Bioadhesive properties of Gantrez nanoparticles

Bioadhesive nanoparticles have been proposed as carriers for the oral delivery of poorly available drugs and facilitate the use of this route. This work summarises some experiments describing the bioadhesive potential of Gantrez nanoparticles fluorescently labeled with rhodamine B isothiocyanate. The adhesive potential of Gantrez was found to be stronger when folded as nanoparticles than in the solubilised form. Conventional nanoparticles displayed a tropism for the upper areas of the gastrointestinal tract, with a maximum of adhesion 30 min post-administration and a decrease in the adhered fraction along the time depending on the given dose. The cross-linkage of nanoparticles with increasing amounts of 1,3-diaminopropane stabilised the resulting carriers and prolonged their half-life in an aqueous environment; although, the adhesive capacity of nanoparticles, the intensity and the relative duration of the adhesive interactions within the gut as a function of the cross-linking degree. Finally, nanoparticles were coated with either gelatin or albumin. In the first case, the presence of gelatin dramatically decreased the initial capacity of these carriers to interact with the gut mucosa and the intensity of these phenomenons. In the latter, bovine serum albumin coated nanoparticles (BSA-NP) showed an important tropism for the stomach mucosa without further significant distribution to other parts of the gut mucosa

DNA bending facilitates the error-free DNA damage tolerance pathway and upholds genome integrity

Abstract DNA replication is sensitive to damage in the template. To bypass lesions and complete replication, cells activate recombination-mediated (error-free) and translesion synthesis-mediated (error-prone) DNA damage tolerance pathways. Crucial for error-free DNA damage tolerance is template switching, which depends on the formation and resolution of damage-bypass intermediates consisting of sister chromatid junctions. Here we show that a chromatin architectural pathway involving the high mobility group box protein Hmo1 channels replication-associated lesions into the error-free DNA damage tolerance pathway mediated by Rad5 and PCNA polyubiquitylation, while preventing mutagenic bypass and toxic recombination. In the process of template switching, Hmo1 also promotes sister chromatid junction formation predominantly during replication. Its C-terminal tail, implicated in chromatin bending, facilitates the formation of catenations/hemicatenations and mediates the roles of Hmo1 in DNA damage tolerance pathway choice and sister chromatid junction formation. Together, the results suggest that replication-associated topological changes involving the molecular DNA bender, Hmo1, set the stage for dedicated repair reactions that limit errors during replication and impact on genome stability

Maria Calderon : comedia original en cuatro actos y en verso

Representada por primea vez con aplauso en el teatro de Variedades,la noche del 24 de diciembre de 1850Pie de imprenta tomado del colofónTexto a dos col.Sign.:1-3(4º)Colección de comedias representadas con éxito en los Teatros de Madri

Dynamics of DNA Ejection From Bacteriophage

The ejection of DNA from a bacterial virus (``phage'') into its host cell is a biologically important example of the translocation of a macromolecular chain along its length through a membrane. The simplest mechanism for this motion is diffusion, but in the case of phage ejection a significant driving force derives from the high degree of stress to which the DNA is subjected in the viral capsid. The translocation is further sped up by the ratcheting and entropic forces associated with proteins that bind to the viral DNA in the host cell cytoplasm. We formulate a generalized diffusion equation that includes these various pushing and pulling effects and make estimates of the corresponding speed-ups in the overall translocation process. Stress in the capsid is the dominant factor throughout early ejection, with the pull due to binding particles taking over at later stages. Confinement effects are also investigated, in the case where the phage injects its DNA into a volume comparable to the capsid size. Our results suggest a series of in vitro experiments involving the ejection of DNA into vesicles filled with varying amounts of binding proteins from phage whose state of stress is controlled by ambient salt conditions or by tuning genome length.Comment: 17 pages, 5 figure

Rate of replenishment and microenvironment contribute to the sexually dimorphic phenotype and function of peritoneal macrophages

International audienceMacrophages reside in the body cavities where they maintain serosal homeostasis and provide immune surveillance. Peritoneal macrophages are implicated in the aetiology of pathologies including peritonitis, endometriosis and metastatic cancer thus understanding the factors that govern their behaviour is vital. Using a combination of fate mapping techniques, we have investigated the impact of sex and age on murine peritoneal macrophage differentiation, turnover and function. We demonstrat

Genome-organizing factors Top2 and Hmo1 prevent chromosome fragility at sites of S phase transcription

Specialized topoisomerases solve the topological constraints arising when replication forks encounter transcription. We have investigated the contribution of Top2 in S phase transcription. Specifically in S phase, Top2 binds intergenic regions close to transcribed genes. The Top2-bound loci exhibit low nucleosome density and accumulate gammaH2A when Top2 is defective. These intergenic loci associate with the HMG protein Hmo1 throughout the cell cycle and are refractory to the histone variant Htz1. In top2 mutants, Hmo1 is deleterious and accumulates at pericentromeric regions in G2/M. Our data indicate that Top2 is dispensable for transcription and that Hmo1 and Top2 bind in the proximity of genes transcribed in S phase suppressing chromosome fragility at the M-G1 transition. We propose that an Hmo1-dependent epigenetic signature together with Top2 mediate an S phase architectural pathway to preserve genome integrity

TREM-2 plays a protective role in cholestasis by acting as a negative regulator of inflammation

Background & Aims: Inflammation, particularly that mediated by bacterial components translocating from the gut to the liver and binding to toll-like receptors (TLRs), is central to cholestatic liver injury. The triggering receptor expressed on myeloid cells-2 (TREM-2) inhibits TLR-mediated signaling and exerts a protective role in hepatocellular injury and carcinogenesis. This study aims to evaluate the role of TREM-2 in cholestasis.Methods: TREM-2 expression was analyzed in the livers of pa-tients with primary biliary cholangitis (PBC) or primary scle-rosing cholangitis (PSC), and in mouse models of cholestasis. Wild-type (WT) and Trem-2 deficient (Trem-2-/-) mice were subjected to experimental cholestasis and gut sterilization. Pri-mary cultured Kupffer cells were incubated with lipopolysac-charide and/or ursodeoxycholic acid (UDCA) and inflammatory responses were analyzed.Results: TREM-2 expression was upregulated in the livers of patients with PBC or PSC, and in murine models of cholestasis. Compared to WT, the response to bile duct ligation (BDL)-induced obstructive cholestasis or alpha-naphtylisothiocyanate (ANIT)-induced cholestasis was exacerbated in Trem-2-/-mice. This was characterized by enhanced necroptotic cell death, in-flammatory responses and biliary expansion. Antibiotic treat-ment partially abrogated the effects observed in Trem-2-/-mice after BDL. Experimental overexpression of TREM-2 in the liver of WT mice downregulated ANIT-induced IL-33 expression and neutrophil recruitment. UDCA regulated Trem-1 and Trem-2 expression in primary cultured mouse Kupffer cells and damp-ened inflammatory gene transcription via a TREM-2-dependent mechanism.Conclusions: TREM-2 acts as a negative regulator of inflamma-tion during cholestasis, representing a novel potential thera-peutic target.Lay summary: Cholestasis (the reduction or cessation of bile flow) causes liver injury. This injury is exacerbated when gut-derived bacterial components interact with receptors (spe-cifically Toll-like receptors or TLRs) on liver-resident immune cells, promoting inflammation. Herein, we show that the anti-inflammatory receptor TREM-2 dampens TLR-mediated signaling and hence protects against cholestasis-induced liver injury. Thus, TREM-2 could be a potential therapeutic target in cholestasis.Spanish Carlos III Health Institute (ISCIII) [J.M. Banales (FIS PI18/01075, PI21/00922 and Miguel Servet Program CPII19/00008); M.J. Perugorria (FIS PI14/00399, PI17/00022 and PI20/00186); J.J.G. Marin (FIS PI16/00598 and PI19/00819); P.M. Rodrigues (Sara Borrell CD19/00254)] cofinanced by “Fondo Europeo de Desarrollo Regional” (FEDER); “Instituto de Salud Carlos III” [CIBERehd: M.J. Monte, J.J.G. Marin, J.M. Banales, M.J. Perugorria, P. Aspichueta, P.M. Rodrigues and L. Bujanda], Spain; “Diputación Foral de Gipuzkoa” (M.J. Perugorria: DFG18/114), Department of Health of the Basque Country (M.J. Perugorria: 2019111024, 2015111100 and J.M. Banales: 2021111021), “Euskadi RIS3” (J.M. Banales: 2019222054, 2020333010, 2021333003), and Department of Industry of the Basque Country (J.M. Banales: Elkartek: KK-2020/00008); “Junta de Castilla y Leon” (J.J.G. Marin: SA063P17). La Caixa Scientific Foundation (J.M. Banales: HR17-00601). “Fundación Científica de la Asociación Española Contra el Cáncer” (AECC Scientific Foundation, to J.M. Banales and J.J.G. Marin); “Centro Internacional sobre el Envejecimiento” (J.J.G. Marin: OLD-HEPAMARKER, 0348_CIE_6_E); Fundació Marato TV3 (J.J.G. Marin: Ref. 201916-31). O Sharif was funded by the Austrian Science Fund (FWF-P35168). Work in the lab of T. Luedde was funded by the European Research Council (ERC) (Grant Agreement 771083), the German Research Foundation (DFG – LU 1360/3-2 (279874820), LU 1360/4-(1461704932) and SFB-CRC 1382-Project A01) and the German Ministry of Health (BMG – DEEP LIVER 2520DAT111). Contributions of M. Marzioni were funded by the Università Politecnica delle Marche PSA2017_UNIVPM grant. Contributions of DAM were supported by programme grants from CRUK (C18342/A23390) and MRC (MR/K0019494/1 and MR/R023026/1). MJ Perugorria was funded by the Spanish Ministry of Economy and Competitiveness (MINECO: “Ramón y Cajal” Programme RYC-2015-17755), I. Labiano, A. Agirre-Lizaso, P. Olaizola, A. Echebarria and F. González-Romero by the Basque Government (PRE_2016_1_0152, PRE_2018_1_0184, PRE_2016_1_0269 PRE_2020_1_0080, PRE_2018_1_0120, respectively), I. Olaizola by the Ministry of Universities (FPU 19/03327) and A. Esparza-Baquer by the University of the Basque Country (PIF2014/11). The funding sources had no involvement in study design, data collection and analysis, decision to publish, or preparation of the article

Occupational pesticide intoxications among farmers in Bolivia: a cross-sectional study

BACKGROUND: Pesticide use and its consequences are of concern in Bolivia due to an intensive and increasing use. METHODS: To assess the magnitude and reasons for occupational pesticide intoxication, a cross-sectional study with interviews and blood-tests was performed among 201 volunteer farmers from 48 villages in the temperate and subtropical valleys in the eastern part of the Andes Mountains in Bolivia. Of these 171 male farmers using pesticides in their agricultural production were used in the statistical analysis, including linear- and logistic regression analysis. RESULTS: This study documented a frequent use of the most toxic pesticides among farmers who have had almost no instructions in how to use pesticides and protect themselves against the dangers of intoxication, reflected in the hazardous practices used when handling pesticides. Symptoms of intoxications were common in connection with spraying operations. The risk of experiencing symptoms and the serum cholinesterase activity were influenced by whether or not organophosphates were used and the number of times sprayed. The experience of symptoms was moreover influenced by the hygienic and personal protective measures taken during spraying operations while this had no influence on the serum cholinesterase level. CONCLUSION: The study showed that occupational pesticide intoxications were common among farmers and did depend on multiple factors. Pesticide use is probably one of the largest toxicological problems in Bolivia, and a coordinated action by authorities, society and international bodies is needed to limit the number of intoxications and the environmental pollution

Involvement of phage ϕ29 DNA polymerase and terminal protein subdomains in conferring specificity during initiation of protein-primed DNA replication

To initiate ϕ29 DNA replication, the DNA polymerase has to form a complex with the homologous primer terminal protein (TP) that further recognizes the replication origins of the homologous TP-DNA placed at both ends of the linear genome. By means of chimerical proteins, constructed by swapping the priming domain of the related ϕ29 and GA-1 TPs, we show that DNA polymerase can form catalytically active heterodimers exclusively with that chimerical TP containing the N-terminal part of the homologous TP, suggesting that the interaction between the polymerase TPR-1 subdomain and the TP N-terminal part is the one mainly responsible for the specificity between both proteins. We also show that the TP N-terminal part assists the proper binding of the priming domain at the polymerase active site. Additionally, a chimerical ϕ29 DNA polymerase containing the GA-1 TPR-1 subdomain could use GA-1 TP, but only in the presence of ϕ29 TP-DNA as template, indicating that parental TP recognition is mainly accomplished by the DNA polymerase. The sequential events occurring during initiation of bacteriophage protein-primed DNA replication are proposed