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Experimental study on gas permeability and radon control performance of red clay covering layer on uranium mill tailings pond
Dynamic investigation of hypoxia-induced L-lactylation
The recently identified histone modification lysine lactylation can be stimulated by L-lactate and glycolysis. Although the chemical group added upon lysine lactylation was originally proposed to be the L-enantiomer of lactate (K L-la ), two isomeric modifications, lysine D-lactylation (K D-la ) and N-ε-(carboxyethyl) lysine (K ce ), also exist in cells, with their precursors being metabolites of glycolysis. The dynamic regulation and differences among these three modifications in response to hypoxia remain poorly understood. In this study, we demonstrate that intracellular K L-la , but not K D-la or K ce , is up-regulated in response to hypoxia. Depletion of glyoxalase enzymes, GLO1 and GLO2, had minimal impact on K D-la , K ce , or hypoxia-induced K L-la . Conversely, blocking glycolytic flux to L-lactate under hypoxic conditions by knocking out lactate dehydrogenase A/B completely abolished the induction of K L-la but increased K D-la and K ce . We further observed a correlation between the level of K L-la and hypoxia-inducible factor 1 alpha (HIF-1α) expression under hypoxic conditions and when small molecules were used to stabilize HIF-1α in the normoxia condition. Our result demonstrated that there is a strong correlation between HIF-1α and K L-la in lung cancer tissues and that patient samples with higher grade tend to have higher K L-la levels. Using a proteomics approach, we quantified 66 K L-la sites that were up-regulated by hypoxia and demonstrated that p300/CBP contributes to hypoxia-induced K L-la . Collectively, our study demonstrates that K L-la , rather than K D-la or K ce , is the prevailing lysine lactylation in response to hypoxia. Our results therefore demonstrate a link between K L-la and the hypoxia-induced adaptation of tumor cells.
Enhancing energy efficiency in buildings using sawdust-based insulation in hot arid climates
Brain aging shows nonlinear transitions, suggesting a midlife “critical window” for metabolic intervention
Understanding the key drivers of brain aging is essential for effective prevention and treatment of neurodegenerative diseases. Here, we integrate human brain and physiological data to investigate underlying mechanisms. Functional MRI analyses across four large datasets (totaling 19,300 participants) show that brain networks not only destabilize throughout the lifetime but do so along a nonlinear trajectory, with consistent temporal “landmarks” of brain aging starting in midlife (40s). Comparison of metabolic, vascular, and inflammatory biomarkers implicate dysregulated glucose homeostasis as the driver mechanism for these transitions. Correlation between the brain’s regionally heterogeneous patterns of aging and gene expression further supports these findings, selectively implicating GLUT4 (insulin-dependent glucose transporter) and APOE (lipid transport protein). Notably, MCT2 (a neuronal, but not glial, ketone transporter) emerges as a potential counteracting factor by facilitating neurons’ energy uptake independently of insulin. Consistent with these results, an interventional study of 101 participants shows that ketones exhibit robust effects in restabilizing brain networks, maximized from ages 40 to 60, suggesting a midlife “critical window” for early metabolic intervention.
A general tribo-dynamic model for lubricated clearance joints in spatial multibody systems
Dynamic and context-dependent keystone species effects in kelp forests
Sea otters are an iconic keystone predator that can maintain kelp forests by preying on grazing invertebrates such as sea urchins. However, the effects of sea otters on kelp forests vary over their geographic range. Here, we analyze two 30-y datasets on kelp forest communities during the reintroduction of sea otters along the west coast of Vancouver Island, BC, Canada, and around San Nicolas Island, CA. We developed a community model to estimate species interactions as dynamic rates, varying with community state. We find evidence of a classic trophic cascade off Vancouver Island; the arrival of otters quickly led to depletion of urchins and recovery of kelp. However, this cascade was muted around San Nicolas Island, with otters, urchins, and kelp all coexisting at intermediate densities for multiple years. Our models show that this difference came from a pulse of strong otter impacts on urchins following recolonization off Vancouver Island, but not off San Nicolas Island. The mean effects of otters on urchins and urchins on kelp were not stronger in the north, indicating that interaction dynamics and not average interaction strength are key to explaining differences in community trajectories. We also find stronger multistep interaction chains in the south, arising from competitive interactions that indirectly buffered otter effects. These findings shed light on long-standing hypotheses about how interspecific interactions can alter the function of keystone species across community contexts. More broadly, we show how community change can be more accurately predicted by considering dynamic interaction strengths.
Melatonin suppresses PD-L1 expression and exerts antitumor activity in hepatocellular carcinoma
Record of paleo water divide locations reveals intermittent divide migration and links to paleoclimate proxies
Drainage divide migration alters the geometry of drainage basins, influencing the distribution of water, erosion, sediments, and ecosystems across Earth’s surface. The rate of divide migration is governed by differences in erosion rates across the divide and is thus sensitive to spatiotemporal variations in tectonics and climate. However, established approaches for quantifying divide migration rates offer only indirect evidence for the motion of the divide and provide only migration rate averages. Consequently, transience in divide migration cannot be resolved, hindering the ability to explore environmental changes that drive the dynamics of such potential transience. Here, we study a set of datable terraces identified as markers of paleo-divide locations, which provide direct evidence for the paleo motion of the divide. The location and age of the terraces reveal intermittent divide migration at timescales of 10 4 to 10 5 y, with phases of rapid migration—at rates more than twice the average—which coincide with documented regional paleoclimate fluctuations. These findings highlight the intermittent nature of divide migration dynamics over geomorphic timescales and its potential sensitivity to climate changes, underscoring the impact of such changes on the planform evolution of drainage basins.
Stability analysis of existing tunnels under dynamic loads during excavation of new tunnels
Mechanical ventilation energy analysis: Recruitment focuses injurious power in the ventilated lung
The progression of acute respiratory distress syndrome (ARDS) from its onset due to disease or trauma to either recovery or death is poorly understood. Currently, there are no generally accepted treatments aside from supportive care using mechanical ventilation. However, this can lead to ventilator-induced lung injury (VILI), which contributes to a 30 to 40% mortality rate. In this study, we develop and demonstrate a technique to quantify forms of energy transport and dissipation during mechanical ventilation to directly evaluate their relationship to VILI. A porcine ARDS model was used, with ventilation parameters independently controlling lung overdistension and alveolar/airway recruitment/derecruitment (RD). Hourly measurements of airflow, tracheal and esophageal pressures, respiratory system impedance, and oxygen transport were taken for six hours following lung injury to track energy transfer and lung function. The final degree of injury was assessed histologically. Total and dissipated energies were quantified from lung pressure–volume relationships and subdivided into contributions from airflow, tissue viscoelasticity, and RD. Only RD correlated with physiologic recovery. Despite accounting for a very small fraction (2 to 5%) of the total energy dissipation, RD is damaging because it occurs quickly over a very small area. We estimate power intensity of RD energy dissipation to be 100 W/m 2 , equivalent to 10% of the Sun’s luminance at the Earth’s surface. Minimizing repetitive RD events may thus be crucial for mitigating VILI.
Muscle transcriptome profiles in elite male ultra-endurance athletes acclimated to a high-carbohydrate versus low-carbohydrate diet
Direct observation of cholesterol monohydrate crystallization
Cholesterol crystallization is integral to the pathology of diseases such as atherosclerosis and gallstones, yet the relevant mechanisms of crystal growth have remained elusive. Here, we use a variety of in situ techniques to examine cholesterol monohydrate crystallization over multiple length scales. In this study, we first identified a biomimetic solvent to generate triclinic monohydrate crystals, while avoiding the formation of nonphysiological solvates and enabling crystallization at rates where the dynamics of surface growth could be captured in real time. Using a binary mixture of water and isopropanol, with the latter serving as a surrogate for lipids in physiological environments, we show that cholesterol monohydrate crystals grow classically by the nucleation and spreading of crystal layers. Time-resolved imaging confirms that layers are generated by dislocations and monomers incorporate into advancing steps after diffusion along the crystal surface and not directly from the solution. In situ atomic force microscopy (AFM) and microfluidics measurements concertedly reveal abundant macrosteps, which engender a self-inhibition mechanism that reduces the rate of crystal growth. This finding stands in contrast to numerous other systems, in which classical mechanisms lead to unhindered growth by spreading of single layers.
Longitudinal observation of psychophysiological data as a novel approach to personalised postural defect rehabilitation
Correction for Huseby et al., Antibiotic class with potent in vivo activity targeting lipopolysaccharide synthesis in Gram-negative bacteria
Quantum speed limit time in two-qubit system by dynamical decoupling method
Specific microbial ratio in the gut microbiome is associated with multiple sclerosis
Gut microbiota dysbiosis is associated with multiple sclerosis (MS), but the causal relationship between specific gut bacteria and MS pathogenesis remains poorly understood. Therefore, we profiled the stool microbiome of people with MS (PwMS) and healthy controls (HC) using shotgun metagenomic sequencing. PwMS showed a distinct microbiome compared to HC, with Prevotella copri ( PC ) and Blautia species as drivers of microbial communities in HC and PwMS, respectively. Administration of MS-driving Blautia species ( Blautia wexlerae; BW ) to mice resulted in increased levels of gut inflammatory markers and altered microbiota with increased capacity to induce proinflammatory cytokines. Utilizing experimental autoimmune encephalomyelitis (EAE), an animal model of MS, we identified a lower gut Bifidobacterium to Akkermansia ratio as a hallmark of the disease. BW -administered mice also showed a lower Bifidobacterium to Akkermansia ratio pre-EAE induction which correlated with increased disease severity post-EAE induction. The importance of the Bifidobacterium to Akkermansia ratio at the species level, lower Bifidobacterium adolescentis to Akkermansia muciniphila ( BA:AM ), was validated in our MS cohort and a large International Multiple Sclerosis Microbiome Study. Thus, our findings highlight the BA:AM ratio as a potential gut microbial marker in PwMS, opening avenues for microbiome-based diagnosis, prognosis, and therapy in MS.
Complementary classification of hypertrophic cardiomyopathy using unsupervised cluster analysis on left ventricular function
Immobile lipopolysaccharides and outer membrane proteins differentially segregate in growing <i>Escherichia coli</i>
The outer membrane (OM) of gram-negative bacteria is a robust, impermeable barrier that excludes many classes of antibiotics. Contrary to the classical model of an asymmetric lipid bilayer, recent evidence suggests the OM is predominantly an asymmetric proteolipid membrane (APLM). Outer leaflet lipopolysaccharides (LPS) that surround integral β-barrel outer membrane proteins (OMPs) are shared with other OMPs to form a supramolecular network in which the levels of OMPs approach those of LPS. Some of the most abundant OMPs in the Escherichia coli OM are trimeric porins. How porins and LPS are incorporated into the OM of growing bacteria is poorly understood. Here, we use live-cell imaging and microfluidics to investigate how LPS, labeled using click chemistry, and the porin OmpF, labeled using the bacteriocin colicin N, are incorporated into the E. coli OM. Diffraction-limited fluorescence microscopy shows OmpF and LPS to be uniformly distributed and immobile. However, clustering of both macromolecules becomes evident by superresolution microscopy, which is also the case for their biogenesis proteins, BamA and LptD, respectively. Notwithstanding these common organizational features, OmpF insertion into the OM is cell-cycle-dependent leading to binary partitioning and strong polar accumulation of old OmpF. Old LPS on the other hand is diluted ~50% at each division cycle by new LPS, resulting in only mild polar accumulation of preexisting LPS. We conclude that although LPS and OMPs are destined to form the APLM their insertion dynamics are fundamentally different, which has major implications for understanding how the OM is assembled.