Phenotype, effector function, and tissue localization of PD-1-expressing human follicular helper T cell subsets

<p>Abstract</p> <p>Background</p> <p>It is well established that PD-1 is expressed by follicular T cells but its function in regulation of human T helper cells has been unclear. We investigated the expression modality and function of PD-1 expressed by human T cells specialized in helping B cells.</p> <p>Results</p> <p>We found that PD-1-expressing T cells are heterogeneous in PD-1 expression. We identified three different PD-1-expressing memory T cell subsets (i.e. PD-1^{low (+)}, PD-1^{medium (++)}, and PD-1^{high (+++)}cells). PD-1⁺⁺⁺T cells expressed CXCR5 and CXCR4 and were localized in the rim of germinal centers. PD-1⁺or PD-1⁺⁺cells expressed CCR7 and were present mainly in the T cell area or other parts of the B cell follicles. Utilizing a novel antigen density-dependent magnetic sorting (ADD-MS) method, we isolated the three T cell subsets for functional characterization. The germinal center-located PD-1⁺⁺⁺T cells were most efficient in helping B cells and in producing IL-21 and CXCL13. Other PD-1-expressing T cells, enriched with Th1 and Th17 cells, were less efficient than PD-1⁺⁺⁺T cells in these capacities. PD-1⁺⁺⁺T cells highly expressed Ki-67 and therefore appear active in cell activation and proliferation in vivo. IL-2 is a cytokine important for proliferation and survival of the PD-1⁺⁺⁺T cells. In contrast, IL-21, while a major effector cytokine produced by the PD-1-expressing T helper cells, had no function in generation, survival, or proliferation of the PD-1-expressing helper T cells at least in vitro. PD-1 triggering has a suppressive effect on the proliferation and B cell-helping function of PD-1⁺⁺⁺germinal center T cells.</p> <p>Conclusion</p> <p>Our results revealed the phenotype and effector function of PD-1-expressing T helper cell subsets and indicate that PD-1 restrains the B cell-helping function of germinal center-localized T cells to prevent excessive antibody response.</p

CDLT: A Dataset with Concept Drift and Long-Tailed Distribution for Fine-Grained Visual Categorization

Data is the foundation for the development of computer vision, and the establishment of datasets plays an important role in advancing the techniques of fine-grained visual categorization~(FGVC). In the existing FGVC datasets used in computer vision, it is generally assumed that each collected instance has fixed characteristics and the distribution of different categories is relatively balanced. In contrast, the real world scenario reveals the fact that the characteristics of instances tend to vary with time and exhibit a long-tailed distribution. Hence, the collected datasets may mislead the optimization of the fine-grained classifiers, resulting in unpleasant performance in real applications. Starting from the real-world conditions and to promote the practical progress of fine-grained visual categorization, we present a Concept Drift and Long-Tailed Distribution dataset. Specifically, the dataset is collected by gathering 11195 images of 250 instances in different species for 47 consecutive months in their natural contexts. The collection process involves dozens of crowd workers for photographing and domain experts for labelling. Extensive baseline experiments using the state-of-the-art fine-grained classification models demonstrate the issues of concept drift and long-tailed distribution existed in the dataset, which require the attention of future researches

The Activity of Small Urea‐γ‐AApeptides Toward Gram‐Positive Bacteria

Host Defense Peptides (HDPs) have gained considerable interest due to the omnipresent threat of bacterial infection as a serious public health concern. However, development of HDPs is impeded by several drawbacks, such as poor selectivity, susceptibility to proteolytic degradation, low‐to‐moderate activity and requiring complex syntheses. Herein we report a class of lipo‐linear α/urea‐γ‐AApeptides with a hybrid backbone and low molecular weight. The heterogeneous backbone not only enhances chemodiversity, but also shows effective antimicrobial activity against Gram‐positive bacteria and is capable of disrupting bacterial membranes and killing bacteria rapidly. Given their low molecular weight and ease of access via facile synthesis, they could be practical antibiotic agents.Double‐AA peptides: We investigated a new class of small linear molecules as potential antibiotic agents against Gram‐positive bacteria. Our studies suggest that these compounds can disrupt bacterial membranes and kill bacteria rapidly. Given their low molecular weight and ease of accessibility through a facile synthesis approach, they are good candidates for development into antibiotic agents.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/152544/1/cmdc201900520-sup-0001-misc_information.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152544/2/cmdc201900520.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/152544/3/cmdc201900520_am.pd

Multilevel Nitrogen Additions Alter Chemical Composition and Turnover of the Labile Fraction Soil Organic Matter via Effects on Vegetation and Microorganisms

Global nitrogen (N) deposition greatly impacts soil carbon sequestration. A 2- yr multiple N addition (0, 10, 20, 40, 80, and 160 kg N·ha- 1·yr- 1) experiment was conducted in alpine grassland to illustrate the mechanisms underlying the observed soil organic matter (SOM) dynamics on the Qinghai- Tibet Plateau (QTP). Labile fraction SOM (LF- SOM) fingerprints were characterized by pyrolysis- gas chromatography/tandem- mass spectrometry, and microbial functional genes (GeoChip 4.6) were analyzed in conjunction with LF- SOM fingerprints to decipher the responses of LF- SOM transformation to N additions. The significant correlations between LF- SOM and microbial biomass, between organic compounds in LF- SOM and compound degradation- related genes, and between LF- SOM and net ecosystem exchange implied LF- SOM were the main fraction utilized by microorganisms and the most sensitive fraction to N additions. The LF- SOM increased at the lowest N addition levels (10 and 20 kg N·ha- 1·yr- 1) and decreased at higher N addition levels (40 to 160 kg N·ha- 1·yr- 1), but the decrease of LF- SOM was weakened at 160 kg N·ha- 1·yr- 1 addition. The nonlinear response of LF- SOM to N additions was due to the mass balance between plant inputs and microbial degradation. Plant- derived compounds in LF- SOM were more sensitive to N addition than microbial- derived and aromatic compounds. It is predicted that when the N deposition rate increased by 10 kg N·ha- 1·yr- 1 on the QTP, carbon sequestration in the labile fraction may increase by nearly 170% compared with that under the current N deposition rate. These findings provide insight into future N deposition impacts on LF- SOM preservation on the QTP.Key PointsThe LF- SOM quantity increased at the lowest N additions (N10 and N20) and decreased from N40 to N160, but the decrease was weakened at the highest N addition (N160)Plant- derived compounds in LF- SOM were more sensitive to N addition than microbial- derived and aromatic compoundsThe organic compounds in LF- SOM were significantly correlated with compound degradation- related genesPeer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154963/1/jgrg21637_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154963/2/jgrg21637.pd

Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency

Acyl-CoA dehydrogenase 9 (ACAD9) is an assembly factor for mitochondrial respiratory chain Complex I (CI), and ACAD9 mutations are recognized as a frequent cause of CI deficiency. ACAD9 also retains enzyme ACAD activity for long-chain fatty acids in vitro, but the biological relevance of this function remains controversial partly because of the tissue specificity of ACAD9 expression: high in liver and neurons and minimal in skin fibroblasts. In this study, we hypothesized that this enzymatic ACAD activity is required for full fatty acid oxidation capacity in cells expressing high levels of ACAD9 and that loss of this function is important in determining phenotype in ACAD9-deficient patients. First, we confirmed that HEK293 cells express ACAD9 abundantly. Then, we showed that ACAD9 knockout in HEK293 cells affected long-chain fatty acid oxidation along with Cl, both of which were rescued by wild type ACAD9. Further, we evaluated whether the loss of ACAD9 enzymatic fatty acid oxidation affects clinical severity in patients with ACAD9 mutations. The effects on ACAD activity of 16 ACAD9 mutations identified in 24 patients were evaluated using a prokaryotic expression system. We showed that there was a significant inverse correlation between residual enzyme ACAD activity and phenotypic severity of ACAD9-deficient patients. These results provide evidence that in cells where it is strongly expressed, ACAD9 plays a physiological role in fatty acid oxidation, which contributes to the severity of the phenotype in ACAD9-deficient patients. Accordingly, treatment of ACAD9 patients should aim at counteracting both CI and fatty acid oxidation dysfunction

The Complete Genome Sequence of ‘Candidatus Liberibacter solanacearum’, the Bacterium Associated with Potato Zebra Chip Disease

Zebra Chip (ZC) is an emerging plant disease that causes aboveground decline of potato shoots and generally results in unusable tubers. This disease has led to multi-million dollar losses for growers in the central and western United States over the past decade and impacts the livelihood of potato farmers in Mexico and New Zealand. ZC is associated with ‘Candidatus Liberibacter solanacearum’, a fastidious alpha-proteobacterium that is transmitted by a phloem-feeding psyllid vector, Bactericera cockerelli Sulc. Research on this disease has been hampered by a lack of robust culture methods and paucity of genome sequence information for ‘Ca. L. solanacearum’. Here we present the sequence of the 1.26 Mbp metagenome of ‘Ca. L. solanacearum’, based on DNA isolated from potato psyllids. The coding inventory of the ‘Ca. L. solanacearum’ genome was analyzed and compared to related Rhizobiaceae to better understand ‘Ca. L. solanacearum’ physiology and identify potential targets to develop improved treatment strategies. This analysis revealed a number of unique transporters and pathways, all potentially contributing to ZC pathogenesis. Some of these factors may have been acquired through horizontal gene transfer. Taxonomically, ‘Ca. L. solanacearum’ is related to ‘Ca. L. asiaticus’, a suspected causative agent of citrus huanglongbing, yet many genome rearrangements and several gene gains/losses are evident when comparing these two Liberibacter. species. Relative to ‘Ca. L. asiaticus’, ‘Ca. L. solanacearum’ probably has reduced capacity for nucleic acid modification, increased amino acid and vitamin biosynthesis functionalities, and gained a high-affinity iron transport system characteristic of several pathogenic microbes