Trimethylamine N-oxide (TMAO) is a gut microbiota-derived metabolite that enhances both platelet responsiveness and in vivo thrombosis potential in animal models, and TMAO plasma levels predict ...incident atherothrombotic event risks in human clinical studies. TMAO is formed by gut microbe-dependent metabolism of trimethylamine (TMA) moiety-containing nutrients, which are abundant in a Western diet. Here, using a mechanism-based inhibitor approach targeting a major microbial TMA-generating enzyme pair, CutC and CutD (CutC/D), we developed inhibitors that are potent, time-dependent, and irreversible and that do not affect commensal viability. In animal models, a single oral dose of a CutC/D inhibitor significantly reduced plasma TMAO levels for up to 3 d and rescued diet-induced enhanced platelet responsiveness and thrombus formation, without observable toxicity or increased bleeding risk. The inhibitor selectively accumulated within intestinal microbes to millimolar levels, a concentration over 1-million-fold higher than needed for a therapeutic effect. These studies reveal that mechanism-based inhibition of gut microbial TMA and TMAO production reduces thrombosis potential, a critical adverse complication in heart disease. They also offer a generalizable approach for the selective nonlethal targeting of gut microbial enzymes linked to host disease limiting systemic exposure of the inhibitor in the host.
Interindividual variation in the composition of the human gut microbiome was examined in relation to demographic and anthropometric traits, and to changes in dietary saturated fat intake and protein ...source. One hundred nine healthy men and women aged 21 to 65, with BMIs of 18 to 36, were randomized, after a two-week baseline diet, to high (15% total energy E)- or low (7%E)-saturated-fat groups and randomly received three diets (four weeks each) in which the protein source (25%E) was mainly red meat (beef, pork) (12%E), white meat (chicken, turkey) (12%E), and nonmeat sources (nuts, beans, soy) (16%E). Taxonomic characterization using 16S ribosomal DNA was performed on fecal samples collected at each diet completion. Interindividual differences in age, body fat (%), height, ethnicity, sex, and alpha diversity (Shannon) were all significant factors, and most samples clustered by participant in the PCoA ordination. The dietary interventions did not significantly alter the overall microbiome community in ordination space, but there was an effect on taxon abundance levels. Saturated fat had a greater effect than protein source on taxon differential abundance, but protein source had a significant effect once the fat influence was removed. Higher alpha diversity predicted lower beta diversity between the experimental and baseline diets, indicating greater resistance to change in people with higher microbiome diversity. Our results suggest that interindividual differences outweighed the influence of these specific dietary changes on the microbiome and that moderate changes in saturated fat level and protein source correspond to modest changes in the microbiome.
The microbiome has proven to influence health and disease, but how combinations of external factors affect the microbiome is relatively unknown. Diet can cause changes, but this is usually achieved by altering macronutrient ratios and has not focused on dietary protein source or saturated fat intake levels. In addition, each individual's unique microbiome profile can be an important factor during studies, and it has even been shown to affect therapeutic outcomes. We show here that the effects of individual differences outweighed the effect of experimental diets and that protein source is less influential than saturated fat level. This suggests that fat and protein composition, separate from macronutrient ratio and carbohydrate composition, is an important consideration in dietary studies.
Gut microbes influence cardiovascular disease and thrombosis risks through the production of trimethylamine N-oxide (TMAO). Microbiota-dependent generation of trimethylamine (TMA)-the precursor to ...TMAO-is rate limiting in the metaorganismal TMAO pathway in most humans and is catalyzed by several distinct microbial choline TMA-lyases, including the proteins encoded by the cutC/D (choline utilization C/D) genes in multiple human commensals.
Direct demonstration that the gut microbial cutC gene is sufficient to transmit enhanced platelet reactivity and thrombosis potential in a host via TMA/TMAO generation has not yet been reported.
Herein, we use gnotobiotic mice and a series of microbial colonization studies to show that microbial cutC-dependent TMA/TMAO production is sufficient to transmit heightened platelet reactivity and thrombosis potential in a host. Specifically, we examine in vivo thrombosis potential employing germ-free mice colonized with either high TMA-producing stable human fecal polymcrobial communities or a defined CutC-deficient background microbial community coupled with a CutC-expressing human commensal±genetic disruption of its cutC gene (ie, Clostridium sporogenes Δ cutC).
Collectively, these studies point to the microbial choline TMA-lyase pathway as a rational molecular target for the treatment of atherothrombotic heart disease.
Global Gangs Hazen, Jennifer M; Rodgers, Dennis
08/2014
eBook
Gangs, often associated with brutality and senseless destructive violence, have not always been viewed as inherently antagonistic. The first studies of gangs depicted them as alternative sources of ...order in urban slums where the state's authority was lacking, and they have subsequently been shown to be important elements in some youth life cycles. Despite their proliferation there is little consensus regarding what constitutes a gang. Used to denote phenomena ranging from organized crime syndicates to groups of youths who gather spontaneously on street corners, even the term "gang" is ambiguous.
Global Gangsoffers a greater understanding of gangs through essays that investigate gangs spanning across nations, from Brazil to Indonesia, China to Kenya, and from El Salvador to Russia. Volume editors Jennifer M. Hazen and Dennis Rodgers bring together contributors who examine gangs from a comparative perspective, discussing such topics as the role the apartheid regime in South Africa played in the emergence of gangs, the politics behind child vigilante squads in India, the relationship between immigration and gangs in France and the United States, and the complex stigmatization of youths in Mexico caused by the arbitrary deployment of the word "gang."
Featuring an afterword by renowned U.S. gang researcher Sudhir Venkatesh, this volume provides a comprehensive look into the experience of gangs across the world and in doing so challenges conventional notions of identity.
Contributors: Enrique Desmond Arias, George Mason U; José Miguel Cruz, Florida International U; Steffen Jensen, DIGNITY-Danish Institute Against Torture; Gareth A. Jones, London School of Economics and Political Science; Marwan Mohammed, École Normale Supérieure, Paris; Jacob Rasmussen, Roskilde U; Loren Ryter, U of Michigan; Rustem R. Safin, National Research Technological U, Russia; Alexander L. Salagaev, National Research Technological U, Russia; Atreyee Sen, U of Manchester; Mats Utas, Nordic Africa Institute; Sudhir Venkatesh, Columbia U; James Diego Vigil, U of California, Irvine; Lening Zhang, Saint Francis U.
Weddell seals (
) are important predators in the Southern Ocean and are among the best-studied pinnipeds on Earth, yet much still needs to be learned about their year-round movements and foraging ...behaviour. Using biologgers, we tagged 62 post-moult Weddell seals in McMurdo Sound and vicinity between 2010 and 2012. Generalized additive mixed models were used to (i) explain and predict the probability of seal presence and foraging behaviour from eight environmental variables, and (ii) examine foraging behaviour in relation to dive metrics. Foraging probability was highest in winter and lowest in summer, and foraging occurred mostly in the water column or just above the bottom; across all seasons, seals preferentially exploited the shallow banks and deeper troughs of the Ross Sea, the latter providing a pathway for Circumpolar Deep Water to flow onto the shelf. In addition, the probability of Weddell seal occurrence and foraging increased with increasing bathymetric slope and where water depth was typically less than 600 m. Although the probability of occurrence was higher closer to the shelf break, foraging was higher in areas closer to shore and over banks. This study highlights the importance of overwinter foraging for recouping body mass lost during the previous summer.
Understanding gangs as armed groups Hazen, Jennifer M.
International review of the Red Cross (2005),
06/2010, Letnik:
92, Številka:
878
Journal Article
Recenzirano
Gangs have long been considered a source of violence and insecurity, but they are increasingly identified as a cause of instability and a threat to the state. Yet gangs operate mainly in non-conflict ...settings, raising questions about whether applying a conflict lens to understand gangs is appropriate. Marked differences appear between armed groups and gangs when considering concepts of ungoverned spaces, the state, violence, and sustainability. Few gangs reach the threshold of posing a direct challenge to the state; this makes comparisons with other armed groups difficult and suggests the need for a more specific analytical lens.
Violence is one of a range of tactics available to social movements. The important question is not whether violence is a tactic, but why certain groups within particular social movements choose a ...violent path. Using the cycle of protest model this study maps the progression from localized protest to armed group in a case study of the Niger Delta People's Volunteer Force. The case study demonstrates how an armed group emerges from a broader social movement, what influences this evolution, and what enables the armed group to sustain itself when facing significantly higher costs for survival. For the Niger Delta People's Volunteer Force, competition for scarce resources, its ideology justifying an aggressive posture toward government, and its capacity to mobilize necessary resources to engage in a violent struggle with the government all played significant roles in the emergence and survival of the group.
Can Peacekeepers Be Peacebuilders? Hazen, Jennifer M.
International peacekeeping (London, England),
06/2007, Letnik:
14, Številka:
3
Journal Article
Recenzirano
The role of UN peacekeeping missions has expanded beyond the traditional tasks of peacekeeping to include a wide range of political, economic, and humanitarian activities. While such expansion ...indicates an improved understanding of the complexities and challenges of post-conflict contexts, it also raises questions about whether UN peacekeeping missions are equipped to handle peacebuilding tasks. Evidence from a study of the peacekeeping mission in Sierra Leone suggests they are not. This article argues that peacekeeping missions are a poor choice for peacebuilding given their limited mandates, capacity, leverage, resources and duration. Peacekeepers should focus on peacekeeping, by which they can lay the foundation for peacebuilding. Peacebuilding should be the primary task of national governments and their populations.
The legacy of mining continues to affect stream water quality throughout the western United States. Traditional remediation, involving treatment of acid mine drainage from portals, is not feasible ...for the thousands of abandoned mines in the West as it is difficult and expensive. Thus, the development of new methods to address acid mine drainage is critical. The purpose of this study was two fold; to identify and test new tools to identify sources of metal pollution within a mine and to identify low-cost treatment alternatives through the use of these tools. Research was conducted at the Mary Murphy Mine in Colorado, a multiple-level underground mine which produced gold, silver, copper, lead and zinc from 1870 to 1951. Source waters and flowpaths within the mine were characterised using analysis of hydrogen and oxygen isotopes of water (water isotopes) in combination with solute analysis and hydrometric techniques. Hydrometric measurements showed that while discharge from a central level portal increased by a factor of 10 during snowmelt runoff (from 0.7 to 7.2 Ls^sup -1^), Zn concentrations increased by a factor of 9 (from 3,100 to 28320μgL^sup -1^). Water isotopes were used as conservative tracers to represent of baseflow and snowmelt inputs in a hydrologic mixing model analysis. The results showed that less than 7% of peak discharge was from snowmelt. Within the mine, approximately 71% of the high-flow Zn loading was caused by a single internal stream characterised by extremely high Zn concentrations (270600μgL^sup -1^) and low pH (3.4). Somewhat surprisingly, hydrologic mixing models using water isotopes showed that new water contributed up to 79% of flow in this high-Zn source during the melt season. Diversion of this high-Zn source within the mine resulted in a decrease in Zn concentrations at the portal by 91% to 2,510μgL^sup -1^, which is lower than the base-flow Zn concentration. The results suggest that in some mines remediation efforts can be concentrated on specific areas within the mine itself. Using the characterisation techniques demonstrated in this study, problem areas can be identified and contaminated flows diverted or isolated. The results also suggest that it may be possible to dewater contamination areas, greatly reducing costs of remediation.PUBLICATION ABSTRACT
Normal platelet function is critical to blood hemostasis and maintenance of a closed circulatory system. Heightened platelet reactivity, however, is associated with cardiometabolic diseases and ...enhanced potential for thrombotic events. We now show gut microbes, through generation of trimethylamine N-oxide (TMAO), directly contribute to platelet hyperreactivity and enhanced thrombosis potential. Plasma TMAO levels in subjects (n > 4,000) independently predicted incident (3 years) thrombosis (heart attack, stroke) risk. Direct exposure of platelets to TMAO enhanced sub-maximal stimulus-dependent platelet activation from multiple agonists through augmented Ca2+ release from intracellular stores. Animal model studies employing dietary choline or TMAO, germ-free mice, and microbial transplantation collectively confirm a role for gut microbiota and TMAO in modulating platelet hyperresponsiveness and thrombosis potential and identify microbial taxa associated with plasma TMAO and thrombosis potential. Collectively, the present results reveal a previously unrecognized mechanistic link between specific dietary nutrients, gut microbes, platelet function, and thrombosis risk.
Display omitted
•Elevated TMAO levels predict incident risk for thrombotic events in human subjects•TMAO enhances sub-maximal stimulus-dependent platelet activation•Dietary choline, gut microbes, and TMAO are linked to thrombotic potential in vivo•Microbial transplantation shows that thrombosis potential is a transmissible trait
The gut microbe-dependent metabolite TMAO directly increases platelet hyperreactivity and thrombosis potential in vivo, both of which are important risk factors for development of cardiometabolic disease complications, such as stroke and heart attack.
PDF
