16 research outputs found
Head-to-head trial of pegunigalsidase alfa versus agalsidase beta in patients with Fabry disease and deteriorating renal function: results from the 2-year randomised phase III BALANCE study
BACKGROUND: Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than -2 mL/min/1.73 m2/year who had received agalsidase beta for â„1âyear. METHODS: Patients were randomly assigned 2:1 to receive 1âmg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms. RESULTS: Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18-60) years, 47 (61%) patients were male, median eGFR was 74.5âmL/min/1.73 m2 and median (range) eGFR slope was -7.3 (-30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was -0.36âmL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths. CONCLUSIONS: Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions. TRIAL REGISTRATION NUMBER: NCT02795676
ATP synthase: evolution, energetics, and membrane interactions
The synthesis of ATP, life's 'universal energy currency', is the most
prevalent chemical reaction in biological systems, and is responsible for
fueling nearly all cellular processes, from nerve impulse propagation to DNA
synthesis. ATP synthases, the family of enzymes that carry out this endless
task, are nearly as ubiquitous as the energy-laden molecule they are
responsible for making. The F-type ATP synthase (F-ATPase) is found in every
domain of life, and is believed to predate the divergence of these lineages
over 1.5 billion years ago. These enzymes have therefore facilitated the
survival of organisms in a wide range of habitats, ranging from the deep-sea
thermal vents to the human intestine. In this review, we present an overview of
the current knowledge of the structure and function of F-type ATPases,
highlighting several adaptations that have been characterized across taxa. We
emphasize the importance of studying these features within the context of the
enzyme's particular lipid environment: Just as the interactions between an
organism and its physical environment shape its evolutionary trajectory,
ATPases are impacted by the membranes within which they reside. We argue that a
comprehensive understanding of the structure, function, and evolution of
membrane proteins -- including ATP synthase -- requires such an integrative
approach.Comment: Review article; 29 pages, 6 figures/1 tabl
Global data set of long-term summertime vertical temperature profiles in 153 lakes
Climate change and other anthropogenic stressors have led to long-term changes in the thermal structure, including surface temperatures, deepwater temperatures, and vertical thermal gradients, in many lakes around the world. Though many studies highlight warming of surface water temperatures in lakes worldwide, less is known about long-term trends in full vertical thermal structure and deepwater temperatures, which have been changing less consistently in both direction and magnitude. Here, we present a globally-expansive data set of summertime in-situ vertical temperature profiles from 153 lakes, with one time series beginning as early as 1894. We also compiled lake geographic, morphometric, and water quality variables that can influence vertical thermal structure through a variety of potential mechanisms in these lakes. These long-term time series of vertical temperature profiles and corresponding lake characteristics serve as valuable data to help understand changes and drivers of lake thermal structure in a time of rapid global and ecological change
Global data set of long-term summertime vertical temperature profiles in 153 lakes
Measurement(s) : temperature of water, temperature profile
Technology Type(s) : digital curation
Factor Type(s) : lake location, temporal interval
Sample Characteristic - Environment : lake, reservoir
Sample Characteristic - Location : global
Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.14619009Climate change and other anthropogenic stressors have led to long-term changes in the thermal structure, including surface temperatures, deepwater temperatures, and vertical thermal gradients, in many lakes around the world. Though many studies highlight warming of surface water temperatures in lakes worldwide, less is known about long-term trends in full vertical thermal structure and deepwater temperatures, which have been changing less consistently in both direction and magnitude. Here, we present a globally-expansive data set of summertime in-situ vertical temperature profiles from 153 lakes, with one time series beginning as early as 1894. We also compiled lake geographic, morphometric, and water quality variables that can influence vertical thermal structure through a variety of potential mechanisms in these lakes. These long-term time series of vertical temperature profiles and corresponding lake characteristics serve as valuable data to help understand changes and drivers of lake thermal structure in a time of rapid global and ecological change
Comparing AgentâBased Delivery of DNA and PNA Forced Intercalation (FIT) Probes for Multicolor mRNA Imaging
Fluorogenic oligonucleotide probes allow mRNA imaging in living cells. A key challenge is the cellular delivery of probes. Most delivery agents, such as cell-penetrating peptides (CPPs) and pore-forming proteins, require interactions with the membrane. Charges play an important role. To explore the influence of charge on fluorogenic properties and delivery efficiency, we compared peptide nucleic acid (PNA)- with DNA-based forced intercalation (FIT) probes. Perhaps counterintuitively, fluorescence signaling by charged DNA FIT probes proved tolerant to CPP conjugation, whereas CPPâFIT PNA conjugates were affected. Live-cell imaging was performed with a genetically engineered HEK293 cell line to allow the inducible expression of a specific mRNA target. Blob-like features and high background were recurring nuisances of the tested CPP and lipid conjugates. By contrast, delivery by streptolysin-O provided high enhancements of the fluorescence of the FIT probe upon target induction. Notably, DNA-based FIT probes were brighter and more responsive than PNA-based FIT probes. Optimized conditions enabled live-cell multicolor imaging of three different mRNA target sequences
Transparency, Geomorphology and Mixing Regime Explain Variability in Trends in Lake Temperature and Stratification across Northeastern North America (1975â2014)
Lake surface water temperatures are warming worldwide, raising concerns about the future integrity of valuable lake ecosystem services. In contrast to surface water temperatures, we know far less about what is happening to water temperature beneath the surface, where most organisms live. Moreover, we know little about which characteristics make lakes more or less sensitive to climate change and other environmental stressors. We examined changes in lake thermal structure for 231 lakes across northeastern North America (NENA), a region with an exceptionally high density of lakes. We determined how lake thermal structure has changed in recent decades (1975â2012) and assessed which lake characteristics are related to changes in lake thermal structure. In general, NENA lakes had increasing near-surface temperatures and thermal stratification strength. On average, changes in deepwater temperatures for the 231 lakes were not significantly different than zero, but individually, half of the lakes experienced warming and half cooling deepwater temperature through time. More transparent lakes (Secchi transparency >5 m) tended to have higher near-surface warming and greater increases in strength of thermal stratification than less transparent lakes. Whole-lake warming was greatest in polymictic lakes, where frequent summer mixing distributed heat throughout the water column. Lakes often function as important sentinels of climate change, but lake characteristics within and across regions modify the magnitude of the signal with important implications for lake biology, ecology and chemistry
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Head-to-head trial of pegunigalsidase alfa versus agalsidase beta in patients with Fabry disease and deteriorating renal function: results from the 2-year randomised phase III BALANCE study.
BACKGROUND: Pegunigalsidase alfa is a PEGylated α-galactosidase A enzyme replacement therapy. BALANCE (NCT02795676) assessed non-inferiority of pegunigalsidase alfa versus agalsidase beta in adults with Fabry disease with an annualised estimated glomerular filtration rate (eGFR) slope more negative than -2 mL/min/1.73 m2/year who had received agalsidase beta for â„1âyear. METHODS: Patients were randomly assigned 2:1 to receive 1âmg/kg pegunigalsidase alfa or agalsidase beta every 2 weeks for 2 years. The primary efficacy analysis assessed non-inferiority based on median annualised eGFR slope differences between treatment arms. RESULTS: Seventy-seven patients received either pegunigalsidase alfa (n=52) or agalsidase beta (n=25). At baseline, mean (range) age was 44 (18-60) years, 47 (61%) patients were male, median eGFR was 74.5âmL/min/1.73 m2 and median (range) eGFR slope was -7.3 (-30.5, 6.3) mL/min/1.73 m2/year. At 2 years, the difference between median eGFR slopes was -0.36âmL/min/1.73 m2/year, meeting the prespecified non-inferiority margin. Minimal changes were observed in lyso-Gb3 concentrations in both treatment arms at 2 years. Proportions of patients experiencing treatment-related adverse events and mild or moderate infusion-related reactions were similar in both groups, yet exposure-adjusted rates were 3.6-fold and 7.8-fold higher, respectively, with agalsidase beta than pegunigalsidase alfa. At the end of the study, neutralising antibodies were detected in 7 out of 47 (15%) pegunigalsidase alfa-treated patients and 6 out of 23 (26%) agalsidase beta-treated patients. There were no deaths. CONCLUSIONS: Based on rate of eGFR decline over 2 years, pegunigalsidase alfa was non-inferior to agalsidase beta. Pegunigalsidase alfa had lower rates of treatment-emergent adverse events and mild or moderate infusion-related reactions. TRIAL REGISTRATION NUMBER: NCT02795676