Epithelial cell-directed efferocytosis in the post-partum mammary gland is necessary for tissue homeostasis and future lactation

<p>Abstract</p> <p>Background</p> <p>Mammary glands harbor a profound burden of apoptotic cells (ACs) during post-lactational involution, but little is known regarding mechanisms by which ACs are cleared from the mammary gland, or consequences if this process is interrupted. We investigated AC clearance, also termed efferocytosis, during post-lactational remodeling, using mice deficient for MerTK, Axl, and Tyro3, three related receptor tyrosine kinases (RTKs) regulating macrophage-mediated efferocytosis in monocytes. MerTK expression, apoptosis and the accumulation of apoptotic debris were examined in histological sections of MerTK-deficient, Axl/Tyro3-deficient, and wild-type mammary glands harvested at specific time points during lactation and synchronized involution. The ability of primary mammary epithelial cells (MECs) to engulf ACs was assessed in culture. Transplant of MerTK-deficient mammary epithelium into cleared WT mammary fat pads was used to assess the contribution of WT mammary macrophages to post-lactational efferocytosis.</p> <p>Results</p> <p>ACs induced MerTK expression in MECs, resulting in elevated MerTK levels at the earliest stages of involution. Loss of MerTK resulted in AC accumulation in post-lactational MerTK-deficient mammary glands, but not in Axl and Tyro3-deficient mammary glands. Increased vascularization, fibrosis, and epithelial hyperproliferation were observed in MerTK-deficient mammary glands through at least 60 days post-weaning, due to failed efferocytosis after lactation, but did not manifest in nulliparous mice. WT host-derived macrophages failed to rescue efferocytosis in transplanted MerTK-deficient mammary epithelium.</p> <p>Conclusion</p> <p>Efferocytosis by MECs through MerTK is crucial for mammary gland homeostasis and function during the post-lactational period. Efferocytosis by MECs thus limits pathologic consequences associated with the apoptotic load following lactation.</p

Reclaiming Global Environmental Leadership: Why the United States Should Ratify Ten Pending Environmental Treaties

For more than a century, the United States has taken the lead in organizing international responses to international environmental problems. In the last two decades, however, U.S. environmental leadership has faltered. The best-known example is the lack of an effective response to climate change, underscored by the U.S. decision not to join the Kyoto Protocol. But that is not the only shortfall. The United States has also failed to join a large and growing number of treaties directed at other environmental threats, including marine pollution, the loss of biological diversity, persistent organic pollutants, and trade in toxic substances. This white paper identifies ten of these critical, pending environmental treaties and explains their importance and the actions needed to fully join them. The failure of the United States to join these treaties undermines global environmental protection and undermines U.S. interests in protecting a wide range of natural resources. The treaties set out standards and create institutions designed to find and implement solutions to problems of critical importance. They have attracted support from other countries, including our closest allies. Indeed, several are among the most widely ratified treaties in history. In every case, the regimes these treaties have established are less successful without U.S. membership than they could be with the full engagement of the country with the largest economy and the largest environmental impact

Walking and Walkability: Is Wayfinding a Missing Link? Implications for Public Health Practice

Research on walking and walkability has yet to focus on wayfinding, the interactive, problem-solving process by which people use environmental information to locate themselves and navigate through various settings

Developing a self‐consistent description of Titan's upper atmosphere without hydrodynamic escape

In this study, we develop a best fit description of Titan's upper atmosphere between 500 km and 1500 km, using a one‐dimensional (1‐D) version of the three‐dimensional (3‐D) Titan Global Ionosphere‐Thermosphere Model. For this modeling, we use constraints from several lower atmospheric Cassini‐Huygens investigations and validate our simulation results against in situ Cassini Ion‐Neutral Mass Spectrometer (INMS) measurements of N 2 , CH 4 , H 2 , 40 Ar, HCN, and the major stable isotopic ratios of 14 N/ 15 N in N 2 . We focus our investigation on aspects of Titan's upper atmosphere that determine the amount of atmospheric escape required to match the INMS measurements: the amount of turbulence, the inclusion of chemistry, and the effects of including a self‐consistent thermal balance. We systematically examine both hydrodynamic escape scenarios for methane and scenarios with significantly reduced atmospheric escape. Our results show that the optimum configuration of Titan's upper atmosphere is one with a methane homopause near 1000 km and atmospheric escape rates of 1.41–1.47 ×10 11 CH 4  m −2 s −1 and 1.08 ×10 14  H 2  m −2 s −1 (scaled relative to the surface). We also demonstrate that simulations consistent with hydrodynamic escape of methane systematically produce inferior fits to the multiple validation points presented here. Key Points The methane homopause is most likely near 1000 km altitude Hydrodynamic escape of methane is not required to match INMS Molecular hydrogen is best fit with a methane homopause of 1000 kmPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/108005/1/jgra51076.pd

Mobility Disability in Older Adults: At the Intersection of People and Places

Mobility disability is associated with poor lower body function among older adults. This study examines whether specific types of neighborhood characteristics moderate that association

Inaccuracies of Nitric Oxide Measurement Methods in Biological Media

Despite growing reports on the biological action of nitric oxide (NO) as a function of NO payload, the validity of such work is often questionable due to the manner in which NO is measured and/or the solution composition in which NO is quantified. To highlight the importance of measurement technique for a given sample type, NO produced from a small molecule NO donor (N-diazeniumdiolated l-proline, PROLI/NO) and a NO-releasing xerogel film were quantified in a number of physiological buffers and fluids, cell culture media, and bacterial broth using the Griess assay, a chemiluminescence analyzer, and an amperometric NO sensor. Despite widespread use, the Griess assay proved to be inaccurate for measuring NO in many of the media tested. In contrast, the chemiluminescence analyzer provided superb kinetic information in most buffers, but was impractical for NO analysis in proteinaceous media. The electrochemical NO sensor enabled greater flexibility across the various media with potential for spatial resolution, albeit at lower than expected NO totals versus either the Griess assay or chemiluminescence. The results of this study highlight the importance of measurement strategy for accurate NO analysis and reporting NO-based biological activity

A two-species continuum model for aeolian sand ripples

We formulate a continuum model for aeolian sand ripples consisting of two species of grains: a lower layer of relatively immobile clusters, with an upper layer of highly mobile grains moving on top. We predict analytically the ripple wavelength, initial ripple growth rate and threshold saltation flux for ripple formation. Numerical simulations show the evolution of realistic ripple profiles from initial surface roughness via ripple growth and merger.Comment: 9 pages, 3 figure

S-Nitrosothiol-modified nitric oxide-releasing chitosan oligosaccharides as antibacterial agents

S-nitrosothiol-modified chitosan oligosaccharides were synthesized by reaction with 2-iminothiolane hydrochloride and 3-acetamido-4,4-dimethylthietan-2-one, followed by the thiol nitrosation. The resulting nitric oxide (NO)-releasing chitosan oligosaccharides stored ~0.3 μmol NO/mg chitosan. Both the chemical structure of the nitrosothiol (i.e., primary and tertiary) and the use of ascorbic acid as a trigger for NO donor decomposition were used to control the NO-release kinetics. With ascorbic acid, the S-nitrosothiol-modified chitosan oligosaccharides elicited a 4-log reduction in Pseudomonas aeruginosa (P. aeruginosa) viability. Confocal microscopy indicated that the primary S-nitrosothiol-modified chitosan oligosaccharides associated more with the bacteria relative to the tertiary S-nitrosothiol system. The primary S-nitrosothiol-modified chitosan oligosaccharides elicited minimal toxicity towards L929 mouse fibroblast cells at the concentration necessary for a 4-log reduction in bacterial viability, further demonstrating the potential of S-nitrosothiol-modified chitosan oligosaccharides as NO-release therapeutics

Direct detection of blood nitric oxide reveals a burn-dependent decrease of nitric oxide in response to Pseudomonas aeruginosa infection

Burn injury is associated with severe immune dysfunction, including an anti-inflammatory state that occurs late after burn injury. While increased nitric oxide (NO) production is associated with severe infection and sepsis, the effect of burn trauma on these levels during a non-lethal infection remains unknown. We hypothesized that in a mouse model, 1) NO levels would be increased after infection without trauma and 2) burn injury would lead to decreased NO production even during infection

Public perceptions about risk and protective factors for cognitive health and impairment: a review of the literature

ABSTRACT Background: Preventing and/or delaying cognitive impairment is a public health priority. To increase awareness of and participation in behaviors that may help maintain cognitive function or reduce risk of impairment, we need to understand public perceptions about risk and protective factors. Methods: We conducted a scoping review of studies examining the public's perceptions about risk and protective factors related to cognitive health and impairment published since the 2007 National Public Health Road Map to Maintaining Cognitive Health . Results: A search of five databases yielded 1,115 documents published between June 2007 and December 2013. Initial review of abstracts identified 90 potentially eligible studies. After full-article review, 30 met inclusion criteria; four additional articles identified in reference lists also met inclusion criteria. Of the 34, 16 studies addressed Alzheimer's disease (AD) specifically, 15 dementia broadly, 5 mild to moderate cognitive impairment, and 8 normal functioning, with some content overlap. Across studies, respondents reported genetics ( n = 14 studies), older age ( n = 8), stress ( n = 7), brain/head injury ( n = 6), and mental illness/brain disease ( n = 6) as perceived risk factors for AD and dementia. Protective factors most commonly identified for maintaining cognitive health were intellectual/mental stimulation ( n = 13), physical activity ( n = 12), healthy diet ( n = 10), and social/leisure activities ( n = 10). Conclusions: Studies identified genetics and older age as key perceived risk factors more so than behaviors such as smoking. Individuals perceived that numerous lifestyle factors (e.g. intellectual stimulation, physical activity) could protect against cognitive impairment, AD, and/or dementia. Results can inform national and international education efforts about AD and other dementias