhood screening, hearing aids, effective management of otitis media and meningitis, and cochlear implants have the potential to ameliorate this burden. Because the burden of moderate-to-complete hearing loss is concentrated in countries with low health-care quality and access, stronger health-care provision mechanisms are needed to reduce the burden of unaddressed hearing loss in these settings

Redox-responsive branched-bottlebrush polymers for \u3ci\u3ein vivo\u3c/i\u3e MRI and fluorescence imaging

Stimuli-responsive multimodality imaging agents have broad potential in medical diagnostics. Herein, we report the development of a new class of branched-bottlebrush polymer dual-modality organic radical contrast agents—ORCAFluors—for combined magnetic resonance and near-infrared fluorescence imaging in vivo. These nitroxide radical-based nanostructures have longitudinal and transverse relaxation times that are on par with commonly used heavy-metal-based magnetic resonance imaging (MRI) contrast agents. Furthermore, these materials display a unique compensatory redox response: fluorescence is partially quenched by surrounding nitroxides in the native state; exposure to ascorbate or ascorbate/glutathione leads to nitroxide reduction and a concomitant 2- to 3.5-fold increase in fluorescence emission. This behaviour enables correlation of MRI contrast, fluorescence intensity and spin concentration with tissues known to possess high concentrations of ascorbate in mice. Our in vitro and in vivo results, along with our modular synthetic approach, make ORCAFluors a promising new platform for multimodality molecular imaging

Redox-responsive branched-bottlebrush polymers for in vivo MRI and fluorescence imaging

Stimuli-responsive multimodality imaging agents have broad potential in medical diagnostics. Herein, we report the development of a new class of branched-bottlebrush polymer dual-modality organic radical contrast agents—ORCAFluors—for combined magnetic resonance and near-infrared fluorescence imaging in vivo. These nitroxide radical-based nanostructures have longitudinal and transverse relaxation times that are on par with commonly used heavy-metal-based magnetic resonance imaging (MRI) contrast agents. Furthermore, these materials display a unique compensatory redox response: fluorescence is partially quenched by surrounding nitroxides in the native state; exposure to ​ascorbate or ​ascorbate/​glutathione leads to nitroxide reduction and a concomitant 2- to 3.5-fold increase in fluorescence emission. This behaviour enables correlation of MRI contrast, fluorescence intensity and spin concentration with tissues known to possess high concentrations of ​ascorbate in mice. Our in vitro and in vivo results, along with our modular synthetic approach, make ORCAFluors a promising new platform for multimodality molecular imaging.Massachusetts Institute of Technology. Department of ChemistryMassachusetts Institute of Technology. Research Support CommitteeLincoln LaboratoryNational Institutes of Health (U.S.) (NIBIB 1R21EB018529-01A1)National Institutes of Health (U.S.) (Ruth L. Kirschstein National Research Service Award 1F32EB017614-01)United States. Dept. of Defense. Ovarian Cancer Research Program (Teal Innovator Award)National Cancer Institute (U.S.) (Koch Institute Support (Core) Grant P30-CA14051

Cysteine mutagenesis improves the production without abrogating antigenicity of a recombinant protein vaccine candidate for human chagas disease

A therapeutic vaccine for human Chagas disease is under development by the Sabin Vaccine Institute Product Development Partnership. The aim of the vaccine is to significantly reduce the parasite burden of Trypanosoma cruzi in humans, either as a standalone product or in combination with conventional chemotherapy. Vaccination of mice with Tc24 formulated with monophosphoryl-lipid A (MPLA) adjuvant results in a Th1 skewed immune response with elevated IgG2a and IFNγ levels and a statistically significant decrease in parasitemia following T. cruzi challenge. Tc24 was therefore selected for scale-up and further evaluation. During scale up and downstream process development, significant protein aggregation was observed due to intermolecular disulfide bond formation. To prevent protein aggregation, cysteine codons were replaced with serine codons which resulted in the production of a non-aggregated and soluble recombinant protein, Tc24-C4. No changes to the secondary structure of the modified molecule were detected by circular dichroism. Immunization of mice with wild-type Tc24 or Tc24-C4, formulated with E6020 (TLR4 agonist analog to MPLA) emulsified in a squalene-oil-in-water emulsion, resulted in IgG2a and antigen specific IFNγ production levels from splenocytes that were not significantly different, indicating that eliminating putative intermolecular disulfide bonds had no significant impact on the immunogenicity of the molecule. In addition, vaccination with either formulated wild type Tc24 or Tc24-C4 antigen also significantly increased survival and reduced cardiac parasite burden in mice. Investigations are now underway to examine the efficacy of Tc24-C4 formulated with other adjuvants to reduce parasite burden and increase survival in pre-clinical studies