Capacity for LDL (Low-Density Lipoprotein) Retention Predicts the Course of Atherogenesis in the Murine Aortic Arch.

BACKGROUND To cause atherosclerosis, LDLs (low-density lipoproteins) must first pass through the endothelium and then become retained in the arterial matrix. Which of these two processes is rate-limiting and predicts the topography of plaque formation remains controversial. To investigate this issue, we performed high-resolution mapping of LDL entry and retention in murine aortic arches before and during atherosclerosis development. METHODS Maps of LDL entry and retention were created by injecting fluorescently labeled LDL followed by near-infrared scanning and whole-mount confocal microscopy after 1 hour (entry) and 18 hours (retention). By comparing arches between normal mice and mice with short-term hypercholesterolemia, we analyzed changes in LDL entry and retention during the LDL accumulation phase that precedes plaque formation. Experiments were designed to secure equal plasma clearance of labeled LDL in both conditions. RESULTS We found that LDL retention is the overall limiting factor for LDL accumulation but that the capacity for LDL retention varied substantially over surprisingly short distances. The inner curvature region, previously considered a homogenous atherosclerosis-prone region, consisted of dorsal and ventral zones with high capacity and a central zone with low capacity for continued LDL retention. These features predicted the temporal pattern of atherosclerosis, which first appeared in the border zones and later in the central zone. The limit to LDL retention in the central zone was intrinsic to the arterial wall, possibly caused by saturation of the binding mechanism, and was lost upon conversion to atherosclerotic lesions. CONCLUSIONS Capacity for continued LDL retention varies over short distances and predicts where and when atherosclerosis develops in the mouse aortic arch.This study was supported by grants from the Ministerio de Economía, Industria y Competitividad (MEIC) with cofunding from the European Regional Development Fund (SAF2016-75580-R and PID2019-108568RB-I00), the Novo Nordisk Foundation (NNF17OC0030688) and the La Caixa Health Research Programme (HR20-00075, AtheroConvergence). V. Labrador-Cantarero is supported by FEDER “Una manera de hacer Europa” for the project In Vivo Advanced Nanoscopy at the ICTS–ReDib–TRIMA–CNIC. CNIC is supported by the Instituto de Salud Carlos III (ISCIII), the Ministerio de Ciencia e Innovación, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505).S

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Roles of SPD-3 during C. elegans meiosis

Correct chromosome segregation during meiosis requires that the paternal and maternal copies of each chromosome, known as homologues, recognise and pair with one another before they can undergo meiotic recombination. Defects in this process lead to sterility and the formation of aneuploid gametes, which is the leading cause of birth defects in humans. In this study the process of homologue pairing during meiosis has been investigated in C. elegans, an organism especially well suited for meiotic studies. During a genetic screen for meiotic mutants, several mutants with defects in meiotic chromosome segregation were isolated. One of these mutants, me85, was identified as a new allele of the spd-3 gene, which had previously been shown to be required for mitotic divisions in the early embryo. spd-3(me85) mutants display defects in homologue pairing similar to those observed in mutants lacking SUN-1 or ZYG-12, two proteins that form a bridge across the nuclear envelope (NE). This bridge transmits cytoskeletal forces generated outside the nucleus to meiotic chromosomes inside the nucleus, thereby facilitating chromosome clustering, a process that is though to facilitate homology search. The localisation of SUN-1 and ZYG-12 to the NE is not affected in spd-3(me85) mutants and chromosomes remain tethered to the NE. However, live imaging experiments in spd-3(me85) mutants demonstrate that the movement of chromosomes through the NE is severely impaired, which results in lack of chromosome clustering. Knocking down the activity of the dynein-dynactin complex by RNAi resulted in a phenocopy of the chromosome clustering defects observed in spd-3(me85) mutants, although dynein localisation is not affected in spd-3(me85) mutants. Interestingly, the SPD-3 protein localizes outside the nucleus in the germline. These observations suggest that SPD-3 affects the earliest steps of homologue pairing by regulating the cytoskeletal forces outside the nucleus

Role of the septin Cdc10 in the virulence of Candida albicans

The relationship between the morphology and virulence of Candida albicans has aroused interest in the study of the proteins involved in its morphogenesis. We present virulence data for one important element in fungal morphogenesis - septins. We disrupted CaCDC10 and studied the virulence in a mouse infection model and the different steps followed by the fungus during the infection: adherence to epithelial cells, organ colonisation, macrophage phagocytosis, and host survival. We found the altered subcellular localisation of Int1 - a C. albicans adhesin - in the septin null mutants. The Int1 mislocalisation and the defects in the cell wall of defective CaCdc10 strains permit us to propose a model for explaining the biological meaning of the absence of virulence presented by these septin mutants.Peer Reviewe

Dbf2 is essential for cytokinesis and correct mitotic spindle formation in Candida albicans

El pdf del artículo es la versión pre-print.We have characterized the DBF2 gene, encoding a protein kinase of the NDR family in Candida albicans, and demonstrate that this gene is essential for cell viability. Conditional mutants were constructed by using the MET3 promoter to analyse the phenotype of cells lacking this kinase. The absence of Dbf2 resulted in cells arrested as large-budded pairs that failed to contract the actomyosin ring, a function similar to that described for its Saccharomyces cerevisiae orthologue. In addition to its role in cytokinesis, Dbf2 regulates mitotic spindle organization and nuclear segregation as Dbf2-depleted cells have abnormal microtubules and severe defects in nuclear migration to the daughter cell, which results in a cell cycle block during mitosis. Taken together, these results imply that Dbf2 performs several functions during exit from mitosis and cytokinesis. Consistent with a role in spindle organization, the protein localizes to the mitotic spindle during anaphase, and it interacts physically with tubulin, as indicated by immunoprecipitation experiments. Finally, DBF2 depletion also resulted in impaired true hyphal growth. © 2009 Blackwell Publishing Ltd.This work was supported by grants from Junta de Castilla y León SA013B05 (to J.J.) and Ministerio de Ciencia y Tecnología BFU2004-00778 and BFU2007-60390 (to C.R. V.) and BFU2006-10318 (to J.C.B.).Peer Reviewe

ULK3 regulates cytokinetic abscission by phosphorylating ESCRT-III proteins

The endosomal sorting complexes required for transport (ESCRT) machinery mediates the physical separation between daughter cells during cytokinetic abscission. This process is regulated by the abscission checkpoint, a genome protection mechanism that relies on Aurora B and the ESCRT-III subunit CHMP4C to delay abscission in response to chromosome missegregation. In this study, we show that Unc-51-like kinase 3 (ULK3) phosphorylates and binds ESCRT-III subunits via tandem MIT domains, and thereby, delays abscission in response to lagging chromosomes, nuclear pore defects, and tension forces at the midbody. Our structural and biochemical studies reveal an unusually tight interaction between ULK3 and IST1, an ESCRT-III subunit required for abscission. We also demonstrate that IST1 phosphorylation by ULK3 is an essential signal required to sustain the abscission checkpoint and that ULK3 and CHMP4C are functionally linked components of the timer that controls abscission in multiple physiological situations. DOI: http://dx.doi.org/10.7554/eLife.06547.00

Cáparra : revista de innovación y experiencias educativas de los Centros de Profesores y Recursos de la Provincia de Cáceres

Se describen las distintas actuaciones llevadas a cabo ante las necesidades específicas de apoyo educativo del alumnado con altas capacidades en cinco centros de la provincia de Cáceres, tres colegios de Educación Infantil y Primaria y dos centros de secundaria. Son actuaciones desarrolladas con diferentes metodologías y con actividades dirigidas a todo el grupo clase, a grupos reducidos o en programas individuales, donde se aúnan enriquecimientos en habilidades cognitivas y afectivas. Las actividades están vinculadas a los programas educativos de los alumnos, centrándose en una o varias asignaturas, atendiendo las necesidades académicas y socioemocionales de los alumnos, respetando los distintos tipos de aprendizajes y la propia realidad escolar, proponiendo aprendizajes innovadores, flexibles y creativosES

Chromosome Movements Promoted by the Mitochondrial Protein SPD-3 Are Required for Homology Search during <i>Caenorhabditis elegans</i> Meiosis

<div><p>Pairing of homologous chromosomes during early meiosis is essential to prevent the formation of aneuploid gametes. Chromosome pairing includes a step of homology search followed by the stabilization of homolog interactions by the synaptonemal complex (SC). These events coincide with dramatic changes in nuclear organization and rapid chromosome movements that depend on cytoskeletal motors and are mediated by SUN-domain proteins on the nuclear envelope, but how chromosome mobility contributes to the pairing process remains poorly understood. We show that defects in the mitochondria-localizing protein SPD-3 cause a defect in homolog pairing without impairing nuclear reorganization or SC assembly, which results in promiscuous installation of the SC between non-homologous chromosomes. Preventing SC assembly in <i>spd-3</i> mutants does not improve homolog pairing, demonstrating that SPD-3 is required for homology search at the start of meiosis. Pairing center regions localize to SUN-1 aggregates at meiosis onset in <i>spd-3</i> mutants; and pairing-promoting proteins, including cytoskeletal motors and polo-like kinase 2, are normally recruited to the nuclear envelope. However, quantitative analysis of SUN-1 aggregate movement in <i>spd-3</i> mutants demonstrates a clear reduction in mobility, although this defect is not as severe as that seen in <i>sun-1(jf18)</i> mutants, which also show a stronger pairing defect, suggesting a correlation between chromosome-end mobility and the efficiency of pairing. SUN-1 aggregate movement is also impaired following inhibition of mitochondrial respiration or dynein knockdown, suggesting that mitochondrial function is required for motor-driven SUN-1 movement. The reduced chromosome-end mobility of <i>spd-3</i> mutants impairs coupling of SC assembly to homology recognition and causes a delay in meiotic progression mediated by HORMA-domain protein HTP-1. Our work reveals how chromosome mobility impacts the different early meiotic events that promote homolog pairing and suggests that efficient homology search at the onset of meiosis is largely dependent on motor-driven chromosome movement.</p></div