Modulation of Kv Channel Expression and Function by TCR and Costimulatory Signals during Peripheral CD4+ Lymphocyte Differentiation

Ionic signaling pathways, including voltage-dependent potassium (Kv) channels, are instrumental in antigen-mediated responses of peripheral T cells. However, how Kv channels cooperate with other signaling pathways involved in T cell activation and differentiation is unknown. We report that multiple Kv channels are expressed by naive CD4+ lymphocytes, and that the current amplitude and kinetics are modulated by antigen receptor–mediated stimulation and costimulatory signals. Currents expressed in naive CD4+ lymphocytes are consistent with Kv1.1, Kv1.2, Kv1.3, and Kv1.6. Effector CD4+ cells generated by optimal TCR and costimulation exhibit only Kv1.3 current, but at approximately sixfold higher levels than naive cells. CD4+ lymphocytes anergized through partial stimulation exhibit similar Kv1.1, Kv1.2, and/or Kv1.6 currents, but approximately threefold more Kv1.3 current than naive cells. To determine if Kv channels contribute to the distinct functions of naive, effector, and anergized T cells, we tested their role in immunoregulatory cytokine production. Each Kv channel is required for maximal IL-2 production by naive CD4+ lymphocytes, whereas none appears to play a role in IL-2, IL-4, or IFN-γ production by effector cells. Interestingly, Kv channels in anergized lymphocytes actively suppress IL-4 production, and these functions are consistent with a role in regulating the membrane potential and calcium signaling

Simultaneous evaluation of treatment efficacy and toxicity for bispecific T-cell engager therapeutics in a humanized mouse model.

Immuno-oncology (IO)-based therapies such as checkpoint inhibitors, bi-specific antibodies, and CAR-T-cell therapies have shown significant success in the treat- ment of several cancer indications. However, these therapies can result in the de- velopment of severe adverse events, including cytokine release syndrome (CRS). Currently, there is a paucity of in vivo models that can evaluate dose-response relationships for both tumor control and CRS-related safety issues. We tested an in vivo PBMC humanized mouse model to assess both treatment efficacy against specific tumors and the concurrent cytokine release profiles for individual human donors after treatment with a CD19xCD3 bispecific T-cell engager (BiTE). Using this model, we evaluated tumor burden, T-cell activation, and cytokine release in response to bispecific T-cell-engaging antibody in humanized mice generated with different PBMC donors. The results show that PBMC engrafted NOD-scid Il2rgnull mice lacking expression of mouse MHC class I and II (NSG-MHC-DKO mice) and implanted with a tumor xenograft predict both efficacy for tumor control by CD19xCD3 BiTE and stimulated cytokine release. Moreover, our find- ings indicate that this PBMC-engrafted model captures variability among donors for tumor control and cytokine release following treatment. Tumor control and cytokine release were reproducible for the same PBMC donor in separate experi- ments. The PBMC humanized mouse model described here is a sensitive and re- producible platform that identifies specific patient/cancer/therapy combinations for treatment efficacy and development of complications

Long-term follow-up of beryllium sensitized workers from a single employer

<p>Abstract</p> <p>Background</p> <p>Up to 12% of beryllium-exposed American workers would test positive on beryllium lymphocyte proliferation test (BeLPT) screening, but the implications of sensitization remain uncertain.</p> <p>Methods</p> <p>Seventy two current and former employees of a beryllium manufacturer, including 22 with pathologic changes of chronic beryllium disease (CBD), and 50 without, with a confirmed positive test were followed-up for 7.4 +/-3.1 years.</p> <p>Results</p> <p>Beyond predicted effects of aging, flow rates and lung volumes changed little from baseline, while D_LCO dropped 17.4% of predicted on average. Despite this group decline, only 8 subjects (11.1%) demonstrated physiologic or radiologic abnormalities typical of CBD. Other than baseline status, no clinical or laboratory feature distinguished those who clinically manifested CBD at follow-up from those who did not.</p> <p>Conclusions</p> <p>The clinical outlook remains favorable for beryllium-sensitized individuals over the first 5-12 years. However, declines in D_LCO may presage further and more serious clinical manifestations in the future. These conclusions are tempered by the possibility of selection bias and other study limitations.</p

The malarial exported PFA0660w is an Hsp40 co-chaperone of PfHsp70-x

Plasmodium falciparum, the human pathogen responsible for the most dangerous malaria infection, survives and develops in mature erythrocytes through the export of proteins needed for remodelling of the host cell. Molecular chaperones of the heat shock protein (Hsp) family are prominent members of the exportome, including a number of Hsp40s and a Hsp70. PFA0660w, a type II Hsp40, has been shown to be exported and possibly form a complex with PfHsp70-x in the infected erythrocyte cytosol. However, the chaperone properties of PFA0660w and its interaction with human and parasite Hsp70s are yet to be investigated. Recombinant PFA0660w was found to exist as a monomer in solution, and was able to significantly stimulate the ATPase activity of PfHsp70-x but not that of a second plasmodial Hsp70 (PfHsp70-1) or a human Hsp70 (HSPA1A), indicating a potential specific functional partnership with PfHsp70-x. Protein binding studies in the presence and absence of ATP suggested that the interaction of PFA0660w with PfHsp70-x most likely represented a co-chaperone/chaperone interaction. Also, PFA0660w alone produced a concentrationdependent suppression of rhodanese aggregation, demonstrating its chaperone properties. Overall, we have provided the first biochemical evidence for the possible role of PFA0660w as a chaperone and as co-chaperone of PfHsp70-x. We propose that these chaperones boost the chaperone power of the infected erythrocyte, enabling successful protein trafficking and folding, and thereby making a fundamental contribution to the pathology of malaria

MARTÍN, ANA Mª [Material gráfico]

Copia digital. Madrid : Ministerio de Educación, Cultura y Deporte. Subdirección General de Coordinación Bibliotecaria, 201

New insights into the pharmacogenomics of antidepressant response from the GENDEP and STAR*D studies: rare variant analysis and high-density imputation

Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. Significant findings were investigated in NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication. A total of 7062 950 SNPs were analyzed in GENDEP (n=738) and STAR*D (n=1409). rs116692768 (P=1.80e-08, ITGA9 (integrin α9)) and rs76191705 (P=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At the gene level, no consistent effect was found. At the pathway level, the Gene Ontology (GO) terms GO: 0005694 (chromosome) and GO: 0044427 (chromosomal part) were associated with improvement (corrected P=0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (P=0.047), whereas rs76191705 was not. The two SNPs did not replicate in NEWMEDS. ITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, replication was partial. Further studies may help in clarifying their role

Observation of gamma-ray emission from the galaxy M87 above 250 GeV with VERITAS

The multiwavelength observation of the nearby radio galaxy M87 provides a unique opportunity to study in detail processes occurring in Active Galactic Nuclei from radio waves to TeV gamma-rays. Here we report the detection of gamma-ray emission above 250 GeV from M87 in spring 2007 with the VERITAS atmospheric Cherenkov telescope array and discuss its correlation with the X-ray emission. The gamma-ray emission is measured to be point-like with an intrinsic source radius less than 4.5 arcmin. The differential energy spectrum is fitted well by a power-law function: dPhi/dE=(7.4+-1.3_{stat}+-1.5_{sys})(E/TeV)^{-2.31+-0.17_{stat}+-0.2_{sys}} 10^{-9}m^{-2}s^{-1}TeV^{-1}. We show strong evidence for a year-scale correlation between the gamma-ray flux reported by TeV experiments and the X-ray emission measured by the ASM/RXTE observatory, and discuss the possible short-time-scale variability. These results imply that the gamma-ray emission from M87 is more likely associated with the core of the galaxy than with other bright X-ray features in the jet.Comment: 10 pages, 7 figures, accepted for publication in The Astrophysical Journa

Complete Chloroplast Genome Sequences of Important Oilseed Crop Sesamum indicum L

Sesamum indicum is an important crop plant species for yielding oil. The complete chloroplast (cp) genome of S. indicum (GenBank acc no. JN637766) is 153,324 bp in length, and has a pair of inverted repeat (IR) regions consisting of 25,141 bp each. The lengths of the large single copy (LSC) and the small single copy (SSC) regions are 85,170 bp and 17,872 bp, respectively. Comparative cp DNA sequence analyses of S. indicum with other cp genomes reveal that the genome structure, gene order, gene and intron contents, AT contents, codon usage, and transcription units are similar to the typical angiosperm cp genomes. Nucleotide diversity of the IR region between Sesamum and three other cp genomes is much lower than that of the LSC and SSC regions in both the coding region and noncoding region. As a summary, the regional constraints strongly affect the sequence evolution of the cp genomes, while the functional constraints weakly affect the sequence evolution of cp genomes. Five short inversions associated with short palindromic sequences that form step-loop structures were observed in the chloroplast genome of S. indicum. Twenty-eight different simple sequence repeat loci have been detected in the chloroplast genome of S. indicum. Almost all of the SSR loci were composed of A or T, so this may also contribute to the A-T richness of the cp genome of S. indicum. Seven large repeated loci in the chloroplast genome of S. indicum were also identified and these loci are useful to developing S. indicum-specific cp genome vectors. The complete cp DNA sequences of S. indicum reported in this paper are prerequisite to modifying this important oilseed crop by cp genetic engineering techniques

Author Correction: The FLUXNET2015 dataset and the ONEFlux processing pipeline for eddy covariance data

The following authors were omitted from the original version of this Data Descriptor: Markus Reichstein and Nicolas Vuichard. Both contributed to the code development and N. Vuichard contributed to the processing of the ERA-Interim data downscaling. Furthermore, the contribution of the co-author Frank Tiedemann was re-evaluated relative to the colleague Corinna Rebmann, both working at the same sites, and based on this re-evaluation a substitution in the co-author list is implemented (with Rebmann replacing Tiedemann). Finally, two affiliations were listed incorrectly and are corrected here (entries 190 and 193). The author list and affiliations have been amended to address these omissions in both the HTML and PDF versions