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The structure of the human gut microbiota is controlled primarily through the degradation of complex dietary carbohydrates, but the extent to which carbohydrate breakdown products are shared between members of the microbiota is unclear. We show here, using xylan as a model, that sharing the breakdown products of complex carbohydrates by key members of the microbiota, such as Bacteroides ovatus, is dependent on the complexity of the target glycan. Characterization of the extensive xylan degrading apparatus expressed by B. ovatus reveals that the breakdown of the polysaccharide by the human gut microbiota is significantly more complex than previous models suggested, which were based on the deconstruction of xylans containing limited monosaccharide side chains. Our report presents a highly complex and dynamic xylan degrading apparatus that is fine-tuned to recognize the different forms of the polysaccharide presented to the human gut microbiota.

Thymidine starvation causes rapid cell death. This enigmatic process known as thymineless death (TLD) is the underlying killing mechanism of diverse antimicrobial and antineoplastic drugs. Despite decades of investigation, we still lack a mechanistic understanding of the causal sequence of events that culminate in TLD. Here, we used a diverse set of unbiased approaches to systematically determine the genetic and regulatory underpinnings of TLD in Escherichia coli . In addition to discovering novel genes in previously implicated pathways, our studies revealed a critical and previously unknown role for intracellular acidification in TLD. We observed that a decrease in cytoplasmic pH is a robust early event in TLD across different genetic backgrounds. Furthermore, we show that acidification is a causal event in the death process, as chemical and genetic perturbations that increase intracellular pH substantially reduce killing. We also observe a decrease in intracellular pH in response to exposure to the antibiotic gentamicin, suggesting that intracellular acidification may be a common mechanistic step in the bactericidal effects of other antibiotics.

Objectives/Goals: To create, train, and evaluate the FAST-PACE (Promoting Academic and Community Engagement) Toolkit that catalyzes academic-community translation science teams during a public health emergency. The toolkit is a road map based on the Research Readiness and Partnership Protocol (R2P2), which was developed from the Flint Water Crisis. Methods/Study Population: A literature review was conducted by the Michigan Institute for Clinical & Health Research Community Engagement (MICHR CE) program and the Community-Based Organization Partners (CBOP), to identify important and common elements in disaster response protocols with a set of key interviews (n = 31) to glean perspectives from community leaders. Key findings were extracted and reviewed to generate guidelines and recommendations for the R2P2 protocol. The co-developed FAST-PACE Toolkit launched its expansion statewide to address emergencies and health disparities of communities in crisis. The iterative process consisted of community report-outs, gathering input from stakeholders, via discussion, and evaluation surveys. The feedback was used to develop, enhance, and tailor the toolkit and training content. Results/Anticipated Results: Data from training (n = 8) of the critical elements of the FAST-PACE Toolkit, which provides guidance for academic and community team members that includes 1) assessing community assets and needs; 2) engaging in clear and bidirectional communication; 3) facilitating transparency and equitable partnering; 4) identifying health equity and justice issues; and 5) conducting the evaluation of research. The training will be disseminated in-person and virtually across the state of Michigan resulting in participants sharing community-identified health issues and social determinants of health to assist MICHR CE to suggest resources to address health impacts. Discussion/Significance of Impact: The FAST-PACE Toolkit borne from the flint water crisis and confounded by other crises used CEnR principles to create a translation science roadmap. It equips communities and collaborating academic institutions across the state to respond to public health crises and fosters equitable translation science partnerships built on respect and trust.

Objectives/Goals: Bacterial dysbiosis has emerged as an accomplice in the progression of many cancers. The pancreas microbiome changes in pancreatic cancer patients. The mechanisms via which components of the microbiome regulate tumor growth is unclear. We seek to determine if bacterial dysbiosis influences cancer cell behavior thereby promoting tumor progression. Methods/Study Population: We performed immunohistochemistry for lipopolysaccharide and observed bacteria preferentially located in close proximity to cancer cells. We utilized an in vitro cell culture system and in vivo mouse models, in the presence and absence of gut bacteria, to assess the effect of bacteria and bacterial metabolites on pro-tumorigenic signaling and transcriptional changes in the cancer cell. We analyzed cancer cells and epithelial cells using RNA sequencing, flow cytometry, and enzyme-linked immunosorbent assay. We also used targeted metabolomics to identify bacterial and cancer cell produced metabolites. Results/Anticipated Results: We found microbial dysbiosis can induce proliferation, an inflammatory response and an increase in tryptophan metabolism via the kynurenine pathway in the pancreatic cancer cell. Along with upregulated expression of IDO1 in vivo, we observe an increase in nicotinic adenine mononucleotide. Also, we observe an increase in nicotinic acid in vitro and nicotinic adenine dinucleotide within the cancer cell compartment in the presence of bacteria and bacteria conditioned media. Due to the critical role in many vital pathways of cell survival, NAD+ production is thought to play a significant role in cancer progression. Nicotinic acid can stimulate NAD production to protect cells from cell death. Discussion/Significance of Impact: Pancreatic cancer is associated with a distinct tumor microbiome and ablation slows disease progression. Our data delineate mechanisms via which microbes modulate the pancreatic cancer cell and provide insight into therapeutic strategies for gut microbial modulation in treating pancreatic cancer.

Exotic earthworm impacts on temperate forest soils are influenced by earthworm community composition and are likely constrained by the degree of organic matter redistribution following earthworm introductions across different soil types; however, the relative importance of these factors remains unknown. We examined how exotic earthworm communities affected leaf litter carbon (C) and nitrogen (N) mineralization and transport in two Spodosols with contrasting textures and organic matter contents. In reconstructed soil mesocosms, we measured organic C pools, quantified C-13 and N-15 transport from isotopically labeled red maple (Acer rubrum) leaf litter, and linked leaf litter redistribution to sub-surface burrow system structures following 150-day incubations. Transport of C and N from surface litter into soil was greatest with multi-species earthworm communities, and A-horizon and burrow pools functioned as dominant sinks for this material. Litter-derived C:N recovery ratios of soil pools revealed higher retention of litter-derived N over litter-derived C; recovery of litter N (mg N-15 m(-2)) transported from surface litter was greater in the sandy loam (98.2 +/- A 2.73 %) than in the sandy soil (66.2 +/- A 4.92 %) following earthworm community additions. Earthworm biomass was as a minor sink for litter C (mg C-13 m(-2)) and N transported from surface litter (0.56 +/- A 0.13 and 2.26 +/- A 0.31 %, respectively). Recovery of litter-derived C and N in earthworm biomass increased with the degree of direct leaf litter consumption (A. trapezoides < E. fetida < L. terrestris). Surface-dwelling epigeic and mineral-soil dwelling endogeic species produced burrow systems with the highest volume, surface connectivity, and density in the A-horizon; these properties were associated with greater CO2 losses and with greater litter C and N transport into A-horizons and burrows. Burrow systems with high continuity and large burrows produced by vertical-burrowing anecic species were associated with greater litter C and N transport into B-horizons, and greater dissolved organic C leaching losses. This study shows that the degree of organic matter redistribution in temperate forest soils following earthworm introductions is directly related to earthworm community composition, while the preferential retention of N over C and the potential stabilization of this material is determined by soil type.

Background The American Urological Association White Paper on Implementation of Shared Decision Making (SDM) into Urological Practice suggested SDM represents the state of the art in counseling for patients who are faced with difficult or uncertain medical decisions. The Michigan Urological Surgery Improvement Collaborative (MUSIC) implemented a decision aid, Personal Patient Profile-Prostate (P3P), in 2018 to help newly diagnosed prostate cancer patients make shared decisions with their clinicians. We conducted a qualitative study to assess statewide implementation of P3P throughout MUSIC. Methods We recruited urologists and staff from 17 MUSIC practices (8 implementation and 9 comparator practices) to understand how practices engaged patients on treatment discussions and to assess facilitators and barriers to implementing P3P. Interview guides were developed based on the Tailored Interventions for Chronic Disease (TICD) Framework. Interviews were transcribed for analysis and coded independently by two investigators in NVivo, PRO 12. Additionally, quantitative program data were integrated into thematic analyses. Results We interviewed 15 urologists and 11 staff from 16 practices. Thematic analysis of interview transcripts indicated three key themes including the following: (i) P3P is compatible as a SDM tool as over 80% of implementation urologists asked patients to complete the P3P questionnaire routinely and used P3P reports during treatment discussions; (ii) patient receptivity was demonstrated by 370 (50%) of newly diagnosed patients ( n = 737) from 8 practices enrolled in P3P with 78% completion rate, which accounts for 39% of all newly diagnosed patients in these practices; and (iii) urologists’ attitudes towards SDM varied. Over a third of urologists stated they did not rely on a decision aid. Comparator practices indicated habit, inertia, or concerns about clinic flow as reasons for not adopting P3P and some were unconvinced a decision aid is needed in their practice. Conclusion Urologists and staff affiliated with MUSIC implementation sites indicated that P3P focuses the treatment discussion on items that are important to patients. Experiences of implementation practices indicate that once initiated, there were no negative effects on clinic flow and urologists indicated P3P saves time during patient counseling, as patients were better prepared for focused discussions. Lack of awareness, personal habits, and inertia are reasons for not implementing P3P among the comparator practices.

Neuron- and glia-like cells derived from induced pluripotent stem cells promise tractable, individualized human models of Alzheimer's, Parkinson's and amyotrophic lateral sclerosis. Ken Garber explores the considerable challenges of recreating such diseases in the laboratory.

PurposeDiverse radionuclide imaging techniques are available for the diagnosis, staging, and follow-up of phaeochromocytoma and paraganglioma (PPGL). Beyond their ability to detect and localise the disease, these imaging approaches variably characterise these tumours at the cellular and molecular levels and can guide therapy. Here we present updated guidelines jointly approved by the EANM and SNMMI for assisting nuclear medicine practitioners in not only the selection and performance of currently available single-photon emission computed tomography and positron emission tomography procedures, but also the interpretation and reporting of the results.MethodsGuidelines from related fields and relevant literature have been considered in consultation with leading experts involved in the management of PPGL. The provided information should be applied according to local laws and regulations as well as the availability of various radiopharmaceuticals.ConclusionSince the European Association of Nuclear Medicine 2012 guidelines, the excellent results obtained with gallium-68 (68Ga)-labelled somatostatin analogues (SSAs) in recent years have simplified the imaging approach for PPGL patients that can also be used for selecting patients for peptide receptor radionuclide therapy as a potential alternative or complement to the traditional theranostic approach with iodine-123 (123I)/iodine-131 (131I)-labelled meta-iodobenzylguanidine. Genomic characterisation of subgroups with differing risk of lesion development and subsequent metastatic spread is refining the use of molecular imaging in the personalised approach to hereditary PPGL patients for detection, staging, and follow-up surveillance.

Soil life supports the functioning and biodiversity of terrestrial ecosystems. Springtails (Collembola) are among the most abundant soil arthropods regulating soil fertility and flow of energy through above- and belowground food webs. However, the global distribution of springtail diversity and density, and how these relate to energy fluxes remains unknown. Here, using a global dataset representing 2470 sites, we estimate the total soil springtail biomass at 27.5 megatons carbon, which is threefold higher than wild terrestrial vertebrates, and record peak densities up to 2 million individuals per square meter in the tundra. Despite a 20-fold biomass difference between the tundra and the tropics, springtail energy use (community metabolism) remains similar across the latitudinal gradient, owing to the changes in temperature with latitude. Neither springtail density nor community metabolism is predicted by local species richness, which is high in the tropics, but comparably high in some temperate forests and even tundra. Changes in springtail activity may emerge from latitudinal gradients in temperature, predation and resource limitation in soil communities. Contrasting relationships of biomass, diversity and activity of springtail communities with temperature suggest that climate warming will alter fundamental soil biodiversity metrics in different directions, potentially restructuring terrestrial food webs and affecting soil functioning.