Notes

Solvent-mediated causes in protein dielectrophoresis.
Magma oceans were once ubiquitous in the early solar system, setting up the initial conditions for different evolutionary paths of planetary bodies. In particular, the redox conditions of magma oceans may have profound influence on the redox state of subsequently formed mantles and the overlying atmospheres. The relevant redox buffering reactions, however, remain poorly constrained. Using first-principles simulations combined with thermodynamic modeling, we show that magma oceans of Earth, Mars, and the Moon are likely characterized with a vertical gradient in oxygen fugacity with deeper magma oceans invoking more oxidizing surface conditions. This redox zonation may be the major cause for the Earth's upper mantle being more oxidized than Mars' and the Moon's. These contrasting redox profiles also suggest that Earth's early atmosphere was dominated by CO2 and H2O, in contrast to those enriched in H2O and H2 for Mars, and H2 and CO for the Moon.Separating molecules or ions with sub-Angstrom scale precision is important but technically challenging. Achieving such a precise separation using membranes requires Angstrom scale pores with a high level of pore size uniformity. Herein, we demonstrate that precise solute-solute separation can be achieved using polyamide membranes formed via surfactant-assembly regulated interfacial polymerization (SARIP). The dynamic, self-assembled network of surfactants facilitates faster and more homogeneous diffusion of amine monomers across the water/hexane interface during interfacial polymerization, thereby forming a polyamide active layer with more uniform sub-nanometre pores compared to those formed via conventional interfacial polymerization. The polyamide membrane formed by SARIP exhibits highly size-dependent sieving of solutes, yielding a step-wise transition from low rejection to near-perfect rejection over a solute size range smaller than half Angstrom. SARIP represents an approach for the scalable fabrication of ultra-selective membranes with uniform nanopores for precise separation of ions and small solutes.Small molecules that selectively kill senescent cells (SCs), termed senolytics, have the potential to prevent and treat various age-related diseases and extend healthspan. The use of Bcl-xl inhibitors as senolytics is largely limited by their on-target and dose-limiting platelet toxicity. Here, we report the use of proteolysis-targeting chimera (PROTAC) technology to reduce the platelet toxicity of navitoclax (also known as ABT263), a Bcl-2 and Bcl-xl dual inhibitor, by converting it into PZ15227 (PZ), a Bcl-xl PROTAC, which targets Bcl-xl to the cereblon (CRBN) E3 ligase for degradation. Compared to ABT263, PZ is less toxic to platelets, but equally or slightly more potent against SCs because CRBN is poorly expressed in platelets. PZ effectively clears SCs and rejuvenates tissue stem and progenitor cells in naturally aged mice without causing severe thrombocytopenia. With further improvement, Bcl-xl PROTACs have the potential to become safer and more potent senolytic agents than Bcl-xl inhibitors.Lymphatic metastases are closely associated with tumor relapse and reduced survival in colorectal cancer (CRC). How tumor cells disseminate within the lymphatic network remains largely unknown. Here, we analyze the subclonal structure of 94 tumor samples, covering the primary tumors, lymph node metastases (LNMs), and liver metastases from 10 CRC patients. We portray a high-resolution lymphatic metastatic map for CRC by dividing LNMs into paracolic, intermediate, and central subgroups. Among the 61 metastatic routes identified, 38 (62.3%) are initiated from the primary tumors, 22 (36.1%) from LNMs, and 1 from liver metastasis (1.6%). In 5 patients, we find 6 LNMs that reseed 2 or more LNMs. We summarize 3 diverse modes of metastasis in CRC and show that skip spreading of tumor cells within the lymphatic network is common. Our study sheds light on the complicated metastatic pattern in CRC and has great clinical implications.Coral reef ecosystems are among the first to fundamentally change in structure due to climate change, which leads to questioning of whether decades of knowledge regarding reef management is still applicable. Here we assess ecological responses to no-take marine reserves over two decades, spanning a major climate-driven coral bleaching event. Pre-bleaching reserve responses were consistent with a large literature, with higher coral cover, more species of fish, and greater fish biomass, particularly of upper trophic levels. However, in the 16 years following coral mortality, reserve effects were absent for the reef benthos, and greatly diminished for fish species richness. Positive fish biomass effects persisted, but the groups of fish benefiting from marine reserves profoundly changed, with low trophic level herbivores dominating the responses. These findings highlight that while marine reserves still have important roles on coral reefs in the face of climate change, the species and functional groups they benefit will be substantially altered.The long external filament of bacterial flagella is composed of several thousand copies of a single protein, flagellin. Here, we explore the role played by lysine methylation of flagellin in Salmonella, which requires the methylase FliB. see more We show that both flagellins of Salmonella enterica serovar Typhimurium, FliC and FljB, are methylated at surface-exposed lysine residues by FliB. A Salmonella Typhimurium mutant deficient in flagellin methylation is outcompeted for gut colonization in a gastroenteritis mouse model, and methylation of flagellin promotes bacterial invasion of epithelial cells in vitro. Lysine methylation increases the surface hydrophobicity of flagellin, and enhances flagella-dependent adhesion of Salmonella to phosphatidylcholine vesicles and epithelial cells. Therefore, posttranslational methylation of flagellin facilitates adhesion of Salmonella Typhimurium to hydrophobic host cell surfaces, and contributes to efficient gut colonization and host infection.The mechanisms by which oligodendroglia modulate CNS angiogenesis remain elusive. Previous in vitro data suggest that oligodendroglia regulate CNS endothelial cell proliferation and blood vessel formation through hypoxia inducible factor alpha (HIFα)-activated Wnt (but not VEGF) signaling. Using in vivo genetic models, we show that HIFα in oligodendroglia is necessary and sufficient for angiogenesis independent of CNS regions. At the molecular level, HIFα stabilization in oligodendroglia does not perturb Wnt signaling but rather activates VEGF. At the functional level, genetically blocking oligodendroglia-derived VEGF but not Wnt significantly decreases oligodendroglial HIFα-regulated CNS angiogenesis. Blocking astroglia-derived Wnt signaling reduces astroglial HIFα-regulated CNS angiogenesis. Together, our in vivo data demonstrate that oligodendroglial HIFα regulates CNS angiogenesis through Wnt-independent and VEGF-dependent signaling. These findings suggest an alternative mechanistic understanding of CNS angiogenesis by postnatal glial cells and unveil a glial cell type-dependent HIFα-Wnt axis in regulating CNS vessel formation.Metabolic switch from oxidative phosphorylation to aerobic glycolysis, which is also called the Warburg effect, is a hallmark of osteosarcoma (OS) and leads to the enhancement of cell chemoresistance, growth, metastasis, and invasion. Emerging evidence indicates that long non-coding RNA (lncRNA) plays a crucial role in the Warburg effect of cancer cells. Here, we report that lncRNA KCNQ1OT1 was upregulated in OS. Meanwhile, functional experiments demonstrated that the KCNQ1OT1 facilitated proliferation and suppressed apoptosis of OS cells. In addition, KCNQ1OT1 contributed to the Warburg effect by stimulating aldolase A (ALDOA) expression. Furthermore, using bioinformatics analysis, luciferase reporter, RNA immunoprecipitation, and RNA pull-down assay, we identified that KCNQ1OT1 functions as a competing endogenous RNA (ceRNA) by sponging miR-34c-5p, which inhibited ALDOA expression by directly targeting its 3'UTR. Taken together, these data identified a key role of KCNQ1OT1 in glucose metabolism reprogramming of OS. Targeting the KCNQ1OT1/miR-34c-5p/ALDOA axis may be a potential therapeutic target in OS treatment.Beta-lactamase inhibitors are increasingly used to counteract antibiotic resistance mediated by beta-lactamase enzymes. These inhibitors compete with the beta-lactam antibiotic for the same binding site on the beta-lactamase, thus generating an evolutionary tradeoff mutations that increase the enzyme's beta-lactamase activity tend to increase also its susceptibility to the inhibitor. Here, we investigate how common and accessible are mutants that escape this adaptive tradeoff. Screening a deep mutant library of the blaampC beta-lactamase gene of Escherichia coli, we identified mutations that allow growth at beta-lactam concentrations far exceeding those inhibiting growth of the wildtype strain, even in the presence of the enzyme inhibitor (avibactam). These escape mutations are rare and drug-specific, and some combinations of avibactam with beta-lactam drugs appear to prevent such escape phenotypes. Our results, showing differential adaptive potential of blaampC to combinations of avibactam and different beta-lactam antibiotics, suggest that it may be possible to identify treatments that are more resilient to evolution of resistance.Accurate discrimination between danger and safety cues is essential for survival. Recent findings in humans indicate that patients suffering from anxiety disorders cannot reliably use safety cues in order to inhibit fear responses. However, the neuroanatomical pathways of conditioned safety are still unclear. Aim of the present study was to investigate whether chronic inhibition of GABA synthesis in the infralimbic (IL) cortex, a critical region for fear inhibition, would lead to enhanced conditioned safety memory. Male Sprague Dawley rats were equipped with osmotic mini-pumps attached to an infusion cannula aimed at the IL. Mini-pumps were either filled with the glutamate decarboxylase (GAD) inhibitor L-allylglycine (L-AG) or the inactive enantiomer D-allylglycine (D-AG). Previous studies demonstrated that chronic infusions of L-AG lead to lower GABA levels and overall enhanced neural activity. The effect of IL disinhibition on conditioned safety was investigated utilizing the acoustic startle response. Chronic disinhibition of the IL facilitated conditioned safety memory, along with reduced contextual fear and lower corticosterone levels. The present findings suggest that the IL is a key brain region for conditioned safety memory. Because anxiety disorder patients are often not capable to use safety cues to inhibit unnecessary fear responses, the present findings are of clinical relevance and could potentially contribute to therapy optimization.Retreating subduction zones such as the Lesser Antilles, Gibraltar and Scotia have been migrating towards the Atlantic Ocean by cutting their way through the oceanic crust. This spontaneously retreating subduction is enabled by the development of faults at the edges of the slab, but the physical mechanisms controlling fault propagation and direction remain unknown. Here, using 3D numerical subduction models we show that oceanic lithosphere recycling is mainly controlled by the intensity of strain-induced weakening of fractures forming at the edges of the slab. Intense strain-induced weakening causes predominantly brittle fault propagation and slab narrowing until detachment. Without weakening, preponderantly ductile slab edge propagation occurs, which causes slab widening. This rheological control is not affected by the proximity of non-weakened passive continental margins. Natural examples suggest that slab edges follow convergent paths that could be controlled by fractures weakening due to deep water penetration into the oceanic lithosphere.
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