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The synergy between drought-responsive traits across different organs is crucial in the whole-plant mechanism influencing drought resilience. These organ interactions, however, are poorly understood, limiting our understanding of drought response strategies at the whole-plant level. Therefore, we need more integrative studies, especially on herbaceous species that represent many important food crops but remain underexplored in their drought response. We investigated inflorescence stems and rosette leaves of six Arabidopsis thaliana genotypes with contrasting drought tolerance, and combined anatomical observations with hydraulic measurements and gene expression studies to assess differences in drought response. The soc1ful double mutant was the most drought-tolerant genotype based on its synergistic combination of low stomatal conductance, largest stomatal safety margin, more stable leaf water potential during non-watering, reduced transcript levels of drought stress marker genes, and reduced loss of chlorophyll content in leaves, in combination with stems showing the highest embolism resistance, most pronounced lignification, and thickest intervessel pit membranes. In contrast, the most sensitive Cvi ecotype shows the opposite extreme of the same set of traits. The remaining four genotypes show variations in this drought syndrome. Our results reveal that anatomical, ecophysiological, and molecular adaptations across organs are intertwined, and multiple (differentially combined) strategies can be applied to acquire a certain level of drought tolerance. ispartof: JOURNAL OF EXPERIMENTAL BOTANY vol:74 issue:3 ispartof: location:England status: Published online

Oratie uitgesproken door prof.dr.R. Offringa bij de aanvaarding van het ambt van hoogleraar op het gebied van Ontwikkelingsgenetica van Planten aan de Universiteit Leiden op vrijdag 16 maart 2018.

The plant hormone auxin is a vital component for plant reproduction as it regulates the development of both male and female reproductive organs, including ovules and gynoecia. Furthermore, auxin plays important roles in the development and growth of seeds and fruits. Auxin responses can be detected in ovules shortly after fertilization, and it has been suggested that this accumulation is a prerequisite for the developmental reprogramming of the ovules to seeds, and of the gynoecium to a fruit. However, the roles of auxin at the final stages of ovule development, and the sources of auxin leading to the observed responses in ovules after fertilization have remained elusive. Here we have characterized the auxin readout in Arabidopsis ovules, at the pre-anthesis, anthesis and in the immediate post-fertilization stages, using the R2D2 auxin sensor. In addition we have mapped the expression of auxin biosynthesis and conjugation genes, as well as that of auxin transporting proteins, during the same developmental stages. These analyses reveal specific spatiotemporal patterns of the different auxin homeostasis regulators. Auxin biosynthesis genes and auxin transport proteins define a pre-patterning of vascular cell identity in the pre-anthesis funiculus. Furthermore, our data suggests that auxin efflux from the ovule is restricted in an anther-dependent manner, presumably to synchronize reproductive organ development and thereby optimizing the chances of successful fertilization. Finally, de novo auxin biosynthesis together with reduced auxin conjugation and transport result in an enhanced auxin readout throughout the sporophytic tissues of the ovules soon after fertilization. Together, our results suggest a sophisticated set of regulatory cascades that allow successful fertilization and the subsequent transition of the female reproductive structures into seeds and fruits.

Germline genetic variability might contribute, at least partially, to the survival of pancreatic ductal adenocarcinoma (PDAC) patients. Two recently performed genome-wide association studies (GWAS) on PDAC overall survival (OS) suggested (P < 10-5) the association between 30 genomic regions and PDAC OS. With the aim to highlight the true associations within these regions, we analyzed 44 single-nucleotide polymorphisms (SNPs) in the 30 candidate regions in 1722 PDAC patients within the PANcreatic Disease ReseArch (PANDoRA) consortium. We observed statistically significant associations for five of the selected regions. One association in the CTNNA2 gene on chromosome 2p12 [rs1567532, hazard ratio (HR) = 1.75, 95% confidence interval (CI) 1.19-2.58, P = 0.005 for homozygotes for the minor allele] and one in the last intron of the RUNX2 gene on chromosome 6p21 (rs12209785, HR = 0.88, 95% CI 0.80-0.98, P = 0.014 for heterozygotes) are of particular relevance. These loci do not coincide with those that showed the strongest associations in the previous GWAS. In silico analysis strongly suggested a possible mechanistic link between these two SNPs and pancreatic cancer survival. Functional studies are warranted to confirm the link between these genes (or other genes mapping in those regions) and PDAC prognosis in order to understand whether these variants may have the potential to impact treatment decisions and design of clinical trials. © The Author 2016. Published by Oxford University Press. All rights reserved.

The authors informed us of problems related to Fig. 3C and Fig. 7D in Development 137, 3245-3255. Both issues were noted by an investigation by the Technical Committee of Utrecht University (UTC) into this publication. Based on the findings provided (detailed below), the journal has decided that the major conclusions of the paper are not affected and that retraction is not required, but that a correction should be provided with an explanation of the circumstances. This course of action complies with our policy on correction of issues in the scientific record, which states: “Should an error appear in a published article that affects scientific meaning or author credibility but does not affect the overall results and conclusions of the paper, our policy is to publish a Correction”.Development 2010 137: 3245-3255; doi: 10.1242/dev.052456

CD4+ Th cells play an important role in the induction and maintenance of specific T cell immunity. Indications for a protective role of CD4+ T cells against HIV-1 infection were found in subjects who were able to control HIV-1 viremia as well as in highly HIV-1-exposed, yet seronegative, individuals. This study describes the identification of an HIV-1-specific Th epitope that exhibits high affinity binding as well as high immunogenicity in the context of at least four different HLA-DR molecules that together cover 50–60% of the Caucasian, Oriental, and Negroid populations. This HIV-1 reverse transcriptase-derived peptide (RT171–190) is highly conserved among different HIV-1 isolates. Importantly, stimulation of PBL cultures from HIV-1 seronegative donors with this peptide resulted in Th1-type lymphocytes capable of efficient recognition of HIV-1-pulsed APCs. Taken together, these data indicate that peptide RT171–190 constitutes an attractive component of vaccines aiming at induction or enhancement of HIV-1-specific T cell immunity.

Dendritic cells (DCs) play a central role in the immune system as they drive activation of T lymphocytes by cognate interactions. However, as DCs express high levels of major histocompatibility complex class I, this intimate contact may also result in elimination of DCs by activated cytotoxic T lymphocytes (CTLs) and thereby limit induction of immunity. We show here that immature DCs are indeed susceptible to CTL-induced killing, but become resistant upon maturation with anti-CD40 or lipopolysaccharide. Protection is achieved by expression of serine protease inhibitor (SPI)-6, a member of the serpin family that specifically inactivates granzyme B and thereby blocks CTL-induced apoptosis. Anti-CD40 and LPS-induced SPI-6 expression is sustained for long periods of time, suggesting a role for SPI-6 in the longevity of DCs. Importantly, T helper 1 cells, which mature DCs and boost CTL immunity, induce SPI-6 expression and subsequent DC resistance. In contrast, T helper 2 cells neither induce SPI-6 nor convey protection, despite the fact that they trigger DC maturation with comparable efficiency. Our data identify SPI-6 as a novel marker for DC function, which protects DCs against CTL-induced apoptosis

We have previously shown that small B16 melanomas can be successfully treated using a combination of anti-cytotoxic T lymphocyte antigen (CTLA)-4 monoclonal antibody with a granulocyte/macrophage colony-stimulating factor (GM-CSF) producing irradiated tumor cell vaccine. Regression of tumors results in long-lasting immunity and is frequently accompanied by autoimmune depigmentation. Here we examine the cellular and molecular mechanisms of this combined treatment. Histological examination of depigmented lesions revealed infiltration of polymorphonuclear cells and deposition of antibody. The combination therapy also induced tumor rejection and skin depigmentation in B cell-deficient and in CD4(+) T cell-depleted mice. Both effects of the treatment absolutely required CD8(+) T cells. Analysis of the response in successfully treated mice revealed elevated levels of CD8(+) T cells specific for a nonameric peptide consisting of residues 180-188 of the melanocyte differentiation antigen tyrosinase-related protein (TRP)2. There was no evidence of reactivity to the melanocyte antigens gp100, tyrosinase, Mart1/MelanA, or TRP1. Fas-FasL interactions and perforin played a role in mounting the effector response, whereas the tumor necrosis factor pathway was not required. The cellular requirements for tumor rejection in this therapeutic setting were strikingly different from those in a prophylactic setting. In particular, if mice received a prophylactic vaccine consisting of anti-CTLA-4 and B16-GM-CSF before tumor challenge, full protection was obtained even in the absence of CD8(+) T cells. Our data demonstrate that therapeutic autoreactive CD8(+) T cell responses can effectively be generated in tumor-bearing mice and stresses the value of studying tumor immunity in a therapeutic rather than a prophylactic setting