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Chemical reaction enhanced graph learning for molecule representation

Abstract Motivation Molecular representation learning (MRL) models molecules with low-dimensional vectors to support biological and chemical applications. Current methods primarily rely on intrinsic molecular information to learn molecular representations, but they often overlook effectively integrating domain knowledge into MRL. Results In this article, we develop a reaction-enhanced graph learning (RXGL) framework for MRL, utilizing chemical reactions as domain knowledge. RXGL introduces dual graph learning modules to model molecule representation. One module employs graph convolutions on molecular graphs to capture molecule structures. The other module constructs a reaction-aware graph from chemical reactions and designs a novel graph attention network on this graph to integrate reaction-level relations into molecular modeling. To refine molecule representations, we design a reaction-based relation learning task, which considers the relations between the reactant and product sides in reactions. In addition, we introduce a cross-view contrastive task to strengthen the cooperative associations between molecular and reaction-aware graph learning. Experiment results show that our RXGL achieves strong performance in various downstream tasks, including product prediction, reaction classification, and molecular property prediction. Availability and implementation The code is publicly available at https://github.com/coder-ACAC/RLM.

Biochemistry & Molecular Biology

Rapid organic carbon spiraling in a headwater stream linked with streamflow, biogeochemistry, and canopy phenology

Headwater streams are abundant worldwide and important to global biogeochemical cycles, serving as critical processors and transporters of C. C spiraling is a useful way to understand the retention and mineralization of organic C (OC) in streams. However, analyses of seasonal and interannual variability in OC spiraling are currently limited. In this study, we aimed to understand the temporal patterns and driving mechanisms of OC spiraling, which will inform our understanding of future OC changes under climate change. We used 7 y of daily data in a small headwater stream (Walker Branch, Tennessee, USA) to assess seasonal and interannual variability in OC spiraling length (S OC ) and mineralization velocity (v fOC ), as well as their potential related variables. On average, S OC in Walker Branch was ~10× shorter than in previously studied small streams, indicating strong connections between the water column and the benthic environment where OC mineralization mostly takes place. OC spiraling was faster during the more biologically active periods of spring and autumn compared with more elongated OC spiraling in summer and winter, when OC retention was lower and downstream transport was higher. Gross primary production (GPP) was most strongly related to S OC and v fOC . Photosynthetically active radiation (PAR) and NO 3 − were also positively and negatively related to v fOC , respectively. Trends toward earlier and longer canopy cover and reduced GPP and PAR may result in longer S OC and slower v fOC , reducing localized instream processing of OC and potentially shunting more OC downstream. However, long-term observations indicate reduced NO 3 − at Walker Branch, suggesting opposing effects to those of GPP and PAR, leading to faster v fOC and greater OC retention. Time-series analyses of OC spiraling in streams can enhance our understanding of current and future responses of OC processing and downstream transport to climate change, as well as implications for downstream OC dynamics.

biological activity

High-throughput protein characterization by complementation using DNA barcoded fragment libraries

Abstract Our ability to predict, control, or design biological function is fundamentally limited by poorly annotated gene function. This can be particularly challenging in non-model systems. Accordingly, there is motivation for new high-throughput methods for accurate functional annotation. Here, we used co mplementation of aux otrophs and DNA barcode seq uencing (Coaux-Seq) to enable high-throughput characterization of protein function. Fragment libraries from eleven genetically diverse bacteria were tested in twenty different auxotrophic strains of Escherichia coli to identify genes that complement missing biochemical activity. We recovered 41% of expected hits, with effectiveness ranging per source genome, and observed success even with distant E. coli relatives like Bacillus subtilis and Bacteroides thetaiotaomicron . Coaux-Seq provided the first experimental validation for 53 proteins, of which 11 are less than 40% identical to an experimentally characterized protein. Among the unexpected function identified was a sulfate uptake transporter, an O-succinylhomoserine sulfhydrylase for methionine synthesis, and an aminotransferase. We also identified instances of cross-feeding wherein protein overexpression and nearby non-auxotrophic strains enabled growth. Altogether, Coaux-Seq’s utility is demonstrated, with future applications in ecology, health, and engineering.

59 BASIC BIOLOGICAL SCIENCES

Bioindicator “fingerprints” of methane-emitting thermokarst features in Alaskan soils

Permafrost thaw increases the bioavailability of ancient organic matter, facilitating microbial metabolism of volatile organic compounds (VOCs), carbon dioxide, and methane (CH 4 ). The formation of thermokarst (thaw) lakes in icy, organic-rich Yedoma permafrost leads to high CH 4 emissions, and subsurface microbes that have the potential to be biogeochemical drivers of organic carbon turnover in these systems. However, to better characterize and quantify rates of permafrost changes, methods that further clarify the relationship between subsurface biogeochemical processes and microbial dynamics are needed. In this study, we investigated four sites (two well-drained thermokarst mounds, a drained thermokarst lake, and the terrestrial margin of a recently formed thermokarst lake) to determine whether biogenic VOCs (1) can be effectively collected during winter, and (2) whether winter sampling provides more biologically significant VOCs correlated with subsurface microbial metabolic potential. During the cold season (March 2023), we drilled boreholes at the four sites and collected cores to simultaneously characterize microbial populations and captured VOCs. VOC analysis of these sites revealed “fingerprints” that were distinct and unique to each site. Total VOCs from the boreholes included > 400 unique VOC features, including > 40 potentially biogenic VOCs related to microbial metabolism. Subsurface microbial community composition was distinct across sites; for example, methanogenic archaea were far more abundant at the thermokarst site characterized by high annual CH 4 emissions. The results obtained from this method strongly suggest that ∼10% of VOCs are potentially biogenic, and that biogenic VOCs can be mapped to subsurface microbial metabolisms. By better revealing the relationship between subsurface biogeochemical processes and microbial dynamics, this work advances our ability to monitor and predict subsurface carbon turnover in Arctic soils.

anaerobic degradation

Solvent selection for a biomass-to-bioproduct pipeline through integrated reductive catalytic fractionation and microbial funneling

The growing significance of lignin-first biorefineries, which focus on upgrading the aromatics resulting from lignin depolymerization, presents opportunities for bioproduct synthesis using microbial strains capable of funneling a diverse array of phenolics into a single commodity chemical. In this study, we evaluated a biomass-to-bioproduct pipeline involving the reductive catalytic fractionation (RCF) of poplar biomass followed by biological funneling with a Novosphingobium aromaticivorans strain that produces 2-pyrone-4,6-dicarboxylic acid (PDC), a potential bioplastic precursor. Considering the impact of solvent on RCF reactor operating pressure, and the potential inhibitory effects of solvent on downstream microbial funneling, we performed an analysis of six pure solvents, namely methanol, ethanol, isopropanol, isobutanol, 1,4-dioxane and ethylene glycol, and different variations of their aqueous mixtures comprising 5 to 50 vol% water. For each pure solvent and solvent/water system, we measured phenolic monomer yields in the RCF process and PDC yields from the phenolic monomers. We then developed correlation models that relate phenolic monomer yields from RCF-derived samples to Hansen solubility parameters to determine solvent descriptors that contribute to high yields. Furthermore, we developed an integrated biorefinery system to estimate the minimum selling price (MSP) of PDC and the associated carbon footprint to identify solvent systems with better costs and sustainability metrics. These analyses resulted in the 50 vol% methanol/water system being identified as optimal because it reduces RCF reactor pressure and is compatible with microbial funneling with N. aromaticivorans. This solvent system produced 63 g PDC per kg biomass (264 g PDC per kg lignin) from 85 g phenolic monomers per kg biomass at a reduced reactor pressure of 48 bar (reduced by 26% compared to our previous poplar-to-PDC pipeline). The MSP for this system is $\$$13.98 per kg of purified PDC (carbon footprint of 1.47 kg CO 2 e per kg), which is about 24% lower than a previously described poplar-to-PDC pipeline and 46% lower than a lignin-to-PDC pipeline that used pure methanol as the solvent. The results from this study illustrate improvements that can be made in lignocellulosic biorefineries that are compatible with the hybrid chemical and biological processes needed to gain value from lignin.

Sripada, Sarada [Great Lakes Bioenergy Research Ce

Reduced Erosion Augments Soil Carbon Storage Under Cover Crops

ABSTRACT Cover crops, a promising strategy to increase soil organic carbon (SOC) storage in croplands and mitigate climate change, have typically been shown to benefit soil carbon (C) storage from increased plant C inputs. However, input‐driven C benefits may be augmented by the reduction of C outputs induced by cover crops, a process that has been tested by individual studies but has not yet been synthesized. Here we quantified the impact of cover crops on organic C loss via soil erosion (SOC erosion) and revealed the geographical variability at the global scale. We analyzed the field data from 152 paired control and cover crop treatments from 57 published studies worldwide using meta‐analysis and machine learning. The meta‐analysis results showed that cover crops widely reduced SOC erosion by an average of 68% on an annual basis, while they increased SOC stock by 14% (0–15 cm). The absolute SOC erosion reduction ranged from 0 to 18.0 Mg C −1 ha −1 year −1 and showed no correlation with the SOC stock change that varied from −8.07 to 22.6 Mg C −1 ha −1 year −1 at 0–15 cm depth, indicating the latter more likely related to plant C inputs. The magnitude of SOC erosion reduction was dominantly determined by topographic slope. The global map generated by machine learning showed the relative effectiveness of SOC erosion reduction mainly occurred in temperate regions, including central Europe, central‐east China, and Southern South America. Our results highlight that cover crop‐induced erosion reduction can augment SOC stock to provide additive C benefits, especially in sloping and temperate croplands, for mitigating climate change.

Huang, Wenjuan [Department of Ecology, Evolution,

Nuclear Safety [Vol. 36, No. 2, July-December 1995]

Nuclear Safety is a journal that covers significant issues in the field of nuclear safety. Its primary scope is safety in the design, construction, operation, and decommissioning of nuclear power reactors worldwide and the research and analysis activities that promote this goal, but it also encompasses the safety aspects of the entire nuclear fuel cycle, including fuel fabrication, spent-fuel processing and handling, and nuclear waste disposal, the handling of fissionable materials and radioisotopes, and the environmental effects of all these activities. Table of Contents for this issue follows. THE CHORNOBYL ACCIDENT: 195 The Chornobyl Accident Revisited, Part III: Chernobyl Source Term Release Dynamics and Reconstruction of Events During the Active Phase, A. R. Sich; GENERAL SAFETY CONSIDERATIONS: 218 Second ANS Workshop on the Safety of Soviet-Designed Nuclear Power Plants, R. A. Bari; 234 Elements of a Nuclear Criticality Safety Program, C. M. Hopper; 243 Rickover, Excellence, and Criticality Safety Programs, R. E. Wilson; ACCIDENT ANALYSIS: 249 Transient Analysis of the PIUS Advanced Reactor Design with the TRAC-PF1/MOD2 Code, B. E. Boyack, J. L Steiner, S. C. Harmony, H. J. Stumpf, and J. F. Lime; 278 The Hierarchy-By-Interval Approach to Identifying Important Models that Need Improvement in Severe-Accident Simulation Codes, T. J. Heames, M. Khatib-Rahbar, J. E. Kelly, R. P. Jenks-Johnson, and Y.-S. Chen; 290 RELAP5/MOD3 Code Coupling Model, R. P. Martin; 299 Missiles Caused by Severe Pressurized-Water Reactor Accidents, R. Krieg; DESIGN FEATURES: 310 Validation of COMMIX with Westinghouse AP-600 PCCS Test Data, J. G. Sun, T. H. Chien, J. Ding, and W T. Sha; ENVIRONMENTAL EFFECTS: 321 Spent Nuclear Fuel Characterization for a Bounding Reference Assembly for the Receiving Basin for Off-Site Fuel, S. D. Kahook, R. L. Garrett, L. R. Canas, and M J. Beckum; OPERATING EXPERIENCES: 332 Reactor Shutdown Experience, Compiled by J. W. Cletcher; U.S. NUCLEAR REGULATORY COMMISSION INFORMATION AND ANALYSES: 335 Reactor Coolant System Blowdown at Wolf Creek on September 17, 1994, J. V. Kauffman and S. L. Israel; RECENT DEVELOPMENTS: 344 Reports, Standards, and Safety Guides, D. S. Oueener; 349 Proposed Rule Changes as of June 30, 1995; ANNOUNCEMENTS: 320 Symposium on Acceptability of Risk From Radiation—Application to Manned Space Flight; 320 24th DOE/NRC Nuclear Air Cleaning and Treatment Conference; 361 Radiation Biology and Radiation Protection— Modern Developments and Tendencies in Radiation Biology; 362 1997 IEEE Sixth Conference on Human Factors and Power Plants; 354 The Authors; 360 Reviewers of Nuclear Safety, Vol. 36.

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS

Integrative analysis of CAM photosynthesis reveals its impact on primary metabolism in Yucca

Crassulacean Acid Metabolism (CAM) is an adaptation that temporally separates carbon uptake at night from photosynthesis during the day. CAM has evolved repeatedly across vascular plants, as its emergence may depend on simple regulatory changes to deeply conserved metabolic pathways. Modern CAM research relies heavily on interpretation of transcriptomic data, though regulation occurs at multiple levels following transcription. Additionally, while most research to date has focused on a handful of genes and metabolites in the core CAM pathway, the co-option of conserved regulatory and functional genes is bound to have wide-ranging effects on other aspects of primary metabolism. In this study, we integrate transcriptomic, proteomic, and metabolomic data to compare primary metabolism between the CAM species Yucca aloifolia and closely related C 3 species, Y. filamentosa. We observe minimal correlation between protein abundance and mRNA expression, suggesting significant post-transcriptional regulation in CAM species. We also find evidence of shifts in gene expression and metabolite accumulation outside of the central CAM pathway, suggesting that the shift to CAM has cascading effects across primary metabolism, especially nitrogen metabolism. Our findings provide insights into the metabolic shifts associated with CAM evolution, and highlight the complexity of its regulation at multiple biological levels.

59 BASIC BIOLOGICAL SCIENCES

Rhamnogalacturonan I is a recalcitrant pectin domain during Clostridium thermocellum -mediated deconstruction of switchgrass biomass

Background Liquid fuels from lignocellulosic feedstocks are required for transition to a sustainable bioeconomy. However, the recalcitrance of carbon-containing feedstock cell walls to deconstruction poses a barrier to cost effective biological conversion of plant biomass to biofuels. One-step consolidated bioprocessing (CBP) in which anaerobic thermophilic bacteria convert lignocellulosic biomass into liquid fuels is a platform for overcoming the recalcitrance of plant biomass. Results The amounts of hemicellulosic and pectic polysaccharides, two complex cell wall glycans that contribute to plant biomass recalcitrance and that are partially solubilized during CBP of switchgrass aerial biomass by Clostridium thermocellum were evaluated in the liquor, solid residues and residue washate recovered during a 120-h CBP process. After 120 h, 24% of milled switchgrass was solubilized in the C. thermocellum CBP platform. Higher concentrations of arabinose, xylose, galactose, and glucose accumulated in the CBP-fermentation liquor and washate compared to fermentation controls without C. thermocellum, indicating that C. thermocellum solubilized hemicelluloses, but did not fully metabolize them. After five days of fermentation, the relative amount of rhamnose in the solid residues increased by 16% compared to controls, and CBP solid residues had more than 23% increased reactivity against RG-I reactive monoclonal antibodies, indicating that the pectic polymer rhamnogalacturonan I (RG-I) was not effectively solubilized from switchgrass biomass by C. thermocellum CBP. Similarly, the amount of mannose (Man) in the CBP solid residues increased by 7% and reactivity against galactomannan reactive antibodies increased by greater than 14%, indicating that the hemicellulosic polymer galactomannan was also resistant to degradation by C. thermocellum during CBP fermentation. Conclusions These findings show that C. thermocellum is unable to effectively degrade RG-I pectic and galactomannan hemicellulosic components in switchgrass biomass. Targeting these polymers for improved solubilization could enhance the efficiency of conversion of grass biomass to biofuels.

09 BIOMASS FUELS

A directional electrode separator improves anodic biofilm current density in a well-mixed single-chamber bioelectrochemical system

In this study, a directional electrode separator (DES) was designed and incorporated into a single-chamber bioelectrochemical system (BES) to reduce migration and reoxidation of hydrogen. This issue arises when H 2 , generated at the cathode, travels to the anode where anodic biofilms use H 2 . To test the feasibility of our design, a 3D-printed BES reactor equipped with a DES was inoculated with anaerobic digestor granules and operated under fed-batch conditions using fermented corn stover effluent. The DES equipped reactor achieved significantly higher current densities (~53 A/m²) compared to a conventional single-chamber BES without a separator (~16 A/m²), showing a 3.3 times improvement. Further, control abiotic electrochemical experiments revealed that the DES exhibited significantly higher proton conductivity (456±127 µS/mm) compared to a proton exchange membrane (67±21 µS/mm) with a statistical significance of P=0.03. The DES also effectively reduced H 2 migration to the anode by 21-fold relative to the control. Overall, incorporating a DES in a single-chamber BES enhanced anodic current density by reducing H 2 migration to the anode.

3D printed BES

Insight into molecular basis and dynamics of full-length CRaf kinase in cellular signaling mechanisms

Raf kinases play key roles in signal transduction in cells for regulating proliferation, differentiation, and survival. Despite decades of research into functions and dynamics of Raf kinases with respect to other cytosolic proteins, understanding Raf kinases is limited by the lack of their full-length structures at the atomic resolution. Here, we present the first model of the full-length CRaf kinase obtained from artificial intelligence/machine learning algorithms with a converging ensemble of structures simulated by large-scale temperature replica exchange simulations. Our model is validated by comparing simulated structures with the latest cryo-EM structure detailing close contacts among three key domains and regions of the CRaf. Our simulations identify potentially new epitopes of intramolecule interactions within the CRaf and reveal a dynamical nature of CRaf kinases, in which the three domains can move back and forth relative to each other for regulatory dynamics. The dynamic conformations are then used in a docking algorithm to shed insight into the paradoxical effect caused by vemurafenib in comparison with a paradox breaker PLX7904. In this study, we propose a model of Raf-heterodimer/KRas-dimer as a signalosome based on the dynamics of the full-length CRaf.

59 BASIC BIOLOGICAL SCIENCES

Nuclear Safety [Vol. 36, No. 2, July-December 1995]

Nuclear Safety is a journal that covers significant issues in the field of nuclear safety. Its primary scope is safety in the design, construction, operation, and decommissioning of nuclear power reactors worldwide and the research and analysis activities that promote this goal, but it also encompasses the safety aspects of the entire nuclear fuel cycle, including fuel fabrication, spent-fuel processing and handling, and nuclear waste disposal, the handling of fissionable materials and radioisotopes, and the environmental effects of all these activities. Table of Contents for this issue follows. THE CHORNOBYL ACCIDENT: 195 The Chornobyl Accident Revisited, Part III: Chernobyl Source Term Release Dynamics and Reconstruction of Events During the Active Phase, A. R. Sich; GENERAL SAFETY CONSIDERATIONS: 218 Second ANS Workshop on the Safety of Soviet-Designed Nuclear Power Plants, R. A. Bari; 234 Elements of a Nuclear Criticality Safety Program, C. M. Hopper; 243 Rickover, Excellence, and Criticality Safety Programs, R. E. Wilson; ACCIDENT ANALYSIS: 249 Transient Analysis of the PIUS Advanced Reactor Design with the TRAC-PF1/MOD2 Code, B. E. Boyack, J. L Steiner, S. C. Harmony, H. J. Stumpf, and J. F. Lime; 278 The Hierarchy-By-Interval Approach to Identifying Important Models that Need Improvement in Severe-Accident Simulation Codes, T. J. Heames, M. Khatib-Rahbar, J. E. Kelly, R. P. Jenks-Johnson, and Y.-S. Chen; 290 RELAP5/MOD3 Code Coupling Model, R. P. Martin; 299 Missiles Caused by Severe Pressurized-Water Reactor Accidents, R. Krieg; DESIGN FEATURES: 310 Validation of COMMIX with Westinghouse AP-600 PCCS Test Data, J. G. Sun, T. H. Chien, J. Ding, and W T. Sha; ENVIRONMENTAL EFFECTS: 321 Spent Nuclear Fuel Characterization for a Bounding Reference Assembly for the Receiving Basin for Off-Site Fuel, S. D. Kahook, R. L. Garrett, L. R. Canas, and M J. Beckum; OPERATING EXPERIENCES: 332 Reactor Shutdown Experience, Compiled by J. W. Cletcher; U.S. NUCLEAR REGULATORY COMMISSION INFORMATION AND ANALYSES: 335 Reactor Coolant System Blowdown at Wolf Creek on September 17, 1994, J. V. Kauffman and S. L. Israel; RECENT DEVELOPMENTS: 344 Reports, Standards, and Safety Guides, D. S. Oueener; 349 Proposed Rule Changes as of June 30, 1995; ANNOUNCEMENTS: 320 Symposium on Acceptability of Risk From Radiation—Application to Manned Space Flight; 320 24th DOE/NRC Nuclear Air Cleaning and Treatment Conference; 361 Radiation Biology and Radiation Protection— Modern Developments and Tendencies in Radiation Biology; 362 1997 IEEE Sixth Conference on Human Factors and Power Plants; 354 The Authors; 360 Reviewers of Nuclear Safety, Vol. 36.

05 NUCLEAR FUELS

What more can be done with XPS? Highly informative but underused approaches to XPS data collection and analysis

Because of the importance of surfaces and interfaces in many scientific and technological areas, the use of x-ray photoelectron spectroscopy (XPS) has been growing exponentially. Although XPS is being used to obtain useful information about the surface composition of samples, much more information about materials and their properties can be extracted from XPS data than commonly obtained. This paper describes some of the areas where alternative analysis methods or experimental design can obtain information about the near-surface region of a sample, often information not available in other ways. Experienced XPS analysts are familiar with many of these methods, but they may not be known to new or casual XPS users, and sometimes, they have not been used because of an inappropriately assumed complexity. The information available includes optical, electronic, and electrical properties; nanostructure; expanded chemical information; and enhanced analysis of biological materials and solid/liquid interfaces. Many of these analyses can be conducted on standard laboratory XPS systems, with either no or relatively minor system alterations. Topics discussed include (1) considerations beyond the “traditional” uniform surface layer composition calculation, (2) using the Auger parameter to determine a sample property, (3) use of the D parameter to identify sp 2 and sp 3 carbon information, (4) information from the XPS valence band, (5) using cryocooling to expand range of samples that can be analyzed and minimize damage, and (6) using electrical potential effects on XPS signals to extract chemically resolved electrical measurements including band alignment and electrical property information.

Baer, Donald R. [Pacific Northwest National Labora

Cooperative effect of local active stresses on the macroscopic contractility of elastic fiber networks

The collective action of actively contractile units embedded in elastic biopolymer networks plays a crucial role in regulating the network's macroscopic mechanical response. Here, in this study, we investigate how the macroscopic boundary stress in model elastic fiber networks depends on the number and nature of embedded contractile units, each exerting an isotropic force dipole, as well as on the bending stiffness of fibers. We find that the macroscopic stress increases nonlinearly with the number of dipoles due to mutual stiffening of initially soft, bending-dominated networks. Using effective medium theory, we relate this enhanced contractility to an increase in the effective average network coordination number due to constraints imposed by the force dipoles. By comparing three distinct force dipole models that differ in their local structures, we demonstrate that the specific manner in which an active unit constrains the network strongly influences the onset and nature of the stiffening transition. Our results highlight that not only the quantity but also the local geometry of force-generating units critically determines the macroscopic mechanical behavior. This framework provides a physical basis for understanding how biological systems—such as molecular motors in the cytoskeleton, or adherent cells in the extracellular matrix—can modulate network-scale nonlinear elastic properties through local tuning of active force-generating units.

Biological and medical sciences

Incorporating the molecular-scale into a hydrodynamic description of confined aqueous systems

Hydrodynamics provides a continuum-level description of fluid motion, but its applicability at the nanoscale becomes uncertain due to the emerging importance of molecular-level effects such as spatial heterogeneity. Hydrodynamic boundary conditions that incorporate molecular details allow us to partition the system into a near-wall region and a bulk fluid region. We identify a hydrodynamic wall located inside the fluid that determines where slip begins. By extending the hydrodynamic wall with the slip length, the position of the extrapolated wall is established. This offers a unified description of both slip and stagnant flow behaviors, with wall hydrophobicity characterized by the relative location of the extrapolated wall with respect to the physical wall. Employing this concept in analyses of equilibrium molecular dynamics (MD) and non-equilibrium MD simulations of Couette and Poiseuille flows, our results demonstrate consistency between equilibrium and non-equilibrium approaches across different flow types and confinement levels. This demonstrates the robust nature of linear response theory. We then explore the effects of fluid-wall and bulk fluid interactions on the hydrodynamic properties. These findings enhance the effectiveness of molecular-based simulations for investigating complex confined systems in nanofluidics, biology, and colloidal science, offering a complementary molecular-scale perspective to traditional continuum approaches.

flow simulations

A multiscale model of the action of a capsid assembly modulator for the treatment of chronic hepatitis B

Chronic hepatitis B virus (HBV) infection is strongly associated with increased risk of liver cancer and cirrhosis. While existing treatments effectively inhibit the HBV life cycle, viral rebound frequently occurs following treatment interruption. Consequently, functional cure rates of chronic HBV infection remain low and there is increased interest in a novel treatment modality, capsid assembly modulators (CAMs). Here, we develop a multiscale mathematical model of CAM treatment in chronic HBV infection. By fitting the model to participant data from a phase I trial of the first-generation CAM vebicorvir, we estimate the drug’s dose-dependent effectiveness and identify the physiological mechanisms that drive the observed biphasic decline in HBV DNA and RNA, and mechanistic differences between HBeAg-positive and negative infection. Finally, we demonstrate analytically and numerically that the relative change of HBV RNA more accurately reflects the antiviral effectiveness of a CAM than the relative change in HBV DNA.

59 BASIC BIOLOGICAL SCIENCES

Novel CHI3L1 ‐Associated Angiogenic Phenotypes Define Glioma Microenvironments: Insights From Multi‐Omics Integration

ABSTRACT The CHI3L1 signaling pathway significantly influences glioma angiogenesis, but its role in the tumor microenvironment (TME) remains elusive. We propose a novelCHI3L1‐associated vascular phenotype classification for glioma through integrative analyses of multiple datasets with bulk and single‐cell transcriptome, genomics, digital pathology, and clinical data. We investigated the biological characteristics, genomic alterations, therapeutic vulnerabilities, and immune profiles within these phenotypes through a comprehensive multi‐omics approach. We constructed the vascular‐related risk (VR) score based onCHI3L1‐associated vascular signatures (CAVS) identified by machine learning algorithms. Utilizing unsupervised consensus clustering, gliomas were stratified into three distinct vascular phenotypes: Cluster A, marked by high vascularization and stromal activation with a relatively low levels of tumor‐infiltrating lymphocytes (TILs); Cluster B, characterized by moderate vascularization and stromal activity, coupled with a high density of TILs; and Cluster C, defined by low vascularization and sparse immune cell infiltration. We observed that the CAVS effectively indicated glioma‐associated angiogenesis and immune suppression by single‐cell RNA‐seq analysis. Moreover, the high‐VR‐score group exhibited enhanced angiogenic activity, reduced immune response, resistance to immunotherapy, and poorer clinical outcomes. The VR score independently predicted glioma prognosis and, combined with a nomogram, provided a robust clinical decision‐making tool. Potential drug prediction based on transcription factors for high‐risk patients was also performed. Our study reveals thatCHI3L1‐associated vascular phenotypes shape distinct immune landscapes in gliomas, offering insights for optimizing therapeutic strategies to improve patient outcomes.

Oncology