Control of intestinal stem cell function and proliferation by mitochondrial pyruvate metabolism.

Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells

Diffusion and dissemination of evidence-based dietary srategies for the prevention of cancer

OBJECTIVE: The purpose was to determine what strategies have been evaluated to disseminate cancer control interventions that promote the uptake of adult healthy diet? METHODS: A systematic review was conducted. Studies were identified by searching MEDLINE, PREMEDLINE, Cancer LIT, EMBASE/Excerpta Medica, PsycINFO, CINAHL, the Cochrane Database of Systematic Reviews, and reference lists and by contacting technical experts. English-language primary studies were selected if they evaluated the dissemination of healthy diet interventions in individuals, healthcare providers, or institutions. Studies of children or adolescents only were excluded. RESULTS: One hundred one articles were retrieved for full text screening. Nine reports of seven distinct studies were included; four were randomized trials, one was a cohort design and three were descriptive studies. Six studies were rated as methodologically weak, and one was rated as moderate. Studies were not meta-analyzed because of heterogeneity, low methodological quality, and incomplete data reporting. No beneficial dissemination strategies were found except one that looks promising, the use of peer educators in the worksite, which led to a short-term increase in fruit and vegetable intake. CONCLUSIONS AND IMPLICATIONS: Overall, the quality of the evidence is not strong and is primarily descriptive rather than evaluative. No clear conclusions can be drawn from these data. Controlled studies are needed to evaluate dissemination strategies, and to compare dissemination and diffusion strategies with different messages and different target audiences

The Impact of Different Antibiotic Regimens on the Emergence of Antimicrobial-Resistant Bacteria

Backgroud: The emergence and ongoing spread of antimicrobial-resistant bacteria is a major public health threat. Infections caused by antimicrobial-resistant bacteria are associated with substantially higher rates of morbidity and mortality compared to infections caused by antimicrobial-susceptible bacteria. The emergence and spread of these bacteria is complex and requires incorporating numerous interrelated factors which clinical studies cannot adequately address. Methods/Principal Findings: A model is created which incorporates several key factors contributing to the emergence and spread of resistant bacteria including the effects of the immune system, acquisition of resistance genes and antimicrobial exposure. The model identifies key strategies which would limit the emergence of antimicrobial-resistant bacterial strains. Specifically, the simulations show that early initiation of antimicrobial therapy and combination therapy with two antibiotics prevents the emergence of resistant bacteria, whereas shorter courses of therapy and sequential administration of antibiotics promote the emergence of resistant strains. Conclusions/Significance: The principal findings suggest that (i) shorter lengths of antibiotic therapy and early interruption of antibiotic therapy provide an advantage for the resistant strains, (ii) combination therapy with two antibiotics prevents the emergence of resistance strains in contrast to sequential antibiotic therapy, and (iii) early initiation of antibiotics is among the most important factors preventing the emergence of resistant strains. These findings provide new insights into strategies aimed at optimizing the administration of antimicrobials for the treatment of infections and the prevention of the emergence of antimicrobial resistance

Rapidity and Centrality Dependence of Proton and Anti-proton Production from Au+Au Collisions at sqrt(sNN) = 130GeV

We report on the rapidity and centrality dependence of proton and anti-proton transverse mass distributions from Au+Au collisions at sqrt(sNN) = 130GeV as measured by the STAR experiment at RHIC. Our results are from the rapidity and transverse momentum range of |y|<0.5 and 0.35 <p_t<1.00GeV/c. For both protons and anti-protons, transverse mass distributions become more convex from peripheral to central collisions demonstrating characteristics of collective expansion. The measured rapidity distributions and the mean transverse momenta versus rapidity are flat within |y|<0.5. Comparisons of our data with results from model calculations indicate that in order to obtain a consistent picture of the proton(anti-proton) yields and transverse mass distributions the possibility of pre-hadronic collective expansion may have to be taken into account.Comment: 4 pages, 3 figures, 1 table, submitted to PR

Azimuthal anisotropy and correlations at large transverse momenta in p+pp+p and Au+Au collisions at sNN\sqrt{s_{_{NN}}}= 200 GeV

Results on high transverse momentum charged particle emission with respect to the reaction plane are presented for Au+Au collisions at $\sqrt{s_{_{NN}}}$= 200 GeV. Two- and four-particle correlations results are presented as well as a comparison of azimuthal correlations in Au+Au collisions to those in $p+p$ at the same energy. Elliptic anisotropy, $v_2$, is found to reach its maximum at $p_t \sim 3$ GeV/c, then decrease slowly and remain significant up to $p_t\approx 7$ -- 10 GeV/c. Stronger suppression is found in the back-to-back high-$p_t$ particle correlations for particles emitted out-of-plane compared to those emitted in-plane. The centrality dependence of $v_2$ at intermediate $p_t$ is compared to simple models based on jet quenching.Comment: 4 figures. Published version as PRL 93, 252301 (2004

Azimuthal anisotropy in Au+Au collisions at sqrtsNN = 200 GeV

The results from the STAR Collaboration on directed flow (v_1), elliptic flow (v_2), and the fourth harmonic (v_4) in the anisotropic azimuthal distribution of particles from Au+Au collisions at sqrtsNN = 200 GeV are summarized and compared with results from other experiments and theoretical models. Results for identified particles are presented and fit with a Blast Wave model. Different anisotropic flow analysis methods are compared and nonflow effects are extracted from the data. For v_2, scaling with the number of constituent quarks and parton coalescence is discussed. For v_4, scaling with v_2^2 and quark coalescence is discussed.Comment: 26 pages. As accepted by Phys. Rev. C. Text rearranged, figures modified, but data the same. However, in Fig. 35 the hydro calculations are corrected in this version. The data tables are available at http://www.star.bnl.gov/central/publications/ by searching for "flow" and then this pape

Is there a special mechanism behind the changes in somatic cell and polymorphonuclear leukocyte counts, and composition of milk after a single prolonged milking interval in cows?

<p>Abstract</p> <p>Background</p> <p>A single prolonged milking interval (PMI) e.g. after a technical stop in an automated milking system is of concern for the producer since it is associated with a short-lasting increase in milk somatic cell count (SCC), which is a major quality criterion used at the dairy plants. The content of polymorphonuclear leukocytes (PMN) and how the milk quality is influenced has not been much investigated. The SCC peak occurs without any obvious antigen challenge, possibly indicating a different leukocyte attraction mechanism after a PMI than we see during mastitis.</p> <p>Methods</p> <p>Composite cow milk samples were taken at the milkings twice daily during 7 days before and 5 days after a PMI of 24 h. Milk was analyzed for SCC, PMN, fat, protein and lactose, and at some occasions also casein and free fatty acids (FFA).</p> <p>Results</p> <p>During the PMI the proportion of milk PMN increased sharply in spite of marginally increased SCC. The peak SCC was not observed until the second milking after the PMI, in the afternoon day 1. However, the peak SCC value in <it>morning </it>milk did not occur until one day later, concomitantly with a <it>decrease </it>in the proportion of PMN. After declining, SCC still remained elevated while PMN proportion was decreased throughout the study as was also the milk yield, after the first accumulation of milk during the PMI. Milk composition was changed the day after the PMI, (increased fat and protein content; decreased lactose, whey protein and FFA content) but the changes in the following days were not consistent except for lactose that remained decreased the rest of the study.</p> <p>Conclusion</p> <p>The PMI resulted in increased SCC and proportion of PMN. Additionally, it gave rise to minor alterations in the milk composition in the following milkings but no adverse effect on milk quality was observed. The recruitment of PMN, which was further enhanced the first day <it>after </it>the PMI, appeared to be independent of milk volume or accumulation of milk per se. Hence, we suggest that there is a special immunophysiological/chemoattractant background to the increased migration of leukocytes into the milk compartment observed during and after the PMI.</p

Comparative Analysis of the 5S rRNA and Its Associated Proteins Reveals Unique Primitive Rather Than Parasitic Features in Giardia lamblia

BACKGROUND: 5S rRNA is a highly conserved ribosomal component. Eukaryotic 5S rRNA and its associated proteins (5S rRNA system) have become very well understood. Giardia lamblia was thought by some researchers to be the most primitive extant eukaryote while others considered it a highly evolved parasite. Previous reports have indicated that some aspects of its 5S rRNA system are simpler than that of common eukaryotes. We here explore whether this is true to its entire system, and whether this simplicity is a primitive or parasitic feature. METHODOLOGY/PRINCIPAL FINDINGS: By collecting and confirming pre-existing data and identifying new data, we obtained almost complete datasets of the system of three isolates of G. lamblia, two other parasitic excavates (Trichomonas vaginalis, Trypanosoma cruzi), and one free-living one (Naegleria gruberi). After comprehensively comparing each aspect of the system among these excavates and also with those of archaea and common eukaryotes, we found all the three Giardia isolates to harbor a same simplified 5S rRNA system, which is not only much simpler than that of common eukaryotes but also the simplest one among those of these excavates, and is surprisingly very similar to that of archaea; we also found among these excavates the system in parasitic species is not necessarily simpler than that in free-living species, conversely, the system of free-living species is even simpler in some respects than those of parasitic ones. CONCLUSION/SIGNIFICANCE: The simplicity of Giardia 5S rRNA system should be considered a primitive rather than parasitically-degenerated feature. Therefore, Giardia 5S rRNA system might be a primitive system that is intermediate between that of archaea and the common eukaryotic model system, and it may reflect the evolutionary history of the eukaryotic 5S rRNA system from the archaeal form. Our results also imply G. lamblia might be a primitive eukaryote with secondary parasitically-degenerated features

Validation Study of Existing Gene Expression Signatures for Anti-TNF Treatment in Patients with Rheumatoid Arthritis

So far, there are no means of identifying rheumatoid arthritis (RA) patients who will fail to respond to tumour necrosis factor blocking agents (anti-TNF), prior to treatment. We set out to validate eight previously reported gene expression signatures predicting therapy outcome. Genome-wide expression profiling using Affymetrix GeneChip Exon 1.0 ST arrays was performed on RNA isolated from whole blood of 42 RA patients starting treatment with infliximab or adalimumab. Clinical response according to EULAR criteria was determined at week 14 of therapy. Genes that have been reported to be associated with anti-TNF treatment were extracted from our dataset. K-means partition clustering was performed to assess the predictive value of the gene-sets. We performed a hypothesis-driven analysis of the dataset using eight existing gene sets predictive of anti-TNF treatment outcome. The set that performed best reached a sensitivity of 71% and a specificity of 61%, for classifying the patients in the current study. We successfully validated one of eight previously reported predictive expression profile. This replicated expression signature is a good starting point for developing a prediction model for anti-TNF treatment outcome that can be used in a daily clinical setting. Our results confirm that gene expression profiling prior to treatment is a useful tool to predict anti-TNF (non) response