Yeast translation elongation factor eEF3 promotes late stages of tRNA translocation

In addition to the conserved translation elongation factors eEF1A and eEF2, fungi require a third essential elongation factor, eEF3. While eEF3 has been implicated in tRNA binding and release at the ribosomal A and E sites, its exact mechanism of action is unclear. Here, we show that eEF3 acts at the mRNA–tRNA translocation step by promoting the dissociation of the tRNA from the E site, but independent of aminoacyl‐tRNA recruitment to the A site. Depletion of eEF3 in vivo leads to a general slowdown in translation elongation due to accumulation of ribosomes with an occupied A site. Cryo‐EM analysis of native eEF3‐ribosome complexes shows that eEF3 facilitates late steps of translocation by favoring non‐rotated ribosomal states, as well as by opening the L1 stalk to release the E‐site tRNA. Additionally, our analysis provides structural insights into novel translation elongation states, enabling presentation of a revised yeast translation elongation cycle.     

Phosphoproteomics identifies microglial Siglec‐F inflammatory response during neurodegeneration

Alzheimer’s disease (AD) is characterized by the appearance of amyloid‐β plaques, neurofibrillary tangles, and inflammation in brain regions involved in memory. Using mass spectrometry, we have quantified the phosphoproteome of the CK‐p25, 5XFAD, and Tau P301S mouse models of neurodegeneration. We identified a shared response involving Siglec‐F which was upregulated on a subset of reactive microglia. The human paralog Siglec‐8 was also upregulated on microglia in AD. Siglec‐F and Siglec‐8 were upregulated following microglial activation with interferon gamma (IFNγ) in BV‐2 cell line and human stem cell‐derived microglia models. Siglec‐F overexpression activates an endocytic and pyroptotic inflammatory response in BV‐2 cells, dependent on its sialic acid substrates and immunoreceptor tyrosine‐based inhibition motif (ITIM) phosphorylation sites. Related human Siglecs induced a similar response in BV‐2 cells. Collectively, our results point to an important role for mouse Siglec‐F and human Siglec‐8 in regulating microglial activation during neurodegeneration.     

Space‐for‐time is not necessarily a substitution when monitoring the distribution of pelagic fishes in the San Francisco Bay‐Delta

Occupancy models are often used to analyze long‐term monitoring data to better understand how and why species redistribute across dynamic landscapes while accounting for incomplete capture. However, this approach requires replicate detection/non‐detection data at a sample unit and many long‐term monitoring programs lack temporal replicate surveys. In such cases, it has been suggested that surveying subunits within a larger sample unit may be an efficient substitution (i.e., space‐for‐time substitution). Still, the efficacy of fitting occupancy models using a space‐for‐time substitution has not been fully explored and is likely context dependent. Herein, we fit occupancy models to Delta Smelt (Hypomesus transpacificus) and Longfin Smelt (Spirinchus thaleichthys) catch data collected by two different monitoring programs that use the same sampling gear in the San Francisco Bay‐Delta, USA. We demonstrate how our inferences concerning the distribution of these species changes when using a space‐for‐time substitution. Specifically, we found the probability that a sample unit was occupied was much greater when using a space‐for‐time substitution, presumably due to the change in the spatial scale of our inferences. Furthermore, we observed that as the spatial scale of our inferences increased, our ability to detect environmental effects on system dynamics was obscured, which we suspect is related to the tradeoffs associated with spatial grain and extent. Overall, our findings highlight the importance of considering how the unique characteristics of monitoring programs influences inferences, which has broad implications for how to appropriately leverage existing long‐term monitoring data to understand the distribution of species.     

Predictable fold switching by the SARS‐CoV‐2 protein ORF9b

Extant fold‐switching proteins remodel their secondary structures and change their functions in response to environmental stimuli. These shapeshifting proteins regulate biological processes and are associated with a number of diseases, including tuberculosis, cancer, Alzheimer''s, and autoimmune disorders. Thus, predictive methods are needed to identify more fold‐switching proteins, especially since all naturally occurring instances have been discovered by chance. In response to this need, two high‐throughput predictive methods have recently been developed. Here we test them on ORF9b, a newly discovered fold switcher and potential therapeutic target from the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2). Promisingly, both methods correctly indicate that ORF9b switches folds. We then tested the same two methods on ORF9b1, the ORF9b homolog from SARS‐CoV‐1. Again, both methods predict that ORF9b1 switches folds, a finding consistent with experimental binding studies. Together, these results (a) demonstrate that protein fold switching can be predicted using high‐throughput computational approaches and (b) suggest that fold switching might be a general characteristic of ORF9b homologs.     

Bioinspiration as a method of problem‐based STEM education: A case study with a class structured around the COVID‐19 crisis

Bioinspiration is a promising lens for biology instruction as it allows the instructor to focus on current issues, such as the COVID‐19 pandemic. From social distancing to oxygen stress, organisms have been tackling pandemic‐related problems for millions of years. What can we learn from such diverse adaptations in our own applications? This review uses a seminar course on the COVID‐19 crisis to illustrate bioinspiration as an approach to teaching biology content. At the start of the class, students mind‐mapped the entire problem; this range of subproblems was used to structure the biology content throughout the entire class. Students came to individual classes with a brainstormed list of biological systems that could serve as inspiration for a particular problem (e.g., absorptive leaves in response to the problem of toilet paper shortages). After exploration of relevant biology content, discussion returned to the focal problem. Students dug deeper into the literature in a group project on mask design and biological systems relevant to filtration and transparency. This class structure was an engaging way for students to learn principles from ecology, evolution, behavior, and physiology. Challenges with this course design revolved around the interdisciplinary and creative nature of the structure; for instance, the knowledge of the participants was often stretched by engineering details. While the present class was focused on the COVID‐19 crisis, a course structured through a bioinspired approach can be applied to other focal problems, or subject areas, giving instructors a powerful method to deliver interdisciplinary content in an integrated and inquiry‐driven way.     

Concordant geographic and genetic structure revealed by genotyping‐by‐sequencing in a New Zealand marine isopod

Population genetic structure in the marine environment can be influenced by life‐history traits such as developmental mode (biphasic, with distinct adult and larval morphology, and direct development, in which larvae resemble adults) or habitat specificity, as well as geography and selection. Developmental mode is thought to significantly influence dispersal, with direct developers expected to have much lower dispersal potential. However, this prediction can be complicated by the presence of geophysical barriers to dispersal. In this study, we use a panel of 8,020 SNPs to investigate population structure and biogeography over multiple spatial scales for a direct‐developing species, the New Zealand endemic marine isopod Isocladus armatus. Because our sampling range is intersected by two well‐known biogeographic barriers (the East Cape and the Cook Strait), our study provides an opportunity to understand how such barriers influence dispersal in direct developers. On a small spatial scale (20 km), gene flow between locations is extremely high, suggestive of an island model of migration. However, over larger spatial scales (600 km), populations exhibit a clear pattern of isolation‐by‐distance. Our results indicate that I. armatus exhibits significant migration across the hypothesized barriers and suggest that large‐scale ocean currents associated with these locations do not present a barrier to dispersal. Interestingly, we find evidence of a north‐south population genetic break occurring between Māhia and Wellington. While no known geophysical barrier is apparent in this area, it coincides with the location of a proposed border between bioregions. Analysis of loci under selection revealed that both isolation‐by‐distance and adaption may be contributing to the degree of population structure we have observed here. We conclude that developmental life history largely predicts dispersal in the intertidal isopod I. armatus. However, localized biogeographic processes can disrupt this expectation, and this may explain the potential meta‐population detected in the Auckland region.     

MicroRNA‐148a‐3p suppresses epithelial‐to‐mesenchymal transition and stemness properties via Wnt1‐mediated Wnt/β‐catenin pathway in pancreatic cancer

Although miR‐148a‐3p has been reported to function as a tumour suppressor in various cancers, the molecular mechanism of miR‐148a‐3p in regulating epithelial‐to‐mesenchymal transition (EMT) and stemness properties of pancreatic cancer (PC) cells remains to be elucidated. In the present study, we demonstrated that miR‐148a‐3p expression was remarkably down‐regulated in PC tissues and cell lines. Moreover, low expression of miR‐148a‐3p was associated with poorer overall survival (OS) in patients with PC. In vitro, gain‐of‐function and loss‐of‐function experiments showed that miR‐148a‐3p suppressed EMT and stemness properties as well as the proliferation, migration and invasion of PC cells. A dual‐luciferase reporter assay demonstrated that Wnt1 was a direct target of miR‐148a‐3p, and its expression was inversely associated with miR‐148a‐3p in PC tissues. Furthermore, miR‐148a‐3p suppressed the Wnt/β‐catenin pathway via down‐regulation of Wnt1. The effects of ectopic miR‐148a‐3p were rescued by Wnt1 overexpression. These biological functions of miR‐148a‐3p in PC were also confirmed in a nude mouse xenograft model. Taken together, these findings suggest that miR‐148a‐3p suppresses PC cell proliferation, invasion, EMT and stemness properties via inhibiting Wnt1‐mediated Wnt/β‐catenin pathway and could be a potential prognostic biomarker as well as a therapeutic target in PC.     

Mitochondrial derived peptide MOTS‐c prevents the development of heart failure under pressure overload conditions in mice

MOTS‐c, a mitochondrial‐derived peptide (MDP), has been shown to have multiple biological activities such as antioxidation, anti‐inflammation, and anti‐apoptosis properties. In the present study, we aimed at evaluating the therapeutic effect of MOTS‐c peptide in an animal model of heart failure. The heart failure mouse model was made by transverse aortic constriction (TAC) operations. The MOTS‐c peptide was administrated subcutaneously by using an osmotic pump. At the end of the animal experiment, cardiac function was evaluated by echocardiography, and heart tissues were subjected to histological and molecular analysis. In vitro cultured H9C2 cells were used to test the effects of MOTS‐c overexpression on cell death in response to H₂O₂ stimulation. Our study showed that MOTS‐c peptide attenuated TAC‐induced cardiac dysfunction and remodelling. In addition, the MOTS‐c peptide reduced the inflammatory response and upregulated the antioxidant capacity, coupled with the activation of the AMPK pathway in the heart of the TAC mouse model. In in vitro cultured cardiac cells, overexpression of MOTS‐c was shown to activate the AMPK pathway and protect cell apoptosis in response to H₂O₂ stimulation. Taken together, our study suggested that MOTS‐c peptides may have therapeutic potential in treating HF.