Defective remodeling and maturation of the lymphatic vasculature in Angiopoietin-2 deficient mice

Molecular mechanisms regulating the remodeling of the lymphatic vasculature from an immature plexus of vessels to a hierarchal network of initial and collecting lymphatics are not well understood. One gene thought to be important for this process is Angiopoietin-2 (Ang-2). Ang2^−/− mice have previously been reported to exhibit an abnormal lymphatic phenotype but the precise nature of the lymphatic defects and the underlying mechanisms have yet to be defined. Here we demonstrate by whole-mount immunofluorescence staining of ear skin and mesentery that lymphatic vessels in Ang2^−/− mice fail to mature and do not exhibit a collecting vessel phenotype. Furthermore, dermal lymphatic vessels in Ang2^−/− pups prematurely recruit smooth muscle cells and do not undergo proper postnatal remodeling. In contrast, Ang2 knock-out Ang1 knock-in mice do develop a hierarchal lymphatic vasculature, suggesting that activation of Tie-2 is required for normal lymphatic development. Taken together, this work pinpoints a specific lymphatic defect of Ang2^−/− mice and further defines the sequential steps in lymphatic vessel remodeling.     

Environmentally persistent free radicals decrease cardiac function before and after ischemia/reperfusion injury in vivo

Exposure to airborne particles is associated with increased cardiovascular morbidity and mortality. During the combustion of chlorine-containing hazardous materials and fuels, chlorinated hydrocarbons chemisorb to the surface of transition metal-oxide-containing particles, reduce the metal, and form an organic free radical. These radical-particle systems can survive in the environment for days and are called environmentally persistent free radicals (EPFRs). This study determined whether EPFRs could decrease left ventricular function before and after ischemia and reperfusion (I/R) in vivo. Male Brown-Norway rats were dosed (8?mg/kg, intratracheal) 24?h prior to testing with particles containing the EPFR of 1, 2-dichlorobenzene (DCB230). DCB230 treatment decreased systolic and diastolic function. DCB230 also produced pulmonary and cardiac inflammation. After ischemia, systolic, but not diastolic function was significantly decreased in DCB230-treated rats. Ventricular function was not affected by I/R in control rats. There was greater oxidative stress in the heart and increased 8-isoprostane (biomarker of oxidative stress) in the plasma of treated vs. control rats after I/R. These data demonstrate for the first time that DCB230 can produce inflammation and significantly decrease cardiac function at baseline and after I/R in vivo. Furthermore, these data suggest that EPFRs may be a risk factor for cardiac toxicity in healthy individuals and individuals with ischemic heart disease. Potential mechanisms involving cytokines/chemokines and/or oxidative stress are discussed.     

Resolving the value of the dingo in ecological restoration

There is global interest in restoring populations of apex predators, both to conserve them and to harness their ecological services. In Australia, reintroduction of dingoes (Canis dingo) has been proposed to help restore degraded rangelands. This proposal is based on theories and the results of studies suggesting that dingoes can suppress populations of prey (especially medium‐ and large‐sized herbivores) and invasive predators such as red foxes (Vulpes vulpes) and feral cats (Felis catus) that prey on threatened native species. However, the idea of dingo reintroduction has met opposition, especially from scientists who query the dingo's positive effects for some species or in some environments. Here, we ask ‘what is a feasible experimental design for assessing the role of dingoes in ecological restoration?’ We outline and propose a dingo reintroduction experiment—one that draws upon the existing dingo‐proof fence—and identify an area suitable for this (Sturt National Park, western New South Wales). Although challenging, this initiative would test whether dingoes can help restore Australia's rangeland biodiversity, and potentially provide proof‐of‐concept for apex predator reintroductions globally.     

Gill monogeneans of the chub mackerel, Scomber japonicus from Madeiran waters of the Atlantic Ocean, Portugal

Five species of monogeneans were recovered from the gill filaments of 181 chub mackerel, Scomber japonicus, from the Madeiran waters of the Atlantic Ocean, Portugal, during 2004/2005. The monogenean Pseudokuhnia minor showed the highest prevalence (98.68%) and a mean intensity of 28.23, followed by Kuhnia scombri (prevalence of 43.71% and mean intensity of 2.69) and K. scombercolias (prevalence of 39.1% and a mean intensity of 1.81). Kuhnia sprostonae and Grubea cochlear were rare, occurring in only one and five fish hosts respectively. No correlation between fish host length and mean intensity of infection with the three most abundant monogeneans was found. However, significant differences in prevalence and abundance were found in relation to date of sampling for P. minor, and all parasites were aggregated in their distribution.     

The predictive power of pollination syndromes: Passerine pollination in heterantherous Meriania macrophylla (Benth.) Triana (Melastomataceae)

The cloud forest species Meriania macrophylla (Benth.) Triana has pseudocampanulate flowers with bulbous stamen appendages, typical for the passerine pollination syndrome found in the Melastomataceae tribe Merianieae. The species is further characterized by strong stamen dimorphism (heteranthery), a condition otherwise associated with pollen‐rewarding bee‐pollinated species (both in Melastomataceae and beyond). In passerine‐pollinated Merianieae, however, flowers usually only show weak stamen dimorphism. Here, we conducted field and laboratory investigations to determine the pollinators of M. macrophylla and assess the potential role of strong heteranthery in this species. Our field observations in Costa Rica confirmed syndrome predictions and indeed proved pollination by passerine birds in M. macrophylla. The large bulbous set of stamens functions as a food‐body reward to the pollinating birds, and as trigger for pollen release (bellows mechanism) as typical for the passerine syndrome in Merianieae. In contrast to other passerine‐pollinated Merianieae, the second set of stamens has seemingly lost its rewarding and pollination function, however. Our results demonstrate the utility of the pollination syndrome concept even in light of potentially misleading traits such as strong heteranthery.     

Mechanistic Issues of the Interaction of the Hairpin-Forming Domain of tBid with Mitochondrial Cardiolipin

Background

The pro-apoptotic effector Bid induces mitochondrial apoptosis in synergy with Bax and Bak. In response to death receptors activation, Bid is cleaved by caspase-8 into its active form, tBid (truncated Bid), which then translocates to the mitochondria to trigger cytochrome c release and subsequent apoptosis. Accumulating evidence now indicate that the binding of tBid initiates an ordered sequences of events that prime mitochondria from the action of Bax and Bak: (1) tBid interacts with mitochondria via a specific binding to cardiolipin (CL) and immediately disturbs mitochondrial structure and function idependently of its BH3 domain; (2) Then, tBid activates through its BH3 domain Bax and/or Bak and induces their subsequent oligomerization in mitochondrial membranes. To date, the underlying mechanism responsible for targeting tBid to mitochondria and disrupting mitochondrial bioenergetics has yet be elucidated.

Principal Findings

The present study investigates the mechanism by which tBid interacts with mitochondria issued from mouse hepatocytes and perturbs mitochondrial function. We show here that the helix αH6 is responsible for targeting tBid to mitochondrial CL and disrupting mitochondrial bioenergetics. In particular, αH6 interacts with mitochondria through electrostatic interactions involving the lysines 157 and 158 and induces an inhibition of state-3 respiration and an uncoupling of state-4 respiration. These changes may represent a key event that primes mitochondria for the action of Bax and Bak. In addition, we also demonstrate that tBid required its helix αH6 to efficiently induce cytochrome c release and apoptosis.

Conclusions

Our findings provide new insights into the mechanism of action of tBid, and particularly emphasize the importance of the interaction of the helix αH6 with CL for both mitochondrial targeting and pro-apoptotic activity of tBid. These support the notion that tBid acts as a bifunctional molecule: first, it binds to mitochondrial CL via its helix αH6 and destabilizes mitochondrial structure and function, and then it promotes through its BH3 domain the activation and oligomerization of Bax and/or Bak, leading to cytochrome c release and execution of apoptosis. Our findings also imply an active role of the membrane in modulating the interactions between Bcl-2 proteins that has so far been underestimated.     

Anti-Cancer Drugs Elicit Re-Expression of UDP-Glucuronosyltransferases in Melanoma Cells

The UDP-glucuronosyltransferase (UGT) family of enzymes plays a vital role in the detoxification of carcinogens as well as clearance of anti-cancer drugs. In humans, 19 UGT family members have been identified and are expressed in a tissue specific manner throughout the body. However, the UGTs have not been previously characterized in melanocytes or melanoma. In the present study, UGT2B7, UGT2B10, and UGT2B15 were identified as being normally expressed in human melanocytes. The same three UGT family members were also expressed in the primary melanoma cell line WM115. No UGT expression was detected in another primary melanoma cell line, WM3211, or in any metastatic melanoma cell line examined. These results suggest that UGT expression is lost during melanoma progression. Treatment of WM3211 or metastatic melanoma cell lines with anti-cancer agents (including vemurafenib) induced expression of UGT2B7, UGT2B10 and UGT2B15 demonstrating that melanoma cells retain the ability to re-express these same three UGTs. The corresponding increase in glucuronidation activity in melanoma cells following anti-cancer treatment was also observed. Furthermore, knockdown of UGT2B7 in WM115 cells sensitized these cells to treatment by adriamycin and epirubicin indicating that UGT2B7 is involved in resistance to these drugs. However, knockdown of UGT2B7 had no effect on temozolomide toxicity. Taken together, these results clearly demonstrate a role for UGTs in melanoma etiology. Since the UGTs are drug metabolism enzymes, we propose that re-expression of the UGTs constitutes a previously unsuspected mechanism for intratumoral drug resistance in melanoma.     

Using Mountain Lion Habitat Selection in Management

Wildlife agencies are generally tasked with managing and conserving species at state and local levels simultaneously. Thus, it is necessary for wildlife agencies to understand basic ecological processes of a given species at multiple scales to aid decision making at commensurately varied spatial and behavioral scales. Mountain lions (Puma concolor) occur throughout California, USA, and are at the center of a variety of management and conservation issues. For example, they are genetically and demographically at risk in 1 region yet apparently stable and negatively affecting endangered species in another. Currently, no formal plan exists for mountain lions in California to deal with these diverse scenarios involving issues of local mountain lion population viability and problems related to predation of endangered species. To facilitate development of a state-wide management and conservation plan, we quantified habitat selection by mountain lions at 2 spatial scales across the range of environmental conditions in which the species is found in California. Our analyses used location data from individuals (n = 263) collared across the state from 2001–2019. At the home range scale, mountain lions selected habitat to prioritize meeting energetic demands. At the within home range scale, mountain lions avoided areas of human activity. Further, our analyses revealed 165,350–170,085 km², depending on season, of suitable mountain lion habitat in California. Fifty percent of the suitable habitat was on unprotected lands and thus vulnerable to development. These habitat selection models will help in the development of a state-wide conservation and management plan for mountain lions in California by guiding mountain lion population monitoring through time, prioritization of habitat to be conserved for maintaining demographic connectivity and gene flow, and efforts to mediate mountain lion-prey interactions. Our work and application area will help with wildlife policy and management decisions related to depredation problems at the local scale and issues of habitat connectivity at the statewide scale. © 2019 The Wildlife Society.     

Development and pilot testing of a model to translate risk assessment data for Great Lakes Native American communities using mobile technology

The Chippewa Ottowa Resource Authority monitors fish contaminants in Anishinaabe (Great Lake Native American) tribal fisheries. A software program (app) was programmed to translate and operationalize these data for the first time in an interactive, personalized, and culturally tailored format. This article reports the process for creation, and preliminary community reception, of interactive fish consumption advisory using software that can be accessed via mobile phones and/or the internet. Response data to previous advisories guided the app presentation and aesthetics. The app “Gigiigoo'inaan’ [Our Fish] presents personalized recommendations based on back-end calculated reference doses as well as a novel risk/benefit quantification originally presented by Ginsberg et al. (Human Ecol Risk Assess, Vol. 21, 2015, pp. 810–39) and Ginsberg and Toal (Environ Health Perspect, Vol. 117, 2009, pp. 267–75) to characterize nutritional benefits. The partnering organization, Inter-Tribal Council of Michigan recruited focus groups to pilot test the app for usability, influence on dietary behavior, and cultural appropriateness. The general concept of the app and the presentation of the data were deemed culturally acceptable and pleasing to the participants. The results suggest that risk-benefit data is valuable to end-users but meal frequency recommendations, typically based on federal guidelines, should also be clearly communicated. How these guidelines are selected and presented will likely impact the reception and adoption of consumption advice.