ABSTRACT
We study the effect of the gas accretion rate ($\dot{M}_{\rm accr}$) on the radial gas metallicity profile (RMP) of galaxies using the eagle cosmological hydrodynamic simulations, focusing ...on central galaxies of stellar mass M⋆ ≳ 109 M⊙ at z ≤ 1. We find clear relations between $\dot{M}_{\rm accr}$ and the slope of the RMP (measured within an effective radius), where higher $\dot{M}_{\rm accr}$ are associated with more negative slopes. The slope of the RMPs depends more strongly on $\dot{M}_{\rm accr}$ than on stellar mass, star formation rate (SFR), or gas fraction, suggesting $\dot{M}_{\rm accr}$ to be a more fundamental driver of the RMP slope of galaxies. We find that eliminating the dependence on stellar mass is essential for pinning down the properties that shape the slope of the RMP. Although $\dot{M}_{\rm accr}$ is the main property modulating the slope of the RMP, we find that it causes other correlations that are more easily testable observationally: At fixed stellar mass, galaxies with more negative RMP slopes tend to have higher gas fractions and SFRs, while galaxies with lower gas fractions and SFRs tend to have flatter metallicity profiles within an effective radius.
Different weak organic acids have significant potential as topical treatments for wounds infected by opportunistic pathogens that are recalcitrant to standard treatments. These acids have long been ...used as bacteriostatic compounds in the food industry, and in some cases are already being used in the clinic. The effects of different organic acids vary with pH, concentration, and the specific organic acid used, but no studies to date on any opportunistic pathogens have examined the detailed interactions between these key variables in a controlled and systematic way. We have therefore comprehensively evaluated the effects of several different weak organic acids on growth of the opportunistic pathogen
. We used a semi-automated plate reader to generate growth profiles for two different strains (model laboratory strain PAO1 and clinical isolate PA1054 from a hospital burns unit) in a range of organic acids at different concentrations and pH, with a high level of replication for a total of 162,960 data points. We then compared two different modeling approaches for the interpretation of this time-resolved dataset: parametric logistic regression (with or without a component to include lag phase) vs. non-parametric Gaussian process (GP) regression. Because GP makes no prior assumptions about the nature of the growth, this method proved to be superior in cases where growth did not follow a standard sigmoid functional form, as is common when bacteria grow under stress. Acetic, propionic and butyric acids were all more detrimental to growth than the other acids tested, and although PA1054 grew better than PAO1 under non-stress conditions, this difference largely disappeared as the levels of stress increased. As expected from knowledge of how organic acids behave, their effect was significantly enhanced in combination with low pH, with this interaction being greatest in the case of propionic acid. Our approach lends itself to the characterization of combinatorial interactions between stressors, especially in cases where their impacts on growth render logistic growth models unsuitable.
Positive-strand RNA (+)RNA viruses are important pathogens of humans, animals, and plants and replicate inside host cells by coopting numerous host factors and subcellular membranes. To gain insights ...into the assembly of viral replicase complexes (VRCs) and dissect the roles of various lipids and coopted host factors, we have reconstituted
(TBSV) replicase using artificial giant unilamellar vesicles (GUVs). We demonstrate that reconstitution of VRCs on GUVs with endoplasmic reticulum (ER)-like phospholipid composition results in a complete cycle of replication and asymmetrical RNA synthesis, which is a hallmark of (+)RNA viruses. TBSV VRCs assembled on GUVs provide significant protection of the double-stranded RNA (dsRNA) replication intermediate against the dsRNA-specific RNase III. The lipid compositions of GUVs have pronounced effects on
TBSV replication, including (-) and (+)RNA synthesis. The GUV-based assay has led to the discovery of the critical role of phosphatidylserine in TBSV replication and a novel role for phosphatidylethanolamine in asymmetrical (+)RNA synthesis. The GUV-based assay also showed stimulatory effects by phosphatidylinositol-3-phosphate PI(3)P and ergosterol on TBSV replication. We demonstrate that eEF1A and Hsp70 coopted replicase assembly factors, Vps34 phosphatidylinositol 3-kinase (PI3K) and the membrane-bending ESCRT factors, are required for reconstitution of the active TBSV VRCs in GUVs, further supporting that the novel GUV-based
approach recapitulates critical steps and involves essential coopted cellular factors of the TBSV replication process. Taken together, this novel GUV assay will be highly suitable to dissect the functions of viral and cellular factors in TBSV replication.
Understanding the mechanism of replication of positive-strand RNA viruses, which are major pathogens of plants, animals, and humans, can lead to new targets for antiviral interventions. These viruses subvert intracellular membranes for virus replication and coopt numerous host proteins, whose functions during virus replication are not yet completely defined. To dissect the roles of various host factors in
(TBSV) replication, we have developed an artificial giant unilamellar vesicle (GUV)-based replication assay. The GUV-based
approach recapitulates critical steps of the TBSV replication process. GUV-based reconstitution of the TBSV replicase revealed the need for a complex mixture of phospholipids, especially phosphatidylserine and phosphatidylethanolamine, in TBSV replication. The GUV-based approach will be useful to dissect the functions of essential coopted cellular factors.
The viral replication proteins of plus-stranded RNA viruses orchestrate the biogenesis of the large viral replication compartments, including the numerous viral replicase complexes, which represent ...the sites of viral RNA replication. The formation and operation of these virus-driven structures require subversion of numerous cellular proteins, membrane deformation, membrane proliferation, changes in lipid composition of the hijacked cellular membranes and intensive viral RNA synthesis. These virus-driven processes require plentiful ATP and molecular building blocks produced at the sites of replication or delivered there. To obtain the necessary resources from the infected cells, tomato bushy stunt virus (TBSV) rewires cellular metabolic pathways by co-opting aerobic glycolytic enzymes to produce ATP molecules within the replication compartment and enhance virus production. However, aerobic glycolysis requires the replenishing of the NAD+ pool. In this paper, we demonstrate the efficient recruitment of pyruvate decarboxylase (Pdc1) and alcohol dehydrogenase (Adh1) fermentation enzymes into the viral replication compartment. Depletion of Pdc1 in combination with deletion of the homologous PDC5 in yeast or knockdown of Pdc1 and Adh1 in plants reduced the efficiency of tombusvirus replication. Complementation approach revealed that the enzymatically functional Pdc1 is required to support tombusvirus replication. Measurements with an ATP biosensor revealed that both Pdc1 and Adh1 enzymes are required for efficient generation of ATP within the viral replication compartment. In vitro reconstitution experiments with the viral replicase show the pro-viral function of Pdc1 during the assembly of the viral replicase and the activation of the viral p92 RdRp, both of which require the co-opted ATP-driven Hsp70 protein chaperone. We propose that compartmentalization of the co-opted fermentation pathway in the tombusviral replication compartment benefits the virus by allowing for the rapid production of ATP locally, including replenishing of the regulatory NAD+ pool by the fermentation pathway. The compartmentalized production of NAD+ and ATP facilitates their efficient use by the co-opted ATP-dependent host factors to support robust tombusvirus replication. We propose that compartmentalization of the fermentation pathway gives an evolutionary advantage for tombusviruses to replicate rapidly to speed ahead of antiviral responses of the hosts and to outcompete other pathogenic viruses. We also show the dependence of turnip crinkle virus, bamboo mosaic virus, tobacco mosaic virus and the insect-infecting Flock House virus on the fermentation pathway, suggesting that a broad range of viruses might induce this pathway to support rapid replication.
Crabeater seals
Lobodon carcinophaga
breed on the Antarctic pack ice. The body composition of seven crabeater seals of various age classes was reported by Bryden and Erickson (J Zool 179:235–247, ...1976); weights of internal organs and sculps (skin with blubber attached) are reported here for four animals from East Antarctica. They died under sedation, two in late April 1993 and one each in late September and early October of 1995. Sculp weights in this study averaged 32% of total body weight, 11.8% higher than the average from the previous study. The difference most likely results from the condition of seals. Those in the previous study were likely to have been in poor condition (moulting or recently moulted). In this study, the animals were likely to have been in good condition (pre-moult or post-moult). Weights of five internal organs are reported; stomach and kidneys expressed as a percentage of total body weight were about 20% lighter in the current study and data for the intestines and liver were about 20% heavier, with little difference for heart weight. This study provides estimates of sculp weight of four crabeater seals and extends the knowledge of weights of five of their visceral organs (stomach, intestines, liver, kidney and heart).
Positive-strand (+)RNA viruses take advantage of the host cells by subverting a long list of host protein factors and transport vesicles and cellular organelles to build membranous viral replication ...organelles (VROs) that support robust RNA replication. How RNA viruses accomplish major recruitment tasks of a large number of cellular proteins are intensively studied. In case of tomato bushy stunt virus (TBSV), a single viral replication protein, named p33, carries out most of the recruitment duties. Yet, it is currently unknown how the viral p33 replication protein, which is membrane associated, is capable of the rapid and efficient recruitment of numerous cytosolic host proteins to facilitate the formation of large VROs. In this paper, we show that, TBSV p33 molecules do not recruit each cytosolic host factor one-by-one into VROs, but p33 targets a cytosolic protein interaction hub, namely Rpn11, which interacts with numerous other cytosolic proteins. The highly conserved Rpn11, called POH1 in humans, is the metalloprotease subunit of the proteasome, which couples deubiquitination and degradation of proteasome substrates. However, TBSV takes advantage of a noncanonical function of Rpn11 by exploiting Rpn11’s interaction with highly abundant cytosolic proteins and the actin network. We provide supporting evidence that the co-opted Rpn11 in coordination with the subverted actin network is used for delivering cytosolic proteins, such as glycolytic and fermentation enzymes, which are readily subverted into VROs to produce ATP locally in support of VRO formation, viral replicase complex assembly and viral RNA replication. Using several approaches, including knockdown of Rpn11 level, sequestering Rpn11 from the cytosol into the nucleus in plants or temperature-sensitive mutation in Rpn11 in yeast, we show the inhibition of recruitment of glycolytic and fermentation enzymes into VROs. The Rpn11-assisted recruitment of the cytosolic enzymes by p33, however, also requires the combined and coordinated role of the subverted actin network. Accordingly, stabilization of the actin filaments by expression of the
Legionella
VipA effector in yeast and plant, or via a mutation of
ACT1
in yeast resulted in more efficient and rapid recruitment of Rpn11 and the selected glycolytic and fermentation enzymes into VROs. On the contrary, destruction of the actin filaments via expression of the
Legionella
RavK effector led to poor recruitment of Rpn11 and glycolytic and fermentation enzymes. Finally, we confirmed the key roles of Rpn11 and the actin filaments
in situ
ATP production within TBSV VROs via using a FRET-based ATP-biosensor. The novel emerging theme is that TBSV targets Rpn11 cytosolic protein interaction hub driven by the p33 replication protein and aided by the subverted actin filaments to deliver several co-opted cytosolic pro-viral factors for robust replication within VROs.
The involvement of host immunity in the gut microbiota-mediated colonization resistance to Clostridioides difficile infection (CDI) is incompletely understood. Here, we show that interleukin (IL)-22, ...induced by colonization of the gut microbiota, is crucial for the prevention of CDI in human microbiota-associated (HMA) mice. IL-22 signaling in HMA mice regulated host glycosylation, which enabled the growth of succinate-consuming bacteria Phascolarctobacterium spp. within the gut microbiome. Phascolarctobacterium reduced the availability of luminal succinate, a crucial metabolite for the growth of C. difficile, and therefore prevented the growth of C. difficile. IL-22-mediated host N-glycosylation is likely impaired in patients with ulcerative colitis (UC) and renders UC-HMA mice more susceptible to CDI. Transplantation of healthy human-derived microbiota or Phascolarctobacterium reduced luminal succinate levels and restored colonization resistance in UC-HMA mice. IL-22-mediated host glycosylation thus fosters the growth of commensal bacteria that compete with C. difficile for the nutritional niche.
Northern lakes are experiencing widespread increases in dissolved organic carbon (DOC) that are likely to lead to changes in pelagic phytoplankton biomass. Pelagic phytoplankton biomass responds to ...trade-offs between light and nutrient availability. However, the influence of DOC light absorbing properties and carbon–nutrient stoichiometry on phytoplankton biomass across seasonal or spatial gradients has not been assessed. Here, we analyzed data from almost 5000 lakes to examine how the carbon–phytoplankton biomass relationship is influenced by seasonal changes in light availability, DOC light absorbing properties (carbon-specific visual absorbance, SVA
420
), and DOC–nutrient total nitrogen (TN) and total phosphorus (TP) stoichiometry, using TOC as a proxy for DOC. We found evidence for trade-offs between light and nutrient availability in the relationship between DOC and phytoplankton biomass chlorophyll (chl)-
a
, with the shape of the relationship varying with season. A clear unimodal relationship was found only in the fall, particularly in the subsets of lakes with the highest TOC:TP. Observed trends of increasing TOC:TP and decreasing TOC:TN suggest that the effects of future browning will be contingent on future changes in carbon–nutrient stoichiometry. If browning continues, phytoplankton biomass will likely increase in most northern lakes, with increases of up to 76% for a 1.7 mg L
−1
increase in DOC expected in subarctic regions, where DOC, SVA
420
, DOC:TN, and DOC:TP are all low. In boreal regions with higher DOC and higher SVA
420
, and thus lower light availability, lakes may experience only moderate increases or even decreases in phytoplankton biomass with future browning.
Background & Aims We previously established long-term culture conditions under which single crypts or stem cells derived from mouse small intestine expand over long periods. The expanding crypts ...undergo multiple crypt fission events, simultaneously generating villus-like epithelial domains that contain all differentiated types of cells. We have adapted the culture conditions to grow similar epithelial organoids from mouse colon and human small intestine and colon. Methods Based on the mouse small intestinal culture system, we optimized the mouse and human colon culture systems. Results Addition of Wnt3A to the combination of growth factors applied to mouse colon crypts allowed them to expand indefinitely. Addition of nicotinamide, along with a small molecule inhibitor of Alk and an inhibitor of p38, were required for long-term culture of human small intestine and colon tissues. The culture system also allowed growth of mouse Apc-deficient adenomas, human colorectal cancer cells, and human metaplastic epithelia from regions of Barrett's esophagus. Conclusions We developed a technology that can be used to study infected, inflammatory, or neoplastic tissues from the human gastrointestinal tract. These tools might have applications in regenerative biology through ex vivo expansion of the intestinal epithelia. Studies of these cultures indicate that there is no inherent restriction in the replicative potential of adult stem cells (or a Hayflick limit) ex vivo.
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