Listeria monocytogenes Multidrug Resistance Transporters and Cyclic Di-AMP,Which Contribute to Type I Interferon Induction,Play a Role in Cell Wall Stress

The intracellular bacterial pathogen Listeria monocytogenes activates a robust type I interferon response upon infection. This response is partially dependent on the multidrug resistance (MDR) transporter MdrM and relies on cyclic-di-AMP (c-di-AMP) secretion, yet the functions of MdrM and cyclic-di-AMP that lead to this response are unknown. Here we report that it is not MdrM alone but a cohort of MDR transporters that together contribute to type I interferon induction during infection. In a search for a physiological function of these transporters, we revealed that they play a role in cell wall stress responses. A mutant with deletion of four transporter genes (ΔmdrMTAC) was found to be sensitive to sublethal concentrations of vancomycin due to an inability to produce and shed peptidoglycan under this stress. Remarkably, c-di-AMP is involved in this phenotype, as overexpression of the c-di-AMP phosphodiesterase (PdeA) resulted in increased susceptibility of the ΔmdrMTAC mutant to vancomycin, whereas overexpression of the c-di-AMP diadenylate cyclase (DacA) reduced susceptibility to this drug. These observations suggest a physiological association between c-di-AMP and the MDR transporters and support the model that MDR transporters mediate c-di-AMP secretion to regulate peptidoglycan synthesis in response to cell wall stress.     

Inhibition of induction of deciduoma by acute administration of antibody to progesterone.

Rabbit antiserum to progesterone was injected i.v. 10 minutes before systematic induction of deciduoma with pyrathiazine. The activity of ornithine decarboxylase 4 hours later was used as a measure of onset of the growth and differentiation of decidual tissue. The antiserum caused complete blockage of the enzyme induction. This implies that progesterone is an agonist in the induction of decidualization.     

Receptor-based targeting of engineered nanocarrier against solid tumors: Recent progress and challenges ahead

BackgroundIn past few decades, the research on engineered nanocarriers (NCs) has gained significant attention in cancer therapy due to selective delivery of drug molecules on the diseased cells thereby preventing unwanted uptake into healthy cells to cause toxicity.Scope of reviewThe applicability of enhanced permeability and retention (EPR) effect for the delivery of nanomedicines in cancer therapy has gained limited success due to poor accessibility of the drugs to the target cells where non-specific payload delivery to the off target region lack substantial reward over the conventional therapeutic systems.Major conclusionsIn spite of the fact, nanomedicines fabricated from the biocompatible nanocarriers have reduced targeting potential for meaningful clinical benefits. However, over expression of receptors on the tumor cells provides opportunity to design functional nanomedicine to bind substantially and deliver therapeutics to the cells or tissues of interest by alleviating the bio-toxicity and unwanted effects. This critique will give insight into the over expressed receptor in various tumor and targeting potential of functional nanomedicine as new therapeutic avenues for effective treatment.General significanceThis review shortly shed light on EPR-based drug targeting using nanomedicinal strategies, their limitation, and advances in therapeutic targeting to the tumor cells.     

Impact of Diabetes Mellitus on the Outcome of Pancreatic Cancer

Introduction

Diabetes mellitus (DM) has the potential to impact the pathogenesis, treatment, and outcome of pancreatic cancer. This study evaluates the impact of DM on pancreatic cancer survival.

Methods

We conducted a retrospective cohort study from the Veterans Affairs (VA) Central Cancer Registry (VACCR) for pancreatic cancer cases between 1995 and 2008. DM and no-DM cases were identified from comorbidity data. Univariate and multivariable analysis was performed. Multiple imputation method was employed to account for missing variables.

Results

Of 8,466 cases of pancreatic cancer DM status was known in 4728 cases that comprised this analysis. Males accounted for 97.7% cases, and 78% were white. Overall survival was 4.2 months in DM group and 3.6 months in the no-DM group. In multivariable analysis, DM had a HR = 0.91 (0.849–0.974). This finding persisted after accounting for missing variables using multiple imputations method with the HR in DM group of 0.93 (0.867–0.997).

Conclusions

Our data suggest DM is associated with a reduction in risk of death in pancreatic cancer. Future studies should be directed towards examining this association, specifically impact of DM medications on cancer outcome.     

Opiate versus psychostimulant addiction: the differences do matter

The publication of the psychomotor stimulant theory of addiction in 1987 and the finding that addictive drugs increase dopamine concentrations in the rat mesolimbic system in 1988 have led to a predominance of psychobiological theories that consider addiction to opiates and addiction to psychostimulants as essentially identical phenomena. Indeed, current theories of addiction - hedonic allostasis, incentive sensitization, aberrant learning and frontostriatal dysfunction - all argue for a unitary account of drug addiction. This view is challenged by behavioural, cognitive and neurobiological findings in laboratory animals and humans. Here, we argue that opiate addiction and psychostimulant addiction are behaviourally and neurobiologically distinct and that the differences have important implications for addiction treatment, addiction theories and future research.     

Opposing activities of LIT-1/NLK and DAF-6/patched-related direct sensory compartment morphogenesis in C. elegans

Glial cells surround neuronal endings to create enclosed compartments required for neuronal function. This architecture is seen at excitatory synapses and at sensory neuron receptive endings. Despite the prevalence and importance of these compartments, how they form is not known. We used the main sensory organ of C. elegans, the amphid, to investigate this issue. daf-6/Patched-related is a glia-expressed gene previously implicated in amphid sensory compartment morphogenesis. By comparing time series of electron-microscopy (EM) reconstructions of wild-type and daf-6 mutant embryos, we show that daf-6 acts to restrict compartment size. From a genetic screen, we found that mutations in the gene lit-1/Nemo-like kinase (NLK) suppress daf-6. EM and genetic studies demonstrate that lit-1 acts within glia, in counterbalance to daf-6, to promote sensory compartment expansion. Although LIT-1 has been shown to regulate Wnt signaling, our genetic studies demonstrate a novel, Wnt-independent role for LIT-1 in sensory compartment size control. The LIT-1 activator MOM-4/TAK1 is also important for compartment morphogenesis and both proteins line the glial sensory compartment. LIT-1 compartment localization is important for its function and requires neuronal signals. Furthermore, the conserved LIT-1 C-terminus is necessary and sufficient for this localization. Two-hybrid and co-immunoprecipitation studies demonstrate that the LIT-1 C-terminus binds both actin and the Wiskott-Aldrich syndrome protein (WASP), an actin regulator. We use fluorescence light microscopy and fluorescence EM methodology to show that actin is highly enriched around the amphid sensory compartment. Finally, our genetic studies demonstrate that WASP is important for compartment expansion and functions in the same pathway as LIT-1. The studies presented here uncover a novel, Wnt-independent role for the conserved Nemo-like kinase LIT-1 in controlling cell morphogenesis in conjunction with the actin cytoskeleton. Our results suggest that the opposing daf-6 and lit-1 glial pathways act together to control sensory compartment size.     

Neonatal Pain-Related Stress Predicts Cortical Thickness at Age 7 Years in Children Born Very Preterm

Background

Altered brain development is evident in children born very preterm (24–32 weeks gestational age), including reduction in gray and white matter volumes, and thinner cortex, from infancy to adolescence compared to term-born peers. However, many questions remain regarding the etiology. Infants born very preterm are exposed to repeated procedural pain-related stress during a period of very rapid brain development. In this vulnerable population, we have previously found that neonatal pain-related stress is associated with atypical brain development from birth to term-equivalent age. Our present aim was to evaluate whether neonatal pain-related stress (adjusted for clinical confounders of prematurity) is associated with altered cortical thickness in very preterm children at school age.

Methods

42 right-handed children born very preterm (24–32 weeks gestational age) followed longitudinally from birth underwent 3-D T1 MRI neuroimaging at mean age 7.9 yrs. Children with severe brain injury and major motor/sensory/cognitive impairment were excluded. Regional cortical thickness was calculated using custom developed software utilizing FreeSurfer segmentation data. The association between neonatal pain-related stress (defined as the number of skin-breaking procedures) accounting for clinical confounders (gestational age, illness severity, infection, mechanical ventilation, surgeries, and morphine exposure), was examined in relation to cortical thickness using constrained principal component analysis followed by generalized linear modeling.

Results

After correcting for multiple comparisons and adjusting for neonatal clinical factors, greater neonatal pain-related stress was associated with significantly thinner cortex in 21/66 cerebral regions (p-values ranged from 0.00001 to 0.014), predominately in the frontal and parietal lobes.

Conclusions

In very preterm children without major sensory, motor or cognitive impairments, neonatal pain-related stress appears to be associated with thinner cortex in multiple regions at school age, independent of other neonatal risk factors.     

The transition between preluteolysis and luteolysis in cattle

Novel characterization of the transition between preluteolysis and luteolysis was done in seven heifers. Blood samples were collected hourly and assayed for progesterone (P4), 13-14-dihydro-15-keto-PGF2α (PGFM), and estradiol (E2). The peaks of P4 oscillations were used to designate the transitional hour in each heifer. The interval from the peak of the last PGFM pulse of preluteolysis to the peak of the first pulse during luteolysis (transitional period) was longer (P < 0.0001) than the interval between the first and second pulses during luteolysis (13.4 ± 1.3 h vs. 7.0 ± 0.9 h). The long intervals from the last PGFM pulse of preluteolysis to the transitional hour (4.0 ± 0.9 h) and from the transitional hour to the first PGFM pulse of luteolysis (9.4 ± 1.3 h) resulted in the illusion that the beginning of luteolysis was not associated temporally with a PGFM pulse. The E2 and PGFM concentrations were less (P < 0.05) during the last PGFM pulse of preluteolysis than during the first pulse of luteolysis. Concentration of P4 was suppressed at the peak of the last PGFM pulse of preluteolysis and consistently rebounded at the transitional hour to the concentrations before the PGFM pulse. In four of seven heifers, one or two P4 rebounds occurred between the peak of the PGFM pulse and the rebound at the transitional hour. Results indicated that the prolonged transitional period may be related, at least in part, to increasing concentration of E2, intervening P4 rebounds between the peak of the last PGFM pulse of preluteolysis and the transitional hour, and the complete P4 rebound at the transitional hour.     

Temporal control of cell-specific transgene expression in Caenorhabditis elegans

Cell-specific promoters allow only spatial control of transgene expression in Caenorhabditis elegans. We describe a method, using cell-specific rescue of heat-shock factor-1 (hsf-1) mutants, that allows spatial and temporal regulation of transgene expression. We demonstrate the utility of this method for timed reporter gene expression and for temporal studies of gene function.