Adenylate Cyclase Toxin promotes bacterial internalisation into non phagocytic cells

Bordetella pertussis causes whooping cough, a respiratory infectious disease that is the fifth largest cause of vaccine-preventable death in infants. Though historically considered an extracellular pathogen, this bacterium has been detected both in vitro and in vivo inside phagocytic and non-phagocytic cells. However the precise mechanism used by B. pertussis for cell entry, or the putative bacterial factors involved, are not fully elucidated. Here we find that adenylate cyclase toxin (ACT), one of the important toxins of B. pertussis, is sufficient to promote bacterial internalisation into non-phagocytic cells. After characterization of the entry route we show that uptake of "toxin-coated bacteria" proceeds via a clathrin-independent, caveolae-dependent entry pathway, allowing the internalised bacteria to survive within the cells. Intracellular bacteria were found inside non-acidic endosomes with high sphingomyelin and cholesterol content, or "free" in the cytosol of the invaded cells, suggesting that the ACT-induced bacterial uptake may not proceed through formation of late endolysosomes. Activation of Tyr kinases and toxin-induced Ca2+-influx are essential for the entry process. We hypothesize that B. pertussis might use ACT to activate the endocytic machinery of non-phagocytic cells and gain entry into these cells, in this way evading the host immune system.

Removing observational noise from fisheries-independent time series data using ARIMA models

Abundance indices derived from fishery-independent surveys typically exhibit much higher interannual variability than is consistent with the within-survey variance or the life history of a species. This extra variability is essentially observation noise (i.e. measurement error); it probably reflects environmentally driven factors that affect catchability over time. Unfortunately, high observation noise reduces the ability to detect important changes in the underlying population abundance. In our study, a noise-reduction technique for uncorrelated observation noise that is based on autoregressive integrated moving average (ARIMA) time series modeling is investigated. The approach is applied to 18 time series of finfish abundance, which were derived from trawl survey data from the U.S. northeast continental shelf. Although the a priori assumption of a random-walk-plus-uncorrelated-noise model generally yielded a smoothed result that is pleasing to the eye, we recommend that the most appropriate ARIMA model be identified for the observed time series if the smoothed time series will be used for further analysis of the population dynamics of a species.

Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness

Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-beta 3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.

A comparison of two fishery-independent survey programs used to define the population structure of American lobster (Homarus americanus) in the Gulf of Maine

The population structure and abundance of the American lobster (Homarus americanus) stock in the Gulf of Maine are defined by data derived from a fishery-independent trawl survey program conducted by the National Marine Fisheries Service (NMFS). Few sampling stations in the survey area are located inshore, in particular along coastal Maine. According to statistics, however, more than two thirds of the lobster landings come from inshore waters within three miles off the coast of Maine. In order to include an inshore survey program, complementary to the NMFS survey, the Maine Department of Marine Resources (DMR) initialized an inshore survey program in 2000. The survey was modeled on the NMFS survey program, making these two survey programs comparable. Using data from both survey programs, we evaluated the population structure of the American lobster in the Gulf of Maine. Our findings indicate that lobsters in the Gulf of Maine tend to have a size-dependent inshore-off-shore distribution; smaller lobsters are more likely to stay inshore and larger lobsters are more likely to stay offshore. The DMR inshore and NMFS survey programs focused on different areas in the Gulf of Maine and likely targeted different segments of the stock. We suggest that data from both survey programs be used to assess the lobster stock and to describe the dynamics of the stock in the Gulf of Maine.

Study on the activation mechanism of BCL-2 related ovarian killer (BOK)

BCL-2 family proteins are key regulators of the mitochondrial apoptotic machinery, controlling the mitochondrial outer membrane (MOM) permeabilization (MOMP). BCL-2 related Ovarian Killer (BOK) is a poorly understood pro-apoptotic member of this protein family. It has been reported that BOK localizes predominantly (although not exclusively) at membranes of the endoplasmic reticulum and of the Golgi apparatus. However, it is unclear whether BOK also operates at the MOM to promote apoptosis, as other pro-apoptotic BCL-2 family members do. Basing on the fact that the other two BAX-like pro-apoptotic members have been reported to oligomerize in order to induce MOMP, site-directed mutagenesis was used to generate two point mutations that predictably eliminated BOK’s oligomerization capacity. Then, the effect of such mutations on BOK’s membrane activity was examined using fluorescence spectroscopy.

Dipeptidyl-Peptidase IV Activity Is Correlated with Colorectal Cancer Prognosis

Background Dipeptidyl-peptidase IV (EC 3.4.14.5) (DPPIV) is a serine peptidase involved in cell differentiation, adhesion, immune modulation and apoptosis, functions that control neoplastic transformation. Previous studies have demonstrated altered expression and activity of tissue and circulating DPPIV in several cancers and proposed its potential usefulness for early diagnosis in colorectal cancer (CRC). Methods and principal findings The activity and mRNA and protein expression of DPPIV was prospectively analyzed in adenocarcinomas, adenomas, uninvolved colorectal mucosa and plasma from 116 CRC patients by fluorimetric, quantitative RT-PCR and immunohistochemical methods. Results were correlated with the most important classic pathological data related to aggressiveness and with 5-year survival rates. Results showed that: 1) mRNA levels and activity of DPPIV increased in colorectal neoplasms (Kruskal-Wallis test, p<0.01); 2) Both adenomas and CRCs displayed positive cytoplasmic immunostaining with luminal membrane reinforcement; 3) Plasmatic DPPIV activity was lower in CRC patients than in healthy subjects (Mann-U test, p<0.01); 4) Plasmatic DPPIV activity was associated with worse overall and disease-free survivals (log-rank p<0.01, Cox analysis p<0.01). Conclusion/significance 1) Up-regulation of DPPIV in colorectal tumors suggests a role for this enzyme in the neoplastic transformation of colorectal tissues. This finding opens the possibility for new therapeutic targets in these patients. 2) Plasmatic DPPIV is an independent prognostic factor in survival of CRC patients. The determination of DPPIV activity levels in the plasma may be a safe, minimally invasive and inexpensive way to define the aggressiveness of CRC in daily practice.

Fishery-independent Bottom Trawl Surveys for Deep-water Fishes and Invertebrates of the U.S. Gulf of Mexico, 2002–08

From 2002 through 2008, the Mississippi Laboratories of the NMFS Southeast Fisheries Science Center, NOAA, conducted fishery-independent bottom trawl surveys for continental shelf and outer-continental shelf deep-water fishes and invertebrates of the U.S. Gulf of Mexico (50–500 m bottom depths). Five-hundred and ninety species were captured at 797 bottom trawl locations. Standardized survey gear and randomly selected survey sites have facilitated development of a fishery-independent time series that characterizes species diversity, distributions, and catch per unit effort. The fishery-independent surveys provide synoptic descriptions of deep-water fauna potentially impacted by various anthropogenic factors.