Purpose To describe the adverse events associated with brolucizumab, in particular the sequence of intraocular inflammation (IOI), retinal vasculitis (RV), and/or retinal vascular occlusion (RO)... Show morePurpose To describe the adverse events associated with brolucizumab, in particular the sequence of intraocular inflammation (IOI), retinal vasculitis (RV), and/or retinal vascular occlusion (RO).Methods This was an unmasked post hoc analysis of the randomized HAWK/HARRIER clinical trials. Patients with neovascular AMD in the brolucizumab arms of the trials were included. IOI-related adverse events reported by study investigators were analyzed to determine early signs and the time course of IOI-related adverse events, using a subgroup of patients with definite/probable IOI cases identified in an independent unmasked post hoc review by an external safety review committee. A limited literature review on MI following anti-VEGF therapy was also conducted.Results Among 50 patients with definite/probable IOI cases identified by the safety review committee, 12 had RV or RO adverse events reported by the investigators. For 6 of 12, IOI (other than RV) was reported before RV or RO. The duration from the first IOI adverse event to the first RV or RO adverse event ranged from 16 to 171 days for 5 patients and was 553 days for 1 patient. Four of the 6 patients received >= 1 brolucizumab injection on or after the date of the first IOI adverse event and before the first RV or RO adverse event.Conclusions IOI may precede RV or RO in some patients treated with brolucizumab. Show less
Context. The physical and chemical conditions in Class 0/I protostars are fundamental in unlocking the protostellar accretion process and its impact on planet formation.Aims: The aim is to... Show moreContext. The physical and chemical conditions in Class 0/I protostars are fundamental in unlocking the protostellar accretion process and its impact on planet formation.Aims: The aim is to determine which physical components are traced by different molecules at subarcsecond scales (<100-400 au).Methods: We used a suite of Atacama Large Millimeter/submillimeter Array (ALMA) datasets in band 6 (1 mm), band 5 (1.8 mm), and band 3 (3 mm) at spatial resolutions 0.″5-3″ for 16 protostellar sources. For a subset of sources, Atacama Compact Array (ACA) data at band 6 with a spatial resolution of 6″ were added. The availability of low- and high-excitation lines and data on small and larger scales, is important to understand the full picture.Results: The protostellar envelope is well traced by C18O, DCO+, and N2D+, which stems from the freeze-out of CO governing the chemistry at envelope scales. Molecular outflows are seen in classical shock tracers such as SiO and SO, but ice-mantle products such as CH3OH and HNCO that are released with the shock are also observed. The molecular jet is a key component of the system. It is only present at the very early stages, and it is prominent not only in SiO and SO, but occasionally also in H2CO. The cavity walls show tracers of UV-irradiation such as C2H, c-C3H2 and CN. In addition to showing emission from complex organic molecules (COMs), the hot inner envelope also presents compact emission from small molecules such as H2S, SO, OCS, and H13CN, which most likely are related to ice sublimation and high-temperature chemistry.Conclusions: Subarcsecond millimeter-wave observations allow us to identify these (simple) molecules that best trace each of the physical components of a protostellar system. COMs are found both in the hot inner envelope (high-excitation lines) and in the outflows (lower-excitation lines) with comparable abundances. COMs can coexist with hydrocarbons in the same protostellar sources, but they trace different components. In the near future, mid-infrared observations with JWST-MIRI will provide complementary information about the hottest gas and the ice-mantle content, at unprecedented sensitivity and at resolutions comparable to ALMA for the same sources. Show less
Gaucher disease (GD) is a lysosomal storage disorder caused by inherited deficiencies in beta-glucocerebrosidase (GBA). Current treatments require rapid disease diagnosis and a means of monitoring... Show moreGaucher disease (GD) is a lysosomal storage disorder caused by inherited deficiencies in beta-glucocerebrosidase (GBA). Current treatments require rapid disease diagnosis and a means of monitoring therapeutic efficacy, both of which may be supported by the use of GBA-targeting activity-based probes (ABPs). Here, we report the synthesis and structural analysis of a range of cyclophellitol epoxide and aziridine inhibitors and ABPs for GBA. We demonstrate their covalent mechanism-based mode of action and uncover binding of the new N-functionalised aziridines to the ligand binding cleft. These inhibitors became scaffolds for the development of ABPs; the O6-fluorescent tags of which bind in an allosteric site at the dimer interface. Considering GBA's preference for O6- and N-functionalised reagents, a bi-functional aziridine ABP was synthesized as a potentially more powerful imaging agent. Whilst this ABP binds to two unique active site clefts of GBA, no further benefit in potency was achieved over our first generation ABPs. Nevertheless, such ABPs should serve useful in the study of GBA in relation to GD and inform the design of future probes. Show less
Sun, Z.; Qiao, D.; Shi, Y.; Barz, M.; Liu, L.; Chen, Y. 2021
It remains unclear how the precise length of one-dimensional nanovehicles influences the characters of vaccination. Here, a unimolecular nanovehicle with tailored size and aspect ratio (AR) is... Show moreIt remains unclear how the precise length of one-dimensional nanovehicles influences the characters of vaccination. Here, a unimolecular nanovehicle with tailored size and aspect ratio (AR) is applied to deliver CpG oligodeoxynucleotide, a Toll-like receptor (TLR) 9 agonist, as an adjuvant of recombinant hepatitis B virus surface antigen (rHBsAg), for treating chronic hepatitis B (CHB). Cationic nanovehicles with fixed width (ca. 45 nm) but varied length (46 nm-180 nm), AR from 1 to 4, are prepared through controlled polymerization and are loaded with CpG by electrostatic interaction. We reveal that the nanoadjuvant with AR = 2 shows the highest retention in proximal lymph nodes. Importantly, it is more easily internalized into antigen-presenting cells and accumulates in the late endosome, where TLR9 is located. Such a nanoadjuvant exhibits the strongest immune response with rHBsAg to clear the hepatitis B virus in the CHB mouse model, showing that the AR of nanovehicles governs the efficiency of vaccination. Show less
Background The hallmarks of cancer provide a highly cited and well-used conceptual framework for describing the processes involved in cancer cell development and tumourigenesis. However, methods... Show moreBackground The hallmarks of cancer provide a highly cited and well-used conceptual framework for describing the processes involved in cancer cell development and tumourigenesis. However, methods for translating these high-level concepts into data-level associations between hallmarks and genes (for high throughput analysis), vary widely between studies. The examination of different strategies to associate and map cancer hallmarks reveals significant differences, but also consensus. Results Here we present the results of a comparative analysis of cancer hallmark mapping strategies, based on Gene Ontology and biological pathway annotation, from different studies. By analysing the semantic similarity between annotations, and the resulting gene set overlap, we identify emerging consensus knowledge. In addition, we analyse the differences between hallmark and gene set associations using Weighted Gene Co-expression Network Analysis and enrichment analysis. Conclusions Reaching a community-wide consensus on how to identify cancer hallmark activity from research data would enable more systematic data integration and comparison between studies. These results highlight the current state of the consensus and offer a starting point for further convergence. In addition, we show how a lack of consensus can lead to large differences in the biological interpretation of downstream analyses and discuss the challenges of annotating changing and accumulating biological data, using intermediate knowledge resources that are also changing over time. Show less
Amylases are key enzymes in the processing of starch in many kingdoms of life. They are important catalysts in industrial biotechnology where they are applied in, among others, food processing and... Show moreAmylases are key enzymes in the processing of starch in many kingdoms of life. They are important catalysts in industrial biotechnology where they are applied in, among others, food processing and the production of detergents. In man amylases are the first enzymes in the digestion of starch to glucose and arguably also the preferred target in therapeutic strategies aimed at the treatment of type 2 diabetes patients through down-tuning glucose assimilation. Efficient and sensitive assays that report selectively on retaining amylase activities irrespective of the nature and complexity of the biomaterial studied are of great value both in finding new and effective human amylase inhibitors and in the discovery of new microbial amylases with potentially advantageous features for biotechnological application. Activity-based protein profiling (ABPP) of retaining glycosidases is inherently suited for the development of such an assay format. We here report on the design and synthesis of 1,6-epi-cyclophellitol-based pseudodisaccharides equipped with a suite of reporter entities and their use in ABPP of retaining amylases from human saliva, murine tissue as well as secretomes from fungi grown on starch. The activity and efficiency of the inhibitors and probes are substantiated by extensive biochemical analysis, and the selectivity for amylases over related retaining endoglycosidases is validated by structural studies. Show less
