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Exposure to aminoglycoside antibiotics can lead to the generation of toxic levels of reactive oxygen species (ROS) within mechanosensory hair cells of the inner ear that have been implicated in hearing and balance disorders. Better understanding of the origin of aminoglycoside-induced ROS could focus the development of therapies aimed at preventing this event. In this work, we used the zebrafish lateral line system to monitor the dynamic behavior of mitochondrial and cytoplasmic oxidation occurring within the same dying hair cell following exposure to aminoglycosides. The increased oxidation observed in both mitochondria and cytoplasm of dying hair cells was highly correlated with mitochondrial calcium uptake. Application of the mitochondrial uniporter inhibitor Ru360 reduced mitochondrial and cytoplasmic oxidation, suggesting that mitochondrial calcium drives ROS generation during aminoglycoside-induced hair cell death. Furthermore, targeting mitochondria with free radical scavengers conferred superior protection against aminoglycoside exposure compared with identical, untargeted scavengers. Our findings suggest that targeted therapies aimed at preventing mitochondrial oxidation have therapeutic potential to ameliorate the toxic effects of aminoglycoside exposure.

Mitochondria play a prominent role in mechanosensory hair cell damage and death. Although hair cells are thought to be energetically demanding cells, how mitochondria respond to these demands and how this might relate to cell death is largely unexplored. Using genetically encoded indicators, we found that mitochondrial calcium flux and oxidation are regulated by mechanotransduction and demonstrate that hair cell activity has both acute and long-term consequences on mitochondrial function. We tested whether variation in mitochondrial activity reflected differences in the vulnerability of hair cells to the toxic drug neomycin. We observed that susceptibility did not correspond to the acute level of mitochondrial activity but rather to the cumulative history of that activity.

We tested the hypothesis that underrepresented students in active-learning classrooms experience narrower achievement gaps than underrepresented students in traditional lecturing classrooms, averaged across all science, technology, engineering, and mathematics (STEM) fields and courses. We conducted a comprehensive search for both published and unpublished studies that compared the performance of underrepresented students to their overrepresented classmates in active-learning and traditional-lecturing treatments. This search resulted in data on student examination scores from 15 studies (9,238 total students) and data on student failure rates from 26 studies (44,606 total students). Bayesian regression analyses showed that on average, active learning reduced achievement gaps in examination scores by 33% and narrowed gaps in passing rates by 45%. The reported proportion of time that students spend on in-class activities was important, as only classes that implemented high-intensity active learning narrowed achievement gaps. Sensitivity analyses showed that the conclusions are robust to sampling bias and other issues. To explain the extensive variation in efficacy observed among studies, we propose the heads-and-hearts hypothesis, which holds that meaningful reductions in achievement gaps only occur when course designs combine deliberate practice with inclusive teaching. Our results support calls to replace traditional lecturing with evidence-based, active-learning course designs across the STEM disciplines and suggest that innovations in instructional strategies can increase equity in higher education.

Although perhaps best known for their use in developmental studies, over the last couple of decades, zebrafish have become increasingly popular model organisms for investigating auditory system function and disease. Like mammals, zebrafish possess inner ear mechanosensory hair cells required for hearing, as well as superficial hair cells of the lateral line sensory system, which mediate detection of directional water flow. Complementing mammalian studies, zebrafish have been used to gain significant insights into many facets of hair cell biology, including mechanotransduction and synaptic physiology as well as mechanisms of both hereditary and acquired hair cell dysfunction. Here, we provide an overview of this literature, highlighting some of the particular advantages of using zebrafish to investigate hearing and hearing loss.

Hair cells are mechanosensory receptors found in the inner ear that mediate hearing and balance. In humans, damage and death of these cells is an underlying cause of hearing loss. Given the high prevalence of hearing loss, understanding the biology of these sensory cells continues to be an important endeavor to inform therapeutic strategies. The zebrafish has become a valuable model organism for advancing these efforts. In addition to hair cells of the inner ear, zebrafish also possess superficial hair cells of the lateral line sensory system, a sense devoted to detection of directional water flow. In combination with other advantages of the zebrafish model, the location of these hair cells has facilitated investigations of both normal hair cell function as well as mechanisms of hair cell death in vivo. In the following pages, I discuss the zebrafish as an auditory system model, highlighting structural and functional similarities between lateral line and cochlear hair cells, including selective susceptibility to environmental toxins. I then focus on a new investigation, relying on zebrafish to explore mitochondrial activity in lateral line hair cells. While this work is motivated by evidence demonstrating that mitochondria play a prominent role in hair cell damage and death, it begins to fill a gap in our understanding of how mitochondria function in response to normal cell activity. More specifically, I report on mitochondrial calcium flux and oxidation, finding that both are regulated by mechanotransduction. I also examine whether variation in mitochondrial activity reflects differences in hair cell vulnerability to the toxic drug neomycin. Overall, this study reveals a relationship between hair cell activity, mitochondrial activity, and susceptibility to damage.

Many neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), lead to the selective degeneration of discrete cell types in the CNS despite the ubiquitous expression of many genes linked to disease. Therapeutic advancement depends on understanding unique cellular adaptations that underlie pathology of vulnerable cells in the context of disease-causing mutations. Here, we employ bacTRAP molecular profiling to elucidate cell type specific molecular responses of cortical upper motor neurons in a preclinical ALS model. Using two bacTRAP mouse lines that label distinct vulnerable or resilient projection neuron populations in motor cortex, we show that the regulation of oxidative phosphorylation (Oxphos) pathways is a common response in both cell types. However, differences in the baseline expression of genes involved in Oxphos and the handling of reactive oxygen species likely lead to the selective degeneration of the vulnerable cells. These results provide a framework to identify cell type-specific processes in neurodegenerative disease. Competing Interest Statement The authors have declared no competing interest.

The aim of this to study was to assess the biological consequences of cyclin D1 silencing in pancreatic cancer cells. A replication-defective lentivirus based small hairpin RNA (shRNA) system targeting cyclin D1 caused a marked reduction in cyclin D1 protein levels in ASPC-1 and BxPC3 pancreatic cancer cell lines in conjunction with decreased cell growth and invasiveness in vitro. Moreover, a single intratumoral injection of the recombinant lentivirus targeting cyclin D1 attenuated the growth of pre-existing tumors arising from two distinct cell lines. This attenuated growth correlated with decreased proliferation and angiogenesis, and attenuated VEGF expression. It is concluded that lentivirus-delivered shRNA targeting cyclin D1 suppresses the growth, invasiveness, tumorigenicity and pro-angiogenic potential of human pancreatic cancer cells, raising the possibility that intra-tumoral injections of viruses targeting cyclin D1 could provide a novel therapeutic approach in pancreatic ductal adenocarcinoma.

We updated a recent meta-analysis of active learning’s impact on student achievement in undergraduate STEM courses by following the same protocol to evaluate studies published from 2010-2017. We screened 1659 papers, coded 1294, and found 210 that met five pre-established inclusion criteria and six pre-established criteria for methodological quality. After further dropping 76 studies with no exam scores data, 134 of these studies contained data on student performance on identical or equivalent exams. We found that on average, active learning’s effect size on exam scores was 0.519 ± 0.049, meaning that when students are in active learning classes, they perform roughly half a standard deviation higher on an identical exam. Funnel plots and sensitivity analyses indicated that these results were not due to sampling bias. Active learning had a positive impact on student outcomes regardless of class size, course level, or STEM discipline, though there was heterogeneity in the effects. All of these results are very similar when compared to earlier meta-analyses, however increased resolution in the studies analyzed here revealed two novel results. First, student performance was significantly better in courses that employed high-intensity active learning, defined as students being on task at least two-thirds of class time, versus lower-intensities. Additionally, there was significant heterogeneity in efficacy across different types of active learning employed. These results suggest that most, if not all types of active learning are effective, and that when innovating in their classes, instructors should continually work to increase active learning intensity. We urge caution in interpreting the results on active learning types, however, and propose a preliminary framework for making more-sophisticated and reliable analyses of variation in course design. Finally, the evidence presented here for active learning’s impact on student outcomes creates a strong foundation for faculty professional development and administration.

Research on urban ecosystems rapidly expanded in the 1990s and is now a central topic in ecosystem science. In this paper, we argue that there are two critical challenges for ecosystem science that are rooted in urban ecosystems: (1) predicting or explaining the assembly and function of novel communities and ecosystems under altered environmental conditions and (2) refining understanding of humans as components of ecosystems in the context of integrated social-ecological systems. We assert that these challenges are also linchpins in the further development of sustainability science and argue that there is a strong need for a new initiative in urban systems science to address these challenges and catalyze the next wave of fundamental advances in ecosystem science, and more broadly in interdisciplinary and transdisciplinary science.

Belting along The Van Allen radiation belts are regions of space encircling the Earth where energetic particles from the solar wind are trapped by Earth's magnetic field. The high energies of these particles — millions of electron volts — make the belts a hazard to spacecraft. A better understanding of the mechanisms that accelerate particles to such high energies will make it easier to predict periods of enhanced risk for satellites, and a recent rare event provided an opportunity to test current models. The ‘Halloween’ solar storms of 2003 disrupted GPS and communications satellites, short-wave radio signals and power grids and caused red auroras as far south as Florida. In space, the outer of the two radiation belts was depleted, then reformed closer to Earth. Electromagnetic waves were seen to be the dominant process involved in accelerating electrons back up to speed, not the radial diffusion that had previously been suspected. The Van Allen radiation belts 1 are two regions encircling the Earth in which energetic charged particles are trapped inside the Earth's magnetic field. Their properties vary according to solar activity 2 , 3 and they represent a hazard to satellites and humans in space 4 , 5 . An important challenge has been to explain how the charged particles within these belts are accelerated to very high energies of several million electron volts. Here we show, on the basis of the analysis of a rare event where the outer radiation belt was depleted and then re-formed closer to the Earth 6 , that the long established theory of acceleration by radial diffusion is inadequate; the electrons are accelerated more effectively by electromagnetic waves at frequencies of a few kilohertz. Wave acceleration can increase the electron flux by more than three orders of magnitude over the observed timescale of one to two days, more than sufficient to explain the new radiation belt. Wave acceleration could also be important for Jupiter, Saturn and other astrophysical objects with magnetic fields.