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Sugarcane, the world's most harvested crop by tonnage, has shaped global history, trade and geopolitics, and is currently responsible for 80% of sugar production worldwide1. While traditional sugarcane breeding methods have effectively generated cultivars adapted to new environments and pathogens, sugar yield improvements have recently plateaued2. The cessation of yield gains may be due to limited genetic diversity within breeding populations, long breeding cycles and the complexity of its genome, the latter preventing breeders from taking advantage of the recent explosion of whole-genome sequencing that has benefited many other crops. Thus, modern sugarcane hybrids are the last remaining major crop without a reference-quality genome. Here we take a major step towards advancing sugarcane biotechnology by generating a polyploid reference genome for R570, a typical modern cultivar derived from interspecific hybridization between the domesticated species (Saccharum officinarum) and the wild species (Saccharum spontaneum). In contrast to the existing single haplotype ('monoploid') representation of R570, our 8.7 billion base assembly contains a complete representation of unique DNA sequences across the approximately 12 chromosome copies in this polyploid genome. Using this highly contiguous genome assembly, we filled a previously unsized gap within an R570 physical genetic map to describe the likely causal genes underlying the single-copy Bru1 brown rust resistance locus. This polyploid genome assembly with fine-grain descriptions of genome architecture and molecular targets for biotechnology will help accelerate molecular and transgenic breeding and adaptation of sugarcane to future environmental conditions.

Abstract Background Colorectal cancer is a public health issue and was the third leading cause of cancer-related death worldwide in 2022. Early diagnosis can improve prognosis, making screening a central part of colorectal cancer management. Blood-based screening, diagnosis and follow-up of colorectal cancer patients are possible with the study of cell-free circulating tumor DNA. This study aimed to identify novel DNA methylation biomarkers of colorectal cancer that can be used for the follow-up of patients with colorectal cancer. Methods A DNA methylation profile was established in the Gene Expression Omnibus (GEO) database (n = 507) using bioinformatics analysis and subsequently confirmed using The Cancer Genome Atlas (TCGA) database (n = 348). The in silico profile was then validated on local tissue and cell-free DNA samples using methylation-specific digital PCR in colorectal cancer patients (n = 35) and healthy donors (n = 35). Results The DNA methylation of COL25A1 and METAP1D was predicted to be a colorectal cancer biomarker by bioinformatics analysis (ROC AUC = 1, 95% CI [0.999–1]). The two biomarkers were confirmed with tissue samples, and the combination of COL25A1 and METAP1D yielded 49% sensitivity and 100% specificity for cell-free DNA. Conclusion Bioinformatics analysis of public databases revealed COL25A1 and METAP1D DNA methylation as clinically applicable liquid biopsies DNA methylation biomarkers. The specificity implies an excellent positive predictive value for follow-up, and the high sensitivity and relative noninvasiveness of a blood-based test make these biomarkers compatible with colorectal cancer screening. However, the clinical impact of these biomarkers in colorectal cancer screening and follow-up needs to be established in further prospective studies.

Black Leaf Streak Disease (BLSD), caused by the fungus Pseudocercospora fijiensis, is a recent pandemic and the most economically and environmentally important leaf disease of banana. To assist breeding of varieties with durable resistance to the rapidly evolving P. fijiensis, we used a diploid genitor ‘IDN 110’ with partial resistance to BLSD to search for QTLs. We assessed diploid progeny of 73 hybrids between ‘IDN 110’ and the diploid cultivar ‘Khai Nai On’, which is susceptible to BLSD. Hybrids were phenotyped with artificial inoculation under controlled conditions. This method allowed us to focus on resistance in the early stages of the interaction already identified as strongly influencing BLSD epidemiology. Progeny were genotyped by sequencing. As both parents are heterozygous for large reciprocal translocations, the distribution of recombination was assessed and revealed regions with low recombination rates. Fourteen non-overlapping QTLs of resistance to BLSD were identified of which four main QTLs from the ‘IDN110‘ parent, located on chromosomes 06, 07, 08, and 09, were shown to be of interest for marker-assisted selection. Genes that underline those four QTLs are discussed in the light of previous literature.

Background and aimsModern sugarcane cultivars (Saccharum spp.) are high polyploids, aneuploids (2n = ~12x = ~120) derived from interspecific hybridizations between the domesticated sweet species Saccharum officinarum and the wild species S. spontaneum.MethodsTo analyse the architecture and origin of such a complex genome, we analysed the sequences of all 12 hom(oe)ologous haplotypes (BAC clones) from two distinct genomic regions of a typical modern cultivar, as well as the corresponding sequence in Miscanthus sinense and Sorghum bicolor, and monitored their distribution among representatives of the Saccharum genus.Key resultsThe diversity observed among haplotypes suggested the existence of three founding genomes (A, B, C) in modern cultivars, which diverged between 0.8 and 1.3 Mya. Two genomes (A, B) were contributed by S. officinarum; these were also found in its wild presumed ancestor S. robustum, and one genome (C) was contributed by S. spontaneum. These results suggest that S. officinarum and S. robustum are derived from interspecific hybridization between two unknown ancestors (A and B genomes). The A genome contributed most haplotypes (nine or ten) while the B and C genomes contributed one or two haplotypes in the regions analysed of this typical modern cultivar. Interspecific hybridizations likely involved accessions or gametes with distinct ploidy levels and/or were followed by a series of backcrosses with the A genome. The three founding genomes were found in all S. barberi, S. sinense and modern cultivars analysed. None of the analysed accessions contained only the A genome or the B genome, suggesting that representatives of these founding genomes remain to be discovered.ConclusionsThis evolutionary model, which combines interspecificity and high polyploidy, can explain the variable chromosome pairing affinity observed in Saccharum. It represents a major revision of the understanding of Saccharum diversity.

This article focuses on the intricate links between violence suffered during childhood and its continuity in adulthood. A mixed-method study enabled us to retrace trajectories of women victims of incest in French Polynesia. During childhood, sexual abuse tends to be combined with physical abuse. Sometimes, this violence is repeated in adulthood, especially in the marital sphere. The women interviewed feel partly responsible for this, and see their vulnerability in terms of individual dispositions. The sociological approach enables us to criticize the idea that victims of incest suffer from an intrinsic vulnerability, regardless of their social background. Isolation, material and emotional dependence, and moral destabilization – processes that are linked to incest – structure the risk of revictimization.

Background:. Presensitized patients awaiting a kidney transplant have a lower graft survival and a longer waiting time because of the limited number of potential donors and the higher risk of antibody-mediated rejection (AMR), particularly in the early posttransplant period, because of preformed donor-specific antibodies binding major histocompatibility complex (MHC) molecules expressed by the graft endothelium followed by the activation of the complement. Advances in kidney preservation techniques allow the development of ex vivo treatment of transplants. We hypothesized that masking MHC ex vivo before transplantation could help to prevent early AMR in presensitized recipients. We evaluated a strategy of MHC I masking by an antibody during ex vivo organ perfusion in a porcine model of kidney transplantation in alloimmunized recipients. Methods:. Through the in vitro calcein-release assay and flow cytometry, we evaluated the protective effect of a monoclonal anti–swine leukocyte antigen class I antibody (clone JM1E3) against alloreactive IgG complement-dependent cytotoxicity toward donor endothelial cells. Kidneys perfused ex vivo with JM1E3 during hypothermic machine perfusion were transplanted to alloimmunized recipients. Results:. In vitro incubation of endothelial cells with JM1E3 decreased alloreactive IgG cytotoxicity (mean complement-dependent cytotoxicity index [% of control condition] with 1 µg/mL 74.13% ± 35.26 [calcein assay] and 66.88% ± 33.46 [cytometry]), with high interindividual variability. After transplantation, acute AMR occurred in all recipients on day 1, with signs of complement activation (C5b-9 staining) as soon as 1 h after transplantation, despite effective JM1E3 binding on graft endothelium. Conclusions:. Despite a partial protective effect of swine leukocyte antigen I masking with JM1E3 in vitro, ex vivo perfusion of the kidney with JM1E3 before transplantation was not sufficient alone at preventing or delaying AMR in highly sensitized recipients.

The Tenant of Wildfell Hall (1848), Anne Brontë’s second novel, has always been the object of much scholarly attention, particularly as regards what was originally thought to be a structural flaw: the use of a frame narrative within which the story of Helen Huntingdon’s flight from a disastrous marriage is embedded. The frame narrator, Gilbert Markham, tells a traditional courtship tale which abruptly turns into Helen’s metanarrative of domestic horror. Recent scholarship has concerned itself with this split in discourse which suggests that Brontë does not challenge the conventional idea that discursive authority is masculine, making it therefore difficult to read her novel as feminist. Studies alternately focus on Brontë’s bold enterprise (the vindication in the metanarrative of a woman’s right to leave an abusive husband) or on the limitations generated by her decision to resort to a male frame narrator. This paper addresses the implications of the novel’s apparently flawed structure, notably exploring the uncertainty surrounding the improvement of Gilbert’s moral character after his reading of Helen’s diary. It contends that critical disagreement on whether or not The Tenant is a feminist novel and the embedded narrative the instrument of Gilbert’s reformation, originates, at least partially, in the generic tension at work within Brontë’s novel, and the presence of Gothic fault-lines. Anne Brontë appears unwilling to espouse realism and social criticism which, if fully embraced, might imply forgoing valued (and cherished) Gothic modes of storytelling. The uneasy co-existence of social realism and Gothic remnants (prominent in the choice of structure and modes of characterisation) may then lie at the heart of the novel’s multi-faceted ambiguity.

One of the acknowledged advantages of patent clearinghouses is that they favor the diffusion of technology. In traditional clearinghouses, patents are usually bundled in pools and sold at a pre-set price. Recently, in the biotechnology industry a new form of clearinghouse has been observed, where patent tariffs are instead bargained over by the clearinghouse members. Exchange is then guaranteed by arbitration agreements to which the negotiating parties are bound, should their bargaining reach a dead end. This paper assesses the effect on technology diffusion of this new type of clearinghouse. We show that such arbitration agreements, through their effect on the outside options, may reduce the incentives of a member of the clearinghouse to license to non-members. This result highlights the role of such arbitration agreements in the diffusion of technology outside the clearinghouse. [ABSTRACT FROM AUTHOR]

Here, the authors show that HPV infection leads to downregulation of host mucosal innate peptides, which are in turn used by predominant Lactobacillus species as amino acid source, promoting ultimately an imbalance in the vaginal flora.

Sugarcane (Saccharum spp.) is a major crop for sugar and bioenergy production. Its highly polyploid, aneuploid, heterozygous, and interspecific genome poses major challenges for producing a reference sequence. We exploited colinearity with sorghum to produce a BAC-based monoploid genome sequence of sugarcane. A minimum tiling path of 4660 sugarcane BAC that best covers the gene-rich part of the sorghum genome was selected based on whole-genome profiling, sequenced, and assembled in a 382-Mb single tiling path of a high-quality sequence. A total of 25,316 protein-coding gene models are predicted, 17% of which display no colinearity with their sorghum orthologs. We show that the two species, S. officinarum and S. spontaneum, involved in modern cultivars differ by their transposable elements and by a few large chromosomal rearrangements, explaining their distinct genome size and distinct basic chromosome numbers while also suggesting that polyploidization arose in both lineages after their divergence.

Based on an experience of creative writing (the turning into a narrative of family history reconstructed by means of birth registers and other public records), this article shows how academic methodologies facilitated every stage of creative writing. More specifically, the critical reading of contemporary British literature made it possible to adequately problematize key issues and formulate responses to questions that arose during the writing process, and thus to transform the archive into a narrative for readers who, in this particular instance, were family members.This paper tracks the writing process, from the initial questions related to the retrieval of a “life”, in the biographical sense, from meagre archival data, to the type of text that can emerge from this type of research and to considering varied solutions to the problem of the integration of fiction into biography. Creative writing thus appears closely linked to the critical reading of much-loved “classics” which become, as such, pillaged sources of inspiration.

Combining immunogenic cell death-inducing chemotherapies and PD-1 blockade can generate remarkable tumor responses. It is now well established that TGF-β1 signaling is a major component of treatment resistance and contributes to the cancer-related immunosuppressive microenvironment. However, whether TGF-β1 remains an obstacle to immune checkpoint inhibitor efficacy when immunotherapy is combined with chemotherapy is still to be determined. Several syngeneic murine models were used to investigate the role of TGF-β1 neutralization on the combinations of immunogenic chemotherapy (FOLFOX: 5-fluorouracil and oxaliplatin) and anti-PD-1. Cancer-associated fibroblasts (CAF) and immune cells were isolated from CT26 and PancOH7 tumor-bearing mice treated with FOLFOX, anti-PD-1 ± anti-TGF-β1 for bulk and single cell RNA sequencing and characterization. We showed that TGF-β1 neutralization promotes the therapeutic efficacy of FOLFOX and anti-PD-1 combination and induces the recruitment of antigen-specific CD8+ T cells into the tumor. TGF-β1 neutralization is required in addition to chemo-immunotherapy to promote inflammatory CAF infiltration, a chemokine production switch in CAF leading to decreased CXCL14 and increased CXCL9/10 production and subsequent antigen-specific T cell recruitment. The immune-suppressive effect of TGF-β1 involves an epigenetic mechanism with chromatin remodeling of CXCL9 and CXCL10 promoters within CAF DNA in a G9a and EZH2-dependent fashion. Our results strengthen the role of TGF-β1 in the organization of a tumor microenvironment enriched in myofibroblasts where chromatin remodeling prevents CXCL9/10 production and limits the efficacy of chemo-immunotherapy.

In yeast, TFIP11 and DHX15 promote the disassembly of spliceosome complex after splicing is completed. Here the authors show that human TFIP11 functions independently of DHX15 and is required for U6 snRNA 2’-O-methylation and U4/U6.U5 tri-snRNP assembly.

Abstract Background In oncology, liquid biopsy is of major relevance from theranostic point of view. The searching for mutations in circulating tumor DNA (ctDNA) in case of colorectal cancers (CRCs) allows the optimization of patient care. In this context, independent of mutation status biomarkers are required for its detection to confirm the presence of ctDNA in liquid biopsies. Indeed, the hypermethylation of NPY and WIF1 genes appear to be an ideal biomarker for the specific detection of ctDNA in CRCs. The objective of this work is to develop the research of hypermethylation of NPY and WIF1 by Crystal Digital PCR™ for the detection of ctDNA in CRCs. Methods Detection of hypermethylated NPY and WIF1 was developed on Cristal digital PCR™. Biological validation was performed from a local cohort of 22 liquid biopsies and 23 tissue samples from patients with CRC. These patients were treated at the University Hospital of Besancon (France). Results The local cohort study confirmed that NPY and WIF1 were significantly hypermethylated in tumor tissues compared to adjacent non-tumor tissues (WIF1 p

Abstract Background Genetically engineered chimeric antigen receptor (CAR) T lymphocytes are promising therapeutic tools for cancer. Four CAR T cell drugs, including tisagenlecleucel (tisa-cel) and axicabtagene-ciloleucel (axi-cel), all targeting CD19, are currently approved for treating B cell malignancies. Flow cytometry (FC) remains the standard for monitoring CAR T cells using a recombinant biotinylated target protein. Nevertheless, there is a need for additional tools, and the challenge is to develop an easy, relevant, highly sensitive, reproducible, and inexpensive detection method. Molecular tools can meet this need to specifically monitor long-term persistent CAR T cells. Methods Based on 2 experimental CAR T cell constructs, IL-1RAP and CS1, we designed 2 quantitative digital droplet (ddPCR) PCR assays. By targeting the 4.1BB/CD3z (28BBz) or 28/CD3z (28z) junction area, we demonstrated that PCR assays can be applied to approved CD19 CAR T drugs. Both 28z and 28BBz ddPCR assays allow determination of the average vector copy number (VCN) per cell. We confirmed that the VCN is dependent on the multiplicity of infection and verified that the VCN of our experimental or GMP-like IL-1RAP CAR T cells met the requirement (