Hearing loss is the most common sensory disorder. While gene therapy has emerged as a promising treatment of inherited diseases like hearing loss, it is dependent on the identification of gene delivery vectors. Adeno-associated virus (AAV) vector-mediated gene therapy has been approved in the US for treating a rare inherited eye disease but no safe and efficient vectors have been identified that can target the diverse types of inner ear cells. Here, we identify an AAV variant, AAV-inner ear (AAV-ie), for gene delivery in mouse inner ear. Our results show that AAV-ie transduces the cochlear supporting cells (SCs) with high efficiency, representing a vast improvement over conventional AAV serotypes. Furthermore, after AAV-ie-mediated transfer of the Atoh1 gene, we find that many SCs trans-differentiated into new HCs. Our results suggest that AAV-ie is a useful tool for the cochlear gene therapy and for investigating the mechanism of HC regeneration.

Figure 3 . Transmittance spectra of a single-layer quarterwave AR coating and an experimental and modeled double-wavelength AR coating.

We report the characterization of BMS-911543, a potent and selective small-molecule inhibitor of the Janus kinase (JAK) family member, JAK2. Functionally, BMS-911543 displayed potent anti-proliferative and pharmacodynamic (PD) effects in cell lines dependent upon JAK2 signaling, and had little activity in cell types dependent upon other pathways, such as JAK1 and JAK3. BMS-911543 also displayed anti-proliferative responses in colony growth assays using primary progenitor cells isolated from patients with JAK2 V617F -positive myeloproliferative neoplasms (MPNs). Similar to these in vitro observations, BMS-911543 was also highly active in in vivo models of JAK2 signaling, with sustained pathway suppression being observed after a single oral dose. At low dose levels active in JAK2-dependent PD models, no effects were observed in an in vivo model of immunosuppression monitoring antigen-induced IgG and IgM production. Expression profiling of JAK2 V617F -expressing cells treated with diverse JAK2 inhibitors revealed a shared set of transcriptional changes underlying pharmacological effects of JAK2 inhibition, including many STAT1-regulated genes and STAT1 itself. Collectively, our results highlight BMS-911543 as a functionally selective JAK2 inhibitor and support the therapeutic rationale for its further characterization in patients with MPN or in other disorders characterized by constitutively active JAK2 signaling.

The increasing electron-donating ability of the donor part is focused to further optimize the lightharvesting capability. Our strategy is to introduce an additional donor group into the indoline unit in the donor part to form a donor-donor structure (D-D moiety). Three different units (carbazole, fluorene and 4-methylphenyl groups) with different degrees of electron-donating capability are incorporated, thus constructing the specific donor-donor-p-acceptor (D-D-p-A) system (C-CA, F-CA and I-3) and giving a systematic view of the absorption evolution. Through molecular engineering, their light-harvesting capabilities, energy levels and photovoltaic performances were studied. As expected, utilizing strong electron-donating carbazole unit as additional donor, the IPCE spectrum of DSSC based on C-CA is successfully broadened to NIR region on the premise of suitable LUMO level, with an extraordinarily high plateau in visible region till around 700 nm. In the system of C-CA and F-CA, the introduction of n-pentyl group in donor part of carbazole and fluorene unit has little effect on preventing the molecular p-aggregation due to the good co-planarity of p-linker (vinyl thiophene), suggesting that the most effective way to prevent p-aggregation is still the incorporation of long alkyl groups into planar p-linker segment. However, the introducing long alkyl group can effectively prevent the electron recombination between electrons in conduction band (CB) of TiO 2 and I 3À ions. Along with the preferable light-harvesting capability, C-CA presents excellent IPCE performance with a short-circuit photocurrent (J sc ) of 18.53 mA cm À2 , an open-circuit photovoltage (V oc ) of 649 mV, a fill factor of 0.71, corresponding to a power conversion efficiency (h) of 8.49%. The internal relations between chemical structure and conversion efficiency provide a strategy for developing highly efficient organic sensitizers working in whole visible region with high photovoltaic performance.

Immunotherapy has fundamentally changed the landscape of cancer treatment. Despite the encouraging results with the checkpoint modulators, response rates vary widely across tumor types, with a majority of patients exhibiting either primary resistance without a significant initial response to treatment or acquired resistance with subsequent disease progression. Hematopoietic progenitor kinase 1 (HPK1) is predominantly expressed in hematopoietic cell linages and serves as a negative regulator in T cells and dendritic cells (DC). While HPK1 gene knockout (KO) studies suggest its role in anti-tumor immune responses, the involvement of kinase activity and thereof its therapeutic potential remain unknown. To investigate the potential of pharmacological intervention using inhibitors of HPK1, we generated HPK1 kinase dead (KD) mice which carry a single loss-of—function point mutation in the kinase domain and interrogated the role of kinase activity in immune cells in the context of suppressive factors or the tumor microenvironment (TME). Our data provide novel findings that HKP1 kinase activity is critical in conferring suppressive functions of HPK1 in a wide range of immune cells including CD4+, CD8+, DC, NK to Tregs, and inactivation of kinase domain was sufficient to elicit robust anti-tumor immune responses. These data support the concept that an HPK1 small molecule kinase inhibitor could serve as a novel agent to provide additional benefit in combination with existing immunotherapies, particularly to overcome resistance to current treatment regimens.