Matriptase regulates c-Met mediated proliferation and invasion in inflammatory breast cancer.

The poor prognosis for patients with inflammatory breast cancer (IBC) compared to patients with other types of breast cancers emphasizes the need to better understand the molecular underpinnings of this disease with the goal of developing effective targeted therapeutics. Dysregulation of matriptase expression, an epithelial-specific member of the type II transmembrane serine protease family, has been demonstrated in many different cancer types. To date, no studies have assessed the expression and potential pro-oncogenic role of matriptase in IBC. We examined the functional relationship between matriptase and the HGF/c-MET signaling pathway in the IBC cell lines SUM149 and SUM190, and in IBC patient samples. Matriptase and c-Met proteins are localized on the surface membrane of IBC cells and their expression is strongly correlated in infiltrating cancer cells and in the cancer cells of lymphatic emboli in patient samples. Abrogation of matriptase expression by silencing with RNAi or inhibition of matriptase proteolytic activity with a synthetic inhibitor impairs the conversion of inactive pro-HGF to active HGF and subsequent c-Met-mediated signaling, leading to efficient impairment of proliferation and invasion of IBC cells. These data show the potential of matriptase inhibitors as a novel targeted therapy for IBC, and lay the groundwork for the development and testing of such drugs

Ecogenomic Perspectives on Domains of Unknown Function: Correlation-Based Exploration of Marine Metagenomes

Background: The proportion of conserved DNA sequences with no clear function is steadily growing in bioinformatics databases. Studies of sequence and structural homology have indicated that many uncharacterized protein domain sequences are variants of functionally described domains. If these variants promote an organism's ecological fitness, they are likely to be conserved in the genome of its progeny and the population at large. The genetic composition of microbial communities in their native ecosystems is accessible through metagenomics. We hypothesize the co-variation of protein domain sequences across metagenomes from similar ecosystems will provide insights into their potential roles and aid further investigation. Methodology/Principal findings: We calculated the correlation of Pfam protein domain sequences across the Global Ocean Sampling metagenome collection, employing conservative detection and correlation thresholds to limit results to well-supported hits and associations. We then examined intercorrelations between domains of unknown function (DUFs) and domains involved in known metabolic pathways using network visualization and cluster-detection tools. We used a cautious "guilty-by-association'' approach, referencing knowledge-level resources to identify and discuss associations that offer insight into DUF function. We observed numerous DUFs associated to photobiologically active domains and prevalent in the Cyanobacteria. Other clusters included DUFs associated with DNA maintenance and repair, inorganic nutrient metabolism, and sodium-translocating transport domains. We also observed a number of clusters reflecting known metabolic associations and cases that predicted functional reclassification of DUFs. Conclusion/Significance: Critically examining domain covariation across metagenomic datasets can grant new perspectives on the roles and associations of DUFs in an ecological setting. Targeted attempts at DUF characterization in the laboratory or in silico may draw from these insights and opportunities to discover new associations and corroborate existing ones will arise as more large-scale metagenomic datasets emerge

Sulfur oxidation genes in diverse deep-sea viruses

Author Posting. © The Author(s), 2014. This is the author's version of the work. It is posted here by permission of AAAS for personal use, not for redistribution. The definitive version was published in Science 344 (2014): 757-760, doi:10.1126/science.1252229.Viruses are the most abundant biological entities in the oceans and a pervasive cause of mortality of microorganisms that drive biogeochemical cycles. Although the ecological and evolutionary impacts of viruses on marine phototrophs are well-recognized, little is known about their impact on ubiquitous marine lithotrophs. Here we report 18 genome sequences of double-stranded DNA viruses that putatively infect widespread sulfur-oxidizing bacteria. Fifteen of these viral genomes contain auxiliary metabolic genes for the alpha and gamma subunits of reverse dissimilatory sulfite reductase (rdsr). This enzyme oxidizes elemental sulfur, which is abundant in the hydrothermal plumes studied here. Our findings implicate viruses as a key agent in the sulfur cycle and as a reservoir of genetic diversity for bacterial enzymes that underpin chemosynthesis in the deep oceans.This project is funded in part by the Gordon and Betty Moore Foundation Grant GBMF2609 and National Science Foundation Grant OCE1038006

Maturation-Dependent Response of the Piglet Brain to Scaled Cortical Impact

Object. The goal of this study was to investigate the relationship between maturational stage and the brain\u27s response to mechanical trauma in a gyrencephalic model of focal brain injury. Age-dependent differences in injury response might explain certain unique clinical syndromes seen in infants and young children and would determine whether specific therapies might be particularly effective or even counterproductive at different ages. Methods. To deliver proportionally identical injury inputs to animals of different ages, the authors have developed a piglet model of focal contusion injury by using specific volumes of rapid cortical displacement that are precisely scaled to changes in size and dimensions of the growing brain. Using this model, the histological response to a scaled focal cortical impact was compared at 7 days after injury in piglets that were 5 days, 1 month, and 4 months of age at the time of trauma. Despite comparable injury inputs and stable physiological parameters, the percentage of hemisphere injured differed significantly among ages, with the youngest animals sustaining the smallest lesions (0.8%, 8.4%, and 21.5%, for 5-day-, 1-month-, and 4-month-old animals, respectively, p = 0.0018). Conclusions. These results demonstrate that, for this particular focal injury type and severity, vulnerability to mechanical trauma increases progressively during maturation. Because of its developmental and morphological similarity to the human brain, the piglet brain provides distinct advantages in modeling age-specific responses to mechanical trauma. Differences in pathways leading to cell death or repair may be relevant to designing therapies appropriate for patients of different ages

Uptake and Retention of Nanoplastics in Quagga Mussels

Here, a set of experiments to assess the feasibility of using an invasive and widespread freshwater mussel (Dreissena rostrformis bugensis) as a sentinel species for nanoplastic detection is reported. Under laboratory experimental conditions, mussels ingest and retain fluorescent polystyrene (PS) beads with carboxylic acid (COOH) termination over a size range of 200- 2000 nm. The number of beads the mussels ingested is quantified using fluorescence spectroscopy and the location of the beads in the mussels is imaged using fluorescence microscopy. PS beads of similar size (1000- 2000 nm) to mussels’ preferred food are trafficked in the ciliated food grooves of the gills. Beads of all sizes are observed in the mussels’ digestive tracts, indicating that the mussels do not efficiently reject the beads as unwanted foreign material, regardless of size. Fluorescence microscopy shows all sizes of beads are concentrated in the siphons and are retained there for longer than one month postexposure. Combined atomic force microscopy- infrared spectroscopy and photothermal infrared spectroscopy are used to locate, image, and chemically identify the beads in the mussel siphons. In sum, these experiments demonstrate the potential for using mussels, specifically their siphons, to monitor environmental accumulation of aquatic nanoplastics.Can quagga mussels (Dreissena rostriformis bugensis), a widespread and invasive freshwater species that alters local ecosystems, act as a sentinel species for detecting nanoplastics? In the laboratory, mussels ingest and retain 200- 2000 nm fluorescent polystyrene beads, which are in the size range for the mussels’ preferred food and are trafficked like food in the ciliated grooves of the gills.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/155884/1/gch2201800104-sup-0001-SuppMat.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155884/2/gch2201800104.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/155884/3/gch2201800104_am.pd

Gender Differences in Head Impacts Sustained by Collegiate Ice Hockey Players

Purpose—This study aims to quantify the frequency, magnitude, and location of head impacts sustained by male and female collegiate ice hockey players over two seasons of play. Methods—Over two seasons, 88 collegiate athletes (51 female, 37 male) on two female and male NCAA varsity ice hockey teams wore instrumented helmets. Each helmet was equipped with 6 single-axis accelerometers and a miniature data acquisition system to capture and record head impacts sustained during play. Data collected from the helmets were post-processed to compute linear and rotational acceleration of the head as well as impact location. The head impact exposure data (frequency, location, and magnitude) were then compared across gender. Results—Female hockey players experienced a significantly lower (p \u3c 0.001) number of impacts per athlete exposure than males (female: 1.7 ± 0.7; male: 2.9 ± 1.2). The frequency of impacts by location was the same between gender (p \u3e 0.278) for all locations except the right side of the head, where males received fewer impacts than females (p = 0.031). Female hockey players were 1.1 times more likely than males to sustain an impact less than 50 g while males were 1.3 times more likely to sustain an impact greater than 100 g. Similarly, males were 1.9 times more likely to sustain an impact with peak rotational acceleration greater than 5,000 rad/s2 and 3.5 times more likely to sustain an impact greater than 10,000 rad/s2. Conclusions—Although the incidence of concussion has typically been higher for female hockey players than male hockey players, female players sustain fewer impacts and impacts resulting in lower head acceleration than males. Further study is required to better understand th

Rotational Head Kinematics in Football Impacts: An Injury Risk Function for Concussion

Recent research has suggested a possible link between sports-related concussions and neurodegen-erative processes, highlighting the importance of developing methods to accurately quantify head impact tolerance. The use of kinematic parameters of the head to predict brain injury has been sug-gested because they are indicative of the inertial response of the brain. The objective of this study is to characterize the rotational kinematics of the head associated with concussive impacts using a large head acceleration dataset collected from human subjects. The helmets of 335 football players were instrumented with accelerometer arrays that measured head acceleration following head impacts sustained during play, resulting in data for 300,977 subconcussive and 57 concussive head impacts. The average subconcussive impact had a rotational acceleration of 1230 rad/s2 and a rotational ve-locity of 5.5 rad/s, while the average concussive impact had a rotational acceleration of 5022 rad/s2 and a rotational velocity of 22.3 rad/s. An injury risk curve was developed and a nominal injury value of 6383 rad/s2 associated with 28.3 rad/s represents 50% risk of concussion. These data provide an increased understanding of the biomechanics associated with concussion, and they provide critical insight into injury mechanisms, human tolerance to mechanical stimuli, and injury prevention tech-niques