When replication forks stall at damaged bases or upon nucleotide depletion, the intra-S phase checkpoint ensures they are stabilized and can restart. In intra-S checkpoint-deficient budding yeast, stalling forks collapse, and ∼10% form pathogenic chicken foot structures, contributing to incomplete replication and cell death (Lopes et al., 2001; Sogo et al., 2002; Tercero and Diffley, 2001). Using fission yeast, we report that the Cds1(Chk2) effector kinase targets Dna2 on S220 to regulate, both in vivo and in vitro, Dna2 association with stalled replication forks in chromatin. We demonstrate that Dna2-S220 phosphorylation and the nuclease activity of Dna2 are required to prevent fork reversal. Consistent with this, Dna2 can efficiently cleave obligate precursors of fork regression-regressed leading or lagging strands-on model replication forks. We propose that Dna2 cleavage of regressed nascent strands prevents fork reversal and thus stabilizes stalled forks to maintain genome stability during replication stress.

Research Methods and Procedures:This pooled post hoc analysis of two long-term trials included all patients who were overweight/obese at baseline (BMI Ͼ 25 kg/m 2 ), and who were treated with either 120 g pramlintide BID (n ϭ 254; HbA 1c 9.2%; weight, 96.1 kg) or placebo (n ϭ 244; HbA 1c 9.4%; weight, 95.0 kg). Statistical endpoints included changes from baseline to week 26 in HbA 1c , body weight, and insulin use. Results: Pramlintide treatment resulted in significant reductions from baseline to week 26, compared with placebo, in HbA 1c and body weight (both, p Ͻ 0.0001), for placebocorrected reductions of Ϫ0.41% and Ϫ1.8 kg, respectively. Approximately three times the number of patients using pramlintide experienced a Ն5% reduction of body weight than with placebo (9% vs. 3%, p ϭ 0.0005). Patients using pramlintide also experienced a proportionate decrease in total daily insulin use (r ϭ 0.39, p Ͻ 0.0001). The greatest placebo-corrected reductions in weight at week 26 were observed in pramlintide-treated patients with a BMI Ͼ40 kg/m 2 and in those concomitantly treated with metformin (both, p Ͻ 0.001), for placebo-corrected reductions of Ϫ3.2 kg and Ϫ2.5 kg, respectively. Discussion: These findings support further evaluation of the weight-lowering potential of pramlintide in obese patients with type 2 diabetes.

SLC2A2 mutations are an autosomal recessive cause of neonatal diabetes that should be considered in consanguineous families or those with TNDM, after excluding common causes, even in the absence of features of FBS. The finding that patients with homozygous SLC2A2 mutations can have neonatal diabetes supports a role for GLUT2 in the human beta cell.

Background: Hyperbilirubinemia is the most common cause of neonatal hospitalization and, although it generally has a good prognosis, a significant percentage of neonatal patients maintain a high bilirubin level, which can lead to severe complications, including lifelong disability such as growth retardation, encephalopathy, autism and hearing impairment. The study of risk factors for neonatal hyperbilirubinemia has been controversial. Therefore, we evaluated the risk factors of neonatal hyperbilirubinemia using a metaanalysis.Methods: Relevant English and Chinese studies that discussed risk factors for neonatal hyperbilirubinemia were retrieved from the PubMed, EMBASE, Medline, Central, China National Knowledge Infrastructure (CNKI), Wanfang and China Science Digital Library (CSDL). The literature took newborns as the research object, set up a control group, and observed the relationship between exposure factors and neonatal hyperbilirubinemia. The combined effect size was expressed by odds ratio (OR) and 95% confidence interval (CI). The Chi-square test was used to test heterogeneity of the studies, and if it existed, subgroup analyses were used to explore the source of heterogeneity, and the random-effects model was selected for the combined analysis. The fixed-effects model was chosen for the combined analysis if there was no heterogeneity. Publication bias was assessed using Egger's test and funnel plot.