Selective N;#8208;Terminal BET Bromodomain Inhibitors by Targeting Non;#8208;Conserved Residues and
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Abstract The distinct organization of Kv2 voltage‐gated potassium channels on and near the cell body of brain neurons enables their regulation of action potentials and specialized membrane contact sites. Somatosensory neurons have a pseudounipolar morphology and transmit action potentials from peripheral nerve endings through axons that bifurcate to the spinal cord and the cell body within ganglia including the dorsal root ganglia (DRG). Kv2 channels regulate action potentials in somatosensory neurons, yet little is known about where Kv2 channels are located. Here, we define the cellular and subcellular localization of the Kv2 paralogs, Kv2.1 and Kv2.2, in DRG somatosensory neurons with a panel of antibodies, cell markers, and genetically modified mice. We find that relative to spinal cord neurons, DRG neurons have similar levels of detectable Kv2.1 and higher levels of Kv2.2. In older mice, detectable Kv2.2 remains similar, while detectable Kv2.1 decreases. Both Kv2 subtypes adopt clustered subcellular patterns that are distinct from central neurons. Most DRG neurons co‐express Kv2.1 and Kv2.2, although neuron subpopulations show preferential expression of Kv2.1 or Kv2.2. We find that Kv2 protein expression and subcellular localization are similar between mouse and human DRG neurons. We conclude that the organization of both Kv2 channels is consistent with physiological roles in the somata and stem axons of DRG neurons. The general prevalence of Kv2.2 in DRG as compared to central neurons and the enrichment of Kv2.2 relative to detectable Kv2.1 in older mice, proprioceptors, and axons suggest more widespread roles for Kv2.2 in DRG neurons.
A search for long-lived heavy neutral leptons (HNLs) is presented, which considers the hadronic final state and coupling scenarios involving all three lepton generations in the 2–20 GeV HNL mass range for the first time. Events comprising two leptons (electrons or muons) and jets are analyzed in a data sample of proton-proton collisions, recorded with the CMS experiment at the CERN LHC at a centre-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 138 fb$^{−1}$. A novel jet tagger, based on a deep neural network, has been developed to identify jets from an HNL decay using various features of the jet and its constituent particles. The network output can be used as a powerful discriminating tool to probe a broad range of HNL lifetimes and masses. Contributions from background processes are determined from data. No excess of events in data over the expected background is observed. Upper limits on the HNL production cross section are derived as functions of the HNL mass and the three coupling strengths V$_{ℓN}$ to each lepton generation ℓ and presented as exclusion limits in the coupling-mass plane, as lower limits on the HNL lifetime, and on the HNL mass. In this search, the most stringent limit on the coupling strength is obtained for pure muon coupling scenarios; values of |$ {V}_{\mu \textrm{N}}^2 $| > 5 (4) × 10$^{−7}$ are excluded for Dirac (Majorana) HNLs with a mass of 10 GeV at a confidence level of 95% that correspond to proper decay lengths of 17 (10) mm.[graphic not available: see fulltext]
This study investigates potential economic and groundwater driven transitions from irrigated maize production—the dominant irrigated cropping system in the High Plains Aquifer (HPA) region—to alternative crops such as sorghum and switchgrass, two common bioenergy feedstocks. Unsustainable groundwater extraction in the U.S. High Plains presents critical challenges including reduced irrigation capacities, diminished crop yields, lower land values, and escalating energy costs. Using a spatially explicit optimization framework combined with comprehensive economic and hydrogeological data, we evaluate optimal land-use strategies and irrigation system investments over a 30-year planning period. Results indicate significant regional variability in the future economic viability of irrigated agriculture, driven by differences in aquifer recharge rates, groundwater availability, and market conditions. Nebraska and parts of northern Texas can sustain irrigated maize profitability due to relatively favorable groundwater conditions and lower land rents, respectively. In contrast, many portions of Kansas and southern Texas are more likely to transition to dryland agriculture within two decades. Colorado and New Mexico show potential for significant adoption of switchgrass production as an alternative biomass-based energy crop. Overall, over the 30-year horizon, our model implies that approximately 23% of currently irrigated maize area across the HPA region may transition to dryland farming under business-as-usual conditions. This transition is complemented by a threefold increase in non-irrigated sorghum production, from 0.20 to 0.77 Mt yr−1, indicating that groundwater-driven shifts in agricultural production may support a larger regional base for bioenergy feedstocks. The study also reveals opportunities for producers to optimize economic returns and biomass production potential.
The expansion of the global macroalgal aquaculture and climate change creates the need for germplasm preservation of valuable aquaculture strains and maintenance of natural biodiversity. Compared to the large number of studies in fish and shellfish species, relative few studies have been conducted on the macroalgal germplasm cryopreservation. The first cryopreservation of macroalgae to –75 °C was reported on Neopyropia tenera (formerly called Porphyra tenera) in 1964. To date, a total of 34 studies reported germplasm cryopreservation in 33 species, including Chlorophyta (7 species), Ochrophyta (14 species), and Rhodophyta (12 species). Here, the goal of this review was to summarize the published studies on macroalgal germplasm cryopreservation, compare the reported protocols for the cryopreservation process, and identify the factors affecting post-thaw viability. Overall, macroalgal germplasm cryopreservation included haploid or diploid thalli, spores, and gametes. Cryotubes (1.5-ml or 2-ml) have been widely used to package germplasm samples for cooling and storage in most studies, and the 0.5-ml straws and 5-ml cryotubes have been used in several studies. Two approaches (programmable controlled cooling and vitrification) were employed for macroalgal germplasm cryopreservation. A two-step programmable controlled cooling (e.g., from initial culture temperature to a frozen temperature, such as –40 °C, and then directly plunging into liquid nitrogen at –196 °C) was determined to be an effective cooling strategy. Vitrification, a super rapid cooling for a sample to form non-crystalline amorphous solid, was applied on macroalgal germplasm cryopreservation with sample encapsulation and dehydration. Survival of post-thaw samples varied significantly in different studies. Based on research updates, recommendations are made for future research. It is expected that this review can serve as a foundation for future germplasm banking of macroalgae for aquaculture and biodiversity preservation.
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In this work, we propose an Exponential DG framework for partial differential equations. We decompose 7 governing equations into linear and nonlinear parts to which we apply the discontinuous Galerkin 8 (DG) spatial discretization. In particular, we construct the linear part using Jacobian that effectively 9 capture stiff characteristics in the system. The former is integrated analytically, whereas the latter 10 is approximated. This approach i) is stable with a large Courant number (Cr > 1); ii) supports 11 high-order solutions both in time and space; iii) is computationally favorable compared to IMEX 12 DG methods with no preconditioner; iv) becomes comparable to explicit RKDG methods on uniform 13 mesh and beneficial on non-uniform grid for Euler equations; v) is scalable in a modern massively 14 parallel computing architecture due to its explicit nature of exponential time integrators and com15 pact communication stencil of DG method. Numerical results demonstrate the performance of our 16 proposed methods through various examples. We also discuss the stability and convergence analysis 17 for our exponential DG scheme in the context of Burgers equation.
In this paper we extend the DGiT multirate framework, developed in Connors and Sockwell (2022) for scalar transmission problems, to a solid–solid interaction (SSI) problem involving two coupled elastic solids and a coupled air–sea model with the rotating, thermal shallow water equations. In so doing we aim to demonstrate the broad applicability of the mathematical theory and governing principles established in Connors and Sockwell (2022) to coupled problems characterized by subproblems evolving at different temporal scales. Further, multirate time integration algorithms employing different time steps, optimized for the dynamics of each subproblem, can significantly improve simulation efficiency for such coupled problems. However, development of multirate algorithms is a highly non-trivial task due to the coupling, which can impact accuracy, stability or other desired properties such as preservation of system invariants. DGiT provides a general template for multirate time integration that can achieve these properties. To elucidate the manner in which DGiT accomplishes this task, we fully detail each step in the application of the framework to the SSI and air–sea coupled problems. Numerical examples illustrate key properties of the resulting multirate schemes for both problems.
Development of particle-in-cell (PIC) methods using finite element based methods (FEMs) have been a topic of renewed interest; this has largely been driven by (a) the ability of finite element methods to better model geometry, (b) better understanding of function spaces that are necessary to represent all Maxwell quantities, and (c) more recently, the fundamental rubrics that should be obeyed in space and time so as to satisfy Gauss' laws and the equation of continuity. In that vein, methods have been developed recently that satisfy these equations and are agnostic to time stepping methods. While this development is indeed a significant advance, it should be noted that implicit FEM transient solvers support an underlying null space that corresponds to a gradient of a scalar potential ∇Φ(r) (or t∇Φ(r) in the case of wave equation solvers). While explicit schemes do not suffer from this drawback, they are only conditionally stable with time step sizes that are mesh dependent and very small. Furthermore, the null space produces spurious charge that can corrupt the desired physics of a PIC simulation. The way to overcome this bottleneck, and indeed, satisfy all four Maxwell's equation is to use a quasi-Helmholtz formulation on a tessellation. In the re-formulation presented, we strictly satisfy the equation of continuity and Gauss' laws for both the electric and magnetic flux densities. Results illustrating the efficacy of this scheme will be demonstrated by analyzing non-neutral beams with space-charge and the adiabatic expansion of a neutral plasma with realistic parameters (Debye length and real mass ratios).