Background
The fecal microbiota, fecal bile acid concentrations, and abundance of Clostridium perfringens and Clostridium difficile are altered in acute and chronic gastrointestinal disease in adult ...dogs. However, less is known in young puppies.
Hypothesis/Objectives
To determine composition of the fecal microbiota, assess development of fecal bile acid profiles, and determine the abundance of Clostridial species in puppies, young adult dogs, and adult dogs.
Animals
Healthy puppies from a whelping kennel (n = 53) and healthy client‐owned dogs <1 year old (n = 20) were separated into 6 age groups, then compared to client‐owned dogs over 1 year of age (n = 13).
Methods
Prospective observational study. Naturally voided fecal samples were analyzed by quantitative polymerase chain reaction to measure bacterial abundances. Fecal bile acids were quantified using gas chromatography‐mass spectrometry.
Results
Puppies up to 5 to 6 weeks of age had increased Dysbiosis Index (median min‐max: 5.39 1.32‐8.6, P < .001), increased abundance of C. difficile (4.1 0.01‐4.85 log DNA, P < .001), decreased secondary bile acid concentrations (0.61 0.28‐5.06 μg/mg, P = .006), and decreased abundance of C. hiranonis (0.84 0.01‐6.71, P = .005) compared to adult dogs (−4.62 −8.36 to −0.61, 0.01 0.01‐0.01, 4.12 0.32‐8.94, and 6.02 5.06‐7.00, respectively). Secondary bile acid concentration positively correlated with C. hiranonis abundance (ρ = 0.77; P < .001).
Conclusions and Clinical Importance
The increase in secondary bile acids and simultaneous decrease of C. difficile and C. perfringens after 5 to 6 weeks of age warrants further investigation into regulatory impacts that secondary bile acids could have on clostridial species in dogs.
Eukaryotes possess mechanisms to limit crossing over during homologous recombination, thus avoiding possible chromosomal rearrangements. We show here that budding yeast Mph1, an ortholog of human ...FancM helicase, utilizes its helicase activity to suppress spontaneous unequal sister chromatid exchanges and DNA double-strand break-induced chromosome crossovers. Since the efficiency and kinetics of break repair are unaffected, Mph1 appears to channel repair intermediates into a noncrossover pathway. Importantly, Mph1 works independently of two other helicases-Srs2 and Sgs1-that also attenuate crossing over. By chromatin immunoprecipitation, we find targeting of Mph1 to double-strand breaks in cells. Purified Mph1 binds D-loop structures and is particularly adept at unwinding these structures. Importantly, Mph1, but not a helicase-defective variant, dissociates Rad51-made D-loops. Overall, the results from our analyses suggest a new role of Mph1 in promoting the noncrossover repair of DNA double-strand breaks.
The Sgs1 DNA helicase and its mammalian homolog BLM control crossover formation in mitotic cells. Zakharyevich et al. and De Muyt et al. now uncover a key role for Sgs1 in meiotic crossover ...regulation, which in turn reveals a joint molecule resolution pathway that produces the majority of crossovers in budding yeast.
RNA:DNA hybrids in the genome are constantly being generated as a by-product of transcription; in this issue, two papers, from
Helmrich et al. (2011) and
Wahba et al. (2011), provide insight into how ...RNA:DNA hybrids lead to genetic instability.
Ribonucleotides can become embedded in DNA from insertion by DNA polymerases, failure to remove Okazaki fragment primers, R-loops that can prime replication, and RNA/cDNA-mediated recombination. ...RNA:DNA hybrids are removed by RNase H enzymes. Single rNMPs in DNA are removed by RNase H2 and if they remain on the leading strand, can lead to mutagenesis in a Top1-dependent pathway. rNMPs in DNA can also stimulate genome instability, among which are homologous recombination gene conversion events. We previously found that, similar to the rNMP-stimulated mutagenesis, rNMP-stimulated recombination was also Top1-dependent. However, in contrast to mutagenesis, we report here that recombination is not stimulated by rNMPs incorporated by the replicative polymerase epsilon. Instead, recombination seems to be stimulated by multiple contiguous rNMPs, which may arise from R-loops or replication priming events.
The replicative DNA polymerases insert ribonucleotides into DNA at a frequency of approximately 1/6500 nucleotides replicated. The rNMP residues make the DNA backbone more susceptible to hydrolysis ...and can also distort the helix, impeding the transcription and replication machineries. rNMPs in DNA are efficiently removed by RNaseH2 by a process called ribonucleotides excision repair (RER). In the absence of functional RNaseH2, rNMPs are subject to cleavage by Topoisomerase I, followed by further processing to result in deletion mutations due to slippage in simple DNA repeats. The topoisomerase I-mediated cleavage at rNMPs results in DNA ends that cannot be ligated by DNA ligase I, a 5′OH end and a 2′-3′ cyclic phosphate end. In the budding yeast, the mutation level in RNaseH2 deficient cells is kept low via the action of the Srs2 helicase and the Exo1 nuclease, which collaborate to process the Top1-induced nick with subsequent non-mutagenic gap filling. We have surveyed other helicases and nucleases for a possible role in reducing mutagenesis at Top1 nicks at rNMPs and have uncovered a novel role for the RecQ family helicase Sgs1 in this process.
Objectives
We highlight the importance of documenting the step-by-step processes used for the selection of comparison areas when evaluating a community-level intervention that targets a large-scale ...community.
Methods
We demonstrate the proposed method using a propensity score matching framework for an impact analysis of the Cure Violence Public Health Model in Philadelphia. To select comparison communities, propensity score models are run using different levels of aggregation to define the intervention site. We discuss the trade-offs made.
Results
We find wide variation in documentation and explanation in the extant literature of the methods used to select comparison communities. The size of the unit of analysis at which a community is measured complicates the decision processes, and in turn, can affect the validity of the counterfactual.
Conclusions
It is important to carefully consider the unit of analysis for measurement of comparison communities. Assessing the geographic clustering of matched communities to mirror that of the treated community holds conceptual appeal and represents a strategy to consider when evaluating community-level interventions taking place at a large scale. Regardless of the final decisions made in the selection of the counterfactual, the field could benefit from more systematic diagnostic tools that document and guide the steps and decisions along the way, and ask: “could there have been another way of doing each step, and what difference would this have made?” Overall, across community-level evaluations that utilize quasi-experimental designs, documentation of the counterfactual selection process will provide a more fine-grained understanding of causal inference.
Objective: To review the past 10 years of published research on psychiatric aspects of child and adolescent obesity and highlight information mental health professionals need for preventing obesity ...in youths and diagnosing and treating it. Method: Researchers performed computerized and manual searches of the literature and summarized the most relevant articles. Results: The growing epidemic of child and adolescent obesity deserves attention for its immediate mental health and long-term medical complications. Mental health professionals working with obese youths should be aware of recent advances in neuroscience, genetics, and etiologies associated with obesity. Those who assess and treat obese youth should view obesity as a chronic disease. Currently, no approved pharmacological or surgical approaches exist to treat childhood obesity. Conclusions: Health care providers should focus on modest weight-loss goals that correlate with significant health benefits. The most effective treatments include substantial parental involvement. Mental health professionals should help obese children build self-esteem to help them lead full lives regardless of weight.
The number of jurisdictions implementing focused deterrence strategies targeted at gangs continues unabated. Although recent research suggests positive impacts of the strategy on reductions in gun ...violence, little is known about the particular mechanisms operating behind the strategy. This article provides a descriptive analysis of the law enforcement activities or levers undertaken after enforcement operations in Philadelphia as a part of the focused deterrence strategy. The article quantifies the execution of levers related to arrest, case processing, and probation sanctioning during enforcement activities after shootings. The results show that Philadelphia achieved success in implementing the enforcement levers as intended, and there was little evidence that arrest practices were overly aggressive. The authors suggest that future evaluations seek to carefully document the wide array of levers used in concert with an assessment of community understanding of and reactions to the strategy as well as an examination of reactions of group members targeted.
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