MicroRNAs in pulmonary arterial remodeling

Pulmonary arterial remodeling is a presently irreversible pathologic hallmark of pulmonary arterial hypertension (PAH). This complex disease involves pathogenic dysregulation of all cell types within the small pulmonary arteries contributing to vascular remodeling leading to intimal lesions, resulting in elevated pulmonary vascular resistance and right heart dysfunction. Mutations within the bone morphogenetic protein receptor 2 gene, leading to dysregulated proliferation of pulmonary artery smooth muscle cells, have been identified as being responsible for heritable PAH. Indeed, the disease is characterized by excessive cellular proliferation and resistance to apoptosis of smooth muscle and endothelial cells. Significant gene dysregulation at the transcriptional and signaling level has been identified. MicroRNAs are small non-coding RNA molecules that negatively regulate gene expression and have the ability to target numerous genes, therefore potentially controlling a host of gene regulatory and signaling pathways. The major role of miRNAs in pulmonary arterial remodeling is still relatively unknown although research data is emerging apace. Modulation of miRNAs represents a possible therapeutic target for altering the remodeling phenotype in the pulmonary vasculature. This review will focus on the role of miRNAs in regulating smooth muscle and endothelial cell phenotypes and their influence on pulmonary remodeling in the setting of PAH

Interactive Feedforward for Improving Performance and Maintaining Intrinsic Motivation in VR Exergaming

Exergames commonly use low to moderate intensity exercise protocols. Their effectiveness in implementing high intensity protocols remains uncertain. We propose a method for improving performance while maintaining intrinsic motivation in high intensity VR exergaming. Our method is based on an interactive adaptation of the feedforward method: a psychophysical training technique achieving rapid improvement in performance by exposing participants to self models showing previously unachieved performance levels. We evaluated our method in a cycling-based exergame. Participants competed against (i) a self model which represented their previous speed; (ii) a self model representing their previous speed but increased resistance therefore requiring higher performance to keep up; or (iii) a virtual competitor at the same two levels of performance. We varied participants' awareness of these differences. Interactive feedforward led to improved performance while maintaining intrinsic motivation even when participants were aware of the interventions, and was superior to competing against a virtual competitor

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)1.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field

Hybrid Watermilfoil Lineages are More Invasive and Less Sensitive to a Commonly used Herbicide than their Exotic Parent (Eurasian watermilfoil)

Hybridization may stimulate the evolution of invasiveness in human-impacted habitats if unique hybrid genotypes have higher fitness than parental genotypes. Human efforts to control invasive taxa frequently involve the intentional alteration of habitats, but few studies have considered whether hybridization can result in decreased sensitivity to control measures. Here, we investigate whether interspecific hybrids between introduced Eurasian watermilfoil (Myriophyllum spicatum) and native northern watermilfoil (M. sibiricum) are more invasive than parental Eurasian watermilfoil, especially in regard to their relative responses to an herbicide commonly applied for their control (2,4-dichlorophenoxyacetic acid; 2,4-D). In two separate laboratory experiments, hybrids on average grew faster and were less sensitive to 2,4-D compared with parental Eurasian watermilfoil. These two invasive traits appear to be common in hybrid watermilfoils, as opposed to being restricted to a few unique lineages, because they were found in a diversity of hybrid genotypes from several independent hybridization events. In addition, we found that hybrids occurred more frequently than parental species in natural lakes previously treated with 2,4-D. Our results provide compelling empirical evidence that hybridization is associated with the evolution of increased invasiveness in watermilfoils, and have important implications for their management

Population Structure of the Invasive Round Goby in Lake Michigan

The recent establishment of the round goby (Neogobius melanostomus), an invasive fish in Lake Michigan, provides a model system to view fine scale evolutionary and ecological processes that can create genetic structure within a population. We used seven nuclear polymorphic microsatellite markers (N = 11-17 per site) and measurements of fish total length, weight, and sex (N = 20-74 per site) on round gobies captured by minnow traps and angling among 12 sites around the entire shore of Lake Michigan to determine if evolutionary processes are present in Lake Michigan by characterizing population structure of the round goby. Specific objectives were to determine whether: 1) there are significant patterns of genetic population structure among sites along the shore of Lake Michigan (e.g., a correlation between genetic diversity and geographic distance), 2) ferry shipping routes create strong deviations from normal population structure observed to occur around the lakeshore, and 3) density, fish size, and condition at the 12 sites differ from each other. Results include: significant pairwise FST values, a pattern of isolation by distance (IBD) along the eastern and western shores of Lake Michigan, no IBD along the entire lakeshore, northern, or southern shores, different catch per unit effort (CPUE) and mean weight between sites. A length/weight relationship between fish at all 12 sites was not different. Results indicate that round goby pierhead sites exhibit population structure in Lake Michigan

Hard to Kill: Hybrid Watermilfoil are Less Sensitive to a Commonly Used Herbicide

PURPOSE: The Eurasian watermilfoil and its hybrid with native northern watermilfoil are both widespread invaders that are extensively managed with herbicides. Recent reports by lake managers suggest this hybrid does not respond as well to commonly used herbicides, but very few studies have tested whether or not hybrids are less susceptible to herbicides. In the Menominee River Watershed, in the Western Upper Peninsula of Michigan, hybrids occur more often than parental species in herbicide (2,4-D) treated lakes than untreated lakes. This suggests hybrids may have a competitive advantage in environments where herbicides are commonly used. To test the hypothesis that hybrids are less 2,4-D susceptible than Eurasian watermilfoil, we conducted a herbicide sensitivity assay. SUBJECTS: We experimentally compared 2,4-D sensitivity of six hybrid and four Eurasian watermilfoil populations from the Menominee River Watershed, in addition to a second experiment where we compared 2,4-D sensitivity of six hybrid and nine Eurasian watermilfoil populations from the Lower Peninsula of Michigan. METHODS AND MATERIALS: 2,4-D sensitivity assays were conducted in mesocosms. ANALYSES: A two-way nested analysis of variance was used to compared hybrid and Eurasian watermilfoil 2,4-D sensitivity. RESULTS: Hybrids were less sensitive to 2, 4-D than Eurasian watermilfoil. CONCLUSIONS: If hybrids are less likely to respond to commonly used herbicides, new management strategies may be needed to increase the efficiency of chemical usage in freshwater ecosystems

Simultaneous Quaternary radiations of three damselfly clades across the Holarctic

If climate change during the Quaternary shaped the macroevolutionary dynamics of a taxon, we expect to see three features in its history: elevated speciation or extinction rates should date to this time, more northerly distributed clades should show greater discontinuities in these rates, and similar signatures of those effects should be evident in the phylogenetic and phylodemographic histories of multiple clades. In accordance with the role of glacial cycles, speciation rates increased in the Holarctic Enallagma damselflies during the Quaternary, with a 4.25x greater increase in a more northerly distributed clade as compared with a more southern clade. Finer-scale phylogenetic analyses of three radiating clades within the northern clade show similar, complex recent histories over the past 250,000 years to produce 17 Nearctic and four Palearctic extant species. All three are marked by nearly synchronous deep splits that date to approximately 250,000 years ago, resulting in speciation in two. This was soon followed by significant demographic expansions in at least two of the three clades. In two, these expansions seem to have preceded the radiations that have given rise to most of the current biodiversity. Each also produced species at the periphery of the clade's range. In spite of clear genetic support for reproductive isolation among almost all species, mtDNA signals of past asymmetric hybridization between species in different clades also suggest a role for the evolution of mate choice in generating reproductive isolation as species recolonized the landscape following deglaciation. These analyses suggest that recent climate fluctuations resulted in radiations driven by similar combinations of speciation processes acting in different lineages.status: publishe

Democratizing Access to Neurosurgical Medical Education: National Efforts in a Medical Student Training Camp During Coronavirus Disease 2019.

BackgroundNational medical student surveys amidst the coronavirus disease 2019 (COVID-19)-driven subinternship cancellations have demonstrated the need for supplemental, standardized subspecialty medical education, mentorship, and career planning nationally. We have presented the first live, cross-institutional virtual medical student subspecialty training camp to deliver standardized neurosurgical educational content to medical students during the COVID-19 pandemic, and its results on medical student anxiety and perceptions of neurosurgery.MethodsThe online training camp used a video conferencing platform that was open to all medical students. A post-training camp survey was administered.ResultsA total of 305 medical students registered for the event from 107 unique U.S. medical schools. Of the 305 medical students, 108 reported intending to apply to neurosurgery residency in 2021. The top medical student objectives for the training camp were program networking and mentorship. Of the 305 participants, 121 (39.7%) completed the post-training survey. Of the respondents, 65.0% reported improved neurosurgical knowledge, 79.8% reported decreased anxiety about subinternships and interviews, 82.5% reported increased enthusiasm about neurosurgery, and 100% desired a future annual virtual training camp because of the increased accessibility and decreased cost. This was especially important for students at institutions without home subspecialty programs and those with financial burdens.ConclusionsCOVID-19-driven innovations in medical education have accelerated changes that may have long been necessary. This virtual structure improved resource usage and scalability compared with in-person training, maintained social distancing, and democratized access to standardized, specialized content not often available through traditional medical curricula. Even as a supplement to in-person events, the virtual training camp model could be implemented by national medical societies, which might significantly increase medical students' preparedness for, and education in, neurosurgery and other subspecialties