Recombinant Listeria promotes tumor rejection by CD8+ T cell-dependent remodeling of the tumor microenvironment.

Agents that remodel the tumor microenvironment (TME), prime functional tumor-specific T cells, and block inhibitory signaling pathways are essential components of effective immunotherapy. We are evaluating live-attenuated, double-deleted Listeria monocytogenes expressing tumor antigens (LADD-Ag) in the clinic. Here we show in numerous mouse models that while treatment with nonrecombinant LADD induced some changes in the TME, no antitumor efficacy was observed, even when combined with immune checkpoint blockade. In contrast, LADD-Ag promoted tumor rejection by priming tumor-specific KLRG1+PD1loCD62L- CD8+ T cells. These IFNγ-producing effector CD8+ T cells infiltrated the tumor and converted the tumor from an immunosuppressive to an inflamed microenvironment that was characterized by a decrease in regulatory T cells (Treg) levels, a proinflammatory cytokine milieu, and the shift of M2 macrophages to an inducible nitric oxide synthase (iNOS)+CD206- M1 phenotype. Remarkably, these LADD-Ag-induced tumor-specific T cells persisted for more than 2 months after primary tumor challenge and rapidly controlled secondary tumor challenge. Our results indicate that the striking antitumor efficacy observed in mice with LADD-based immunotherapy stems from TME remodeling which is a direct consequence of eliciting potent, systemic tumor-specific CD8+ T cells

Attitudes and preferences towards self-help treatments for depression in comparison to psychotherapy and antidepressant medication

Background: Self-help is an effective treatment for depression. Less is known, however, about how acceptable people find different self-help treatments for depression. Aims: To investigate preferences and attitudes toward different self-help treatments for depression in comparison to psychotherapy and antidepressants. Method:N = 536 people who were not actively seeking treatment for depression were randomly assigned to read about one of five treatment options (bibliotherapy, Internet-based self-help, guided self-help, antidepressants, or psychotherapy) before rating how acceptable they found the treatment. Participants also ranked the treatments in order of preference. Results: Psychotherapy and guided self-help were found to be the most acceptable and preferred treatment options. Antidepressants and bibliotherapy were found to be the least acceptable treatments, with antidepressants rated as the most likely to have side effects. Preference data reflected the above findings – psychotherapy and guided self-help were the most preferred treatment options. Conclusions: The findings highlight differences in attitudes and preferences between guided and unguided self-help interventions; and between self-help interventions and psychotherapy. Future research should focus on understanding why unguided self-help interventions are deemed to be less acceptable than guided self-help interventions for treating depression

Provenance and Paleogeography of the 25-17 Ma Rainbow Gardens Formation: Evidence for Tectonic Activity at Ca. 19 Ma and Internal Drainage rather than Throughgoing Paleorivers on the Southwestern Colorado Plateau

The paleogeographic evolution of the Lake Mead region of southern Nevada and northwest Arizona is crucial to understanding the geologic history of the U.S. Southwest, including the evolution of the Colorado Plateau and formation of the Grand Canyon. The ca. 25–17 Ma Rainbow Gardens Formation in the Lake Mead region, the informally named, roughly coeval Jean Conglomerate, and the ca. 24–19 Ma Buck and Doe Conglomerate southeast of Lake Mead hold the only stratigraphic evidence for the Cenozoic pre-extensional geology and paleogeography of this area. Building on prior work, we present new sedimentologic and stratigraphic data, including sandstone provenance and detrital zircon data, to create a more detailed paleogeographic picture of the Lake Mead, Grand Wash Trough, and Hualapai Plateau region from 25 to 18 Ma. These data confirm that sediment was sourced primarily from Paleozoic strata exposed in surrounding Sevier and Laramide uplifts and active volcanic fields to the north. In addition, a distinctive signal of coarse sediment derived from Proterozoic crystalline basement first appeared in the southwestern corner of the basin ca. 25 Ma at the beginning of Rainbow Gardens Formation deposition and then prograded north and east ca. 19 Ma across the southern half of the basin. Regional thermochronologic data suggest that Cretaceous deposits likely blanketed the Lake Mead region by the end of Sevier thrusting. Post-Laramide northward cliff retreat off the Kingman/Mogollon uplifts left a stepped erosion surface with progressively younger strata preserved northward, on which Rainbow Gardens Formation strata were deposited. Deposition of the Rainbow Gardens Formation in general and the 19 Ma progradational pulse in particular may reflect tectonic uplift events just prior to onset of rapid extension at 17 Ma, as supported by both thermochronology and sedimentary data. Data presented here negate the California and Arizona River hypotheses for an “old” Grand Canyon and also negate models wherein the Rainbow Gardens Formation was the depocenter for a 25–18 Ma Little Colorado paleoriver flowing west through East Kaibab paleocanyons. Instead, provenance and paleocurrent data suggest local to regional sources for deposition of the Rainbow Gardens Formation atop a stripped low-relief western Colorado Plateau surface and preclude any significant input from a regional throughgoing paleoriver entering the basin from the east or northeast

Collection of indirect excitons in a diamond-shaped electrostatic trap

We report on the principle and realization of a new trap for excitons -- the diamond electrostatic trap -- which uses a single electrode to create a confining potential for excitons. We also create elevated diamond traps which permit evaporative cooling of the exciton gas. We observe collection of excitons towards the trap center with increasing exciton density. This effect is due to screening of disorder in the trap by the excitons. As a result, the diamond trap behaves as a smooth parabolic potential which realizes a cold and dense exciton gas at the trap center.Comment: 4 Pages, 5 figure

A Potent and Effective Suicidal Listeria Vaccine Platform.

Live-attenuated Listeria monocytogenes has shown encouraging potential as an immunotherapy platform in preclinical and clinical settings. However, additional safety measures will enable application across malignant and infectious diseases. Here, we describe a new vaccine platform, termed Lm-RIID (L. monocytogenes recombinase-induced intracellular death), that induces the deletion of genes required for bacterial viability yet maintains potent T cell responses to encoded antigens. Lm-RIID grows normally in broth but commits suicide inside host cells by inducing Cre recombinase and deleting essential genes flanked by loxP sites, resulting in a self-limiting infection even in immunocompromised mice. Lm-RIID vaccination of mice induces potent CD8+ T cells and protects against virulent challenges, similar to live L. monocytogenes vaccines. When combined with α-PD-1, Lm-RIID is as effective as live-attenuated L. monocytogenes in a therapeutic tumor model. This impressive efficacy, together with the increased clearance rate, makes Lm-RIID ideal for prophylactic immunization against diseases that require T cells for protection

Experiences with a universal mindfulness and wellbeing programme at a UK medical school

Evaluation of a universal, mental wellbeing and mindfulness programme in a UK graduate entry medical school Design: Mixed methods: measurement of mental wellbeing and mindfulness in 2 cohorts at 3 time points over 15mths; descriptive, regression and repeated measures analysis with post hoc pairwise comparisons; qualitative interviews with purposive sample of 13 students after 1yr analysed thematically; spontaneous anonymous feedback on the course. Findings: The course was a surprise to students, and reactions mixed. Respect for its contents grew over the first year. Most students had actively implemented a wellbeing strategy by the end of the course and an estimated quarter were practicing some mindful activity. In the context of an overall decline in wellbeing and limited engagement with mindfulness practice, increases in mindfulness were protective against this decline in both cohorts (p<001). A small minority of students thought the course was a waste of time. Their attitudes influenced engagement by their peers. The mindfulness and wellbeing practices of the facilitators were evident to students and influenced perceived effects. Research Limitations: The uncontrolled nature of this observational study and low response rates to the survey limit conclusions. Further research in other medical education settings is needed. Practice Implications: Results are encouraging, suggesting modest benefit in terms of changing attitudes and practices and a modest protective effect on the wellbeing of students who engaged. Originality/value: This is the first study of a universal wellbeing and mindfulness programme in a UK medical school. Universal programmes are rare and evaluation studies are scarce

Genomic and Experimental Evidence for Multiple Metabolic Functions in the RidA/YjgF/YER057c/UK114 (Rid) Protein Family

BACKGROUND: It is now recognized that enzymatic or chemical side-reactions can convert normal metabolites to useless or toxic ones and that a suite of enzymes exists to mitigate such metabolite damage. Examples are the reactive imine/enamine intermediates produced by threonine dehydratase, which damage the pyridoxal 5\u27-phosphate cofactor of various enzymes causing inactivation. This damage is pre-empted by RidA proteins, which hydrolyze the imines before they do harm. RidA proteins belong to the YjgF/YER057c/UK114 family (here renamed the Rid family). Most other members of this diverse and ubiquitous family lack defined functions. RESULTS: Phylogenetic analysis divided the Rid family into a widely distributed, apparently archetypal RidA subfamily and seven other subfamilies (Rid1 to Rid7) that are largely confined to bacteria and often co-occur in the same organism with RidA and each other. The Rid1 to Rid3 subfamilies, but not the Rid4 to Rid7 subfamilies, have a conserved arginine residue that, in RidA proteins, is essential for imine-hydrolyzing activity. Analysis of the chromosomal context of bacterial RidA genes revealed clustering with genes for threonine dehydratase and other pyridoxal 5\u27-phosphate-dependent enzymes, which fits with the known RidA imine hydrolase activity. Clustering was also evident between Rid family genes and genes specifying FAD-dependent amine oxidases or enzymes of carbamoyl phosphate metabolism. Biochemical assays showed that Salmonella enterica RidA and Rid2, but not Rid7, can hydrolyze imines generated by amino acid oxidase. Genetic tests indicated that carbamoyl phosphate overproduction is toxic to S. enterica cells lacking RidA, and metabolomic profiling of Rid knockout strains showed ten-fold accumulation of the carbamoyl phosphate-related metabolite dihydroorotate. CONCLUSIONS: Like the archetypal RidA subfamily, the Rid2, and probably the Rid1 and Rid3 subfamilies, have imine-hydrolyzing activity and can pre-empt damage from imines formed by amine oxidases as well as by pyridoxal 5\u27-phosphate enzymes. The RidA subfamily has an additional damage pre-emption role in carbamoyl phosphate metabolism that has yet to be biochemically defined. Finally, the Rid4 to Rid7 subfamilies appear not to hydrolyze imines and thus remain mysterious

The Mahogany Peaks fault, a late Cretaceous-Paleocene(?) normal fault in the hinterland of the Sevier orogen

The contact separating Ordovician rocks from the underlying lower part of the Raft River Mountains sequence, northwestern Utah, is reinterpreted as a large-displacement low-angle normal fault, the Mahogany Peaks fault, that excised 4-5 km of structural section. High delta(13)C values identified in marble in the lower part of the Raft River Mountains sequence suggest a Proterozoic, rather than Cambrian age. Metamorphic conditions of hanging wall Ordovician and footwall Proterozoic strata are upper greenschist and middle amphibolite facies, respectively, and quantitative geothermometry indicates a temperature discontinuity of about 100 degrees C. A discordance in muscovite Ar-40/Ar-39 cooling ages between hanging wall and footwall strata in eastern exposures, and the lack of a corresponding cooling age discordance in western exposures, suggest a component of west dip for the fault. The juxtaposition of younger over older and colder over hotter rocks, the muscovite cooling age discordance with older over younger, and top-to-the-west shearing down-structure are consistent with an extensional origin. The age of faulting is bracketed between 90 and 47 Ma, and may be synchronous with footwall cooling at about 60-70 Ma. Recognition of the Mahogany Peaks fault, its extensional origin, and its probable latest Cretaceous to Paleocene age provides further evidence that episodes of extension at mid-crustal levels in the hinterland of the Sevier orogenic belt were synchronous with protracted shortening in the foreland fold and thrust belt, and that the Sevier orogen acted as a dynamic orogenic wedge

Insights Into the Mineralogy and Surface Chemistry of Extracellular Biogenic S0 Globules Produced by Chlorobaculum tepidum

Elemental sulfur (S0) is produced and degraded by phylogenetically diverse groups of microorganisms. For Chlorobaculum tepidum, an anoxygenic phototroph, sulfide is oxidized to produce extracellular S0 globules, which can be further oxidized to sulfate. While some sulfur-oxidizing bacteria (e.g., Allochromatium vinosum) are also capable of growth on commercial S0 as an electron donor, C. tepidum is not. Even colloidal sulfur sols, which appear indistinguishable from biogenic globules, do not support the growth of C. tepidum. Here, we investigate the properties that make biogenic S0 globules distinct from abiotic forms of S0. We found that S0 globules produced by C. tepidum and abiotic S0 sols are quite similar in terms of mineralogy and material properties, but the two are distinguished primarily by the properties of their surfaces. C. tepidum’s globules are enveloped by a layer of organics (protein and polysaccharides), which results in a surface that is fundamentally different from that of abiotic S0 sols. The organic coating on the globules appears to slow the aging and crystallization of amorphous sulfur, perhaps providing an extended window of time for microbes in the environment to access the more labile forms of sulfur as needed. Overall, our results suggest that the surface of biogenic S0 globules may be key to cell–sulfur interactions and the reactivity of biogenic S0 in the environment