Unlike in land plants, photosynthesis in many aquatic plants relies on bicarbonate in addition to carbon dioxide (CO
) to compensate for the low diffusivity and potential depletion of CO
in water. ...Concentrations of bicarbonate and CO
vary greatly with catchment geology. In this study, we investigate whether there is a link between these concentrations and the frequency of freshwater plants possessing the bicarbonate use trait. We show, globally, that the frequency of plant species with this trait increases with bicarbonate concentration. Regionally, however, the frequency of bicarbonate use is reduced at sites where the CO
concentration is substantially above the air equilibrium, consistent with this trait being an adaptation to carbon limitation. Future anthropogenic changes of bicarbonate and CO
concentrations may alter the species compositions of freshwater plant communities.
•Venetoclax resistance is mediated by methylation and silencing of PUMA.•Treatment algorithms should consider the PUMA, MCL1, and BAX status.
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The BCL2 inhibitor venetoclax has been ...approved to treat different hematological malignancies. Because there is no common genetic alteration causing resistance to venetoclax in chronic lymphocytic leukemia (CLL) and B-cell lymphoma, we asked if epigenetic events might be involved in venetoclax resistance. Therefore, we employed whole-exome sequencing, methylated DNA immunoprecipitation sequencing, and genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 screening to investigate venetoclax resistance in aggressive lymphoma and high-risk CLL patients. We identified a regulatory CpG island within the PUMA promoter that is methylated upon venetoclax treatment, mediating PUMA downregulation on transcript and protein level. PUMA expression and sensitivity toward venetoclax can be restored by inhibition of methyltransferases. We can demonstrate that loss of PUMA results in metabolic reprogramming with higher oxidative phosphorylation and adenosine triphosphate production, resembling the metabolic phenotype that is seen upon venetoclax resistance. Although PUMA loss is specific for acquired venetoclax resistance but not for acquired MCL1 resistance and is not seen in CLL patients after chemotherapy-resistance, BAX is essential for sensitivity toward both venetoclax and MCL1 inhibition. As we found loss of BAX in Richter’s syndrome patients after venetoclax failure, we defined BAX-mediated apoptosis to be critical for drug resistance but not for disease progression of CLL into aggressive diffuse large B-cell lymphoma in vivo. A compound screen revealed TRAIL-mediated apoptosis as a target to overcome BAX deficiency. Furthermore, antibody or CAR T cells eliminated venetoclax resistant lymphoma cells, paving a clinically applicable way to overcome venetoclax resistance.
Two complementary articles shed new light on resistance to venetoclax in lymphoid malignancies. Thijssen et al use single-cell studies to reveal the multilayered nature of the mechanisms underpinning the recurrence of chronic lymphocytic leukemia in patients on long-term venetoclax, identifying a range of recurring genetic and epigenetic changes in apoptotic regulators. Overlying this heterogeneity, heightened expression of MCL1 driven by NF-κB is ubiquitous but reversible upon drug discontinuation. Thomalla and colleagues use B-lineage cell lines and patient samples to elegantly demonstrate how methylation and silencing of PUMA, a pro-apoptotic, causes failure of venetoclax. Both articles provide clinically applicable suggestions for circumventing emergent resistance to venetoclax.
This paper reviews key characteristics and requirements for Two-Way Satellite Time and Frequency Transfer (TWSTFT) links. The outline and perspective of two concepts are described: 1. The classical ...bend-pipe transponder, without special equipment on board, with the potential of 10-17 day frequency transfer uncertainty; 2. The ACES-MWL (Atomic Clock Ensemble in Space Microwave Link) like active on-board equipment, with the potential down to few 10-19 day, using both high-rate modulation and carrier-phase. An outlook to advanced links is given. The aim of these proposed links is to provide a unique platform for the demanding requirements in the field of time and frequency metrology and to support improved orbit determination and relativistic geodesy for the next decades.
The benthic foodweb structure of Lake Võrtsjärv, a large (270 km2), shallow, and turbid Estonian lake, was evaluated based on C and N stable-isotope signatures (δ13C, δ15N). Variation in δ13C between ...sampling sites was not related to site proximity to the littoral zone or the more vegetated southern part of the lake, but rather appeared to be influenced by in-situ site peculiarities. δ13C was stable temporally and between functional feeding groups, a result implying that the whole benthic food web of the lake relies largely on the same C source admixture, essentially particulate organic matter (POM). Thus, the foodweb composition of Lake Võrtsjärv is remarkably homogeneous given the lake’s large surface area. Apparent trophic-level δ15N fractionation between total collectors and total predators (mean 1.7‰) was lower than the value of 3.4‰ generally adopted in foodweb studies, but the higher value was valid for specific prey–predator links. The low δ13C signature of some chironomid samples indicated probable assimilation of methane-oxidizing bacteria (MOB) by these sediment-dwelling invertebrates. However, the lack of similar13C depletion in benthic filterers (mussels) indicated that the MOB layer is essentially confined to the sediments and does not reach the water column, which probably constrains transfer of methane-derived C through the food web to fish in this lake. Our study demonstrates that the benthic food web of shallow turbid lakes like Võrtsjärv is simplified and is mostly sustained by phytoplanktonic C sources.
The nonlinear behaviour of epoxy resins is studied on standard tensile tests. A strain field measurement system is applied (Aramis) in order to monitor local strains. The residual strain is measured ...by recovering the specimens for up to 68 hours after unloading. The time span the specimen is exposed to load has a large influence on the creeping process and the residual strain after recovering. This is studied by comparison of instantaneous unloading with keeping the specimen under permanent load for thirty minutes. It is shown that moderate differences in the initial strain can lead to large differences in the creep behaviour as well as in the residual strain.
To study the role of large and shallow hemiboreal lakes in carbon processing, we calculated a 3-year carbon mass balance for Lake Võrtsjärv (Estonia) based on in situ measurements. This balance took ...into account hydrological and biogeochemical processes affecting dissolved inorganic (DIC), dissolved organic (DOC) and particulate organic (POC) carbon species. Accumulation varied greatly on a seasonal and yearly basis. The lake exported carbon during most of the year except during spring floods and in late autumn. In-lake processes were responsible for exporting POC and storing DOC while DIC switched between storage and export. The carbon cycle was alternatively dominated in 2009 by biogeochemical processes and in 2011 by riverine fluxes, whereas in 2010 the two process types were of the same magnitude. These results suggest that the role of large shallow lakes like Võrtsjärv in the global C cycle is equally driven by hydrological factors, in particular seasonal water level changes, and by biogeochemical in-lake reactions.
We develop a systematic framework for exclusive rare B decays of the type B→K(∗)l+l− at large dilepton invariant mass q2. It is based on an operator product expansion (OPE) for the required matrix ...elements of the nonleptonic weak Hamiltonian in this kinematic regime. Our treatment differs from previous work by a simplified operator basis, the explicit calculation of matrix elements of subleading operators, and by a quantitative estimate of duality violation. The latter point is discussed in detail, including the connection with the existence of an OPE and an illustration within a simple toy model.
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