A Minimal Threshold of c-di-GMP Is Essential for Fruiting Body Formation and Sporulation in Myxococcus xanthus

Generally, the second messenger bis-(3’-5’)-cyclic dimeric GMP (c-di-GMP) regulates the switch between motile and sessile lifestyles in bacteria. Here, we show that c-di-GMP is an essential regulator of multicellular development in the social bacterium Myxococcus xanthus. In response to starvation, M. xanthus initiates a developmental program that culminates in formation of spore-filled fruiting bodies. We show that c-di-GMP accumulates at elevated levels during development and that this increase is essential for completion of development whereas excess c-di-GMP does not interfere with development. MXAN3735 (renamed DmxB) is identified as a diguanylate cyclase that only functions during development and is responsible for this increased c-di-GMP accumulation. DmxB synthesis is induced in response to starvation, thereby restricting DmxB activity to development. DmxB is essential for development and functions downstream of the Dif chemosensory system to stimulate exopolysaccharide accumulation by inducing transcription of a subset of the genes encoding proteins involved in exopolysaccharide synthesis. The developmental defects in the dmxB mutant are non-cell autonomous and rescued by co-development with a strain proficient in exopolysaccharide synthesis, suggesting reduced exopolysaccharide accumulation as the causative defect in this mutant. The NtrC-like transcriptional regulator EpsI/Nla24, which is required for exopolysaccharide accumulation, is identified as a c-diGMP receptor, and thus a putative target for DmxB generated c-di-GMP. Because DmxB can be—at least partially—functionally replaced by a heterologous diguanylate cyclase, these results altogether suggest a model in which a minimum threshold level of c-di-GMP is essential for the successful completion of multicellular development in M. xanthus

Effects of radiotherapy and surgery in early breast cancer: an overview of the randomized trials

Background Randomized trials of radiotherapy and surgery for early breast cancer may have been too small to detect differences in long-term survival and recurrence reliably. We therefore performed a systematic overview (meta-analysis) of the results of such trials. Methods Information was sought on each subject from investigators who conducted trials that began before 1985 and that compared local therapies for early breast cancer. Data on mortality were available from 36 trials comparing radiotherapy plus surgery with the same type of surgery alone, 10 comparing more-extensive surgery with less-extensive surgery, and 18 comparing more-extensive surgery with less-extensive surgery plus radiotherapy. Information on mortality was available for 28,405 women (97.4 percent of the 29,175 women in the trials). Results The addition of radiotherapy to surgery resulted in a rate of local recurrence that was three times lower than the rate with surgery alone, but there was no significant difference in 10-year survival; among a total of 17,273 women enrolled in such trials, mortality was 40.3 percent with radiotherapy and 41.4 percent without radiotherapy (P = 0.3). Radiotherapy was associated with a reduced risk of death due to breast cancer (odds ratio, 0.94; 95 percent confidence interval, 0.88 to 1.00; P = 0.03), which indicates that, after 10 years, there would be about 0 to 5 fewer deaths due to breast cancer per 100 women. However, there was an increased risk of death from other causes (odds ratio, 1.24; 95 percent confidence interval, 1.09 to 1.42; P = 0.002). This, together with the age-specific death rates, implies, after 10 years, a few extra deaths not due to breast cancer per 100 older women or per 1000 younger women. During the first decade or two after diagnosis, the excess in the rate of such deaths that was associated with radiotherapy was much greater among women who were over 60 years of age at randomization (15.3 percent vs. 11.1 percent [339 vs. 249 deaths]) than among those under 50 (2.5 percent vs. 2.0 percent [62 vs. 49 deaths]). Breast-conserving surgery involved some risk of recurrence in the remaining tissue, but no significant differences in overall survival at 10 years were found in the studies of mastectomy versus breast-conserving surgery plus radiotherapy (4891 women), more-extensive surgery versus less-extensive surgery (4818 women), or axillary clearance versus radiotherapy as adjuncts to mastectomy (4370 women). Conclusions Some of the local therapies for breast cancer had substantially different effects on the rates of local recurrence — such as the reduced recurrence with the addition of radiotherapy to surgery — but there were no definite differences in overall survival at 10 years

The Continuing Relevance of 19th-Century Philosophy of Psychology: Brentano and the Autonomy of Psychological Methods

This paper provides an analysis of Franz Brentano’s thesis that psychology employs a distinctive method, which sets it apart from physiology. The aim of the paper is two-fold: First, I situate Brentano’s thesis (and the broader metaphysical system that underwrites it) within the context of specific debates about the nature and status of psychology, arguing that we regard him as engaging in a form of boundary work. Second, I explore the relevance of Brentano’s considerations to more recent debates about autonomy on the one hand and theoretical and/or methodological integration on the other. I argue that Brentano puts his finger on the idea that an integrated research process presupposes the existence of distinct methods and approaches, and that he highlights the philosophical challenge of accounting for such distinct methods. I suggest that Brentano’s ideas offer unconventional perspectives on current debates, in particular regarding first-person methods and the investigative process in cognitive science

Liraglutide enhances insulin secretion and prolongs the remission period in adults with newly diagnosed type 1 diabetes (the NewLira study):A randomized, double-blind, placebo-controlled trial

Aim: To test the effect of the glucagon-like peptide-1 receptor agonist, liraglutide, on residual beta-cell function in adults with newly diagnosed type 1 diabetes. Materials and Methods: In a multicentre, double-blind, parallel-group trial, adults with newly diagnosed type 1 diabetes and stimulated C-peptide of more than 0.2 nmol/L were randomized (1:1) to 1.8-mg liraglutide (Victoza) or placebo once daily for 52 weeks with 6 weeks of follow-up with only insulin treatment. The primary endpoint was the between-group difference in C-peptide area under the curve (AUC) following a liquid mixed-meal test after 52 weeks of treatment. Results: Sixty-eight individuals were randomized. After 52 weeks, the 4-hour AUC C-peptide response was maintained with liraglutide, but decreased with placebo (P =.002). Six weeks after end-of-treatment, C-peptide AUCs were similar for liraglutide and placebo. The average required total daily insulin dose decreased from 0.30 to 0.23 units/kg/day with liraglutide, but increased from 0.29 to 0.43 units/kg/day in the placebo group at week 52 (P &lt;.001). Time without the need for insulin treatment was observed in 13 versus two patients and lasted for 22 weeks (from 3 to 52 weeks) versus 6 weeks (from 4 to 8 weeks) on average for liraglutide and placebo, respectively. Patients treated with liraglutide had fewer episodes of hypoglycaemia compared with placebo-treated patients. The adverse events with liraglutide were predominantly gastrointestinal and transient. Conclusions: Treatment with liraglutide improves residual beta-cell function and reduces the dose of insulin during the first year after diagnosis. Beta-cell function was similar at 6 weeks postliraglutide treatment.</p