Americas Hidden Common Ground: Putting Partisan Animosity in Perspective

This Public Agenda/USA TODAY Hidden Common Ground report focuses on affective polarization, meaning negative feelings towards people whose political views differ from one's own. Findings from this nationally representative survey of American adults, fielded in September 2021, include:Americans are united in thinking that partisan hostility and divisiveness harm the country and want a less contentious nation.Most Americans actually do not have strongly unfavorable feelings towards either Democratic or Republican voters.Most Americans believe in the value of differences of opinion and dialogue, and many are trying to connect across partisan lines.A strong cross-partisan majority of Americans believe that the federal government should ensure voting rights for all, and a more modest majority believe that doing so would actually bring the country together. By contrast, partisan differences of opinion emerge starkly when people are asked about federal policies directly aimed at combating racism.To bring the country together, Americans agree on the need for better news and information; and, most want social media to stop amplifying divisiveness.Across partisan lines, most Americans agree that reducing the influence of money in politics would help bring the country together. Many people also believe that educational approaches would help unify the country.The report concludes with reflections on the findings and implications for addressing affective polarization

Americas Hidden Common Ground on Renewing Democracy

This Public Agenda/USA TODAY Hidden Common Ground survey, which is also part of Public Agenda's ongoing series of Yankelovich Democracy Monitor surveys, was fielded in May 2021. The research updates and expands on findings from Public Agenda's two previous Yankelovich Democracy Monitor surveys, published in 2019 and 2020. The report concludes with reflections on the findings and implications for moving towards a less divisive, more collaborative, and healthier democracy

Selective Polytopic Protein Degradation by Organelle Membrane Fusion

Lysosomes are dynamic organelles most notably known as the terminal compartments of the endocytic and autophagy pathways in eukaryotic cells. However, lysosome function is not simply for the elimination and catabolism of biomaterials. Rather lysosomes have emerged as critical and dynamic signaling hubs via their ability to sense and provide nutrients, and communicate this information to biosynthetic or metabolic processes. Lysosome physiology relies on membrane transporter activity, best signified by loss-of-function mutations linked to lysosomal storage disorders. These include nutrient transporter proteins that export products of catabolism to the cytoplasm for cellular reuse, as well as Ca2+ pumps and transporters important for signaling, and transporters for metal storage and homeostasis. Eukaryotic cells, and their lysosomes, undergo continuous renovation to clear damaged or unused proteins or to alter their proteome accommodating functional changes in response to the environment, physiological cues, or aging. Despite the importance of lysosomal transporters to cell physiology, little is known about their lifetimes and it remains unclear how they are degraded. Here, I used Saccharomyces cerevisiae and its vacuolar lysosome as models to study lysosomal transporter lifetimes and discovered a new cellular protein degradation pathway, the IntraLumenal Fragment (ILF) pathway: During membrane fusion events between lysosomes, transporters are selectively labeled for recognition and sorting by the fusion protein machinery into an area of membrane spanning the apposed organelles. Upon fusion, this membrane and proteins embedded within it are internalized into the lumen as a byproduct for degradation by hydrolases. I find the ILF pathway selectively degrades lysosomal transporters when misfolded, in response to TOR signaling or changes in substrate levels. I also find that protein clients are not limited to lysosomal transporters, as this pathway degrades internalized surface membrane proteins that bypass entry into the canonical MultiVesicular Body pathway, which was previously thought to be the exclusive mechanism for selective surface protein degradation. Finally, I find the ILF pathway cooperates with a second, independent protein degradation pathway, the vReD pathway, to change the lysosomal membrane proteome. The underlying machinery and transporters studied are evolutionarily conserved, suggesting the ILF pathway contributes to lysosome physiology in all eukaryotic cells

Computational Model of a Left Ventricle: Showing the Effects of Inertia on Cardiac Dyssynchrony

In an effort to research heart failure, a leading cause of death in the industrialized world, this research team has developed a segmented lumped parameter model of the left ventricle. The computations model developed focuses on dyssynchrony, a heart condition where some regions of the heart vary significantly in properties like internal muscle resistance, mass, or elastance. Inertial effects are often assumed as negligible by cardiovascular models. One primary function of this model is to investigate inertial effects as they relate to mechanical cardiac dyssynchrony. An added dimension of this analysis is to observe the thermodynamics of the cardiac cycle as one long term indicator of heart failure. This model was developed using an electrical analog to the hemodynamic system. The parameters of a heart wall segment were represented by resistance, inductance, and capacitance. The calculations were done using state space and programmed into Matlab for simulation. This research shows waveforms of volume outputs as well as pressure volume loops for synchronous waveforms as well as dyssychronous waveforms caused by a time delay, varied resistance, varied elastance, and varied mass. The variation seen in the mass dyssynchrony waveforms suggest that inertial effect may be a significant factor in modeled cardiovascular systems

The intralumenal fragment pathway mediates ESCRT-independent surface transporter down-regulation

Surface receptor and transporter protein down-regulation is assumed to be exclusively mediated by the canonical multivesicular body (MVB) pathway and ESCRTs (Endosomal Sorting Complexes Required for Transport). However, few surface proteins are known to require ESCRTs for down-regulation, and reports of ESCRT-independent degradation are emerging, suggesting that alternative pathways exist. Here, using Saccharomyces cerevisiae as a model, we show that the hexose transporter Hxt3 does not require ESCRTs for down-regulation conferring resistance to 2-deoxyglucose. This is consistent with GFP-tagged Hxt3 bypassing ESCRT-mediated entry into intralumenal vesicles at endosomes. Instead, Hxt3-GFP accumulates on vacuolar lysosome membranes and is sorted into an area that, upon fusion, is internalized as an intralumenal fragment (ILF) and degraded. Moreover, heat stress or cycloheximide trigger degradation of Hxt3-GFP and other surface transporter proteins (Itr1, Aqr1) by this ESCRT-independent process. How this ILF pathway compares to the MVB pathway and potentially contributes to physiology is discussed

Biosynthesis of UDP-N-acetyl-L-fucosamine, a precursor to the biosynthesis of lipopolysaccharide in Pseudomonas aeruginosa serotype O11.

Abstract UDP-N-acetyl-l-fucosamine is a precursor to l-fucosamine in the lipopolysaccharide of Pseudomonas aeruginosa serotype O11 and the capsule of Staphylococcus aureus type 5. We have demonstrated previously the involvement of three enzymes, WbjB, WbjC, and WbjD, in the biosynthesis of UDP-2-acetamido-2,6-dideoxy-l-galactose or UDP-N-acetyl-l-fucosamine (UDP-l-FucNAc). An intermediate compound from the coupled-reaction of WbjB-WbjC with the initial substrate UDP-2-acetamido-2-deoxy-α-d-glucose or UDP-N-acetyl-d-glucosamine (UDP-GlcNAc) was purified, and the structure was determined by NMR spectroscopy to be UDP-2-acetamido-2,6-dideoxy-l-talose (UDP-l-PneNAc). WbjD could then convert this intermediate into a new product with the same mass, consistent with a C-2 epimerization reaction. Those results led us to propose a pathway for the biosynthesis of UDP-l-FucNAc; however, the exact enzymatic activity of each of these proteins has not been defined. Here, we describe a fast protein liquid chromatography (FPLC)-based anion-exchange procedure, which allowed the separation and purification of the products of C-2 epimerization due to WbjD. Also, the application of a cryogenically cooled probe in NMR spectrometry offers the greatest sensitivity for determining the structures of minute quantities of materials, allowing the identification of the final product of the pathway. Our results showed that WbjB is bifunctional, catalyzing firstly C-4, C-6 dehydration and secondly C-5 epimerization in the reaction with the substrate UDP-d-GlcNAc, producing two intermediates. WbjC is also bifunctional, catalyzing C-3 epimerization of the second intermediate followed by reduction at C-4. The FPLC-based procedure provided good resolution of the final product of WbjD reaction from its epimer/substrate UDP-l-PneNAc, and the use of the cryogenically cooled probe in NMR revealed unequivocally that the final product is UDP-l-FucNAc

Mapping Physiological Suitability Limits for Malaria in Africa Under Climate Change

We mapped current and future temperature suitability for malaria transmission in Africa using a published model that incorporates nonlinear physiological responses to temperature of the mosquito vector Anopheles gambiae and the malaria parasite Plasmodium falciparum. We found that a larger area of Africa currently experiences the ideal temperature for transmission than previously supposed. Under future climate projections, we predicted a modest increase in the overall area suitable for malaria transmission, but a net decrease in the most suitable area. Combined with human population density projections, our maps suggest that areas with temperatures suitable for year-round, highest-risk transmission will shift from coastal West Africa to the Albertine Rift between the Democratic Republic of Congo and Uganda, whereas areas with seasonal transmission suitability will shift toward sub-Saharan coastal areas. Mapping temperature suitability places important bounds on malaria transmissibility and, along with local level demographic, socioeconomic, and ecological factors, can indicate where resources may be best spent on malaria control

Understanding uncertainty in temperature effects on vector-borne disease: A Bayesian approach

Extrinsic environmental factors influence the distribution and population dynamics of many organisms, including insects that are of concern for human health and agriculture. This is particularly true for vector-borne infectious diseases, like malaria, which is a major source of morbidity and mortality in humans. Understanding the mechanistic links between environment and population processes for these diseases is key to predicting the consequences of climate change on transmission and for developing effective interventions. An important measure of the intensity of disease transmission is the reproductive number $R_0$. However, understanding the mechanisms linking $R_0$ and temperature, an environmental factor driving disease risk, can be challenging because the data available for parameterization are often poor. To address this we show how a Bayesian approach can help identify critical uncertainties in components of $R_0$ and how this uncertainty is propagated into the estimate of $R_0$. Most notably, we find that different parameters dominate the uncertainty at different temperature regimes: bite rate from 15-25$^\circ$ C; fecundity across all temperatures, but especially $\sim$25-32$^\circ$ C; mortality from 20-30$^\circ$ C; parasite development rate at $\sim$15-16$^\circ$C and again at $\sim$33-35$^\circ$C. Focusing empirical studies on these parameters and corresponding temperature ranges would be the most efficient way to improve estimates of $R_0$. While we focus on malaria, our methods apply to improving process-based models more generally, including epidemiological, physiological niche, and species distribution models.Comment: 27 pages, including 1 table and 3 figure

A Survey of New Temperature-Sensitive, Embryonic-Lethal Mutations in C. elegans: 24 Alleles of Thirteen Genes

To study essential maternal gene requirements in the early C. elegans embryo, we have screened for temperature-sensitive, embryonic lethal mutations in an effort to bypass essential zygotic requirements for such genes during larval and adult germline development. With conditional alleles, multiple essential requirements can be examined by shifting at different times from the permissive temperature of 15°C to the restrictive temperature of 26°C. Here we describe 24 conditional mutations that affect 13 different loci and report the identity of the gene mutations responsible for the conditional lethality in 22 of the mutants. All but four are mis-sense mutations, with two mutations affecting splice sites, another creating an in-frame deletion, and one creating a premature stop codon. Almost all of the mis-sense mutations affect residues conserved in orthologs, and thus may be useful for engineering conditional mutations in other organisms. We find that 62% of the mutants display additional phenotypes when shifted to the restrictive temperature as L1 larvae, in addition to causing embryonic lethality after L4 upshifts. Remarkably, we also found that 13 out of the 24 mutations appear to be fast-acting, making them particularly useful for careful dissection of multiple essential requirements. Our findings highlight the value of C. elegans for identifying useful temperature-sensitive mutations in essential genes, and provide new insights into the requirements for some of the affected loci