Machine learning (ML) is used to derive local stability information for density functional theory calculations of systems in relation to the recently discovered SnO_{2}(110)-(4×1) reconstruction. The ...ML model is trained on (structure, total energy) relations collected during global minimum energy search runs with an evolutionary algorithm (EA). While being built, the ML model is used to guide the EA, thereby speeding up the overall rate by which the EA succeeds. Inspection of the local atomic potentials emerging from the model further shows chemically intuitive patterns.
During antibody affinity maturation, germinal center (GC) B cells cycle between affinity-driven selection in the light zone (LZ) and proliferation and somatic hypermutation in the dark zone (DZ). ...Although selection of GC B cells is triggered by antigen-dependent signals delivered in the LZ, DZ proliferation occurs in the absence of such signals. We show that positive selection triggered by T cell help activates the mechanistic target of rapamycin complex 1 (mTORC1), which promotes the anabolic program that supports DZ proliferation. Blocking mTORC1 prior to growth prevented clonal expansion, whereas blockade after cells reached peak size had little to no effect. Conversely, constitutively active mTORC1 led to DZ enrichment but loss of competitiveness and impaired affinity maturation. Thus, mTORC1 activation is required for fueling B cells prior to DZ proliferation rather than for allowing cell-cycle progression itself and must be regulated dynamically during cyclic re-entry to ensure efficient affinity-based selection.
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•Positive selection of GC B cells triggers mTORC1 activation prior to clonal expansion•mTORC1 is required for biomass accumulation but dispensable for cell-cycle progression•Deregulated mTORC1 promotes DZ phenotype and leads to loss of GC competitiveness•Rapamycin-resistant mouse strain is used for cell-intrinsic mTORC1 inhibition
During germinal center selection, signals from Tfh cells in the light zone dictate the extent of B cell proliferation in the dark zone. Ersching et al. (2017) show that Tfh help induces mTORC1 activation in light zone B cells, leading to cell growth that sustains the subsequent dark zone proliferative burst.
If the potential for a boom in the global hydrogen economy is realized, there will be an increase in the need for accurate hydrogen thermodynamic property standards. Based on current and anticipated ...needs, new fundamental equations of state for parahydrogen, normal hydrogen, and orthohydrogen were developed to replace the existing property models. To accurately predict thermophysical properties near the critical region and in liquid states, the quantum law of corresponding states was applied to improve the normal hydrogen and orthohydrogen formulations in the absence of available experimental data. All three equations of state have the same maximum pressure of
2000
MPa
and upper temperature limit of
1000
K
. Uncertainty estimates in this paper can be considered to be estimates of a combined expanded uncertainty with a coverage factor of 2 for primary data sets. The uncertainty in density is 0.04% in the region between 250 and
450
K
and at pressures up to
300
MPa
. The uncertainties of vapor pressures and saturated liquid densities vary from 0.1% to 0.2%. Heat capacities are generally estimated to be accurate to within 1%, while speed-of-sound values are accurate to within 0.5% below
100
MPa
.
New fundamental equations of state for parahydrogen, normal hydrogen, and orthohydrogen were developed. To accurately predict thermophysical properties in the critical region and in liquid states, the quantum law of corresponding states was applied to improve the normal hydrogen and orthohydrogen formulations. All three equations of state have a maximum pressure of 2000 MPa and upper temperature limit of 1000 K.
Antibodies somatically mutate to attain high affinity in germinal centers (GCs). There, competition between B cell clones and among somatic mutants of each clone drives an increase in average ...affinity across the population. The extent to which higher-affinity cells eliminating competitors restricts clonal diversity is unknown. By combining multiphoton microscopy and sequencing, we show that tens to hundreds of distinct B cell clones seed each GC and that GCs lose clonal diversity at widely disparate rates. Furthermore, efficient affinity maturation can occur in the absence of homogenizing selection, ensuring that many clones can mature in parallel within the same GC. Our findings have implications for development of vaccines in which antibodies with nonimmunodominant specificities must be elicited, as is the case for HIV-1 and influenza.
Mirror-image proteins (composed of d -amino acids) are promising therapeutic agents and drug discovery tools, but as synthesis of larger d -proteins becomes feasible, a major anticipated challenge is ...the folding of these proteins into their active conformations. In vivo, many large and/or complex proteins require chaperones like GroEL/ES to prevent misfolding and produce functional protein. The ability of chaperones to fold d -proteins is unknown. Here we examine the ability of GroEL/ES to fold a synthetic d -protein. We report the total chemical synthesis of a 312-residue GroEL/ES-dependent protein, DapA, in both l - and d -chiralities, the longest fully synthetic proteins yet reported. Impressively, GroEL/ES folds both l - and d -DapA. This work extends the limits of chemical protein synthesis, reveals ambidextrous GroEL/ES folding activity, and provides a valuable tool to fold d -proteins for drug development and mirror-image synthetic biology applications.
Brain inflammation is a double-edged sword. It is required for brain repair in acute damage, whereas chronic inflammation and autoimmune disorders are neuropathogenic. Certain proinflammatory ...cytokines and chemokines are closely related to cognitive dysfunction and neurodegeneration. Representative anti-inflammatory cytokines, such as interleukin (IL)-10, can suppress neuroinflammation and have significant therapeutic potentials in ameliorating neurodegenerative disorders such as Alzheimer's disease (AD). Here, we show that adeno-associated virus (AAV) serotype 2/1 hybrid-mediated neuronal expression of the mouse IL-10 gene ameliorates cognitive dysfunction in amyloid precursor protein+ presenilin-1 bigenic mice. AAV2/1 infection of hippocampal neurons resulted in sustained expression of IL-10 without its leakage into the blood, reduced astro/microgliosis, enhanced plasma amyloid-β peptide (Aβ) levels and enhanced neurogenesis. Moreover, increased levels of IL-10 improved spatial learning, as determined by the radial arm water maze. Finally, IL-10-stimulated microglia enhanced proliferation but not differentiation of primary neural stem cells in the co-culture system, whereas IL-10 itself had no effect. Our data suggest that IL-10 gene delivery has a therapeutic potential for a non-Aβ-targeted treatment of AD.
Abstract
This review gives first a brief view of the potential availability of sustainable energy. It is clear that over 100 times more solar photovoltaic energy than necessary is readily accessible ...and that practically available wind alone may deliver sufficient energy supply to the world. Due to the intermittency of these sources, effective and inexpensive energy-conversion and storage technology is needed. Motivation for the possible electrolysis application of reversible solid-oxide cells (RSOCs), including a comparison of power-to-fuel/fuel-to-power to other energy-conversion and storage technologies is presented. RSOC electrochemistry and chemistry of H2O, CO2, H2, CO, CnHm (hydrocarbons) and NH3, including thermodynamics and cell performance, are described. The mechanical strength of popular cell supports is outlined, and newly found stronger materials are mentioned. Common cell-degradation mechanisms, including the effect of common impurities in gases and materials (such as S and Si), plus the deleterious effects of carbon deposition in the fuel electrode are described followed by explanations of how to avoid or ease the consequences. Visions of how RSOCs powered by sustainable energy may be applied on a large scale for the transportation sector via power-to-fuel technology and for integration with the electrical grid together with seasonal storage are presented. Finally, a brief comparison of RSOCs to other electrolysis cells and an outlook with examples of actions necessary to commercialize RSOC applications are sketched.
Cytokines play an emerging role as neurotransmitters, neuromodulators, and neurohormones in the brain. This paradigm shift in cytokine function offers a new framework to understand their roles in ...ameliorating neurodegenerative disorders, such as Alzheimer's disease (AD). Molecular adjuvant therapy of AD animal models with glatiramer acetate induces anti-inflammatory responses and therapeutic effects. Although these effects are potentially mediated through anti-inflammatory cytokine signaling, the exact molecular identities and pathways are poorly understood. Here, we show that virus-mediated expression of the mouse interleukin (IL)-4 gene in β-amyloid precursor protein + presenilin-1 (APP+PS1) bigenic mice attenuates AD pathogenesis. Introduction of an adeno-associated viral (AAV) vector encoding IL-4 into the hippocampus resulted in sustained expression of IL-4, reduced astro/microgliosis, amyloid-β peptide (Aβ) oligomerization and deposition, and enhanced neurogenesis. Moreover, increased levels of IL-4 improved spatial learning, promoted phosphorylation of N-methyl-D-aspartate receptor subunit 2B at Tyr 1472, and enhanced its cell surface retention both in vivo and in vitro. Our data suggest that neuronal anti-inflammatory cytokine signaling may be a potential alternative target for non-Aβ-mediated treatment of AD.--Kiyota, T., Okuyama, S., Swan, R. J., Jacobsen, M. T., Gendelman, H. E., Ikezu, T. CNS expression of anti-inflammatory cytokine interleukin-4 attenuates Alzheimer's disease-like pathogenesis in APP+PS1 bigenic mice. FASEB J.
The Alzheimer's amyloid precursor protein (APP) belongs to a conserved gene family that also includes the mammalian APLP1 and APLP2, the Drosophila APPL, and the C. elegans APL-1. The biological ...function of APP is still not fully clear. However, it is known that the APP family proteins have redundant and partly overlapping functions, which demonstrates the importance of studying all APP family members to gain a more complete picture. When APP was first cloned, it was speculated that it could function as a receptor. This theory has been further substantiated by studies showing that APP and its homologues bind both extracellular ligands and intracellular adaptor proteins. The APP family proteins undergo regulated intramembrane proteolysis (RIP), generating secreted and cytoplasmic fragments that have been ascribed different functions. In this review, we will discuss the APP family with focus on biological functions, binding partners, and regulated processing.
Intervertebral disc (IVD) degeneration is associated with elevated levels of inflammatory cytokines implicated in disease aetiology and matrix degradation. Toll-like receptor-4 (TLR4) has been shown ...to participate in the inflammatory responses of the nucleus pulposus (NP) and its levels are upregulated in disc degeneration. Activation of TLR4 in NP cells leads to significant, persistent changes in cell biophysical properties, including hydraulic permeability and osmotically active water content, as well as alterations to the actin cytoskeleton. The study hypothesis was that inflammation-induced changes to cellular biomechanical properties and actin cytoskeleton of NP cells could be prevented by inhibiting TLR4 signalling. Isolated NP cells from bovine discs were treated with lipopolysaccharide (LPS), the best studied TLR4 agonist, with or without treatment with the TLR4 inhibitor TAK-242. Cellular volume regulation responses to step osmotic loading were measured and the transient volume-response was captured by time-lapse microscopy. Volume-responses were analysed using mixture theory framework to investigate hydraulic permeability and osmotically active intracellular water content. Hydraulic permeability and cell radius were significantly increased with LPS treatment and these changes were blocked in cells treated with TAK-242. LPS-induced remodelling of cortical actin and IL-6 upregulation were also mitigated by TAK-242 treatment. These findings indicated that TLR4 signalling participated in NP cell biophysical regulation and may be an important target for mitigating altered cell responses observed in IVD inflammation and degeneration.
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