Peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) restores carbapenem susceptibility to NDM-1-positive pathogens in vitro and in vivo

The objective of this study was to test the efficacy of an inhibitor of the New Delhi metallo-β- lactamase (NDM-1). Inhibiting expression of this type of antibiotic-resistance gene has the potential to restore antibiotic susceptibility in all bacteria carrying the gene.Methods: We have constructed a peptide-conjugated phosphorodiamidate morpholino oligomer (PPMO) that selectively inhibits the expression of NDM-1 and examined its ability to restore susceptibility to meropenem in vitro and in vivo.Results:In vitro, the PPMO reduced the MIC of meropenem for three different genera of pathogens that express NDM-1. In a murine model of lethal E. coli sepsis, the PPMO improved survival (92%) and reduced systemic bacterial burden when given concomitantly with meropenem.Conclusions: These data show that a PPMO can restore antibiotic susceptibility in vitro and in vivo and that the combination of PPMO and meropenem may have therapeutic potential against certain class B carbapenem- resistant infections in multiple genera of Gram-negative pathogens

Leucine-rich alpha-2-glycoprotein-1 is upregulated in sera and tumors of ovarian cancer patients

<p>Abstract</p> <p>Background</p> <p>New biomarkers that replace or are used in conjunction with the current ovarian cancer diagnostic antigen, CA125, are needed for detection of ovarian cancer in the presurgical setting, as well as for detection of disease recurrence. We previously demonstrated the upregulation of leucine-rich alpha-2-glycoprotein-1 (LRG1) in the sera of ovarian cancer patients compared to healthy women using quantitative mass spectrometry.</p> <p>Methods</p> <p>LRG1 was quantified by ELISA in serum from two relatively large cohorts of women with ovarian cancer and benign gynecological disease. The expression of LRG1 in ovarian cancer tissues and cell lines was examined by gene microarray, reverse-transcriptase polymerase chain reaction (RT-PCR), Western blot, immunocytochemistry and mass spectrometry.</p> <p>Results</p> <p>Mean serum LRG1 was higher in 58 ovarian cancer patients than in 56 healthy women (89.33 ± 77.90 vs. 42.99 ± 9.88 ug/ml; p = 0.0008) and was highest among stage III/IV patients. In a separate set of 193 pre-surgical samples, LRG1 was higher in patients with serous or clear cell ovarian cancer (145.82 ± 65.99 ug/ml) compared to patients with benign gynecological diseases (82.53 ± 76.67 ug/ml, p < 0.0001). CA125 and LRG1 levels were moderately correlated (r = 0.47, p < 0.0001). <it>LRG1 </it>mRNA levels were higher in ovarian cancer tissues and cell lines compared to their normal counterparts when analyzed by gene microarray and RT-PCR. LRG1 protein was detected in ovarian cancer tissue samples and cell lines by immunocytochemistry and Western blotting. Multiple iosforms of LRG1 were observed by Western blot and were shown to represent different glycosylation states by digestion with glycosidase. LRG1 protein was also detected in the conditioned media of ovarian cancer cell culture by ELISA, Western blotting, and mass spectrometry.</p> <p>Conclusions</p> <p>Serum LRG1 was significantly elevated in women with ovarian cancer compared to healthy women and women with benign gynecological disease, and was only moderately correlated with CA125. Ovarian cancer cells secrete LRG1 and may contribute directly to the elevated levels of LRG1 observed in the serum of ovarian cancer patients. Future studies will determine whether LRG1 may serve as a biomarker for presurgical diagnosis, disease recurrence, and/or as a target for therapy.</p

An Analysis of Private School Closings

We add to the small literature on private school supply by exploring exits of K-12 private schools. We find that the closure of private schools is not an infrequent event, and use national survey data from the National Center for Education Statistics to study closures of private schools. We assume that the probability of an exit is a function of excess supply of private schools over the demand, as well as the school's characteristics such as age, size, and religious affiliation. Our empirical results generally support the implications of the model. Working Paper 07-0

A global biodiversity observing system to unite monitoring and guide action

The rate and extent of global biodiversity change is surpassing our ability to measure, monitor and forecast trends. We propose an interconnected worldwide system of observation networks — a global biodiversity observing system (GBiOS) — to coordinate monitoring worldwide and inform action to reach international biodiversity targets.acceptedVersio

Six Novel Susceptibility Loci for Early-Onset Androgenetic Alopecia and Their Unexpected Association with Common Diseases

Androgenetic alopecia (AGA) is a highly heritable condition and the most common form of hair loss in humans. Susceptibility loci have been described on the X chromosome and chromosome 20, but these loci explain a minority of its heritable variance. We conducted a large-scale meta-analysis of seven genome-wide association studies for early-onset AGA in 12,806 individuals of European ancestry. While replicating the two AGA loci on the X chromosome and chromosome 20, six novel susceptibility loci reached genome-wide significance (p = 2.62×10−9–1.01×10−12). Unexpectedly, we identified a risk allele at 17q21.31 that was recently associated with Parkinson's disease (PD) at a genome-wide significant level. We then tested the association between early-onset AGA and the risk of PD in a cross-sectional analysis of 568 PD cases and 7,664 controls. Early-onset AGA cases had significantly increased odds of subsequent PD (OR = 1.28, 95% confidence interval: 1.06–1.55, p = 8.9×10−3). Further, the AGA susceptibility alleles at the 17q21.31 locus are on the H1 haplotype, which is under negative selection in Europeans and has been linked to decreased fertility. Combining the risk alleles of six novel and two established susceptibility loci, we created a genotype risk score and tested its association with AGA in an additional sample. Individuals in the highest risk quartile of a genotype score had an approximately six-fold increased risk of early-onset AGA [odds ratio (OR) = 5.78, p = 1.4×10−88]. Our results highlight unexpected associations between early-onset AGA, Parkinson's disease, and decreased fertility, providing important insights into the pathophysiology of these conditions

Meta‐Analysis of Genome‐wide Linkage Studies in BMI and Obesity

Objective: The objective was to provide an overall assessment of genetic linkage data of BMI and BMI‐defined obesity using a nonparametric genome scan meta‐analysis. Research Methods and Procedures: We identified 37 published studies containing data on over 31,000 individuals from more than >10,000 families and obtained genome‐wide logarithm of the odds (LOD) scores, non‐parametric linkage (NPL) scores, or maximum likelihood scores (MLS). BMI was analyzed in a pooled set of all studies, as a subgroup of 10 studies that used BMI‐defined obesity, and for subgroups ascertained through type 2 diabetes, hypertension, or subjects of European ancestry. Results: Bins at chromosome 13q13.2‐ q33.1, 12q23‐q24.3 achieved suggestive evidence of linkage to BMI in the pooled analysis and samples ascertained for hypertension. Nominal evidence of linkage to these regions and suggestive evidence for 11q13.3‐22.3 were also observed for BMI‐defined obesity. The FTO obesity gene locus at 16q12.2 also showed nominal evidence for linkage. However, overall distribution of summed rank p values <0.05 is not different from that expected by chance. The strongest evidence was obtained in the families ascertained for hypertension at 9q31.1‐qter and 12p11.21‐q23 (p < 0.01). Conclusion: Despite having substantial statistical power, we did not unequivocally implicate specific loci for BMI or obesity. This may be because genes influencing adiposity are of very small effect, with substantial genetic heterogeneity and variable dependence on environmental factors. However, the observation that the FTO gene maps to one of the highest ranking bins for obesity is interesting and, while not a validation of this approach, indicates that other potential loci identified in this study should be investigated further.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/93663/1/oby.2007.269.pd

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe