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When panic rocker Udo Lindenberg goes on tour it becomes total art for the eyes and ears
In his locker Lindenberg has everything that makes a show the absolute highlight: artists
which create a light and video show with extra class and perfect sound
This was certainly the case with the recently completed tour of the new album Stronger than Time (Stärker als die Zeit)
The 71-year-old does not think he will ever stop
and promises his fans another 30 years of well-refined panic with orchestra
his lighting designer and operator for many years
is likely to be at his side for many years to come
the design was created in the show lab of Michael Schenk’s company
As with the previous tours of the panic-rockers
Jäckle is again using a lot of fixtures from Karlsbad-based GLP
24 impression X4 Bar10 as well as 24 GT-1 hybrids
“The JDC1 was a genuine premiere for me,” admitted Jäckle
who for the first time ever abandoned conventional strobes and instead directly integrated the new JDC1 LED strobes into his design
“This lamp — a synthesis of strobe and floodlight — has never existed until now,” he said
describing the unusual characteristic of the JDC1
“And the tilt function comes on top of that”
he also talked positively about the GLP’s GT-1 hybrids
They are absolutely reliable – but what else would you expect?” Both lamps are used not only as floor effects on the elevated rear stage
but also on ladders to the right and left of the stage
where the GT-1 and JDC1 are mounted alternately
In addition to the GT-1 hybrid and the JDC1 strobe
Jäckle once again relied on GLP’s impression X4 Bars
A total of 24 pieces of the shorter impression X4 Bar10 were used in a battery above the stage and ensured an entire range of dynamics
from scattered beams to glittering floodlight effects
“Designing and lighting an arena tour is still a discipline quite different from the upcoming open-air gigs with Udo
much more atmospheric,” Jäckle continued
outlining the differences with the upcoming show at the Meyer shipyard in Papenburg and the Panikliner
which sets sail for five days at the beginning of September
From his long history with the primordial German rock scene
Jäckle knows to always expect the unexpected: “Udo is always close at hand
how he imagines certain parts and ultimately also decides how the show should look
And you might have to be prepared to create that special green ‘private eye’ light
Even Jäckle doesn’t know if a look like this will be part of the show in Papenburg — but you can bet that lamps from GLP will be there at the start again
https://www.glp.de/en/
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By Fred Meintjes2015-11-11T10:19:51+00:00
A new range of apples with red and pink flesh appears set to arrive on supermarket shelves across Europe and beyond after a group of growers and marketers agreed to produce and sell the fruit under licence
Efforts to bring the apples to market took a significant step forward last month
when an evaluation panel consisting of 17 different companies known to be interested in the apples met in Edingen-Neckarhausen
South African plant breeder Re:inc Innovation and UK-based fruit science centre East Malling Research (EMR)
the panel sampled various apple types from experimental orchards in Germany and Belgium before recommending the immediate commercial release of three new varieties and suggesting one further variety for potential future development
“The delegates tasted ten selections – two red-fleshed and eight pink-fleshed apples – and the consensus was that three or perhaps four selections are commercial varieties in terms of their appearance and taste,” says one of Re:inc’s directors
Re:inc and EMR have been working together on the breeding programme since 2008
Re:inc topfruit breeder Dr Iwan Labuschagne
who put together the range from varieties bred at EMR
describes the red-fleshed selections as crunchy
juicy and sweeter than any of the current crop of competitors
are “snappy (like a Honeycrisp) with lots of wonderful juice and aromas,” he says
Re:inc has assembled a club of international growers alongside a handful of selected marketers who will be granted exclusive access to its apple and pear breeding programme
“These licensees will have the exclusive rights to the new varieties in their countries,” explains Riaan van Wyk
this will also ensure supply of the varieties for 12 months of the year.”
New types of fruit emerging from the programme are going to deliver new tastes and flavours for consumers to enjoy
fully coloured pink apples as well as blushed
fully coloured and brilliant pink and red pears that offer a crisp
“The consumers can eat these pears from the tree or fridge like an apple
but with a lot more aromas and flavour [than] ever previously experienced.”
Re:inc’s plan is to roll out a comprehensive breeding programme that taps into international expertise
working with other breeders and variety owners to run production trials in both the Northern and Southern Hemispheres
“We have sourced a range of unique breeding parents from international breeding programmes since 2008 which we are evaluating and using in our new variety development programme,” Dr Labuschagne adds
Kriegler says there is a lot of work that must now be done to expand the whole operation
“It is also important to find the correct international and South African partners and licensees for commercial plantings
increase the size of the breeding operation in the Northern Hemisphere to 5,000 to 8,000 seedlings per annum – in order to be at the same level as the South African operations – and to introduce modern technology
like marker-assisted selection (non-GMO) where applicable.”
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Elimination of suppressive T cells may enable and enhance cancer immunotherapy
we demonstrate that the cell membrane protein SLAMF7 was highly expressed on immunosuppressive CD8+CD28-CD57+ Tregs in multiple myeloma (MM)
SLAMF7 expression associated with T cell exhaustion surface markers and exhaustion-related transcription factor signatures
T cells from patients with a high frequency of SLAMF7+CD8+ T cells exhibited decreased immunoreactivity towards the MART-1aa26–35*A27L antigen
A monoclonal anti-SLAMF7 antibody (elotuzumab) specifically depleted SLAMF7+CD8+ T cells in vitro and in vivo via macrophage-mediated antibody-dependent cellular phagocytosis (ADCP)
Anti-SLAMF7 treatment of MM patients depleted suppressive T cells in peripheral blood
These data highlight SLAMF7 as a marker for suppressive CD8+ Treg and suggest that anti-SLAMF7 antibodies can be used to boost anti-tumoral immune responses in cancer patients
SLAMF7 is a highly expressed marker on the surface of suppressive CD8+ T cells and its expression correlates with an exhausted phenotype in T cells
SLAMF7+ CD8+ Treg cells could be eliminated using anti-SLAMF7 antibody Elotuzumab via antibody-dependent cellular phagocytosis in vitro and in vivo
this activation in NK cells occurred only with the full-length isoform of SLAMF7 (SLAMF7-L) since the truncated isoform (SLAMF7-S) lacks the EAT-2 binding site in the immunoreceptor tyrosine-based switch motif
EAT-2 was expressed in NK cells but not myeloma cells
This finding might explain the different modes of action of elotuzumab in these two cell populations
Little is known about SLAMF7 and EAT-2 expression patterns and the signaling consequences of SLAMF7 in T cells
especially in those derived from MM patients
Based on the expression patterns of SLAMF7 and its signaling intermediates in various T cell subsets
elotuzumab may have distinct effects in various T cell subsets
To analyze SLAMF7 protein expression in T cells
PB/buffy coats from HDs (Institute for Immunology/IKTZ
Germany) and PB/BM from patients with MM were used
In accordance with the Declaration of Helsinki
all human studies were performed after obtaining written informed consent
all human studies were approved by the Ethics Committee of the Medical Faculty at Heidelberg University
Data safety management was performed according to the data protection regulations of University Hospital Heidelberg
proteins were labeled at an adjusted concentration with scioDye 1 and scioDye 2 (Sciomics)
The samples were incubated competitively using a dual-color approach on 10 scioCD antibody microarrays (Sciomics)
Slide scanning was conducted using a Powerscanner (Tecan) with identical instrument laser power and constant PMT settings
Spot segmentation was performed with GenePix Pro 6.0 (Molecular Devices)
Acquired raw data were analyzed using the linear models for microarray data (LIMMA) package of R-Bioconductor including normalization (specialized invariant Lowess method)
For analysis of the samples a one-factorial linear model was fitted with LIMMA resulting in a two-sided t-test or F-test based on moderated statistics
The false discovery rate was controlled according to Benjamini and Hochberg
generated macrophages were co-incubated with isolated CPD (Cell Proliferation Dye eFluor® 670
Thermo Fisher) labeled T cells in the absence or presence of elotuzumab (10 µg/ml
37 °C) or an irrelevant IgG1 antibody (isotype control)
Phagocytosis was monitored after 2 h by FACS or confocal microscopy (LSM700
freshly isolated tumor cells (from sacrificed animals) were dissociated by mincing the tissue with scalpels into 0.5-mm small pieces
Dissociated tissue was further triturated and filtered through a 100-mm cell strainer to obtain single-cell suspension
Cell suspension was then analyzed by flow cytometry to determine the frequency of the specific T cell populations
Animal experiments were performed according to approved protocol from the local animal welfare authorities of Rheinland-Pfalz (protocol AZ 23 177-07/G16-1-016)
CD8+ T cells were isolated from MNCs of patients or HDs using a CD8+ T Cell Isolation Kit (Miltenyi Biotec
Germany) according to the manufacturer’s protocol
The cells were then stained with antibodies and sorted using FACS according to a standard protocol into the SLAMF7+ and SLAMF7−CD8+ T cell populations
RNA was isolated using an RNeasy Mini Kit (Qiagen
and RNA-Seq libraries were prepared using an Illumina RNA-Seq Preparation Kit and sequenced by a HiSeq 4000 with paired-end 100-bp sequencing
yielding 200 million reads per lane after passing quality control (QC) analyses in the Genomics and Proteomics Core Facility
All raw data have been deposited at the European Genome-Phenome Archive (EGAS00001004915)
The impact of elotuzumab on T cells expressing SLAMF7 was evaluated by analyzing paired patient samples before and after induction therapy by Wilcoxon’s signed rank test using the R computing environment (version 3.6.1)
Other comparisons between different patient groups were performed by t-tests using GraphPad (version 8.0) software
A result was considered significant at p < 0.05 with ∗
a Representative gating strategy used to identify the percentage of SLAMF7-expressing CD8+ T cells (CD45+CD3+CD8+SLAMF7+) by flow cytometry
b The percentages of SLAMF7+ and SLAMF7− T cells in each state (CD8+ effector: CD62L–CD45RA+; CD8+ naïve: CD62L+CD45RA+; CD8+ central memory: CD62L+CD45RA−; and CD8+ effector memory: CD62L–CD45RA–); T cells were analyzed in BM samples from NDMM patients (n = 9)
c Representative histogram of modal SLAMF7 expression on the surface of CD8+ and CD4+ cells analyzed in BM samples from NDMM patients
d The percentages of SLAMF7-positive CD8+CD28+CD57− (left) and CD8+CD28−CD57+ (right) cells from the BM of NDMM patients (n = 6)
e The percentage of cells expressing exhaustion markers (PD-1
and LAG-3) among SLAMF7+ and SLAMF7-CD8+ cells from the BM of NDMM patients (n = 4)
Differences between groups were compared using either Student’s t-test or Wilcoxon matched-pairs signed rank test; ∗p < 0.05
these findings suggested that SLAMF7+CD8+ T cells are in an exhaustion state
SLAMF7 was unlikely to initiate CD8+ T cell exhaustion pathways
a Heatmap showing the differential expression of the top 300 significantly up- and downregulated genes (LFC > 2, adjusted p value < 0.05) in SLAMF7+/SLAMF7− CD8+ T cells (n = 3). A full list of all DE genes in SLAMF7+/SLAMF7− T cells is shown in Data Table 1
b Heatmap showing the differential expression of exhaustion markers that were significantly elevated in CD8+ SLAMF7+ T cells compared with those in CD8+ SLAMF7− T cells and exhaustion markers that were not consistently elevated (n = 3)
c Relative expression of CD8+ Treg markers in SLAMF7+ and SLAMF7−CD8+ T cells (n = 3)
d Relative expression of exhaustion-related transcripts in SLAMF7+ and SLAMF7−CD8+ T cells (n = 3)
e GSEA plots showing the enrichment of “positive regulation of interleukin-6 production” and “reactome immunoregulatory interactions between a lymphoid and a nonlymphoid cell” in SLAMF7+CD8+ T cells (n = 3)
Differences in gene expression levels were tested by Wald tests within negative binomial generalized linear models
The procedure of Benjamini and Hochberg (BH) was then applied to calculate the adjusted p values to control the false discovery rate at 0.05
further indicating the exhausted state of these cells
a Schematic figure describing the MART-1aa26–35*A27L ELISPOT antigen-specific T cell model
b Scatter plots showing the effect of adding CD8+SLAMF7+ from the BM of NDMM during the expansion of HD antigen-specific T cells (n = 7)
c Microscopic photo highlights the difference in the frequency of IFN-γ spots between CD8+ T cells cultured with (right) or without (left) SLAMF7+CD8+ cells in the ELISPOT wells
d Volcano plot showing the differential expressed proteins in the supernatants of T cell cultures
Green dots represent proteins differentially expressed in the CD8+SLAMF7+ containing cell cultures
red dots represent proteins differentially expressed in the control cell cultures (n = 5)
e Heatmap showing the top differentially expressed proteins
f Scatter plots showing the effect of CD8+SLAMF7+ abundance on antigen-specific T cell response (measured by the mean of IFN-γ spots) in 45 NDMM patients (p = 0.01)
Differences between groups were compared using Mann Whitney test; ∗p < 0.05
a–c Scatter plots showing the difference in the frequencies of CD8+ T cells expressing SLAMF7 (of total CD8+ cells) before (T1) and after (T2) induction therapy
with each dot representing one patient (n = 73 in study arm A
d–f Scatter plots showing the difference in the percentage of CD8+ Treg cells (of total CD8+ cells) before (T1) and after (T2) induction therapy
with each dot representing one patient (n = 22 in study arm A
g–i Scatter plots showing the difference in NK cell percentages (of total lymphocytes) before (T1) and after (T2) induction therapy
with each dot representing one patient (n = 20 in study arm A
Differences between groups were evaluated using Student’s t-test; ∗p < 0.05
a Macrophages were co-incubated with autologous CPD-labeled T cells (E:T = 1:1) in the presence or absence of elotuzumab (10 μg/ml) or control IgG1 antibody for 24 h
To distinguish between phagocytosed CPD-positive T cells and free T cells
macrophages were counterstained with an anti-CD11b antibody and analyzed by flow cytometry
b Bar graph showing the mean percentage of phagocytosed T cells (CD11b+ and CPD+) from six independent experiments
c CPD-labeled T cells (red) were added to autologous macrophages (stained with CFSE
green) as effectors at an E/T ratio of 1:1 in the presence or absence of elotuzumab or control IgG1 antibody (10 μg/ml)
Samples were counterstained with DAPI (blue)
phagocytosis was analyzed by confocal microscopy at 630X
d Representative figure describing the mouse model experiment
e Bar graph showing the mean percentage of CD8+ T cells per tumor with or without elotuzumab therapy from 4 different mice (p = 0.043)
f Scatter plot showing the percentage of NK (from total lymphocytes) and CD8+ T cells expressing SLAMF7 (from total CD8+ compartment) from the PB of NDMM patients (n = 42 and n = 146
respectively); each dot represents a single patient (p < 0.0001)
g Scatter plot showing the mean fluorescence intensity (MFI) of CD47 for both NK and CD8+ T cells from the PB of NDMM patients (n = 8
h Bar graph showing the mean frequency of apoptotic CD8 + T cells (% of total CD8+) in varying concentrations of elotuzumab (n = 4)
The current study provides evidence that exhausted cytotoxic T cells which express TIGIT and share the Treg phenotype can be depleted by ADCP using anti-SLAMF7 antibody
Data from the GMMG HD6 trial (NCT02495922)
in which patients with NDMM were randomized for induction therapy with 4 cycles of either VRD only or VRD and elotuzumab
showed no clinical correlation of SLAMF7 expression on T cells with the response after induction (data not shown)
This likely reflects the challenge in detecting such a significant correlation during highly efficient first line therapy of MM
which results in remission for most patients
As SLAMF7 expression in macrophages was not determined in this clinical study
we cannot conclude whether SLAMF7 expression on this ADCP-mediating cell type plays a role in enhancing the elotuzumab-mediated elimination of SLAMF7+CD8+ T cells in MM patients
Management of relapsed and refractory multiple myeloma: novel agents
Multiple myeloma epidemiology and survival: a unique malignancy
a novel human natural killer cell receptor belonging to the CD2 subset of the immunoglobulin superfamily
2B4 (CD244) and CS1: novel members of the CD2 subset of the immunoglobulin superfamily molecules expressed on natural killer cells and other leukocytes
a potential new therapeutic antibody target for the treatment of multiple myeloma
Molecular and functional characterization of a CS1 (CRACC) splice variant expressed in human NK cells that does not contain immunoreceptor tyrosine-based switch motifs
Plasma membrane proteomics identifies biomarkers associated with MMSET overexpression in T(4;14) multiple myeloma
CS1 promotes multiple myeloma cell adhesion
and tumorigenicity via c-maf-mediated interactions with bone marrow stromal cells
Elotuzumab in combination with thalidomide and low-dose dexamethasone: a phase 2 single-arm safety study in patients with relapsed/refractory multiple myeloma
Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised
Elotuzumab therapy for relapsed or refractory multiple myeloma
Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth
Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma
The anti-SLAMF7 antibody elotuzumab mediates NK cell activation through both CD16-dependent and -independent mechanisms
Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC
Elotuzumab enhances natural killer cell activation and myeloma cell killing through interleukin-2 and TNF-α pathways
PD-1 blockade enhances elotuzumab efficacy in mouse tumor models
SLAMF7-CAR T cells eliminate myeloma and confer selective fratricide of SLAMF7+ normal lymphocytes
The cytotoxicity receptor CRACC (CS-1) recruits EAT-2 and activates the PI3K and phospholipase C signaling pathways in human NK cells
Non-antigen specific CD8+ T suppressor lymphocytes
CD8+ CD28- T regulatory lymphocytes inhibiting T cell proliferative and cytotoxic functions infiltrate human cancers
IL-10 inducible CD8+ regulatory T-cells are enriched in patients with multiple myeloma and impact the generation of antigen-specific T-cells
Rationale and design of the German-speaking myeloma multicenter group (GMMG) trial HD6: a randomized phase III trial on the effect of elotuzumab in VRD induction/consolidation and lenalidomide maintenance in patients with newly diagnosed myeloma
The prognostic and predictive value of IKZF1 and IKZF3 expression in T-cells in patients with multiple myeloma
Novel recurrent chromosomal aberrations detected in clonal plasma cells of light chain amyloidosis patients show potential adverse prognostic effect: first results from a genome-wide copy number array analysis
and treatment affecting prognosis of deletion 17p in newly diagnosed myeloma
IKZF1 expression is a prognostic marker in newly diagnosed standard-risk multiple myeloma treated with lenalidomide and intensive chemotherapy: a study of the German Myeloma Study Group (DSMM)
Lenalidomide enhances MOR202-dependent macrophage-mediated effector functions via the vitamin D pathway
A potent tumor-reactive p53-specific single-chain TCR without on- or off-target autoimmunity in vivo
Sambamba: fast processing of NGS alignment formats
The sequence alignment/map format and SAMtools
RNA-SeQC: RNA-seq metrics for quality control and process optimization
featureCounts: an efficient general purpose program for assigning sequence reads to genomic features
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2
Love MI Heavy-tailed prior distributions for sequence count data: removing the noise and preserving large differences
clusterProfiler: an R package for comparing biological themes among gene clusters
The molecular signatures database (MSigDB) hallmark gene set collection
TIGIT: a key inhibitor of the cancer immunity cycle
TIGIT immune checkpoint blockade restores CD8+ T-cell immunity against multiple myeloma
Myeloma escape after stem cell transplantation is a consequence of T-cell exhaustion and is prevented by TIGIT blockade
The transcription factor NFAT promotes exhaustion of activated CD8+ T cells
Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles
Lenalidomide overcomes the immunosuppression of regulatory CD8+CD28- T-cells
Identification of a new HLA-A2-restricted T-cell epitope within HM1.24 as immunotherapy target for multiple myeloma
Effects of IL-8 up-regulation on cell survival and osteoclastogenesis in multiple myeloma
Role of INTERLEUKIN-6 in the pathogenesis of multiple myeloma
Preclinical validation of interleukin 6 as a therapeutic target in multiple myeloma
Expansion of activated regulatory T cells by myeloid-specific chemokines via an alternative pathway in CSF of bacterial meningitis patients
controls NK cell activation through phospholipase Cγ
a SLAM family receptor coupled to the adaptor EAT-2
Nivolumab in patients with relapsed or refractory hematologic malignancy: preliminary results of a phase Ib study
Targeting the PD-1/PD-L1 axis in multiple myeloma: a dream or a reality
SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via Mac-1 integrin
Cancer cell-expressed SLAMF7 is not required for CD47-mediated phagocytosis
CD8 T cells expressing NK associated receptors are increased in melanoma patients and display an effector phenotype
Foxp3 expressing CD4+ CD25+ and CD8+CD28- T regulatory cells in the peripheral blood of patients with lung cancer and pleural mesothelioma
Origin of CD57+ T cells which increase at tumour sites in patients with colorectal cancer
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the study nurses and all the members of the study teams at the participating GMMG trial sites
the coordination centers for clinical trials (KKS) in Heidelberg and Leipzig
the participating patients and their families
Georg Steinbuß for his great help and suggestions
This study was supported by grants from Celgene
Hakim Echchannaoui and Markus Munder were supported by grants from Deutsche Forschungsgemeinschaft (SFB 1292/1
Open Access funding enabled and organized by Projekt DEAL
Hartmut Goldschmidt & Michael Hundemer
University Medical Center (UMC) of the Johannes Gutenberg University
Clinical Cooperation Unit Molecular Hematology/Oncology
German Cancer Research Center and Department of Internal Medicine V
Carsten Müller-Tidow & Hartmut Goldschmidt
University Medical Center of Hamburg-Eppendorf
MHSA: Research funding from BMS and Celgene
HB: Research grant by Morphosys and Celgene Corporation
MSR: Research Support (Institutions): Amgen
KW: Received honoraria and is advisory board member of Amgen
Janssen and received research funding (to the institution) from Amgen
RF: Honoraria and Travelgrants Celgene from BMS
HG: Grants and/or provision of Investigational Medicinal Product (IMP*): Amgen
Novartis Advisory Boards (Institutions): Adaptive Biotechnology
Takeda Honoraria (Speakers Bureaus): ArtTempi
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DOI: https://doi.org/10.1038/s41375-021-01172-x
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By Fred Meintjes2016-04-27T10:11:11+01:00
The Re:inc Innovation tasting session in Paarl
A number of international and South African growers and marketers have tasted the new apple and pear varieties that are emerging from Re:inc Innovation's breeding programmes
The group included one leading supermarket and the tasting took place during a mini conference aimed at reviewing the progress of re:inc innovations’ new cultivar programme
The visitors tasted 16 pear and 18 apple selections from the breeding programme and the response was very positive according to Riaan van Wyk
“Every visitor was requested to complete evaluation sheets and the results show that many of the selections have clear commercial potential,” he said
Re:inc director Liezel Kriegler noted that six licensees have already signed up for the breeding programmes and The company was in negotiations with 14 further groups to take up licenses
“There are a few more licenses open for discussion and re:inc hopes to finalise them all during 2016,' she explained
The Licensees will have the exclusive or semi- exclusive rights to all the seedlings or selections in the breeding programme for their country
This will give the licensees a major advantage both now and in the long-term
Re:inc and East Malling Service launched a range of red and pink flesh apples in Edingen-Neckarhausen in Germany
where re:inc also breeds apples and pears on an annual basis
five of these selections scored high points and they are now in a process of multiplying the planting material for licensees to plant these selections on a commercial scale
“Re:inc Innovation focuses on bi-colour and bright red pears that are crispy
We believe that the pears of the future will be eaten like an apple
from the tree or refrigerator,” he continued
The apple sector is becoming more competitive with a number of bi–coloured apples entering the market over the last few years
“Re:inc Innovation is focused on brighter red and pink apples with a lot more flavour
snappiness and high juice contents,' Kriegler continued
outlining that there are still many gaps in the market and predicting that pink-
yellow- and orange-fleshed apples would make a difference to the global industry