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Through an analysis of Le Sacristain II (Du Segretain Moine) and Le Bouchier d’Abeville (or Eustache d’Amiens), this study theorizes a common theme in the Old French fabliaux, that of the anticlerical conflict between the merchant and priest, by identifying the “appropriate” use of social spaces of production and reproduction in the text, as defined by Lefebvre (La Production de l’espace, Editions anthropos, Paris, 1974). The successful management of space in the fabliaux—from the marketplace, to the home, to the church—promotes and protects bourgeois values as they emerge at pivotal moments of exchange in the text. The bourgeois’ wit and the ability to manage space equate to both a successful trade and a shift in power in these tales, with the fabliaux providing a literary space to envision and play out a new social order. Situating the fabliaux in its historical context, this article argues that the genre’s preoccupation with “appropriate” behavior within certain social spaces communicates an increasingly cohesive cultural ideology for the rising merchant class in thirteenth century that marginalizes the authority of the church while strengthening these ideas in northern France and throughout the European trading community.

The recovery of a cache of lithic bifaces (the Bouchier Cache) is reported from an ecotonal area located between the southern High Plains (Llano Estacado) and Central Lowlands (western Rolling Plains). The homogenous nature of the bifacial cores suggests that the cache represents a resource stockpile, and, therefore, is important to understanding hunter-gatherer logistical mobility strategies on the southern Plains. Bifacial core caches are a distinctly recognizable component of caching behavior that do not appear to be restricted to particular cultural groups, time periods, or geographic locations. The age and cultural association of this cache is not known. Morphological and technological examination suggests the cache would fit well with models of high residential mobility typically attributed to early and middle Holocene populations.

The third report of the expert group on Cryptosporidium in Water Supplies is a comprehensive document which builds on the previous Badenoch reports of 1990 and 1995. It reviews recent waterborne outbreaks, and makes many sensible recommendations, for example that human cryptosporidiosis should be made a laboratory reportable disease in England and Wales, and that consideration should be given to making it notifiable. Highly detailed advice is given to water utilities on risk assessment, water treatment, groundwater abstraction etc., this probably reflects the interests of most members of the group, which includes representatives of Water UK, Scottish Water Authorities, the Water Research Centre and even the British Geological Survey. While microbiologists and epidemiologists with a special interest in cryptosporidiosis are included in the group, it is surprising that it does not include an infection control doctor or CCDC, and that professional associations representing these specialists do not appear to have been invited to comment on the report before it was published. The report makes the recommendation that “all water, from whatever source, that might be consumed by immunocompromized persons should be brought to the boil and allowed to cool before use”. The definition of immunocompromized individuals used encompasses such diverse conditions as hypogammaglobulinaemia, HIV infection, SCID, leukaemia and immunosuppressive therapy. The recommendation applies to all HIV positive patients regardless of CD4

Overactive inflammatory responses are central to the pathophysiology of many hemolytic conditions including sickle cell disease. Excessive hemolysis leads to elevated serum levels of heme due to saturation of heme scavenging mechanisms. Extracellular heme has been shown to activate the NLRP3 inflammasome, leading to activation of caspase-1 and release of pro-inflammatory cytokines IL-1β and IL-18. Heme also activates the non-canonical inflammasome pathway, which may contribute to NLRP3 inflammasome formation and leads to pyroptosis, a type of inflammatory cell death. Some clinical studies indicate there is a benefit to blocking the NLRP3 inflammasome pathway in patients with sickle cell disease and other hemolytic conditions. However, a thorough understanding of the mechanisms of heme-induced inflammasome activation is needed to fully leverage this pathway for clinical benefit. This review will explore the mechanisms of heme-induced NLRP3 inflammasome activation and the role of this pathway in hemolytic conditions including sickle cell disease.

A significant number of patients admitted for aneurysmal subarachnoid hemorrhage (aSAH) are active smokers and are at risk of developing nicotine withdrawal symptoms (e.g., cravings, irritability, insomnia, headaches, etc.). This study aimed to evaluate the use of nicotine replacement therapy (NRT) regarding headache severity and analgesics consumption.A retrospective study was conducted using prospectively collected data from 2014 to 2019 in the neurointensive care unit of the Hospices Civils in Lyon, France. We performed a propensity score matching analysis. The covariables used were age, sex, initial World Federation of Neurosurgical Societies score, Hijdra sum score, and factors associated with pain following aSAH (history of chronic pain, anxiety, or depression). Smokers received NRT through a transdermal device. The primary end point was headache control. Secondary end points were mean numerical pain rating scale score and analgesics consumption.One hundred and fifty-five patients were included among 523 patients hospitalized for aSAH. Fifty-one patients underwent nicotine substitution and were matched to 51 unsubstituted patients. The headache control rate was not different between the two groups (43.1% vs. 31.4%, p = 0.736). The mean numeric pain rating scale score in the substituted group was 2.2 (1.1-3.5) and 2.4 (1.6-3.1) in the unsubstituted group (p = 0.533). The analgesics consumption (acetaminophen, tramadol, and morphine) was the same in the two groups.The use of NRT in the acute phase of aSAH does not seem to have an impact on the intensity of headaches or analgesics consumption.

Mutation in nucleophosmin (NPM1) causes relocalization of this normally nucleolar protein to the cytoplasm (NPM1c+). Despite NPM1 mutation being the most common driver mutation in cytogenetically normal adult acute myeloid leukemia (AML), the mechanisms of NPM1c+-induced leukemogenesis remain unclear. Caspase-2 is a pro-apoptotic protein activated by NPM1 in the nucleolus. Here, we show that caspase-2 is also activated by NPM1c+ in the cytoplasm, and DNA damage-induced apoptosis is caspase-2-dependent in NPM1c+ AML but not in NPM1wt cells. Strikingly, in NPM1c+ cells, loss of caspase-2 results in profound cell cycle arrest, differentiation, and down-regulation of stem cell pathways that regulate pluripotency including impairment in the AKT/mTORC1 and Wnt signaling pathways. In contrast, there were minimal differences in proliferation, differentiation, or the transcriptional profile of NPM1wt cells with and without caspase-2. Together, these results show that caspase-2 is essential for proliferation and self-renewal of AML cells that have mutated NPM1. This study demonstrates that caspase-2 is a major effector of NPM1c+ function and may even be a druggable target to treat NPM1c+ AML and prevent relapse.

This case report summarises the case of a 56-year-old man with low-flow, ischaemic priapism requiring urgent insertion of a penile prosthesis following prophylactic anticoagulation with tinzaparin. Low-molecular-weight heparin (LMWH) has been proposed as a cause of ischaemic priapism, although reported cases of this are rare. This particular side effect of tinzaparin has been reported once in a case report in 2018, and there are scant other reports of LMWH-induced priapism. This case was refractory to the full treatment algorithm, including multiple aspirations, phenylephrine injection, cavernosal shunt and required transfer for implantation of a penile prosthesis. Only one other case of such a severe case of priapism has been documented, involving LMWH and warfarin. Documented evidence of possible causes of priapism are vital, given the rarity of this condition, the frequency of LMWH and the potentially devastating complications.

Supplementary Figure S1. NB cells infected with Ad5ÃŽ?24 do not upregulate GD2, Fas, TRAIL receptors and costimulatory molecules

Omont Henri. Une édition de l'Histoire ecclésiastique des Francs de Grégoire de Tours, préparée par le P. Gilles Bouchier au XVIIe siècle.. In: Bibliothèque de l'école des chartes. 1894, tome 55. pp. 515-518.

Aneurysmal subarachnoid hemorrhage (SAH) is a rare event affecting relatively young patients therefore leading to a high social impact. The management of SAH follows a biphasic course with early brain injuries in the first 72 hours followed by a phase at risk of secondary deterioration due to delayed cerebral ischemia (DCI) in 20 to 30% patients. Cerebral infarction from DCI is the most preventable cause of mortality and morbidity after SAH. DCI prevention, early detection and treatment is therefore advocated. Formerly limited to the occurrence of vasospasm, DCI is now associated with multiple pathophysiological processes involving for instance the macrocirculation, the microcirculation, neurovascular units, and inflammation. Therefore, the therapeutic targets and management strategies are also evolving and are not only focused on proximal vasospasm. In this review, we describe the current knowledge of DCI pathophysiology. We then discuss the diagnosis strategies that may guide physicians at the bedside with a multimodal approach in the unconscious patient. We will present the prevention strategies that have proven efficient as well as future targets and present the therapeutic approach that is currently being developed when a DCI occurs.

Nucleophosmin 1 (NPM1) mutation is the primary genetic lesion in adult acute myeloid leukemia (AML). Typically, a nucleolar protein, NPM1 mutations cause cytoplasmic delocalization of NPM1(NPM1c+), triggering leukemogenesis. Interestingly, NPM1c+ mutation confers enhanced chemosensitivity. However, the mechanism underlying NPM1c+ mutation-induced oncogenesis or chemosensitivity remains unclear. We previously reported that, in response to genotoxic stimuli, NPM1 forms a platform for caspase-2 activation in the nucleolus. Caspase-2 is a pro-apoptotic protein and a known tumor suppressor. Our results indicate that nucleolar caspase-2 activation is specific to NPM1wt cells. In the NPM1c+ cells, caspase-2 activation is exclusively cytosolic, suggesting that caspase-2 is activated in the same sub-cellular compartment as NPM1 localization. Loss of caspase-2 rescued the increased sensitivity of NPM1c+ cells to apoptotic cell death. This is accompanied by reduced cleavage of the apoptotic substrate, caspase-3. Notably, caspase-2 deficient NPM1wt cells showed no significant difference in the percentage of apoptotic cell death or endogenous substrate cleavage compared to its caspase-2 wild-type counterpart. This suggests that caspase-2 may contribute to the chemosensitivity of NPM1c+ cells. Strikingly, in unstimulated cells, loss of caspase-2 leads to prolonged G1 arrest and progressive loss of cell viability. Immunophenotyping of NPM1c+ cells revealed a remarkable increase in the CD14+population representing monocyte/macrophage-like features, suggesting that loss of caspase-2 results in terminal differentiation. Exogenous expression of NPM1c+ in caspase-2 deficient NPM1wt cells impaired viability, confirming that NPM1c+ cells require caspase-2 for its growth and proliferation. Transcriptomic analysis revealed that loss of caspase-2 significantly downregulates pathways involved in stem cell pluripotency. In particular, FGF2, IGFR, WNT, LIF, and one of the core members of the self-renewal transcription factor, OCT 4, were downregulated in the absence of caspase-2 in NPM1c+ cells. This reveals a novel role for caspase-2 in maintaining NPM1c+ AML stemness. Taken together, our study shows that NPM1c+ mediated caspase-2 activation regulates AML cell death and survival cascades, a key determinant of chemosensitivity and leukemogenesis. Citation Format: Dharaniya Sakthivel, Alexandra Brown-Suedel, Francesca Keane, F. Kenneth McSherry, Chloe I. Charendoff, Kevin Dunne, Dexter Robichaux, Jonathan M. Flanagan, Lisa Bouchier-Hayes. The role of nucleophosmin1 mediated caspase2 activation in acute myeloid leukemia cell death and cell survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB035.

In addition to its classical role in apoptosis, accumulating evidence suggests that caspase-2 has non-apoptotic functions, including regulation of cell division. Loss of caspase-2 is known to increase proliferation rates but how caspase-2 is regulating this process is currently unclear. We show that caspase-2 is activated in dividing cells in G1-phase of the cell cycle. In the absence of caspase-2, cells exhibit numerous S-phase defects including delayed exit from S-phase, defects in repair of chromosomal aberrations during S-phase, and increased DNA damage following S-phase arrest. In addition, caspase-2-deficient cells have a higher frequency of stalled replication forks, decreased DNA fiber length, and impeded progression of DNA replication tracts. This indicates that caspase-2 protects from replication stress and promotes replication fork protection to maintain genomic stability. These functions are independent of the pro-apoptotic function of caspase-2 because blocking caspase-2-induced cell death had no effect on cell division, DNA damage-induced cell cycle arrest, or DNA damage. Thus, our data supports a model where caspase-2 regulates cell cycle and DNA repair events to protect from the accumulation of DNA damage independently of its pro-apoptotic function.

Delayed cerebral ischemia (DCI) is a poorly predictable complication occurring after aneurysmal subarachnoid hemorrhage (SAH) that can have dramatic functional consequences. Identifying the patients with the highest risk of DCI may help to institute more suitable monitoring and therapy. Early brain injuries and aneurysm-securing procedure complications could be regarded as confounding factors leading to severity misjudgment. After an early resuscitation phase, a subacute assessment may be more relevant to integrate the intrinsic SAH severity. A retrospective analysis was performed upon patients prospectively included in the registry of SAH patients between July 2015 to April 2020. The amount of cisternal and intraventricular blood were assessed semi-quantitatively on acute and subacute CT scans performed after early resuscitation. A clot clearance rate was calculated from their comparison. The primary endpoint was the occurrence of a DCI. A total of 349 patients were included in the study; 80 (22.9%) experienced DCI. In those patients, higher Fisher grades were observed on acute (p = 0.026) and subacute (p = 0.003) CT scans. On the subacute CT scan, patients who experienced DCI had a higher amount of blood, either at the cisternal (median Hijdra sum score: 11 vs 5, p 0.001) or intraventricular (median Graeb score: 4 vs 2, p 0.001) level. There was a negative linear relationship between the cisternal clot clearance rate and the risk of DCI. The assessment of the amount of subarachnoid blood and clot clearance following resuscitation after aneurysmal SAH can be useful for the prediction of neurological outcome.

A core component of nearly all bacteria, the cell wall is an ideal target for broad spectrum antibiotics. Many bacteria have evolved strategies to sense and respond to antibiotics targeting cell wall synthesis, especially in the soil where antibiotic-producing bacteria compete with one another. Here we show that cell wall stress caused by both chemical and genetic inhibition of the essential, bifunctional penicillin-binding protein PBP1a prevents microcolony formation and activates the canonical host-invasion two-component system ChvG-ChvI in Agrobacterium tumefaciens. Using RNA-seq, we show that depletion of PBP1a for 6 hours results in a downregulation in transcription of flagellum-dependent motility genes and an upregulation in transcription of type VI secretion and succinoglycan biosynthesis genes, a hallmark of the ChvG-ChvI regulon. Depletion of PBP1a for 16 hours, results in differential expression of many additional genes and may promote a general stress response. Remarkably, the overproduction of succinoglycan causes cell spreading and deletion of the succinoglycan biosynthesis gene exoA restores microcolony formation. Treatment with cefsulodin phenocopies depletion of PBP1a and we correspondingly find that chvG and chvI mutants are hypersensitive to cefsulodin. This hypersensitivity only occurs in response to treatment with β-lactam antibiotics and moenomycin, suggesting that the ChvG-ChvI pathway may play a key role in resistance to antibiotics targeting cell wall synthesis. Finally, we provide evidence that ChvG-ChvI likely has a conserved role in conferring resistance to cell wall stress within the Alphaproteobacteria.AUTHOR SUMMARYSoil dwelling bacteria reside in changing environments requiring them to frequently adapt to stressful conditions to ensure survival. The bacterial envelope provides structural integrity and protection against osmotic stress and turgor pressure imposed by the environment. While the mechanisms of cell membrane and cell wall biogenesis have been extensively studied, our understanding of how diverse microbes respond to cell envelope and cell wall stress to increase their fitness remains limited. In this work, we identify ChvG-ChvI regulon as an envelope stress response system that confers protection under cell wall stress conditions in the bacterial plant pathogen Agrobacterium tumefaciens. This is a new function for the well-characterized ChvG-ChvI pathway which is also acid induced and promotes plant host invasion. Our results suggest that the ChvG-ChvI pathway has a broadly conserved role in protecting Alphaproteobacterial cells from extracellular stress and a more specific role in response to acid stress and promoting plant-microbe interactions.

International audience; Strains of the freshwater cyanobacterium Synechococcus elongatus were first isolated approximately 60 years ago, and PCC 7942 is well established as a model for photosynthesis, circadian biology, and biotechnology research. The recent isolation of UTEX 3055 and subsequent discoveries in biofilm and phototaxis phenotypes suggest that lab strains of S. elongatus are highly domesticated. We performed a comprehensive genome comparison among the available genomes of S. elongatus and sequenced two additional laboratory strains to trace the loss of native phenotypes from the standard lab strains and determine the genetic basis of useful phenotypes. The genome comparison analysis provides a pangenome description of S. elongatus, as well as correction of extensive errors in the published sequence for the type strain PCC 6301. The comparison of gene sets and single nucleotide polymorphisms (SNPs) among strains clarifies strain isolation histories and, together with large-scale genome differences, supports a hypothesis of laboratory domestication. Prophage genes in laboratory strains, but not UTEX 3055, affect pigmentation, while unique genes in UTEX 3055 are necessary for phototaxis. The genomic differences identified in this study include previously reported SNPs that are, in reality, sequencing errors, as well as SNPs and genome differences that have phenotypic consequences. One SNP in the circadian response regulator rpaA that has caused confusion is clarified here as belonging to an aberrant clone of PCC 7942, used for the published genome sequence, that has confounded the interpretation of circadian fitness research.IMPORTANCE Synechococcus elongatus is a versatile and robust model cyanobacterium for photosynthetic metabolism and circadian biology research, with utility as a biological production platform. We compared the genomes of closely related S. elongatus strains to create a pangenome annotation to aid gene discovery for novel phenotypes. The comparative genomic analysis revealed the need for a new sequence of the species type strain PCC 6301 and includes two new sequences for S. elongatus strains PCC 6311 and PCC 7943. The genomic comparison revealed a pattern of early laboratory domestication of strains, clarifies the relationship between the strains PCC 6301 and UTEX 2973, and showed that differences in large prophage regions, operons, and even single nucleotides have effects on phenotypes as wide-ranging as pigmentation, phototaxis, and circadian gene expression.

Inflammatory caspases include caspase-1, -4, -5, -11, and -12 and belong to the subgroup of initiator caspases. Caspase-1 is required to ensure correct regulation of inflammatory signaling and is activated by proximity-induced dimerization following recruitment to inflammasomes. Caspase-1 is abundant in the monocytic cell lineage and induces maturation of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18 to active secreted molecules. The other inflammatory caspases, caspase-4 and -5 (and their murine homolog caspase-11) promote IL-1β release by inducing pyroptosis. Caspase Bimolecular Fluorescence Complementation (BiFC) is a tool used to measure inflammatory caspase induced proximity as a readout of caspase activation. The caspase-1, -4, or -5 prodomain, which contains the region that binds to the inflammasome, is fused to non-fluorescent fragments of the yellow fluorescent protein Venus (Venus-N [VN] or Venus-C [VC]) that associate to reform the fluorescent Venus complex when the caspases undergo induced proximity. This protocol describes how to introduce these reporters into primary human monocyte-derived macrophages (MDM) using nucleofection, treat the cells to induce inflammatory caspase activation, and measure caspase activation using fluorescence and confocal microscopy. The advantage of this approach is that it can be used to identify the components, requirements, and localization of the inflammatory caspase activation complex in living cells. However, careful controls need to be considered to avoid compromising cell viability and behavior. This technique is a powerful tool for the analysis of dynamic caspase interactions at the inflammasome level as well as for the interrogation of the inflammatory signaling cascades in living MDM and monocytes derived from human blood samples.

Members of the caspase family are well known for their roles in the initiation and execution of cell death. Due to their function in the removal of damaged cells that could otherwise become malignant, caspases are important players in the DNA damage response (DDR), a network of pathways that prevent genomic instability. However, emerging evidence of caspases positively or negatively impacting the accumulation of DNA damage in the absence of cell death demonstrates that caspases play a role in the DDR that is independent of their role in apoptosis. This review highlights the apoptotic and non-apoptotic roles of caspases in the DDR and how they can impact genomic stability and cancer treatment.

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Members of the Rhizobiales are polarly growing bacteria that lack homologs of the canonical Rod complex. To investigate the mechanisms underlying polar cell wall synthesis, we systematically probed the function of cell wall synthesis enzymes in the plant pathogen Agrobacterium tumefaciens. The development of fluorescent d-amino acid dipeptide (FDAAD) probes, which are incorporated into peptidoglycan by penicillin-binding proteins in A. tumefaciens, enabled us to monitor changes in growth patterns in the mutants. Use of these fluorescent cell wall probes and peptidoglycan compositional analysis demonstrate that a single class A penicillin-binding protein is essential for polar peptidoglycan synthesis. Furthermore, we find evidence of an additional mode of cell wall synthesis that requires ld-transpeptidase activity. Genetic analysis and cell wall targeting antibiotics reveal that the mechanism of unipolar growth is conserved in Sinorhizobium and Brucella. This work provides insights into unipolar peptidoglycan biosynthesis employed by the Rhizobiales during cell elongation.

Resume L’ischemie cerebrale retardee (ICR) reste une complication frequente et dramatique de l’hemorragie meningee anevrismale, dont l’incidence, elevee avant le onzieme jour post-saignement, impose une surveillance continue. Le diagnostic clinique d’une anomalie de perfusion avec un deficit neurologique peut etre rendu difficile chez les patients qui ont des troubles de la conscience. La surveillance clinique seule est a risque de diagnostic trop tardif pour une prevention efficace de la lesion cerebrale definitive. Une approche multimodale pour un diagnostic precoce du risque d’ICR peut associer le Doppler transcrânien, de l’electrophysiologie, de l’oxymetrie ou du metabolisme cerebral, ou encore un biomarqueur plasmatique, qui devra etre confirme par une imagerie de perfusion. Cette difficulte diagnostique reflete la complexite des mecanismes a l’origine de l’ICR que les etudes experimentales ont bien mis en evidence. En accord avec cette complexite, differentes strategies de prevention therapeutique ont cible la spasticite vasculaire, l’inflammation, l’agregation plaquettaire, le metabolisme cerebral, ou l’elimination du sang dans les espaces sous-arachnoidiens. Les resultats inconstants des etudes cliniques ont confirme la complexite de la lesion d’ICR. La nimodipine reste le seul traitement preventif recommande avec un impact sur le devenir neurologique. Plus recemment, l’antagoniste du recepteur a l’endotheline semblait efficace sur la vasomotricite des arteres cerebrales sans amelioration du devenir neurologique. Les prochaines etudes cliniques devraient preciser l’interet des inhibiteurs des phosphodiesterases ou du drainage du liquide cephalorachidien. La encore, une approche multimodale des therapeutiques devrait permettre la prevention optimale de cette complication redoutable.