Ion–Molecule Rate Constants for Reactions of Sulfuric Acid with Acetate and Nitrate Ions

Atmospheric nucleation from precursor gases is a significant source of cloud condensation nuclei in the troposphere and thus can affect the Earth's radiative balance. Sulfuric acid, ammonia, and amines have been identified as key nucleation precursors in the atmosphere. Studies have also shown that atmospheric ions can react with sulfuric acid to form stable clusters in a process referred to as ion-induced nucleation (IIN). IIN follows similar reaction pathways as chemical ionization, which is used to detect and measure nucleation precursors via atmospheric pressure chemical ionization mass spectrometers. The rate at which ions form clusters depends on the ion-molecule rate constant. However, the rate constant varies based on the ion composition, which is often not known in the atmosphere. Previous studies have examined ion-molecule rate constants for sulfuric acid and nitrate ions but not for other atmospherically relevant ions like acetate. We report the relative rate constants of ion- molecule reactions between nitrate and acetate ions reacting with sulfuric acid. The ion- molecule rate constant for acetate and sulfuric acid is estimated to be a factor of 1.9-2.4 times higher than that of the known rate constant for nitrate and sulfuric acid. Using quantum chemistry, we find that acetate has a higher dipole moment and polarizability than nitrate. This may contribute to an increase in the collision cross-sectional area between acetate and sulfuric acid and lead to a greater reaction rate constant than nitrate. The ion- molecule rate constant for acetate with sulfuric acid will help quantify the contribution of acetate ions to atmospheric ion-induced new particle formation.Peer reviewe

Peptide exchange on MHC-I by TAPBPR is driven by a negative allostery release cycle.

Chaperones TAPBPR and tapasin associate with class I major histocompatibility complexes (MHC-I) to promote optimization (editing) of peptide cargo. Here, we use solution NMR to investigate the mechanism of peptide exchange. We identify TAPBPR-induced conformational changes on conserved MHC-I molecular surfaces, consistent with our independently determined X-ray structure of the complex. Dynamics present in the empty MHC-I are stabilized by TAPBPR and become progressively dampened with increasing peptide occupancy. Incoming peptides are recognized according to the global stability of the final pMHC-I product and anneal in a native-like conformation to be edited by TAPBPR. Our results demonstrate an inverse relationship between MHC-I peptide occupancy and TAPBPR binding affinity, wherein the lifetime and structural features of transiently bound peptides control the regulation of a conformational switch located near the TAPBPR binding site, which triggers TAPBPR release. These results suggest a similar mechanism for the function of tapasin in the peptide-loading complex

HIV's evasion of the cellular immune response

Despite a strong cytotoxic T-lymphocyte (CTL) response directed against viral antigens, untreated individuals infected with the human immunodeficiency virus (HIV-1) develop AIDS, We have found that primary T cells infected with HIV-1 downregulate surface MHC class I antigens and are resistant to lysis by HLA-A2-restricted CTL clones. In contrast, cells infected with an HIV-1 in which the nef gene is disrupted are sensitive to CTLs in an MHC and peptide-specific manner. In primary T cells HLA-A2 antigens are downmodulated more dramatically than total MHC class I antigens, suggesting that nef selectively downmodulates certain MHC class I antigens. In support of this, studies on ceils expressing individual MHC class I alietes have revealed that nef does not downmodulate HLA-C and HLA-E antigens, This selective downmodulation allows Infected cells to maintain resistance to certain natural killer cells that lyse infected cells expressing low levels of MHC class I antigens. Downmodulation of MHC class I HLA-A2 antigens occurs not only in primary T cells, but also in B and astrocytoma cell lines. No effect of other HIV-1 accessory proteins such as vpu and vpr was observed. Thus Nef is a protein that may promote escape of HIV-1 from immune surveillance.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75570/1/j.1600-065X.1999.tb01283.x.pd

A missense mutation in TRAPPC6A leads to build-up of the protein, in patients with a neurodevelopmental syndrome and dysmorphic features.

Childhood onset clinical syndromes involving intellectual disability and dysmorphic features, such as polydactyly, suggest common developmental pathways link seemingly unrelated phenotypes. We identified a consanguineous family of Saudi origin with varying complex features including intellectual disability, speech delay, facial dysmorphism and polydactyly. Combining, microarray based comparative genomic hybridisation (CGH) to identify regions of homozygosity, with exome sequencing, led to the identification of homozygous mutations in five candidate genes (RSPH6A, ANKK1, AMOTL1, ALKBH8, TRAPPC6A), all of which appear to be pathogenic as predicted by Proven, SIFT and PolyPhen2 and segregate perfectly with the disease phenotype. We therefore looked for differences in expression levels of each protein in HEK293 cells, expressing either the wild-type or mutant full-length cDNA construct. Unexpectedly, wild-type TRAPPC6A appeared to be unstable, but addition of the proteasome inhibitor MG132 stabilised its expression. Mutations have previously been reported in several members of the TRAPP complex of proteins, including TRAPPC2, TRAPPC9 and TRAPPC11, resulting in disorders involving skeletal abnormalities, intellectual disability, speech impairment and developmental delay. TRAPPC6A joins a growing list of proteins belonging to the TRAPP complex, implicated in clinical syndromes with neurodevelopmental abnormalities

Новые языковые реальности употребления претерита в немецком гипотаксисе

Целью статьи являются обобщение и теоретическое обоснование нового употребления претерита в относительном значении в конкретных видах придаточных предложений с презенсом в главном предложении. В статье анализируются коннотативные нюансы относительного значения претерита, регулярность замены префекта-пассива и перфекта именного составного сказуемого с глаголом "sein" на претеритальные формы в гипотаксисе, а также особое место претерита в системе немецких временных форм.Метою статті є узагальнення та теоретичне обґрунтування нового вживання претериту у релятивному значенні у конкретних видах сурядно-підрядних речень з презентом у сурядному реченні. У статті подано аналіз конототивні нюанси претериту і регулярність зміни перфекту пасиву та іменного присудка з дієсловом "sein" на претеритальні форми у гіпотаксису, а також особливе місце претериту у системі німецьких часових форм.The article aims at generalization and theoretical Explanation of modern preterit usage in relative meaning in certain types of clauses, with the Present tense in the main clause. The article deals with the analysis of connotative component meanings of the relative preterit and the regularity of substitution of preterit forms in hypotaxes for the passive perfect tense and the perfect form of the nominal compound predicate with the verb 'sein' as well as the specificity of preterit in the system of German tenses

Comprehensive Pharmacogenomic Profiling of Malignant Pleural Mesothelioma Identifies a Subgroup Sensitive to FGFR Inhibition

PURPOSE: Despite intense research, treatment options for patients with mesothelioma are limited and offer only modest survival advantage. We screened a large panel of compounds in multiple mesothelioma models and correlated sensitivity with a range of molecular features to detect biomarkers of drug response. EXPERIMENTAL DESIGN: We utilized a high-throughput chemical inhibitor screen in a panel of 889 cancer cell lines, including both immortalized and primary early-passage mesothelioma lines, alongside comprehensive molecular characterization using Illumina whole-exome sequencing, copy-number analysis and Affymetrix array whole transcriptome profiling. Subsequent validation was done using functional assays such as siRNA silencing and mesothelioma mouse xenograft models. RESULTS: A subgroup of immortalized and primary MPM lines appeared highly sensitive to FGFR inhibition. None of these lines harbored genomic alterations of FGFR family members, but rather BAP1 protein loss was associated with enhanced sensitivity to FGFR inhibition. This was confirmed in an MPM mouse xenograft model and by BAP1 knockdown and overexpression in cell line models. Gene expression analyses revealed an association between BAP1 loss and increased expression of the receptors FGFR1/3 and ligands FGF9/18. BAP1 loss was associated with activation of MAPK signaling. These associations were confirmed in a cohort of MPM patient samples. CONCLUSIONS: A subgroup of mesotheliomas cell lines harbor sensitivity to FGFR inhibition. BAP1 protein loss enriches for this subgroup and could serve as a potential biomarker to select patients for FGFR inhibitor treatment. These data identify a clinically relevant MPM subgroup for consideration of FGFR therapeutics in future clinical studies

A Detailed Analysis of the Murine TAP Transporter Substrate Specificity

The transporter associated with antigen processing (TAP) supplies cytosolic peptides into the endoplasmic reticulum for binding to major histocompatibility complex (MHC) class I molecules. Its specificity therefore influences the repertoire of peptides presented by MHC molecules. Compared to human TAP, murine TAP's binding specificity has not been characterized as well, even though murine systems are widely used for basic studies of antigen processing and presentation.We performed a detailed experimental analysis of murine TAP binding specificity by measuring the binding affinities of 323 peptides. Based on this experimental data, a computational model of murine TAP specificity was constructed. The model was compared to previously generated data on human and murine TAP specificities. In addition, the murine TAP specificities for known epitopes and random peptides were predicted and compared to assess the impact of murine TAP selectivity on epitope selection.Comparisons to a previously constructed model of human TAP specificity confirms the well-established differences for peptide substrates with positively charged C-termini. In addition these comparisons show that several residues at the N-terminus of peptides which strongly influence binding to human TAP showed little effect on binding to murine TAP, and that the overall influence of the aminoterminal residues on peptide affinity for murine TAP is much lower than for the human transporter. Murine TAP also partly prefers different hydrophobic amino acids than human TAP in the carboxyterminal position. These species-dependent differences in specificity determined in vitro are shown to correlate with the epitope repertoire recognized in vivo. The quantitative model of binding specificity of murine TAP developed herein should be useful for interpreting epitope mapping and immunogenicity data obtained in humanized mouse models

Endosomal MR1 Trafficking Plays a Key Role in Presentation of Mycobacterium tuberculosis Ligands to MAIT Cells

Mucosal-Associated Invariant T (MAIT) cells, present in high frequency in airway and other mucosal tissues, have Th1 effector capacity positioning them to play a critical role in the early immune response to intracellular pathogens, including Mycobacterium tuberculosis (Mtb). MR1 is a highly conserved Class I-like molecule that presents vitamin B metabolites to MAIT cells. The mechanisms for loading these ubiquitous small molecules are likely to be tightly regulated to prevent inappropriate MAIT cell activation. To define the intracellular localization of MR1, we analyzed the distribution of an MR1-GFP fusion protein in antigen presenting cells. We found that MR1 localized to endosomes and was translocated to the cell surface upon addition of 6-formyl pterin (6-FP). To understand the mechanisms by which MR1 antigens are presented, we used a lentiviral shRNA screen to identify trafficking molecules that are required for the presentation of Mtb antigen to HLA-diverse T cells. We identified Stx18, VAMP4, and Rab6 as trafficking molecules regulating MR1-dependent MAIT cell recognition of Mtb-infected cells. Stx18 but not VAMP4 or Rab6 knockdown also resulted in decreased 6-FP-dependent surface translocation of MR1 suggesting distinct pathways for loading of exogenous ligands and intracellular mycobacterially-derived ligands. We postulate that endosome-mediated trafficking of MR1 allows for selective sampling of the intracellular environment.Career Development Award: (#IK2 CX000538); U.S. Department of Veterans Affairs Clinical Sciences Research and Development Program (MJH); U.S.Department of Veterans Affairs Biomedical Laboratory Research and Development Program (DML) Merit Award: (#I01 BX000533); American Lung Association: (RT-350058)

Diagnostic performance of exercise bicycle testing and single-photon emission computed tomography: Comparison with 64-slice computed tomography coronary angiography

To conduct a comparison of the diagnostic performance of exercise bicycle testing and singlephoton emission computed tomography (SPECT) with computed tomography coronary angiography (CTCA) for the detection of obstructive coronary artery disease (CAD) in patients with stable angina. 376 symptomatic patients (254 men, 122 women, mean age 60.4 ± 10.0 years) referred for noninvasive stress testing (exercise bicycle test and/or SPECT) and invasive coronary angiography were included. All patients underwent additional 64-slice CTCA. The diagnostic performance of exercise bicycle testing (ST segment depression), SPECT (reversible perfusion defect) and CTCA (≥50% lumen diameter reduction) was presented as sensitivity, specificity, positive and negative predictive value (PPV and NPV) to detect or rule out obstructive CAD with quantitative coronary angiography as reference standard. Comparisons of exercise bicycle testing versus CTCA (n = 334), and SPECT versus CTCA (n = 61) were performed. The diagnostic performance of exercise bicycle testing was significantly (P value0.05): 77% (95% CI, 50-92) vs. 82% (95% CI, 56-95). We observed a PPV of 91% (95% CI, 77-97) vs. 93% (95% CI, 81-98); andNPVof 72% (95%, 46-89) vs. 93% (95%, 66-100). SPECT and CTCA yielded higher diagnostic performance compared to traditional exercise bicycle testing for the detection and rule out of obstructive CAD in patients with stable angina