Platelet-derived lysophosphatidic acid (LPA) supports the progression of breast and ovarian cancer metastasis to bone. The mechanisms through which LPA promotes bone metastasis formation are, ...however, unknown. Here we report that silencing of the type 1 LPA receptor (LPA₁) in cancer cells blocks the production of tumor-derived cytokines that are potent activators of osteoclastmediated bone destruction and significantly reduces the progression of osteolytic bone metastases. Moreover, functional blockade of LPA action on its cognate receptor LPA₁ using a pharmacological antagonist mimics the effects of silencing LPA₁ in tumor cells in vitro and substantially reduces bone metastasis progression in animals. Overall, these results suggest that inhibition of platelet-derived LPA action on LPA₁ expressed by tumor cells may be a promising therapeutic target for patients with bone metastases.
Seropositive rheumatoid arthritis (RA) is characterized by the presence of rheumatoid factor (RF) and anti-citrullinated protein autoantibodies (ACPA) with different fine-specificities. Yet, other ...serum anti-modified protein autoantibodies (AMPA), e.g. anti-carbamylated (Carb), -acetylated (KAc), and malondialdehyde acetaldehyde (MAA) modified protein antibodies, have been described. In this comprehensive study, we analyze 30 different IgG and IgA AMPA reactivities to Cit, Carb, KAc, and MAA antigens detected by ELISA and autoantigen arrays in N=1985 newly diagnosed RA patients. Association with patient characteristics such as smoking and disease activity were explored. Carb and KAc reactivities by different assays were primarily seen in patients also positive for anti-citrulline reactivity. Modified vimentin (mod-Vim) peptides were used for direct comparison of different AMPA reactivities, revealing that IgA AMPA recognizing mod-Vim was mainly detected in subsets of patients with high IgG anti-Cit-Vim levels and a history of smoking. IgG reactivity to acetylation was mainly detected in a subset of patients with Cit and Carb reactivity. Anti-acetylated histone reactivity was RA-specific and associated with high anti-CCP2 IgG levels, multiple ACPA fine-specificities, and smoking status. This reactivity was also found to be present in CCP2+ RA-risk individuals without arthritis. Our data further demonstrate that IgG autoreactivity to MAA was increased in RA compared to controls with highest levels in CCP2+ RA, but was not RA-specific, and showed low correlation with other AMPA. Anti-MAA was instead associated with disease activity and was not significantly increased in CCP2+ individuals at risk of RA. Notably, RA patients could be subdivided into four different subsets based on their AMPA IgG and IgA reactivity profiles. Our serology results were complemented by screening of monoclonal antibodies derived from single B cells from RA patients for the same antigens as the RA cohort. Certain CCP2+ clones had Carb or Carb+KAc+ multireactivity, while such reactivities were not found in CCP2- clones. We conclude that autoantibodies exhibiting different patterns of ACPA fine-specificities as well as Carb and KAc reactivity are present in RA and may be derived from multireactive B-cell clones. Carb and KAc could be considered reactivities within the “Cit-umbrella” similar to ACPA fine-specificities, while MAA reactivity is distinctly different.
In the recent paper 21, the second author proved a divergence-quasiconcavity inequality for the following functional D(A)=∫Tndet(A(x))1n−1dx defined on the space of positive definite matrices in ...Lp(Tn,Sym+(n)) with zero divergence. We consider the space Xp of tensor-fields in Lp(Tn,Sym+(n)) whose divergence is a Radon measure. We endow Xp with the weak topology given by the weak convergence in Lp and the weak-⁎ convergence of the measures representing the divergence of the tensor-fields. Our main result proves the weak upper semicontinuity of the functional D(⋅) on Xp if and only if p>nn−1. We also consider the case p≤nn−1 and show that D(⋅) is upper semicontinuous along sequences satisfying additional conditions. We use the positive result to show some properties of multi-dimensional Burgers equation.
The crosstalk between microtubules and actin is essential for cellular functions. However, mechanisms underlying the microtubule-actin organization by cross-linkers remain largely unexplored. Here, ...we report that tau, a neuronal microtubule-associated protein, binds to microtubules and actin simultaneously, promoting in vitro co-organization and coupled growth of both networks. By developing an original assay to visualize concomitant microtubule and actin assembly, we show that tau can induce guided polymerization of actin filaments along microtubule tracks and growth of single microtubules along actin filament bundles. Importantly, tau mediates microtubule-actin co-alignment without changing polymer growth properties. Mutagenesis studies further reveal that at least two of the four tau repeated motifs, primarily identified as tubulin-binding sites, are required to connect microtubules and actin. Tau thus represents a molecular linker between microtubule and actin networks, enabling a coordination of the two cytoskeletons that might be essential in various neuronal contexts.
Purpose
We aimed to describe the ethical issues encountered by health care workers during the first COVID-19 outbreak in French intensive care units (ICUs), and the factors associated with their ...emergence.
Methods
This descriptive multicentre survey study was conducted by distributing a questionnaire to 26 French ICUs, from 1 June to 1 October 2020. Physicians, residents, nurses, and orderlies who worked in an ICU during the first COVID-19 outbreak were included. Multiple logistic regression models were performed to identify the factors associated with ethical issues.
Results
Among the 4,670 questionnaires sent out, 1,188 responses were received, giving a participation rate of 25.4%. Overall, 953 participants (80.2%) reported experiencing issue(s) while caring for patients during the first COVID-19 outbreak. The most common issues encountered concerned the restriction of family visits in the ICU (91.7%) and the risk of contamination for health care workers (72.3%). Nurses and orderlies faced this latter issue more than physicians (adjusted odds ratio OR
a
, 2.98; 95% confidence interval CI, 1.87 to 4.76;
P
< 0.001 and OR
a
, 4.35; 95% CI, 2.08 to 9.12;
P
< 0.001, respectively). They also faced more the issue “act contrary to the patient's advance directives” (OR
a
, 4.59; 95% CI, 1.74 to 12.08;
P
< 0.01 and OR
a
, 10.65; 95% CI, 3.71 to 30.60;
P
< 0.001, respectively). A total of 1,132 (86.9%) respondents thought that ethics training should be better integrated into the initial training of health care workers.
Conclusion
Eight out of ten responding French ICU health care workers experienced ethical issues during the first COVID-19 outbreak. Identifying these issues is a first step towards anticipating and managing such issues, particularly in the context of potential future health crises.
A hallmark of gastrulation is the establishment of germ layers by internalization of cells initially on the exterior. In C. elegans the end of gastrulation is marked by the closure of the ventral ...cleft, a structure formed as cells internalize during gastrulation, and the subsequent rearrangement of adjacent neuroblasts that remain on the surface. We found that a nonsense allele of srgp-1/srGAP leads to 10-15% cleft closure failure. Deletion of the SRGP-1/srGAP C-terminal domain led to a comparable rate of cleft closure failure, whereas deletion of the N-terminal F-BAR region resulted in milder defects. Loss of the SRGP-1/srGAP C-terminus or F-BAR domain results in defects in rosette formation and defective clustering of HMP-1/âº-catenin in surface cells during cleft closure. A mutant form of HMP-1/âº-catenin with an open M domain can suppress cleft closure defects in srgp-1 mutant backgrounds, suggesting that this mutation acts as a gain-of-function allele. Since SRGP-1 binding to HMP-1/âº-catenin is not favored in this case, we sought another HMP-1 interactor that might be recruited when HMP-1/âº-catenin is constitutively open. A good candidate is AFD-1/afadin, which genetically interacts with cadherin-based adhesion later during embryonic elongation. AFD-1/afadin is prominently expressed at the vertex of neuroblast rosettes in wildtype, and depletion of AFD-1/afadin increases cleft closure defects in srgp-1/srGAP and hmp-1.sup.R551/554A /âº-catenin backgrounds. We propose that SRGP-1/srGAP promotes nascent junction formation in rosettes; as junctions mature and sustain higher levels of tension, the M domain of HMP-1/âº-catenin opens, allowing maturing junctions to transition from recruitment of SRGP-1/srGAP to AFD-1/afadin. Our work identifies new roles for âº-catenin interactors during a process crucial to metazoan development.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The contributions of the viral component of the microbiome—the virome—to the development of innate and adaptive immunity are largely unknown. Here, we systematically defined the host response in mice ...to a panel of eukaryotic enteric viruses representing six different families. Infections with most of these viruses were asymptomatic in the mice, the magnitude and duration of which was dependent on the microbiota. Flow cytometric and transcriptional profiling of mice mono-associated with these viruses unveiled general adaptations by the host, such as lymphocyte differentiation and IL-22 signatures in the intestine, as well as numerous viral-strain-specific responses that persisted. Comparison with a dataset derived from analogous bacterial mono-association in mice identified bacterial species that evoke an immune response comparable with the viruses we examined. These results expand an understanding of the immune space occupied by the enteric virome and underscore the importance of viral exposure events.
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•Profiling enteric viruses highlight role of microbiota in infection and persistence•Viruses can induce enduring changes in the immune system in absence of disease•Diverse strain-specific responses occur alongside common IL-22- and Th1-mediated immunity•Comparison of viral and bacterial exposure reveals commonalities and differences
Comprehensive profiling of immune responses to a panel of eukaryotic viruses reveals a widespread capacity for asymptomatic intestinal infection and durable alterations that are both strain-specific and common to multiple viruses. Cross-comparisons highlight overlapping yet distinct immune space occupied by viral and bacterial members of the gut microbiota.
Depuis plusieurs décennies, l’habitat individuel est resté le mode de vie privilégié des Français et, plus largement, des Européens (Damon, 2017). Tributaires de l’action privée, les quartiers ...résidentiels périurbains continuent à se développer tous azimuts et ce malgré les orientations politiques visant à « faire la ville sur la ville » (ALUR, 2014). La vivacité du débat qu’ils suscitent illustre les clivages et les convergences, mais aussi les avantages et les inconvénients de ces espaces urbanisés en cours de formation. Cette évolution des points de vue pose le pavillonnaire comme un espace en pleine mutation. Or la fabrique de la ville sur elle-même impose de faire avec les habitants en place, ce qui conduit à deux types de questionnements : • Un premier sur ce qui existe : quelle place occupent les habitants déjà là ? Quelles sont les forces en place ? • Un second interrogeant les logiques de renouvellement donc à la fois la vision (ce qu’il peut être fait) et la place des parties prenantes dans le processus : comment impliquer les habitants en place ? Quelle place pour les futurs habitants ? Pour y répondre, cet article rend compte de recherche action explorant les processus de capacity building, définis comme les processus de construction de compétences collectives. Ces expérimentations testent des leviers d’action permettant de déclencher des logiques de projet. Un cadrage théorique sur les processus de capacity building posera d’abord les bases de la réflexion et explicitera les outils conceptuels mobilisés pour faire émerger des scènes de débat et favoriser la montée en compétences collectives des acteurs impliqués. Ensuite, une analyse comparative des deux cas étudiés mettra en évidence la diversité des espaces périurbains, tout en révélant les enjeux communs auxquels ils font face. Enfin, les processus de recherche action seront analysés et montreront de quelle manière les habitants prennent place dans les processus de transformation à l’œuvre. In fine, cet article mettra en évidence les points de convergence possibles entre « projet individuel » et « projet collectif », en s’appuyant sur la création de nouveaux espaces de négociation et de coopération.
Abstract
Saccharomyces cerevisiae requirement for reduced sulfur to synthesize methionine and cysteine during alcoholic fermentation, is mainly fulfilled through the sulfur assimilation pathway. ...Saccharomyces cerevisiae reduces sulfate into sulfur dioxide (SO2) and sulfide (H2S), whose overproduction is a major issue in winemaking, due to its negative impact on wine aroma. The amount of H2S produced is highly strain-specific and also depends on SO2 concentration, often added to grape must. Applying a bulk segregant analysis to a 96-strain-progeny derived from two strains with different abilities to produce H2S, and comparing allelic frequencies along the genome of pools of segregants producing contrasting H2S quantities, we identified two causative regions involved in H2S production in the presence of SO2. A functional genetic analysis allowed the identification of variants in four genes able to impact H2S formation, viz; ZWF1, ZRT2, SNR2, and YLR125W, and involved in functions and pathways not associated with sulfur metabolism until now. These data point out that, in wine fermentation conditions, redox status, and zinc homeostasis are linked to H2S formation while providing new insights into the regulation of H2S production, and a new vision of the interplay between the sulfur assimilation pathway and cell metabolism.
The hydrogen sulfide production of Saccharomyces cerevisiae during alcoholic fermentation is regulated by zinc homeostasis and interconnected with cell metabolism.
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