T-cell derived acetylcholine aids host defenses during enteric bacterial infection with Citrobacter rodentium.

The regulation of mucosal immune function is critical to host protection from enteric pathogens but is incompletely understood. The nervous system and the neurotransmitter acetylcholine play an integral part in host defense against enteric bacterial pathogens. Here we report that acetylcholine producing-T-cells, as a non-neuronal source of ACh, were recruited to the colon during infection with the mouse pathogen Citrobacter rodentium. These ChAT+ T-cells did not exclusively belong to one Th subset and were able to produce IFNγ, IL-17A and IL-22. To interrogate the possible protective effect of acetylcholine released from these cells during enteric infection, T-cells were rendered deficient in their ability to produce acetylcholine through a conditional gene knockout approach. Significantly increased C. rodentium burden was observed in the colon from conditional KO (cKO) compared to WT mice at 10 days post-infection. This increased bacterial burden in cKO mice was associated with increased expression of the cytokines IL-1β, IL-6, and TNFα, but without significant changes in T-cell and ILC associated IL-17A, IL-22, and IFNγ, or epithelial expression of antimicrobial peptides, compared to WT mice. Despite the increased expression of pro-inflammatory cytokines during C. rodentium infection, inducible nitric oxide synthase (Nos2) expression was significantly reduced in intestinal epithelial cells of ChAT T-cell cKO mice 10 days post-infection. Additionally, a cholinergic agonist enhanced IFNγ-induced Nos2 expression in intestinal epithelial cell in vitro. These findings demonstrated that acetylcholine, produced by specialized T-cells that are recruited during C. rodentium infection, are a key mediator in host-microbe interactions and mucosal defenses

Fortification and health: challenges and opportunities.

Fortification is the process of adding nutrients or non-nutrient bioactive components to edible products (e.g., food, food constituents, or supplements). Fortification can be used to correct or prevent widespread nutrient intake shortfalls and associated deficiencies, to balance the total nutrient profile of a diet, to restore nutrients lost in processing, or to appeal to consumers looking to supplement their diet. Food fortification could be considered as a public health strategy to enhance nutrient intakes of a population. Over the past century, fortification has been effective at reducing the risk of nutrient deficiency diseases such as beriberi, goiter, pellagra, and rickets. However, the world today is very different from when fortification emerged in the 1920s. Although early fortification programs were designed to eliminate deficiency diseases, current fortification programs are based on low dietary intakes rather than a diagnosable condition. Moving forward, we must be diligent in our approach to achieving effective and responsible fortification practices and policies, including responsible marketing of fortified products. Fortification must be applied prudently, its effects monitored diligently, and the public informed effectively about its benefits through consumer education efforts. Clear lines of authority for establishing fortification guidelines should be developed and should take into account changing population demographics, changes in the food supply, and advances in technology. This article is a summary of a symposium presented at the ASN Scientific Sessions and Annual Meeting at Experimental Biology 2014 on current issues involving fortification focusing primarily on the United States and Canada and recommendations for the development of responsible fortification practices to ensure their safety and effectiveness

Dynamic Low-Stretch Trees via Dynamic Low-Diameter Decompositions

Spanning trees of low average stretch on the non-tree edges, as introduced by Alon et al. [SICOMP 1995], are a natural graph-theoretic object. In recent years, they have found significant applications in solvers for symmetric diagonally dominant (SDD) linear systems. In this work, we provide the first dynamic algorithm for maintaining such trees under edge insertions and deletions to the input graph. Our algorithm has update time $n^{1/2 + o(1)}$ and the average stretch of the maintained tree is $n^{o(1)}$, which matches the stretch in the seminal result of Alon et al. Similar to Alon et al., our dynamic low-stretch tree algorithm employs a dynamic hierarchy of low-diameter decompositions (LDDs). As a major building block we use a dynamic LDD that we obtain by adapting the random-shift clustering of Miller et al. [SPAA 2013] to the dynamic setting. The major technical challenge in our approach is to control the propagation of updates within our hierarchy of LDDs: each update to one level of the hierarchy could potentially induce several insertions and deletions to the next level of the hierarchy. We achieve this goal by a sophisticated amortization approach. We believe that the dynamic random-shift clustering might be useful for independent applications. One of these applications is the dynamic spanner problem. By combining the random-shift clustering with the recent spanner construction of Elkin and Neiman [SODA 2017]. We obtain a fully dynamic algorithm for maintaining a spanner of stretch $2k - 1$ and size $O (n^{1 + 1/k} \log{n})$ with amortized update time $O (k \log^2 n)$ for any integer $2 \leq k \leq \log n$. Compared to the state-of-the art in this regime [Baswana et al. TALG '12], we improve upon the size of the spanner and the update time by a factor of $k$.Comment: To be presented at the 51st Annual ACM Symposium on the Theory of Computing (STOC 2019); abstract shortened to respect the arXiv limit of 1920 character

Phosphorylation in the serine/threonine 2609–2647 cluster promotes but is not essential for DNA-dependent protein kinase-mediated nonhomologous end joining in human whole-cell extracts

Previous work suggested that phosphorylation of DNA-PKcs at several serine/threonine (S/T) residues at positions 2609–2647 promotes DNA-PK-dependent end joining. In an attempt to clarify the role of such phosphorylation, end joining was examined in extracts of DNA-PKcs-deficient M059J cells. Joining of ends requiring gap filling prior to ligation was completely dependent on complementation of these extracts with exogenous DNA-PKcs. DNA-PKcs with either S/T → A or S/T → D substitutions at all six sites in the 2609–2647 cluster also supported end joining, but with markedly lower efficiency than wild-type protein. The residual end joining was greater with the S/T → D-substituted than with the S/T → A-substituted protein. A specific inhibitor of the kinase activity of DNA-PK, KU57788, completely blocked end joining promoted by wild type as well as both mutant forms of DNA-PK, while inhibition of ATM kinase did not. The fidelity of end joining was not affected by the mutant DNA-PKcs alleles or the inhibitors. Overall, the results support a role for autophosphorylation of the 2609–2647 cluster in promoting end joining and controlling the accessibility of DNA ends, but suggest that DNA-PK-mediated phosphorylation at other sites, on either DNA-PKcs or other proteins, is at least as important as the 2609–2647 cluster in regulating end joining

The Grizzly, September 8, 2016

Marcon Under Fire for Controversial Tweets • First-Year Class Smaller Than Usual • Ursinus Offers Gateway to Success • Ursinus\u27 Students Mourn the Loss of Beloved Wawa • History Department Welcomes New Professor • Student Researchers Spend Summer with NASA • Opinions: Ostrum to Marcon: Let\u27s Work Toward Inclusion; Students Happily Embrace Changes to Wismer • Spike! Ursinus Volleyball is Back in Action! • The Bears and the Bisonhttps://digitalcommons.ursinus.edu/grizzlynews/1647/thumbnail.jp

Determining the nature of the faint X-ray source population near the Galactic Centre

We present results of a multi-wavelength program to study the faint discrete X-ray source population discovered by Chandra in the Galactic Centre (GC). From IR imaging obtained with the VLT we identify candidate K-band counterparts to 75% of the X-ray sources in our sample. By combining follow-up VLT K-band spectroscopy of a subset of these candidate counterparts with the magnitude limits of our photometric survey, we suggest that only a small percentage of the sources are HMXBs, while the majority are likely to be canonical LMXBs and CVs at the distance of the GC. In addition, we present our discovery of highly structured small-scale (5-15") extinction towards the Galactic Centre. This is the finest-scale extinction study of the Galactic Centre to date. Finally, from these VLT observations we are able to place constraints on the stellar counterpart to the ``bursting pulsar'' GRO J1744-28.Comment: 9 pages, in Proceedings of "VI Microquasar Workshop: Microquasars and Beyond, 18-22 September 2006, Como, Italy; paper in PDF format with full-resolution figures available at http://www.astro.ufl.edu/~reba/mqw_rmb.pd

Acceptance and commitment therapy delivered via a mobile phone messaging robot to decrease postoperative opioid use in patients with orthopedic trauma: Randomized controlled trial

BACKGROUND: Acceptance and commitment therapy (ACT) is a pragmatic approach to help individuals decrease avoidable pain. OBJECTIVE: This study aims to evaluate the effects of ACT delivered via an automated mobile messaging robot on postoperative opioid use and patient-reported outcomes (PROs) in patients with orthopedic trauma who underwent operative intervention for their injuries. METHODS: Adult patients presenting to a level 1 trauma center who underwent operative fixation of a traumatic upper or lower extremity fracture and who used mobile phone text messaging were eligible for the study. Patients were randomized in a 1:1 ratio to either the intervention group, who received twice-daily mobile phone messages communicating an ACT-based intervention for the first 2 weeks after surgery, or the control group, who received no messages. Baseline PROs were completed. Two weeks after the operative intervention, follow-up was performed in the form of an opioid medication pill count and postoperative administration of PROs. The mean number of opioid tablets used by patients was calculated and compared between groups. The mean PRO scores were also compared between the groups. RESULTS: A total of 82 subjects were enrolled in the study. Of the 82 participants, 76 (38 ACT and 38 controls) completed the study. No differences between groups in demographic factors were identified. The intervention group used an average of 26.1 (SD 21.4) opioid tablets, whereas the control group used 41.1 (SD 22.0) tablets, resulting in 36.5% ([41.1-26.1]/41.1) less tablets used by subjects receiving the mobile phone-based ACT intervention (P=.004). The intervention group subjects reported a lower postoperative Patient-Reported Outcome Measure Information System Pain Intensity score (mean 45.9, SD 7.2) than control group subjects (mean 49.7, SD 8.8; P=.04). CONCLUSIONS: In this study, the delivery of an ACT-based intervention via an automated mobile messaging robot in the acute postoperative period decreased opioid use in selected patients with orthopedic trauma. Participants receiving the ACT-based intervention also reported lower pain intensity after 2 weeks, although this may not represent a clinically important difference. TRIAL REGISTRATION: ClinicalTrials.gov NCT03991546; https://clinicaltrials.gov/ct2/show/NCT03991546

Patterns of primary care and mortality among patients with schizophrenia or diabetes: a cluster analysis approach to the retrospective study of healthcare utilization

Abstract Background Patients with schizophrenia have difficulty managing their medical healthcare needs, possibly resulting in delayed treatment and poor outcomes. We analyzed whether patients reduced primary care use over time, differentially by diagnosis with schizophrenia, diabetes, or both schizophrenia and diabetes. We also assessed whether such patterns of primary care use were a significant predictor of mortality over a 4-year period. Methods The Veterans Healthcare Administration (VA) is the largest integrated healthcare system in the United States. Administrative extracts of the VA's all-electronic medical records were studied. Patients over age 50 and diagnosed with schizophrenia in 2002 were age-matched 1:4 to diabetes patients. All patients were followed through 2005. Cluster analysis explored trajectories of primary care use. Proportional hazards regression modelled the impact of these primary care utilization trajectories on survival, controlling for demographic and clinical covariates. Results Patients comprised three diagnostic groups: diabetes only (n = 188,332), schizophrenia only (n = 40,109), and schizophrenia with diabetes (Scz-DM, n = 13,025). Cluster analysis revealed four distinct trajectories of primary care use: consistent over time, increasing over time, high and decreasing, low and decreasing. Patients with schizophrenia only were likely to have low-decreasing use (73% schizophrenia-only vs 54% Scz-DM vs 52% diabetes). Increasing use was least common among schizophrenia patients (4% vs 8% Scz-DM vs 7% diabetes) and was associated with improved survival. Low-decreasing primary care, compared to consistent use, was associated with shorter survival controlling for demographics and case-mix. The observational study was limited by reliance on administrative data. Conclusion Regular primary care and high levels of primary care were associated with better survival for patients with chronic illness, whether psychiatric or medical. For schizophrenia patients, with or without comorbid diabetes, primary care offers a survival benefit, suggesting that innovations in treatment retention targeting at-risk groups can offer significant promise of improving outcomes.http://deepblue.lib.umich.edu/bitstream/2027.42/78274/1/1472-6963-9-127.xmlhttp://deepblue.lib.umich.edu/bitstream/2027.42/78274/2/1472-6963-9-127.pdfPeer Reviewe