Peptide density targets and impedes triple negative breast cancer metastasis

The C-X-C chemokine receptor type 4 (CXCR4, CD184) pathway is a key regulator of cancer metastasis. Existing therapeutics that block CXCR4 signaling are dependent on single molecule-receptor interactions or silencing CXCR4 expression. CXCR4 localizes in lipid rafts and forms dimers therefore CXCR4 targeting and signaling may depend on ligand density. Herein, we report liposomes presenting a CXCR4 binding peptide (DV1) as a threedimensional molecular array, ranging from 9k to 74k molecules μm−2, target triple negative breast cancer (TNBC). TNBC cells exhibit a maxima in binding and uptake of DV1functionalized liposomes (L-DV1) in vitro at a specific density, which yields a significant reduction in cell migration. This density inhibits metastasis from a primary tumor for 27 days, resulting from peptide density dependent gene regulation. We show that complementing cell membrane receptor expression may be a strategy for targeting cells and regulating signaling

Transfer of noncoding DNA drives regulatory rewiring in bacteria

Understanding the mechanisms that generate variation is a common pursuit unifying the life sciences. Bacteria represent an especially striking puzzle, because closely related strains possess radically different metabolic and ecological capabilities. Differences in protein repertoire arising from gene transfer are currently considered the primary mechanism underlying phenotypic plasticity in bacteria. Although bacterial coding plasticity has been extensively studied in previous decades, little is known about the role that regulatory plasticity plays in bacterial evolution. Here, we show that bacterial genes can rapidly shift between multiple regulatory modes by acquiring functionally divergent nonhomologous promoter regions. Through analysis of 270,000 regulatory regions across 247 genomes, we demonstrate that regulatory “switching” to nonhomologous alternatives is ubiquitous, occurring across the bacterial domain. Using comparative transcriptomics, we show that at least 16% of the expression divergence between Escherichia coli strains can be explained by this regulatory switching. Further, using an oligonucleotide regulatory library, we establish that switching affects bacterial promoter architecture. We provide evidence that regulatory switching can occur through horizontal regulatory transfer, which allows regulatory regions to move across strains, and even genera, independently from the genes they regulate. Finally, by experimentally characterizing the fitness effect of a regulatory transfer on a pathogenic E. coli strain, we demonstrate that regulatory switching elicits important phenotypic consequences. Taken together, our findings expose previously unappreciated regulatory plasticity in bacteria and provide a gateway for understanding bacterial phenotypic variation and adaptation.National Science Foundation (U.S.) (Grant DEB-0936234

A Systematic Review and Meta-Analysis of Practices Exposing Humans to Avian Influenza Viruses, Their Prevalence, and Rationale

Almost all human infections by avian influenza viruses (AIVs) are transmitted from poultry. A systematic review was conducted to identify practices associated with human infections, their prevalence, and rationale. Observational studies were identified through database searches. Meta-analysis produced combined odds ratio estimates. The prevalence of practices and rationales for their adoptions were reported. Of the 48,217 records initially identified, 65 articles were included. Direct and indirect exposures to poultry were associated with infection for all investigated viral subtypes and settings. For the most frequently reported practices, association with infection seemed stronger in markets than households, for sick and dead than healthy poultry, and for H7N9 than H5N1. Practices were often described in general terms and their frequency and intensity of contact were not provided. The prevalence of practices was highly variable across studies, and no studies comprehensively explored reasons behind the adoption of practices. Combining epidemiological and targeted anthropological studies would increase the spectrum and detail of practices that could be investigated and should aim to provide insights into the rationale(s) for their existence. A better understanding of these rationales may help to design more realistic and acceptable preventive public health measures and messages

Nanoparticle elasticity directs tumor uptake

To date, the role of elasticity in drug delivery remains elusive due to the inability to measure microscale mechanics and alter rheology without affecting chemistry. Herein, we describe the in vitro cellular uptake and in vivo tumor uptake of nanolipogels (NLGs). NLGs are composed of identical lipid bilayers encapsulating an alginate core, with tunable elasticity. The elasticity of NLGs was evaluated by atomic force microscopy, which demonstrated that they exhibit Young’s moduli ranging from 45 ± 9 to 19,000 ± 5 kPa. Neoplastic and non-neoplastic cells exhibited significantly greater uptake of soft NLGs (Young’s modulus 13.8 MPa). In an orthotopic breast tumor model, soft NLGs accumulated significantly more in tumors, whereas elastic NLGs preferentially accumulated in the liver. Our findings demonstrate that particle elasticity directs tumor accumulation, suggesting that it may be a design parameter to enhance tumor delivery efficiency

Does global progress on sanitation really lag behind water? An analysis of global progress on community- and household-level access to safe water and sanitation.

Safe drinking water and sanitation are important determinants of human health and wellbeing and have recently been declared human rights by the international community. Increased access to both were included in the Millennium Development Goals under a single dedicated target for 2015. This target was reached in 2010 for water but sanitation will fall short; however, there is an important difference in the benchmarks used for assessing global access. For drinking water the benchmark is community-level access whilst for sanitation it is household-level access, so a pit latrine shared between households does not count toward the Millennium Development Goal (MDG) target. We estimated global progress for water and sanitation under two scenarios: with equivalent household- and community-level benchmarks. Our results demonstrate that the "sanitation deficit" is apparent only when household-level sanitation access is contrasted with community-level water access. When equivalent benchmarks are used for water and sanitation, the global deficit is as great for water as it is for sanitation, and sanitation progress in the MDG-period (1990-2015) outstrips that in water. As both drinking water and sanitation access yield greater benefits at the household-level than at the community-level, we conclude that any post-2015 goals should consider a household-level benchmark for both

Silk as a Multifunctional Biomaterial Substrate for Reduced Glial Scarring around Brain‐Penetrating Electrodes

The reliability of chronic, brain‐penetrating electrodes must be improved for these ‐neural recording technologies to be viable in widespread clinical applications. One approach to improving electrode reliability is to reduce the foreign body response at the probe‐tissue interface. In this work, silk fibroin is investigated as a candidate material for fabricating mechanically dynamic neural probes with enhanced biocompatibility compared to traditional electrode materials. Silk coatings are applied to flexible cortical electrodes to produce devices that transition from stiff to flexible upon hydration. Theoretical modeling and in vitro testing show that the silk coatings impart mechanical properties sufficient for the electrodes to penetrate brain tissue. Further, it is demonstrated that silk coatings may reduce some markers of gliosis in an in vitro model and that silk can encapsulate and release the gliosis‐modifying enzyme chondroitinase ABC. This work establishes a basis for future in vivo studies of silk‐based brain‐penetrating electrodes, as well as the use of silk materials for other applications in the central nervous system where gliosis must be controlled. Silk fibroin is investigated as a novel material for fabricating brain‐penetrating electrodes with dynamic mechanical properties and the capacity to deliver sensitive therapeutics. Silk coatings are shown to natively reduce some markers of gliosis in vitro, and a further reduction is demonstrated by encapsulation and release of the enzyme chondroitinase ABC.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98822/1/3185_ftp.pd

Pre-neoplastic alterations define CLL DNA methylome and persist through disease progression and therapy

Most human cancers converge to a deregulated methylome with reduced global levels and elevated methylation at select CpG islands. To investigate the emergence and dynamics of the cancer methylome, we characterized genome-wide DNA methylation in preneoplastic monoclonal B-cell lymphocytosis (MBL) and chronic lymphocytic leukemia (CLL), including serial samples collected across disease course. We detected the aberrant tumor-associated methylation landscape at CLL diagnosis and found no significant differentially methylated regions in the high-count MBL-to-CLL transition. Patient methylomes showed remarkable stability with natural disease and posttherapy progression. Single CLL cells were consistently aberrantly methylated, indicating a homogeneous transition to the altered epigenetic state and a distinct expression profile together with MBL cells compared with normal B cells. Our longitudinal analysis reveals the cancer methylome to emerge early, which may provide a platform for subsequent genetically driven growth dynamics, and, together with its persistent presence, suggests a central role in disease onset. SigNifiCANCe: DNA methylation data from a large cohort of patients with MBL and CLL show that epigenetic transformation emerges early and persists throughout disease stages with limited subsequent changes. Our results indicate an early role for this aberrant landscape in the normal-to-preneoplastic transition that may reflect a pan-cancer mechanism

Tourism and Pilgrimage: Paying Homage to Literary Heroes

By exploring the experiences of visiting the grave of famous authors, this study highlights the place of literary tourism in the tourism pilgrimage literature. It is based on an observational study of visitors to the grave of Jean-Paul Sartre and Simone de Beauvoir in Paris. Analysis reveals that visitors were motivated by a desire for closeness, a wish to pay their respects and to acknowledge the influence on their life of the two writers. The study notes a strong parallel between the religious and the literary pilgrim, and contributes to knowledge on the phenomenon of the secular pilgrimage

An RNA-based transcription activator derived from an inhibitory aptamer

According to the recruitment model of transcriptional activation, an activator helps initiate transcription by bringing the RNA polymerase to a specific location on the DNA through interaction with components of the transcriptional machinery. However, it is difficult to isolate and define the activities of specific activator–target pairs experimentally through rearranging existing protein parts. Here we designed and constructed an RNA-based transcriptional activator to study specificity from both sides of the activator–target interface. Utilizing a well-characterized site-specific RNA aptamer for TFIIB, we were able to delineate some key features of this process. By rationally converting an inhibitory aptamer into the activation domain of the activator, we also introduced a new source of submolecular building blocks to synthetic biology

The Gonadotropin-Inhibitory Hormone: What We Know and What We Still Have to Learn From Fish

Gonadotropin-inhibitory hormone, GnIH, is named because of its function in birds and mammals; however, in other vertebrates this function is not yet clearly established. More than half of the vertebrate species are teleosts. This group is characterized by the 3R whole genome duplication, a fact that could have been responsible for the great phenotypic complexity and great variability in reproductive strategies and sexual behavior. In this context, we revise GnIH cell bodies and fibers distribution in adult brains of teleosts, discuss its relationship with GnRH variants and summarize the few reports available about the ontogeny of the GnIH system. Considering all the information presented in this review, we propose that in teleosts, GnIH could have other functions beyond reproduction or act as an integrative signal in the reproductive process. However, further studies are required in order to clarify the role of GnIH in this group including its involvement in development, a key stage that strongly impacts on adult life