The influence of accessory dwelling unit (ADU) policy on the contributing factors to ADU development: an assessment of the city of Los Angeles.

Since the accessory dwelling unit (ADU) has emerged as a policy alternative to increase housing stock and provide affordable options for areas impacted by housing shortages, many local governments recently adopted ADU policies that promote the construction of ADUs. Taking the City of Los Angeles as the study area, this paper examines how the city's ADU ordinance impacts the relationship of the characteristics of the properties and neighborhoods with ADU development by constructing multilevel logistic regression models. The outputs of the models suggest that the ordinance contributes to diversifying the types and locations of the properties and neighborhoods where ADUs are built. The influence of the property characteristics associated with ADU development before the implementation of the ordinance significantly diminished after the ordinance. The outputs also indicate that the ordinance probably attracted ADU developments in the areas with higher accessibility to bus transit. These findings will help planners take appropriate actions and policies that support ADU developments.

The Potential Beneficial Effects of Vaccination on Antigenically Evolving Pathogens.

AbstractAlthough vaccines against antigenically evolving pathogens such as seasonal influenza ; and are designed to protect against circulating strains by affecting the emergence and transmission of antigenically divergent strains, they might in theory also be able to change the rate of antigenic evolution. Vaccination might slow antigenic evolution by increasing immunity, reducing the overall prevalence or population size of the pathogen. This reduction could decrease the supply and growth rates of mutants and might thereby slow adaptation. But vaccination might accelerate antigenic evolution by increasing the transmission advantage of more antigenically diverged strains relative to less diverged strains (i.e., by positive selection). Such evolutionary effects could affect vaccination's direct benefits to individuals and indirect benefits to the host population (i.e., the private and social benefits). To investigate these potential impacts, we simulated vaccination against a continuously circulating influenza-like pathogen in a simple population. On average, more vaccination decreased the incidence of infection. Notably, this decrease was driven partly by a vaccine-induced decline in the rate of antigenic evolution. To understand how the evolutionary effects of vaccines might affect their social and private benefits, we fitted linear panel models to simulated data. By slowing evolution, vaccination increased the social benefit and decreased the private benefit. Thus, vaccination's potential social and private benefits may differ from current theory, which omits evolutionary effects. These results suggest that conventional vaccines against influenza and other antigenically evolving pathogens, if protective against transmission and given to the appropriate populations, could further reduce disease burden by slowing antigenic evolution.

Explaining the geographical origins of seasonal influenza A (H3N2).

Most antigenically novel and evolutionarily successful strains of seasonal influenza A (H3N2) originate in East, South and Southeast Asia. To understand this pattern, we simulated the ecological and evolutionary dynamics of influenza in a host metapopulation representing the temperate north, tropics and temperate south. Although seasonality and air traffic are frequently used to explain global migratory patterns of influenza, we find that other factors may have a comparable or greater impact. Notably, a region's basic reproductive number (R0) strongly affects the antigenic evolution of its viral population and the probability that its strains will spread and fix globally: a 17-28% higher R0 in one region can explain the observed patterns. Seasonality, in contrast, increases the probability that a tropical (less seasonal) population will export evolutionarily successful strains but alone does not predict that these strains will be antigenically advanced. The relative sizes of different host populations, their birth and death rates, and the region in which H3N2 first appears affect influenza's phylogeography in different but relatively minor ways. These results suggest general principles that dictate the spatial dynamics of antigenically evolving pathogens and offer predictions for how changes in human ecology might affect influenza evolution.

Criteria to make animal studies more relevant to treating human cancer.

Certain aspects of experimental tumor models in mice most accurately reflect the biology and immunology of cancer in patients. A survey of experimental cancer immunotherapy papers published in 2020 shows most do not achieve cancer shrinkage although treatment is initiated at an early time point after cancer cell injection, which does not reflect cancer immunotherapy in patients. Even then, few current experimental approaches eradicate the injected malignant cells, most only delay outgrowth. The value of targeting mutation-encoded tumor-specific antigens becomes increasingly evident while problems of finding normal gene-encoded tumor-associated antigens as safe, effective targets persist. It might be time to refocus on realistic experimental settings and truly cancer-specific targets. These antigens are associated with the least risk of side effects.

Exploring the modeling and site-ranking performance of Bayesian spatiotemporal crash frequency models with mixture components.

The current study introduces the flexible approach of mixture components to model the spatiotemporal interaction for ranking of hazardous sites and compares the model performance with the conventional methods. In case of predictive accuracy based on in-sample errors (posterior deviance), the Mixture-5 demonstrated superior performance in majority of the cases, indicating the advantage of mixture approach to accurately predict crash counts. LPML (log pseudo marginal likelihood) was also calculated as a cross-validation measure based on out-of-sample errors and this criterion also established the dominance of Mixture-5, further reinforcing the superiority of the mixture approach from different perspectives. The site ranking evaluation results demonstrated the advantages of adopting the mixture approach. In terms of total rank difference (TRD) results, there were several discrepancies between the two approaches, suggesting that two approaches designate unsafe sites differently. Another site ranking criterion, site consistency test (SCT), was employed to explore the difference in identification of unsafe sites based on two datasets: estimated crash count (traditional) and the spatial variability across time. The advantage of mixture models to act as a complimentary approach for site ranking was revealed by the spatial variability SCT results. The method consistency test (MCT) results also indicate the advantages of mixture models over the Base one. These findings suggested that mixture approach may prove helpful in the network screening step of safety management process to identify sites which may turn unsafe in the future and escape the detection from traditional methods.

SLIT2/ROBO1-signaling inhibits macropinocytosis by opposing cortical cytoskeletal remodeling.

Macropinocytosis is essential for myeloid cells to survey their environment and for growth of RAS-transformed cancer cells. Several growth factors and inflammatory stimuli are known to induce macropinocytosis, but its endogenous inhibitors have remained elusive. Stimulation of Roundabout receptors by Slit ligands inhibits directional migration of many cell types, including immune cells and cancer cells. We report that SLIT2 inhibits macropinocytosis in vitro and in vivo by inducing cytoskeletal changes in macrophages. In mice, SLIT2 attenuates the uptake of muramyl dipeptide, thereby preventing NOD2-dependent activation of NF-κB and consequent secretion of pro-inflammatory chemokine, CXCL1. Conversely, blocking the action of endogenous SLIT2 enhances CXCL1 secretion. SLIT2 also inhibits macropinocytosis in RAS-transformed cancer cells, thereby decreasing their survival in nutrient-deficient conditions which resemble tumor microenvironment. Our results identify SLIT2 as a physiological inhibitor of macropinocytosis and challenge the conventional notion that signals that enhance macropinocytosis negatively regulate cell migration, and vice versa.

Multiple cancer-specific antigens are targeted by a chimeric antigen receptor on a single cancer cell.

Human cancer cells were eradicated by adoptive transfer of T cells transduced with a chimeric antigen receptor (CAR) made from an antibody (237Ab) that is highly specific for the murine Tn-glycosylated podoplanin (Tn-PDPN). The objectives were to determine the specificity of these CAR-transduced T (CART) cells and the mechanism for the absence of relapse. We show that although the 237Ab bound only to cell lines expressing murine Tn-PDPN, the 237Ab-derived 237CART cells lysed multiple different human and murine cancers not predicted by the 237Ab binding. Nevertheless, the 237CART cell reactivities remained cancer specific because all recognitions were dependent on the Tn glycosylation that resulted from COSMC mutations that were not present in normal tissues. While Tn was required for the recognition by 237CART, Tn alone was not sufficient for 237CART cell activation. Activation of 237CART cells required peptide backbone recognition but tolerated substitutions of up to 5 of the 7 amino acid residues in the motif recognized by 237Ab. Together, these findings demonstrate what we believe is a new principle whereby simultaneous recognition of multiple independent Tn-glycopeptide antigens on a cancer cell makes tumor escape due to antigen loss unlikely.

Estimating Vaccine-Driven Selection in Seasonal Influenza.

Vaccination could be an evolutionary pressure on seasonal influenza if vaccines reduce the transmission rates of some ("targeted") strains more than others. In theory, more vaccinated populations should have a lower prevalence of targeted strains compared to less vaccinated populations. We tested for vaccine-induced selection in influenza by comparing strain frequencies between more and less vaccinated human populations. We defined strains in three ways: first as influenza types and subtypes, next as lineages of type B, and finally as clades of influenza A/H3N2. We detected spatial differences partially consistent with vaccine use in the frequencies of subtypes and types and between the lineages of influenza B, suggesting that vaccines do not select strongly among all these phylogenetic groups at regional scales. We did detect a significantly greater frequency of an H3N2 clade with known vaccine escape mutations in more vaccinated countries during the 2014⁻2015 season, which is consistent with vaccine-driven selection within the H3N2 subtype. Overall, we find more support for vaccine-driven selection when large differences in vaccine effectiveness suggest a strong effect size. Variation in surveillance practices across countries could obscure signals of selection, especially when strain-specific differences in vaccine effectiveness are small. Further examination of the influenza vaccine's evolutionary effects would benefit from improvements in epidemiological surveillance and reporting.

Tumor relapse prevented by combining adoptive T cell therapy with Salmonella typhimurium.

We recently reported that therapeutic vaccination with live tumor antigen-producing Salmonella typhimurium rescues dysfunctional endogenous T cell responses and eradicates long-established tumors refractory to αCTLA-4 and αPD-L1 checkpoint inhibitor blockade. Here, we show that live intravenously injected or heat-killed (HK) intratumorally injected Salmonella typhimurium, even when not producing tumor antigen, synergize with adoptive T cell therapy to eradicate tumors. These data demonstrate that the combination of adoptive T cell transfer with the injection of live or dead Salmonella typhimurium is a promising approach for cancer treatment.

A systematic analysis of experimental immunotherapies on tumors differing in size and duration of growth.

We conducted a systematic analysis to determine the reason for the apparent disparity of success of immunotherapy between clinical and experimental cancers. To do this, we performed a search of PubMed using the keywords "immunotherapy" AND "cancer" for the years of 1980 and 2010. The midspread of experimental tumors used in all the relevant literature published in 2010 were between 0.5-121 mm(3) in volume or had grown for four to eight days. Few studies reported large tumors that could be considered representative of clinical tumors, in terms of size and duration of growth. The predominant effect of cancer immunotherapies was slowed or delayed outgrowth. Regression of tumors larger than 200 mm(3) was observed only after passive antibody or adoptive T cell therapy. The effectiveness of other types of immunotherapy was generally scattered. By comparison, very few publications retrieved by the 1980 search could meet our selection criteria; all of these used tumors smaller than 100 mm(3), and none reported regression. In the entire year of 2010, only 13 used tumors larger than 400 mm(3), and nine of these reported tumor regression. Together, these results indicate that most recent studies, using many diverse approaches, still treat small tumors only to report slowed or delayed growth. Nevertheless, a few recent studies indicate effective therapy against large tumors when using passive antibody or adoptive T cell therapy. For the future, we aspire to witness the increased use of experimental studies treating tumors that model clinical cancers in terms of size and duration of growth.