Meniscus formation during tracheal instillation of surfactant

The method ofsurfactant instillation into the lungs for treatment of neonatalrespiratory distress syndrome is an important attribute of delivery,and it may determine the overall efficacy of treatment. Previousstudies primarily focused on the rate at which the bolus is instilled.These findings show that rapid injections lead to a more homogenousdistribution, whereas slow infusions drain into the dependent lung withrespect to gravity, resulting in a heterogeneous deposition. Theseresults suggest that it is beneficial to form a meniscus, from which amore homogenous dispersal can proceed. The objective of the presentstudy was to develop a functional criterion for meniscus formationduring bolus injection. An in vitro experiment was used to examine theclinical setting of surfactant instillation. The physical variablesexamined were the bolus viscosity (µ) and density (), gravity(g), injection rate (Q), orientation of thetrachea with respect to gravity (), tracheal size(D), surface tension (), andcatheter size (d). All quantitieswere varied, except gravity and catheter size. Experimental resultsshow that a meniscus will form whenN_St > 0.004Re^2/3, whereN_St is Stokesnumber and Re is Reynolds number,N_St = µQ/D⁴gsin,a ratio of viscous effects to gravitational effects, and Re = QD/d²µ,a ratio of inertial effects to viscous effects. Rapid injections, highviscosity, and small inclination with respect to gravity promotemeniscus formation. These results can be used to refine the guidelinesfor administration of surfactant replacement therapy.

     

Pancreatic ductal adenocarcinomas from Mexican patients present a distinct genomic mutational pattern

Molecular Biology Reports - Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in humans, with less than 5% 5-year survival rate. PDAC is characterized by a small number of...     

Therapeutic Targeting of MLL Degradation Pathways in MLL-Rearranged Leukemia

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Replication of the promiscuous plasmid pLSI: a region encompassing the minus origin of replication is associated with stable plasmid inheritance

Deletion of a region of the promiscuous plasmid pLS1 encompassing the initiation signals for the synthesis of the plasmid lagging strand led to plasmid instability in Streptococcus pneumoniae and Bacillus subtilis. This defect could not be alleviated by increasing the number of copies (measured as double-stranded plasmid DNA) to levels similar to those of the wild-type plasmid pLS1. Our results indicate that in the vicinity of, or associated with the single-stranded origin region of pLS1 there is a plasmid component involved in its stable inheritance. Homology was found between the DNA gyrase binding site within the par region of plasmid pSC101 and the pLS1 specific recombination site RS_R.     

A specific immunological probe for the major myelin proteolipid. Confirmation of a deletion in DM-20

Major myelin proteolipid (MMPL, also called PLP) and DM-20 are the two major intrinsic membrane proteins of CNS myelin. A specific immunological probe was obtained for MMPL by raising antibodies against the synthetic tridecapeptide 117-129 of MMPL. Antibodies against this peptide reacted with the MMPL but did not cross react with DM-20, while both proteolipids had been shown previously to be recognized by antibodies directed against the C-terminal hexapeptide of MMPL. This is in accordance with previous findings showing that DM-20 differs only from MMPL by a deletion of residues 100-140 (+/- few units). Furthermore, this site-specific immunological probe also recognizes MMPL in its native form in oligodendrocytes in primary glial cell cultures.     

Differential Targeting of SLC30A10/ZnT10 Heterodimers to Endolysosomal Compartments Modulates EGF‐Induced MEK/ERK1/2 Activity

The solute carrier 30A (SLC30A) family of zinc exporters transports zinc into the lumen of intracellular organelles in order to prevent zinc toxicity. We reported that formation of tyrosine dimers is required for ZnT3 (zinc transporter 3) zinc transport activity and targeting to synaptic‐like microvesicles (SLMVs) in PC12 cells and the formation of ZnT3/ZnT10 heterodimers. Here, we focused on ZnT10 to determine the role of heterodimerization in the sorting of ZnTs in the endolysosomal pathway. Using cell fractionation, immunoprecipitation and immunofluorescence approaches, we found that ZnT10 resides in transferrin receptor and Rab5‐positive endosomes and forms covalent heterodimers and oligomers with ZnT2, ZnT3 and ZnT4. The interaction of ZnT10 with ZnT3, mediated by dityrosine bonds, was unable to target ZnT10 into SLMVs in vitro or into synaptic vesicles isolated from mouse brain in vivo. However, ZnT3/ZnT10 heterodimers regulate epidermal growth factor receptor (EGF‐R) signaling by increasing the phosphorylation of mitogen‐activated protein kinase kinase (MEK) and extracellular signal‐regulated kinase (ERK1/2), but not EGF‐R, C‐Raf or Akt phosphorylation in response to EGF. Further, mutation of tyrosine 4 in ZnT10 reduced ZnT3/ZnT10 dityrosine‐mediated heterodimerization and zinc transport, as well as MEK and ERK1/2 phosphorylation, which were also reduced by the zinc chelator TPEN. Phosphorylation of these kinases is likely to occur in the cytosol as no differences in phosphorylation were observed in membrane fractions of control and ZnT3/ZnT10‐expressing cells. We propose that ZnT10 plays a role in signal transduction, which is mediated by homo and heterodimerization with other ZnTs.      

ATM regulates cell fate choice upon p53 activation by modulating mitochondrial turnover and ROS levels

Despite extensive study, the mechanisms of cell fate choice upon p53 activation remain poorly understood. Using genome-wide shRNA screening, we recently identified the ATM kinase as synthetic lethal with Nutlin-3, an MDM2 inhibitor that leads to non-genotoxic p53 activation. Here, we demonstrate that while this synthetic lethal interaction relies upon components of both the intrinsic and extrinsic apoptotic pathways (e.g., BAX and BID), it is not due to significant ATM effects on the expression of p53 target genes. Instead, loss of ATM activity results in increased mitochondria and reactive oxygen species that drive apoptosis. Finally, we provide evidence that pharmacologic inhibition of ATM blocks autophagy in direct opposition to p53, which activates this process, and that inhibition of autophagy is sufficient to elicit an apoptotic response when combined with Nutlin-3.     

CDKN3 mRNA as a Biomarker for Survival and Therapeutic Target in Cervical Cancer

The cyclin-dependent kinase inhibitor 3 (CDKN3) gene, involved in mitosis, is upregulated in cervical cancer (CC). We investigated CDKN3 mRNA as a survival biomarker and potential therapeutic target for CC. CDKN3 mRNA was measured in 134 CC and 25 controls by quantitative PCR. A 5-year survival study was conducted in 121 of these CC patients. Furthermore, CDKN3-specific siRNAs were used to investigate whether CDKN3 is involved in proliferation, migration, and invasion in CC-derived cell lines (SiHa, CaSki, HeLa). CDKN3 mRNA was on average 6.4-fold higher in tumors than in controls (p = 8 x 10⁻⁶, Mann-Whitney). A total of 68.2% of CC patients over expressing CDKN3 gene (fold change ≥ 17) died within two years of diagnosis, independent of the clinical stage and HPV type (Hazard Ratio = 5.0, 95% CI: 2.5–10, p = 3.3 x 10⁻⁶, Cox proportional-hazards regression). In contrast, only 19.2% of the patients with lower CDKN3 expression died in the same period. In vitro inactivation of CDKN3 decreased cell proliferation on average 67%, although it had no effect on cell migration and invasion. CDKN3 mRNA may be a good survival biomarker and potential therapeutic target in CC.     

Structure and injuries of octocoral communities (Octocorallia: Alcyonacea) of Ecological Reserve Siboney-Juticí, Santiago de Cuba, Cuba

In the spur-and-groove reefs of the Ecological Reserve Siboney-Juticí (Southeast Cuba) octocorals are one of the predominant components of the sessile fauna. Main objectives of the present paper are characterizing the composition, structure and conservation status of the octocoral communities and assessing on the prevailing environmental conditions in the study area. For data collection, six sampling sites were located every 2-3 km ranging from 12 m to 17 m depth along the spur-and-groove reefs. In each site, 22-26 lm2 quadrants were zigzag arranged every 2 m. The density of colonies was determined per site. The severity degree and predictability of environmental conditions were inferred by using the Heterogeneity and Equitability indexes, respectively. Hydrodynamic stress and the Comparative Pollution Index were also assessed. Current affectations of the octocoral communities were also determined and classified into four main categories: mechanical damage, diseases, predation and invertebrate and macroalgae overgrowth. As a result, 25 species represented by 752 colonies were recorded and Eunicea flexuosa and Gorgonia ventalina were the most abundant. The occurrence of Eunicea succinea forma succinea constituted the first report for Eastern Cuba. Site densities ranged from 3.58 +/- 1.84 to 7.58 +/- 2.16 colonies/m2 and considered from moderate to low. The biggest densities were reported at both sides of the San Juan River mouth. Despite of the composition and structure of the octocoral communities, low to high hydrodynamic stress and low and moderate levels of contamination were inferred, it is likely that these indexes could have been overestimated due to the sensitivity of the indicator species to other factors such as sedimentation. The environmental conditions were mostly favorable and stable. In general, the number of dead colonies was low and mostly caused by the detachment of the substrate and overgrowth of Millepora alcicornis. Injuries were mainly brought about by mechanical damage, followed by coenenchyme loss, predation by Cyphoma gibbosum and macroalgae overgrowth. On the other hand, negative effects by Hermodice carunculata predation, bleaching, Red Band and Black Band Disease were not observed. Among sampled species, G. ventalina colonies were the most severely damaged within the community. As a whole, octocoral communities of spur-and-groove reefs in the Ecological Reserve Siboney-Juticí showed a good conservation status.