In recent decades, an increase in the abundance and frequency of bloom events has been reported for the scyphozoan
Rhizostoma pulmo
in the Mediterranean Sea. Understanding such events requires a ...thorough assessment of the species’ population dynamics through environmental windows allowing species development. The semi-enclosed coastal lagoon of Bages Sigean, France (43°05′12.72″N; 3°00′35.3″E) offers an exceptional framework for investigating the population dynamics of the species, and how its growth rates and environmental niches vary over time. Three cohorts starting in April, May and June 2019 were identified, while the overall population growth reached the maximum biomass (10.2 g m
−3
) in July. Bell diameter and total length were identified as the best morphological proxies of biomass estimation. The abundances of the two most abundant copepods’ species appear to drive
R. pulmo
’s dynamics in the lagoon. Based on multinomial analysis and using the von Bertalanffy model, different growth rates for juveniles (4.7 and 2.4 mm day
−1
) and adults (1.8 and 0.9 mm day
−1
) were determined for the first two cohorts. Thermohaline niches varied during ontogeny, but also among populations in three coastal Mediterranean lagoons: Bages Sigean (France), Mar Menor (Spain) and Bizerte (Tunisia), shedding light on the metapopulation dynamics of
R. pulmo
inhabiting the Mediterranean Sea. The pressing need for understanding the dynamics of jellyfish abundances and their impacts on ecosystems, calls for increased efforts on monitoring these populations and their life history traits to parametrize and build reliable ecosystem models.
Sporadic early onset colorectal carcinoma (EOCRC) which has by definition no identified hereditary predisposition is a growing problem that remains poorly understood. Molecular analysis could improve ...identification of distinct sub-types of colorectal cancers (CRC) with therapeutic implications and thus can help establish that sporadic EOCRC is a distinct entity. From 954 patients resected for CRC at our institution, 98 patients were selected. Patients aged 45-60 years were excluded to help define "young" and "old" groups. Thirty-nine cases of sporadic EOCRC (patients ≤ 45 years with microsatellite stable tumors) were compared to both microsatellite stable tumors from older patients (36 cases, patients>60 years) and to groups of patients with microsatellite instability. Each group was tested for TP53, KRAS, BRAF, PIK3CA mutations and the presence of a methylator phenotype. Gene expression profiles were also used for pathway analysis. Compared to microsatellite stable CRC from old patients, sporadic EOCRC were characterized by distal location, frequent synchronous metastases and infrequent synchronous adenomas but did not have specific morphological characteristics. A familial history of CRC was more common in sporadic EOCRC patients despite a lack of identified hereditary conditions (p = 0.013). Genetic studies also showed the absence of BRAF mutations (p = 0.022) and the methylator phenotype (p = 0.005) in sporadic EOCRC compared to older patients. Gene expression analysis implicated key pathways such as Wnt/beta catenin, MAP Kinase, growth factor signaling (EGFR, HGF, PDGF) and the TNFR1 pathway in sporadic EOCRC. Wnt/beta catenin signaling activation was confirmed by aberrant nuclear beta catenin immunostaining (p = 0.01). This study strongly suggests that sporadic EOCRC is a distinct clinico-molecular entity presenting as a distal and aggressive disease associated with chromosome instability. Furthermore, several signaling pathways including the TNFR1 pathway have been identified as potential biomarkers for both the diagnosis and treatment of this disease.
Immunohistochemistry (IHC) and/or MSI-PCR (microsatellite instability-polymerase chain reaction) tests are performed routinely to detect mismatch repair deficiency (MMR-D). Classical MMR-D tumors ...present a loss of MLH1/PMS2 or MSH2/MSH6 with MSI-High. Other profiles of MMR-D tumors have been described but have been rarely studied. In this study, we established a classification of unusual MMR-D tumors and determined their frequency and clinical impact. All MMR-D tumors identified between 2007 and 2017 were selected. Any profile besides the classical MMR-D phenotype was defined as unusual. For patients with unusual MMR-D tumors, IHC, and PCR data were reviewed, the tumor mutation burden (TMB) was evaluated and clinical and genetic features were collected. Of the 4948 cases of MMR testing, 3800 had both the available IHC and MSI-PCR results and 585 of these had MMR-D. After reviewing the IHC and PCR, 21% of the cases initially identified as unusual MMR-D were reclassified, which resulted in a final identification of 89 unusual MMR-D tumors (15%). Unusual MMR-D tumors were more often associated with non-CRC than classical MMR-D tumors. Unusual MMR-D tumors were classified into four sub-groups: i) isolated loss of PMS2 or MSH6, ii) classical loss of MLH1/PMS2 or MSH2/MSH6 without MSI, iii) four MMR proteins retained with MSI and, iv) complex loss of MMR proteins, with clinical characteristics for each sub-group. TMB-high or -intermediate was shown in 96% of the cancers studied (24/25), which confirmed MMR deficiency. Genetic syndromes were identified in 44.9% (40/89) and 21.4% (106/496) of patients with unusual and classical MMR-D tumors, respectively (P < 0.001). Five patients treated with an immune checkpoint inhibitor (ICI) had a prolonged clinical benefit. Our classification of unusual MMR-D phenotype helps to identify MMR deficiency. Unusual MMR-D phenotype occurs in 15% of MMR-D tumors. A high frequency of genetic syndromes was noted in these patients who could benefit from ICI.
Excessive use of nickel oxide nanoparticles (NiO NPs) in various industrial and commercial products can lead to various negative effects in human and environmental health due to their possible ...discharge into the environment. Nerveless, information about their ecotoxicological effects on marine organisms are lacking. Copepods are good ecotoxicological models because of their high sensitivity to environmental stress and their key role in the marine food webs. In this study, 48 h acute tests were conducted on the marine planktonic copepod
Centropages ponticus
to assess lethal and sublethal toxicities of NiO NPs. The results revealed LC
50
(48 h) of 4 mg/L for adult females. Aggregation and settling of NiO NPs were observed at concentrations ≥ 2 mg/L. Exposure to sublethal concentrations (≥ 0.02 mg/L for 48 h) had significant negative effects on reproductive success in
C. ponticus
. Egg production after 24 h and 48 h decreased by 32% and 46%, respectively at 0.02 mg/L and 70% and 82%, respectively, at 2 mg/L. Hatching success was reduced by 70% and 79% at 2 mg/L for eggs produced after 24 h and 48 h respectively. Antioxidant enzymatic activity increased significantly with NiO NP concentration and time, indicating that NiO NPs can cause oxidative stress in
C. ponticus
even under short-term exposure, while significant inhibition of acetylcholinesterase activity at 2 mg/L after 48 h suggests neurotoxic effects of NiO NPs.
The earth is warming at an alarming rate, especially in the Arctic, where a marked decline in sea ice cover may have far-ranging consequences for endemic species. Little auks, endemic Arctic ...seabirds, are key bioindicators as they forage in the marginal ice zone and feed preferentially on lipid-rich Arctic copepods and ice-associated amphipods sensitive to the consequences of global warming. We tested how little auks cope with an ice-free foraging environment during the breeding season. To this end, we took advantage of natural variation in sea ice concentration along the east coast of Greenland. We compared foraging and diving behaviour, chick diet and growth and adult body condition between two years, in the presence versus nearby absence of sea ice in the vicinity of their breeding site. Moreover, we sampled zooplankton at sea when sea ice was absent to evaluate prey location and little auk dietary preferences. Little auks foraged in the same areas both years, irrespective of sea ice presence/concentration, and targeted the shelf break and the continental shelf. We confirmed that breeding little auks showed a clear preference for larger copepod species to feed their chick, but caught smaller copepods and nearly no ice-associated amphipod when sea ice was absent. Nevertheless, these dietary changes had no impact on chick growth and adult body condition. Our findings demonstrate the importance of bathymetry for profitable little auk foraging, whatever the sea-ice conditions. Our investigations, along with recent studies, also confirm more flexibility than previously predicted for this key species in a warming Arctic.
While proteases are essential in gastrointestinal physiology, accumulating evidence indicates that dysregulated proteolysis plays a pivotal role in the pathophysiology of inflammatory bowel disease ...(IBD). Nonetheless, the identity of overactive proteases released by human colonic mucosa remains largely unknown. Studies of protease abundance have primarily investigated expression profiles, not taking into account their enzymatic activity. Herein we have used serine protease-targeted activity-based probes (ABPs) coupled with mass spectral analysis to identify active forms of proteases secreted by the colonic mucosa of healthy controls and IBD patients. Profiling of (Pro-Lys)-ABP bound proteases revealed that most of hyperactive proteases from IBD secretome are clustered at 28-kDa. We identified seven active proteases: the serine proteases cathepsin G, plasma kallikrein, plasmin, tryptase, chymotrypsin-like elastase 3 A, and thrombin and the aminopeptidase B. Only cathepsin G and thrombin were overactive in supernatants from IBD patient tissues compared to healthy controls. Gene expression analysis highlighted the transcription of genes encoding these proteases into intestinal mucosae. The functional ABP-targeted proteomic approach that we have used to identify active proteases in human colonic samples bears directly on the understanding of the role these enzymes may play in the pathophysiology of IBD.
The investigation of jellyfish gastrovascular systems mainly focused on stain injections and dissections, negatively affected by thickness and opacity of the mesoglea. Therefore, descriptions are ...incomplete and data about tridimensional structures are scarce. In this work, morphological and functional anatomy of the gastrovascular system of Rhizostoma pulmo (Macri 1778) was investigated in detail with innovative techniques: resin endocasts and 3D X-ray computed microtomography. The gastrovascular system consists of a series of branching canals ending with numerous openings within the frilled margins of the oral arms. Canals presented a peculiar double hemi-canal structure with a medial adhesion area which separates centrifugal and centripetal flows. The inward flow involves only the "mouth" openings on the internal wing of the oral arm and relative hemi-canals, while the outward flow involves only the two outermost wings' hemi-canals and relative "anal" openings on the external oral arm. The openings differentiation recalls the functional characteristics of a through-gut apparatus. We cannot define the gastrovascular system in Rhizostoma pulmo as a traditional through-gut, rather an example of adaptive convergence, that partially invalidates the paradigm of a single oral opening with both the uptake and excrete function.
Bevacizumab, an anti-VEGF monoclonal antibody, has recently emerged as a new option for severe forms of hereditary hemorrhagic telangiectasia (HHT). Its utilization in this orphan disease has rapidly ...spread despite the lack of randomized trials and international guidelines. The objective of this study is to report the main clinical data (baseline characteristics, dose schedule, efficacy, adverse events and deaths) of HHT patients treated by intravenous bevacizumab in France.
Retrospective observational study of HHT patients treated with bevacizumab for a severe form of the disease in the 14 centers of the French HHT network.
Forty-six patients (median age: 68 years) were treated between March 2009 and May 2015. Ten patients were treated for high output cardiac failure, 20 patients for severe hemorrhages and 16 for both indications. The standard protocol (6 infusions of 5mg/kg every 2 weeks) was initially used in 89% of the cases but diverse strategies were subsequently applied. A clinical improvement was noted by the referent physician for 74% of the patients with a median effect's duration of 6 months. Wound healing complications led to 2 amputations. Arthralgia/arthritis and arterial hypertension occurred in 5 patients each. One third of the patients were dead at the time of the final update, coherently with age and the poor prognosis of these highly symptomatic patients.
Intravenous bevacizumab seems to provide a clinical benefice in severe HHT patients. Precautions concerning wound healing and vascular pathologies must be respected. Prospective double blinded versus placebo trials are needed.
Proteolytic homeostasis is important at mucosal surfaces, but its actors and their precise role in physiology are poorly understood. Here we report that healthy human and mouse colon epithelia are a ...major source of active thrombin. We show that mucosal thrombin is directly regulated by the presence of commensal microbiota. Specific inhibition of luminal thrombin activity causes macroscopic and microscopic damage as well as transcriptomic alterations of genes involved in host-microbiota interactions. Further, luminal thrombin inhibition impairs the spatial segregation of microbiota biofilms, allowing bacteria to invade the mucus layer and to translocate across the epithelium. Thrombin cleaves the biofilm matrix of reconstituted mucosa-associated human microbiota. Our results indicate that thrombin constrains biofilms at the intestinal mucosa. Further work is needed to test whether thrombin plays similar roles in other mucosal surfaces, given that lung, bladder and skin epithelia also express thrombin.
Inflammatory Bowel Diseases (IBD) are chronic inflammatory disorders, where epithelial defects drive, at least in part, some of the pathology. We reconstituted human intestinal epithelial organ, by ...using three-dimension culture of human colon organoids. Our aim was to characterize morphological and functional phenotypes of control (non-IBD) organoids, compared to inflamed organoids from IBD patients. The results generated describe the epithelial defects associated with IBD in primary organoid cultures, and evaluate the use of this model for pharmacological testing of anti-inflammatory approaches. Human colonic tissues were obtained from either surgical resections or biopsies, all harvested in non-inflammatory zones. Crypts were isolated from controls (non-IBD) and IBD patients and were cultured up to 12-days. Morphological (size, budding formation, polarization, luminal content), cell composition (proliferation, differentiation, immaturity markers expression), and functional (chemokine and tight junction protein expression) parameters were measured by immunohistochemistry, RT-qPCR or western-blot. The effects of inflammatory cocktail or anti-inflammatory treatments were studied in controls and IBD organoid cultures respectively. Organoid cultures from controls or IBD patients had the same cell composition after 10 to 12-days of culture, but IBD organoid cultures showed an inflammatory phenotype with decreased size and budding capacity, increased cell death, luminal debris, and inverted polarization. Tight junction proteins were also significantly decreased in IBD organoid cultures. Inflammatory cytokine cocktail reproduced this inflammatory phenotype in non-IBD organoids. Clinically used treatments (5-ASA, glucocorticoids, anti-TNF) reduced some, but not all parameters. Inflammatory phenotype is associated with IBD epithelium, and can be studied in organoid cultures. This model constitutes a reliable human pre-clinical model to investigate new strategies targeting epithelial repair.
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