Methylammonium and ammonium (MEP) permeases of Saccharomyces cerevisiae belong to a ubiquitous family of cytoplasmic membrane proteins that transport only ammonium (NH 4 ؉ ؉ NH 3 ). Transport and accumulation of the ammonium analog [14 C]methylammonium, a weak base, led to the proposal that members of this family were capable of energy-dependent concentration of the ammonium ion, NH 4 ؉ . In bacteria, however, ATP-dependent conversion of methylammonium to ␥-N-methylglutamine by glutamine synthetase precludes its use in assessing concentrative transport across the cytoplasmic membrane. We have confirmed that methylammonium is not metabolized in the yeast S. cerevisiae and have shown that it is little metabolized in the filamentous fungus Neurospora crassa. However, its accumulation depends on the energy-dependent acidification of vacuoles. A ⌬vph1 mutant of S. cerevisiae and a ⌬vma1 mutant, which lack vacuolar H ؉ -ATPase activity, had large (fivefold or greater) defects in the accumulation of methylammonium, with little accompanying defect in the initial rate of transport. A vma-1 mutant of N. crassa largely metabolized methylammonium to methylglutamine. Thus, in fungi as in bacteria, subsequent energy-dependent utilization of methylammonium precludes its use in assessing active transport across the cytoplasmic membrane. The requirement for a proton gradient to sequester the charged species CH 3 NH 3 ؉ in acidic vacuoles provides evidence that the substrate for MEP proteins is the uncharged species CH 3 NH 2 . By inference, their natural substrate is NH 3 , a gas. We postulate that MEP proteins facilitate diffusion of NH 3 across the cytoplasmic membrane and speculate that human Rhesus proteins, which lie in the same domain family as MEP proteins, facilitate diffusion of CO 2 .Methylammonium and ammonium permeases MEP1, MEP2, and MEP3 of Saccharomyces cerevisiae (35) and the ammonium and methylammonium transport B (AmtB) protein of enteric bacteria (64) are members of a unique family of cytoplasmic membrane transporters that are specific for ammonium (48). (We use ammonium to designate both the charged and uncharged species.) The MEP/Amt family (nomenclature, TC 2.49) occurs ubiquitously in bacteria, archaea, and eukarya (19,36). Beginning with the pioneering studies of Hackette et al. (16), the activity of MEP/Amt proteins has been assessed by studying transport and accumulation of the ammonium analog methylammonium, which can be 14 C labeled. Based on studies with methylammonium it has been proposed that members of the MEP/Amt family transport the charged species NH 4 ϩ across the cytoplasmic membrane and concentrate it in an energy-dependent manner (19, 65).We showed previously that enteric bacteria convert methylammonium to ␥-N-methylglutamine in the ATP-dependent reaction catalyzed by glutamine synthetase and hence that methylammonium cannot be used to assess energy-dependent concentrative uptake (62). The same metabolic conversion occurs in other proteobacteria, including methylotrophic pseudomonads (2, 1...
The presence of an interpreter increases the difficulty of achieving good physician-patient communication. Physicians and interpreters should be trained in the process of communication and interpretation, to minimize conversational loss and maximize the information and relational exchange with interpreted patients.
A collaborative professional development program that engaged nearly 90% of faculty in a biology department in more than 40 hours of training on scientific teaching was instituted. Participating instructors integrated active learning in their courses, as shown through a variety of methods, and reported positive effects on teaching and departmental community.
Background: Signifying the 2-compartments/1-disease paradigm, allergic rhinoconjunctivitis (ARC) and asthma (AA) are prevalent, comorbid conditions triggered by environmental factors (eg, house dust mites [HDMs]). However, despite the ubiquity of triggers, progression to severe ARC/AA is infrequent, suggesting either resilience or adaptation. Objective: We sought to determine whether ARC/AA severity relates to maladaptive responses to disease triggers. Methods: Adults with HDM-associated ARC were challenged repetitively with HDMs in an aeroallergen challenge chamber. Mechanistic traits associated with disease severity were identified. Results: HDM challenges evoked maladaptive (persistently higher ARC symptoms), adaptive (progressive symptom reduction), and resilient (resistance to symptom induction) phenotypes. Symptom severity in the natural environment was an imprecise correlate of the phenotypes. Nasal airway traits, defined by low inflammation-effectual epithelial integrity, moderate inflammation-effectual epithelial integrity, and higher inflammation-ineffectual epithelial integrity, were hallmarks of the resilient, adaptive, and maladaptive evoked phenotypes, respectively. Highlighting a crosstalk mechanism, peripheral blood inflammatory tone calibrated these traits: ineffectual epithelial integrity associated with CD8 1 T cells, whereas airway inflammation associated with both CD8 1 T cells and eosinophils. Hallmark peripheral blood maladaptive traits were increased natural killer and CD8 1 T cells, lower CD4 1 mucosal-associated invariant T cells, and deficiencies along the TLR-IRF-IFN antiviral pathway. Maladaptive traits tracking HDM-associated ARC also contributed to AA risk and severity models. Conclusions: Repetitive challenges with HDMs revealed that maladaptation to disease triggers may underpin ARC/AA disease severity. A combinatorial therapeutic approach may involve reversal of loss-of-beneficial-function traits (ineffectual epithelial integrity, TLR-IRF-IFN deficiencies), mitigation of gain-ofadverse-function traits (inflammation), and blocking of a detrimental crosstalk between the peripheral blood and airway compartments.
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