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At least 847 records · Page 47

Novel small molecule FGF 23 inhibitors increase serum phosphate and improve skeletal abnormalities in Hyp mice

We report that excess fibroblast growth factor 23 (FGF23) causes hereditary hypophosphatemic rickets, such as X-linked hypophosphatemia (XLH) and tumor induced osteomalacia (TIO). A small molecule that specifically binds to FGF23 to prevent activation of the FGFR/a-Klotho complex has potential advantages over the currently approved systemically administered FGF23 blocking antibody. Using structure-based drug design we previously identified ZINC13407541 (N-[[2-(2-phenylethenyl)cyclopenten-1-yl]methylidene]hydroxylamine) as a small molecule antagonist for FGF23. Additional structure-activity studies developed a series of ZINC13407541 analogues with enhanced drug-like properties. In this study, we tested in a pre-clinical Hyp mouse homologue of XLH a direct connect analogue (8n) [(E)-2-(4-(tert-butyl)phenyl)cyclopent-1-ene-1-carbaldehyde oxime] that exhibited the greatest stability in microsomal assays, and 13a [(E)-2-((E)-4-methylstyryl)benzaldehyde oxime] that exhibited increased in vitro potency. Using cryo-electron microscopy (Cryo-EM) structure and computational docking, we identified a key binding residue (Q156) of the FGF23 antagonists, ZINC13407541 and its analogues (8n and 13a) in the N-terminal domain of FGF23 protein. Site-directed mutagenesis and bimolecular fluorescence complementation (BiFC)-fluorescence resonance energy transfer (FRET) assay confirmed the binding site of these three antagonists. We found that pharmacological inhibition of FGF23 with either of these compounds blocked FGF23 signaling and increased serum phosphate and 1,25(OH)2D concentrations in Hyp mice. Long-term parenteral treatment with 8n or 13a also enhanced linear bone growth, increased mineralization of bone, and narrowed the growth plate in Hyp mice. The more potent 13a compound had greater therapeutic effects in Hyp mice. Further optimization of these FGF23 inhibitors may lead to versatile drugs to treat excess FGF23-mediated disorders.

60 APPLIED LIFE SCIENCES↗

Increased fluxes of shelf-derived materials to the central Arctic Ocean

Rising temperatures in the Arctic Ocean region are responsible for changes such as reduced ice cover, permafrost thawing, and increased river discharge, which, together, alter nutrient and carbon cycles over the vast Arctic continental shelf. We show that the concentration of radium-228, sourced to seawater through sediment-water exchange processes, has increased substantially in surface waters of the central Arctic Ocean over the past decade. A mass balance model for 228Ra suggests that this increase is due to an intensification of shelf-derived material inputs to the central basin, a source that would also carry elevated concentrations of dissolved organic carbon and nutrients. Therefore, we suggest that significant changes in the nutrient, carbon, and trace metal balances of the Arctic Ocean are underway, with the potential to affect biological productivity and species assemblages in Arctic surface waters.

54 ENVIRONMENTAL SCIENCES↗

Multidimensional risk in a nonstationary climate: Joint probability of increasingly severe warm and dry conditions

We present a framework for quantifying the spatial and temporal co-occurrence of climate stresses in a nonstationary climate. We find that, globally, anthropogenic climate forcing has doubled the joint probability of years that are both warm and dry in the same location (relative to the 1961–1990 baseline). In addition, the joint probability that key crop and pasture regions simultaneously experience severely warm conditions in conjunction with dry years has also increased, including high statistical confidence that human influence has increased the probability of previously unprecedented co-occurring combinations. Further, we find that ambitious emissions mitigation, such as that in the United Nations Paris Agreement, substantially curbs increases in the probability that extremely hot years co-occur with low precipitation simultaneously in multiple regions. Our methodology can be applied to other climate variables, providing critical insight for a number of sectors that are accustomed to deploying resources based on historical probabilities.

54 ENVIRONMENTAL SCIENCES↗

Climate change increases risk of extreme rainfall following wildfire in the western United States

Post-wildfire extreme rainfall events can have destructive impacts in the western United States. Using two climate model large ensembles, we assess the future risk of extreme fire weather events being followed by extreme rainfall in this region. By mid-21st century, in a high warming scenario (RCP8.5), we report large increases in the number of extreme fire weather events followed within 1 year by at least one extreme rainfall event. By 2100, the frequency of these compound events increases by 100% in California and 700% in the Pacific Northwest in the Community Earth System Model v1 Large Ensemble. We further project that more than 90% of extreme fire weather events in California, Colorado, and the Pacific Northwest will be followed by at least three spatially colocated extreme rainfall events within five years. Our results point to a future with substantially increased post-fire hydrologic risks across much of the western United States.

54 ENVIRONMENTAL SCIENCES↗

β-(1,3)-Glucan Unmasking in Some Candida albicans Mutants Correlates with Increases in Cell Wall Surface Roughness and Decreases in Cell Wall Elasticity

Candida albicans is among the most common human fungal pathogens, causing a broad range of infections, including life-threatening systemic infections. The cell wall of C. albicans is the interface between the fungus and the innate immune system. The cell wall is composed of an outer layer enriched in mannosylated glycoproteins (mannan) and an inner layer enriched in β-(1,3)-glucan and chitin. Detection of C. albicans by Dectin-1, a C-type signaling lectin specific for β-(1,3)-glucan, is important for the innate immune system to recognize systemic fungal infections. Increased exposure of β-(1,3)-glucan to the immune system occurs when the mannan layer is altered or removed in a process called unmasking. Nanoscale changes to the cell wall during unmasking were explored in this paper in live cells with atomic force microscopy (AFM). Two mutants, the cho1Δ/Δ and kre5Δ/Δ mutants, were selected as representatives that exhibit modest and strong unmasking, respectively. Comparisons of the cho1Δ/Δ and kre5Δ/Δ mutants to the wild type reveal morphological changes in their cell walls that correlate with decreases in cell wall elasticity. In addition, AFM tips functionalized with Dectin-1 revealed that the forces of binding of Dectin-1 to all of the strains were similar, but the frequency of binding was highest for the kre5Δ/Δ mutant, decreased for the cho1Δ/Δ mutant, and rare for the wild type. These data show that nanoscale changes in surface topology are correlated with increased Dectin-1 adhesion and decreased cell wall elasticity. Finally, AFM, using tips functionalized with immunologically relevant molecules, can map epitopes of the cell wall and increase our understanding of pathogen recognition by the immune system.

59 BASIC BIOLOGICAL SCIENCES↗

Gas spark switches with increased operating life for Marx generator of lightning test complex

A new design of gas spark switches with an increased operating life and stable dynamic characteristics for the Marx generator of the lightning test complex has been developed. The switches are characterized by the following parameters in the mode of operation: voltage up to 80 kV, discharge current up to 50 kA, flowing charge up to 3.5 C/pulse. An increased operating life is achieved by using torus-shaped electrodes with increased working surface area and a trigger electrode in the form of a thick disk with a hole located between them. Low breakdown delay time and high stability of breakdown voltage under dynamic conditions are provided by gas preionization in the spark gap using UV radiation of an additional corona discharge in the axial region.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Increasing Saturated Electron-Drift Velocity in Donor–Acceptor Doped pHEMT Heterostructures

Field dependences of the electron-drift velocity in typical pseudomorphic high-electron-mobility transistor (pHEMT) heteroepitaxial structures (HESs) and in those with donor–acceptor doped (DApHEMT) heterostructures with quantum-well (QW) depth increased by 0.8–0.9 eV with the aid of acceptor layers have been studied by a pulsed technique. It is established that the saturated electron-drift velocity in DA-pHEMT-HESs is 1.2–1.3 times greater than that in the usual pHEMT-HESs. The electroluminescence (EL) spectra of DA-pHEMT-HESs do not contain emission bands related to the recombination in widebandgap layers (QW barriers). The EL intensity in these HESs is not saturated with increasing electric field. This is indicative of a suppressed real-space transfer of hot electrons from QW to barrier layers, which accounts for the observed increase in the saturated electron-drift velocity.

77 NANOSCIENCE AND NANOTECHNOLOGY↗

Exposure and genetics increase risk of beryllium sensitisation and chronic beryllium disease in the nuclear weapons industry

Beryllium sensitisation (BeS) and chronic beryllium disease (CBD) are caused by exposure to beryllium with susceptibility affected by at least one well-studied genetic host factor, a glutamic acid residue at position 69 (E69) of the HLA-DPb chain (DPbE69). However, the nature of the relationship between exposure and carriage of the DPbE69 genotype has not been well studied. The goal of this study was to determine the relationship between DP{beta}E69 and exposure in BeS and CBD. Current and former workers (n=181) from a US nuclear weapons production facility, the Y-12 National Security Complex (Oak Ridge, Tennessee, USA), were enrolled in a case-control study including 35 individuals with BeS and 19 with CBD. HLA-DPB1 genotypes were determined by PCR-SSP. Beryllium exposures were assessed through worker interviews and industrial hygiene assessment of work tasks. After removing the confounding effect of potential beryllium exposure at another facility, multivariate models showed a sixfold (OR 6.06, 95% CI 1.96 to 18.7) increased odds for BeS and CBD combined among DP{beta}E69 carriers and a fourfold (OR 3.98, 95% CI 1.43 to 11.0) increased odds for those exposed over an assigned lifetime-weighted average exposure of 0.1 {micro}g/m{sup 3}. Those with both risk factors had higher increased odds (OR 24.1, 95% CI 4.77 to 122). DP{beta}E69 carriage and high exposure to beryllium appear to contribute individually to the development of BeS and CBD. Among workers at a beryllium-using facility, the magnitude of risk associated with either elevated beryllium exposure or carriage of DP{beta}E69 alone appears to be similar.

59 BASIC BIOLOGICAL SCIENCES↗

Hantavirus is Associated With Open Developed Areas and Arid Climates, Highlighting Increased Risk in the Western United States

In the United States, hantaviruses can cause hantavirus pulmonary syndrome (HPS) in humans, an acute respiratory illness with a high mortality rate. Most people contract HPS from exposure to infected rodent excrement. The interannual dynamics of hantavirus transmission are tied to both environmental and human-related factors, including changes in annual climate conditions, rodent populations, and the built environment in which humans are more likely to be exposed. Similar environmental conditions and socioeconomic factors also likely determine the long-term risk of hantavirus exposure. Here, we use ecological niche models and human cases of HPS in the U.S. from 1993 to 2022 to assess hantavirus risk using four socioeconomic variables, 17 land use variables, one variable of rodent richness, and seven climate variables to determine both the geographical locations of highest exposure risk and leading environmental predictors. We found that areas with higher relative risk tend to be where it is drier, higher social vulnerability, increased rodent richness, and more open to low levels of development—this largely mapped to the western U.S. We found evidence that fringe ecosystems may be important areas of hantavirus transmission, similar to other emerging diseases. Increased rodent richness was associated with increased hantavirus risk, warranting further investigation into how the abundance and community composition of rodents could impact long-term risk. These risk maps can help public health officials develop plans for mitigating hantavirus, especially for the most susceptible populations. They can also be used to further investigate regions estimated to be at high risk for hantavirus where disease cases have not been as common but may be underreported.

54 ENVIRONMENTAL SCIENCES↗

High-fat and high-carbohydrate diets increase bone fragility through TGF-β–dependent control of osteocyte function

Obesity can increase the risk of bone fragility, even when bone mass is intact. This fragility stems from poor bone quality, potentially caused by deficiencies in bone matrix material properties. However, cellular and molecular mechanisms leading to obesity-related bone fragility are not fully understood. Using male mouse models of obesity, we discovered TGF-β signaling plays a critical role in mediating the effects of obesity on bone. High-carbohydrate and high-fat diets increase TGF-β signaling in osteocytes, which impairs their mitochondrial function, increases cellular senescence, and compromises perilacunar/canalicular remodeling and bone quality. By specifically inhibiting TGF-β signaling in mouse osteocytes, some of the negative effects of high-fat and high-carbohydrate diets on bones, including the lacunocanalicular network, perilacunar/canalicular remodeling, senescence, and mechanical properties such as yield stress, were mitigated. DMP1-Cre–mediated deletion of TGF-β receptor II also blunted adverse effects of high-fat and high-carbohydrate diets on energy balance and metabolism. These findings suggest osteocytes are key in controlling bone quality in response to high-fat and high-carbohydrate diets. Calibrating osteocyte function could mitigate bone fragility associated with metabolic diseases while reestablishing energy balance.

59 BASIC BIOLOGICAL SCIENCES↗

Testing for the Possible Influence of Unknown Climate Forcings upon Global Temperature Increases from 1950-2000

Global-scale variations in the climate system over the last half of the twentieth century, including long-term increases in global-mean near-surface temperatures, are consistent with concurrent human-induced emissions of radiatively active gases and aerosols. However, such consistency does not preclude the possible influence of other forcing agents, including internal modes of climate variability or unaccounted for aerosol effects. To test whether other unknown forcing agents may have contributed to multidecadal increases in global-mean near-surface temperatures from 1950 to 2000, data pertaining to observed changes in global-scale sea surface temperatures and observed changes in radiatively active atmospheric constituents are incorporated into numerical global climate models. Results indicate that the radiative forcing needed to produce the observed long-term trends in sea surface temperatures—and global-mean near-surface temperatures—is provided predominantly by known changes in greenhouse gases and aerosols. Further, results indicate that less than 10% of the long-term historical increase in global-mean near-surface temperatures over the last half of the twentieth century could have been the result of internal climate variability. In addition, they indicate that less than 25%of the total radiative forcing needed to produce the observed long-term trend in global-mean near-surface temperatures could have been provided by changes in net radiative forcing from unknown sources (either positive or negative). These results, which are derived from simple energy balance requirements, emphasize the important role humans have played in modifying the global climate over the last half of the twentieth century.

Anderson, Bruce T↗

Responses in the Subpolar North Atlantic in Two Climate Model Sensitivity Experiments with Increased Stratospheric Aerosols

Abstract The subpolar North Atlantic (SPNA) shows contrasting responses in two sensitivity experiments with increased stratospheric aerosols, offering insight into the physical processes that may impact the Atlantic meridional overturning circulation (AMOC) in a warmer climate. In one, the upper ocean becomes warm and salty, but in the other it becomes cold and fresh. The changes are accompanied by diverging AMOC responses. The first experiment strengthens the AMOC, opposing the weakening trend in the reference simulation. The second experiment shows a much smaller impact. Both simulations use the Community Earth System Model with the Whole Atmosphere Community Climate Model component (CESM-WACCM) but differ in model versions and stratospheric aerosol specifications. Despite both experiments using similar approaches to increase stratospheric aerosols to counteract the rising global temperature, the contrasting SPNA and AMOC responses indicate a considerable dependency on model physics, climate states, and model responses to forcings. This study focuses on examining the physical processes involved with the impact of stratospheric aerosols on the SPNA salinity changes and their potential connections with the AMOC and the Arctic. We find that in both cases, increased stratospheric aerosols act to enhance the SPNA upper-ocean salinity by reducing freshwater export from the Arctic, which is closely tied to the Arctic sea ice changes. The impact on AMOC is primarily through the thermal component of the surface buoyancy fluxes, with negligible contributions from the freshwater component. These experiments shed light on the physical processes that dictate the important connections between the SPNA, the Arctic, the AMOC, and their subsequent feedbacks on the climate system.

54 ENVIRONMENTAL SCIENCES↗

Reinforcement learning applied to dilute combustion control for increased fuel efficiency

To reduce the modeling burden for control of spark-ignition engines, reinforcement learning (RL) has been applied to solve the dilute combustion limit problem. Q-learning was used to identify an optimal control policy to adjust the fuel injection quantity in each combustion cycle. A physics-based model was used to determine the relevant states of the system used for training the control policy in a data-efficient manner. The cost function was chosen such that high cycle-to-cycle variability (CCV) at the dilute limit was minimized while maintaining stoichiometric combustion as much as possible. Experimental results demonstrated a reduction of CCV after the training period with slightly lean combustion, contributing to a net increase in fuel conversion efficiency of 1.33%. To ensure stoichiometric combustion for three-way catalyst compatibility, a second feedback loop based on an exhaust oxygen sensor was incorporated into the fuel quantity controller using a slow proportional-integral (PI) controller. The closed-loop experiments showed that both feedback loops can cooperate effectively, maintaining stoichiometric combustion while reducing combustion CCV and increasing fuel conversion efficiency by 1.09%. Finally, a modified cost function was proposed to ensure stoichiometric combustion with a single controller. In addition, the learning period was shortened by half to evaluate the RL algorithm performance on limited training time. Experimental results showed that the modified cost function could achieve the desired CCV targets, however, the learning time was reduced by half and the fuel conversion efficiency increased only by 0.30%.

33 ADVANCED PROPULSION SYSTEMS↗

Elimination of hydrogenase active site assembly blocks H2 production and increases ethanol yield in Clostridium thermocellum

The native ability of Clostridium thermocellum to rapidly consume cellulose and produce ethanol makes it a leading candidate for a consolidated bioprocessing (CBP) biofuel production strategy. C. thermocellum also synthesizes lactate, formate, acetate, H2, and amino acids that compete with ethanol production for carbon and electrons. Elimination of H2 production could redirect carbon flux towards ethanol production by making more electrons available for acetyl-CoA reduction to ethanol. C. thermocellum encodes four hydrogenases and rather than delete each individually, we targeted a hydrogenase maturase gene (hydG), involved in converting the three [FeFe] hydrogenase apoenzymes into holoenzymes. Further deletion of the [NiFe] hydrogenase (ech) resulted in a mutant that functionally lacks all four hydrogenases. H2 production in hydG ech was undetectable and ethanol yield increased nearly 2-fold compared to wild type. Interestingly, mutant growth improved upon the addition of acetate, which led to increased expression of genes related to sulfate metabolism, suggesting these mutants may use sulfate as a terminal electron acceptor to balance redox reactions. Genomic analysis of hydG revealed a mutation in adhE, resulting in a strain with both NADH- and NADPH-dependent alcohol dehydrogenase activities. While this same adhE mutation is found in ethanol tolerant C. thermocellum strain E50C, hydG and hydG ech are not more ethanol tolerant than wild type, illustrating the complicated interactions between redox balancing and ethanol tolerance in C. thermocellum. The dramatic increase in ethanol production here suggests that targeting protein post-translational modification is a promising new approach for inactivation of multiple enzymes simultaneously for metabolic engineering.

09 BIOMASS FUELS↗

Progerin, the protein responsible for the Hutchinson-Gilford progeria syndrome, increases the unrepaired DNA damages following exposure to ionizing radiation

Introduction: Progerin, the protein responsible for the Hutchinson-Gilford Progeria Syndrome (HGPS), is a partially deleted form of nuclear lamin A, and its expression has been suggested as a cause for dysfunctional nuclear membrane and premature senescence. To examine the role of nuclear envelop architecture in regulating cellular aging and DNA repair, we used ionizing radiation to increase the number of DNA double strand breaks (DSBs) in normal and HGPS cells, and analyzed possible relationship between unrepaired DSBs and cellular aging. Results: We found that HGPS cells are normal in repairing a major fraction of radiation-induced double strand breaks (M-DSBs)but abnormal to show increased amount of residual unrepaired DSBs (R-DSBs). Such unrepaired DSBs were 2.6 times (CI 95 %: 2.2–3.2) higher than that in normal cells one week after the irradiation, and 1.6 times (CI 95 %: 1.3–1.9) higher even one month after the irradiation. These damages tend to increase as the nuclear envelope become abnormal, a characteristic of both HGPS and normal human cells which undergo replicative senescence. The artificial, enforced over-expression of progerin further impaired the repair of M-DSBs, implying lamin A-associated nuclear membrane has an important role for DNA DSB repair. Introduction of telomerase gene function in HGPS cells reversed such aging phenotypes along with upregulation of lamin B1 and downregulation of progerin, which is a hallmark of young cells. Conclusion: We suggest that lamin A- or progerin-associated nuclear envelope is involved in cellular aging associated with DNA damage repair.

59 BASIC BIOLOGICAL SCIENCES↗

Neoadjuvant Chemotherapy does not Increase Complications in Oncoplastic Breast-Conserving Surgery

Background: Oncoplastic breast-conserving surgery (OBCS) broadens the indications for breast conservation. Neoadjuvant systemic chemotherapy (NAC) is used increasingly in the treatment of patients with early-stage and locally advanced breast cancer. This study aimed to evaluate the outcomes for patients who received NAC followed by OBCS. Methods: A retrospective chart review was performed for all patients who underwent OBCS involving the mastopexy/breast-reduction technique, including synchronous mastopexy/breast reduction for symmetry, at the University of Texas MD Anderson Cancer Center between January 2010 and January 2016. Patients who had received NAC were compared with those who had undergone surgery first. Demographic, treatment, and outcomes data were collected. Results: The study included 429 patients, corresponding to 713 breasts. Of these patients, 122, corresponding to 199 breasts, received NAC. The patients who received NAC were younger (p < 0.001) and had a more advanced cancer stage (p < 0.001). The overall complication rate per patient was 25.9%, with major complications occurring in 9.1% of the patients. After adjustment for risk factors, NAC was not shown to be associated with an increased risk of complications or delayed adjuvant radiation therapy (p = 0.37), irrespective of the chemotherapy regimen used or whether the interval between NAC and surgery was 4 weeks or longer. Conclusions: In a high-volume center, OBCS can be performed safely for carefully selected patients after NAC without an increased risk of complications or delayed adjuvant radiation therapy. An interval of at least 4 weeks between completion of NAC and surgery can be regarded as safe irrespective of the chemotherapy regimen used.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

Data for Soil Fertility Management for Sustainable Miscanthus × giganteus Production: Increased Tiller Weight from Nitrogen Management Explains Yield Gains in Aged Miscanthus

Aging-related yield decline in Miscanthus × giganteus (miscanthus) remains a major constraint to sustainable biomass production. This study evaluated how nitrogen (N) management and soil fertility influence yield-component traits and productivity in aging miscanthus. Trials were conducted at two sites established in 2008 at the University of Illinois Energy Farm, Urbana, IL. (i) The Sun Grant trial received 0, 60, and 120 kg N ha−1 annually until 2015. Starting 2021, half of each plot received 60 or 120 kg N ha−1, resulting in six legacy-contemporary treatments: 0N–0N, 0N–120N, 60N–0N, 60N–60N, 120N–0N, 120N–120N. (ii) The Energy Farm trial remained unfertilized until 2014, when one half of each plot received 56 kg N ha−1, forming two treatments: 0N–0N, 0N–56N. Sun Grant trial results showed N fertilization increased tiller density (tillers m−2) and tiller weight (g tiller−1) in juvenile to early-mature miscanthus (2011–2015). After N withdrawal, both traits declined (20 % and 40 %), though legacy effects persisted in tiller weight in the aging stands (2020–2023). Contemporary N had little effect on tiller density but increased tiller weight by 34 %–77 %, resulting in 23 %–106 % higher machine-harvested biomass yield in 0–120N, 60-60N, and 120-120N plots. At the Energy Farm trial, 0N–56N plots yielded 59 %–108 % more biomass than 0N–0N. Soil total N increased (Sun Grant: 47 % by 2020; Energy Farm: 58 % by 2023), while Mehlich-3 P (42 %–44 %) and K (21 %–46 %) declined. These findings identify tiller weight as a key determinant of biomass yield in aging miscanthus and highlight the need for P and K management for long-term productivity.

miscanthus↗

Historical review and proof-of-concept future method demonstration of adaptive mesh refinement in nuclear engineering for increased fidelity and computational efficiency

As the nuclear industry's use of computational tool increases, the need for increased fidelity and computational efficiency is well known. While most approaches to increased fidelity rely on applying a fine mesh over the problem domain, a more efficient method is to apply an adaptive mesh refinement (AMR) algorithm to the mesh definition. In the field of nuclear engineering, AMR has previously been used in conjunction with deterministic methods, including: S{sub N} transport methods, Lattice Boltzmann Methods, and COMSOL. The future of AMR in nuclear engineering is to couple it to a Monte Carlo code with the goal of reducing calculation time. A proof-of-concept example yielded positive results for using the gradient of the flux as a refinement criteria. The refinement criteria was varied from 0.01 to 0.10, which yielded a recommended range of 0.01 to 0.04, and the number of refinement iterations was varied from 0 to 7, with diminishing returns seen after 5 iterations. After the success of the proof-of-concept exercise, work began on creating a full program coupling MCNP6.2 and the AMR algorithm in the deal.II library. (authors)

22 GENERAL STUDIES OF NUCLEAR REACTORS↗