Abstract Plasmid persistence in bacterial populations is strongly influenced by the fitness effects associated with plasmid carriage. However, plasmid fitness effects in wild-type bacterial hosts remain largely unexplored. In this study, we determined the fitness effects of the major antibiotic resistance plasmid pOXA-48_K8 in wild-type, ecologically compatible enterobacterial isolates from the human gut microbiota. Our results show that although pOXA-48_K8 produced an overall reduction in bacterial fitness, it produced small effects in most bacterial hosts, and even beneficial effects in several isolates. Moreover, genomic results showed a link between pOXA-48_K8 fitness effects and bacterial phylogeny, helping to explain plasmid epidemiology. Incorporating our fitness results into a simple population dynamics model revealed a new set of conditions for plasmid stability in bacterial communities, with plasmid persistence increasing with bacterial diversity and becoming less dependent on conjugation. These results help to explain the high prevalence of plasmids in the greatly diverse natural microbial communities.
Feet must mediate substrate interactions across an animal's entire range of limb poses used in life. Metatarsals, the ‘bones of the sole,’ are the dominant pedal skeletal elements for most tetrapods. In plantigrade species that walk on the entirety of their sole, such as living crocodylians, intermetatarsal mobility offers the potential for a continuum of reconfiguration within the foot itself. Alligator hindlimbs are capable of postural extremes from a belly sprawl to a high walk to sharp turns—how does the foot morphology dynamically accommodate these diverse demands? We implemented a hybrid combination of marker-based and markerless X-ray Reconstruction of Moving Morphology (XROMM) to measure 3-D metatarsal kinematics in three juvenile American alligators (Alligator mississippiensis) across their locomotor and maneuvering repertoire on a motorized treadmill and flat-surfaced arena. We found that alligators adaptively conformed their metatarsals to the ground, maintaining plantigrade contact throughout a spectrum of limb placements with non-planar feet. Deformation of the metatarsus as a whole occurred through variable abduction (two-fold range of spread) and differential metatarsal pitching (45° arc of skew). Internally, metatarsals also underwent up to 65° of long axis rotation. Such reorientation, which correlated with skew, was constrained by the overlapping arrangement of the obliquely expanded metatarsal bases. Such a proximally overlapping metatarsal morphology is shared by fossil archosaurs and archosaur relatives. In these extinct taxa, we suggest that intermetatarsal mobility likely played a significant role in maintaining ground contact across plantigrade postural extremes.
Myocardial infarction (MI) promotes a range of systemic effects, many of which are unknown. Here, we investigated the alterations associated with MI progression in heart and other metabolically active tissues (liver, skeletal muscle, and adipose) in a mouse model of MI (induced by ligating the left ascending coronary artery) and sham-operated mice. We performed a genome-wide transcriptomic analysis on tissue samples obtained 6- and 24-hours post MI or sham operation. By generating tissue-specific biological networks, we observed: (1) dysregulation in multiple biological processes (including immune system, mitochondrial dysfunction, fatty-acid beta-oxidation, and RNA and protein processing) across multiple tissues post MI; and (2) tissue-specific dysregulation in biological processes in liver and heart post MI. Finally, we validated our findings in two independent MI cohorts. Overall, our integrative analysis highlighted both common and specific biological responses to MI across a range of metabolically active tissues.
Extended phase-space isokinetic methods in their deterministic [Minary et al., Phys. Rev. Lett. 93, 150201 (2004)] and stochastic forms [Leimkuhler et al., Mol. Phys. 111, 3579 (2013)] have proved tremendously successful in allowing multiple time-scale molecular dynamics simulations to be performed with very large time steps. These methods work by coupling the physical degrees of freedom to a set of Nosé-Hoover chain or Nosé-Hoover Langevin thermostats via an isokinetic constraint, which has the effect of avoiding resonance artifacts that plague multiple time-step algorithms. In this paper, we introduce a new resonance-free approach that achieves the same gains in time step but without the imposition of isokinetic constraints or the introduction of extended phase-space variables. Rather, we modify the physical Hamiltonian that effects the same regulation of resonances achieved by the isokinetic constraints. In so doing, we show that sampling errors can be controlled and performance improvements are possible within a simpler Hamiltonian framework. The method is demonstrated in simulations of the structure of liquid water and, in conjunction with enhanced sampling, in generation of the Ramachandran free-energy surface of the solvated alanine dipeptide.
Background The decision of whether to pursue a tenure-track faculty position has become increasingly difficult for undergraduate, graduate, and postdoctoral trainees considering a career in research. Trainees express concerns over job availability, financial insecurity, and other perceived challenges associated with pursuing an academic position. Methods To help further elucidate the benefits, challenges, and strategies for pursuing an academic career, a diverse sample of postdoctoral scholars (“postdocs”) from across the United States were asked to provide advice on pursuing a research career in academia in response to an open-ended survey question. 994 responses were qualitatively analyzed using both content and thematic analyses. 177 unique codes, 20 categories, and 10 subthemes emerged from the data and were generalized into two thematic areas: Life in Academia and Strategies for Success . Results On life in academia, postdoc respondents overwhelmingly agree that academia is most rewarding when you are truly passionate about scientific research and discovery. ‘Passion’ emerged as the most frequently cited code, referenced 189 times. Financial insecurity, work-life balance, securing grant funding, academic politics, and a competitive job market emerged as challenges of academic research. The survey respondents note that while passion and hard work are necessary, they are not always sufficient to overcome these challenges. The postdocs encourage trainees to be realistic about career expectations and to prepare broadly for career paths that align with their interests, skills, and values. Strategies recommended for perseverance include periodic self-reflection, mental health support, and carefully selecting mentors. Conclusions For early-career scientists along the training continuum, this advice deserves critical reflection before committing to an academic research career. For advisors and institutions, this work provides a unique perspective from postdoctoral scholars on elements of the academic training path that can be improved to increase retention, career satisfaction, and preparation for the scientific workforce.