Generation of an expandable intermediate mesoderm restricted progenitor cell line from human pluripotent stem cells.

The field of tissue engineering entered a new era with the development of human pluripotent stem cells (hPSCs), which are capable of unlimited expansion whilst retaining the potential to differentiate into all mature cell populations. However, these cells harbor significant risks, including tumor formation upon transplantation. One way to mitigate this risk is to develop expandable progenitor cell populations with restricted differentiation potential. Here, we used a cellular microarray technology to identify a defined and optimized culture condition that supports the derivation and propagation of a cell population with mesodermal properties. This cell population, referred to as intermediate mesodermal progenitor (IMP) cells, is capable of unlimited expansion, lacks tumor formation potential, and, upon appropriate stimulation, readily acquires properties of a sub-population of kidney cells. Interestingly, IMP cells fail to differentiate into other mesodermally-derived tissues, including blood and heart, suggesting that these cells are restricted to an intermediate mesodermal fate

Comparison of Upper Extremity Function in Women With and Women Without a History of Breast Cancer

Design: This was an observational cross-sectional study. Methods: Women who were diagnosed with breast cancer and had a mean post–surgical treatment time of 51 months (range = 12–336 months) were compared with women who did not have breast cancer (CTRL group). Self-reported upper extremity function using the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire and shoulder range of motion, strength, and muscular endurance were measured. Participants were divided into 3 groups: breast cancer involving the nondominant limb (BC-ND), breast cancer involving the dominant limb (BC-DOM), and CTRL. Results: A total of 59 women in the CTRL group, 23 women in the BC-ND group, and 28 women in the BC-DOM group completed measures. Mean DASH scores in women with breast cancer were higher than those of women in the CTRL group, regardless of the limb on which cancer occurred (Cohen d = 1.13; 95% CI = 2.20 to 16.21) Range of motion for the BC-ND group was significantly less for flexion (Cohen d = 1.19, 95% CI = −13.08 to −0.11) and external rotation (Cohen d = 1.11, 95% CI = −18.62 to −1.98) compared with the CTRL group. Strength in the BC-ND group was 23% to 25% lower in the CTRL group for external (Cohen’s d = 0.89, 95% CI = 0.09 to 0.12) and internal rotation (Cohen d = 0.92, 95% CI = 0.10 to 0.13). Endurance was not significantly different in the 3 groups. Limitations: Some participants had rehabilitation, which may have skewed results. The range of post–surgical treatment times was broad, making it difficult to determine when function returned. Muscular endurance measures demonstrated a ceiling effect and large variance, limiting the ability to distinguish differences among participants. These results may not be generalizable to the subset of women who were treated with lumpectomy, sentinel node biopsy, or chest wall radiation alone or who underwent a contralateral prophylactic mastectomy. Conclusion: In the long term, women with breast cancer have lower self-reported shoulder function than women without breast cancer. Motion and strength are lower among women who have experienced cancer on the nondominant limb

The 2009 US Federal Cigarette Tax Increase and Quitline Utilization in 16 States

Background. On April 1, 2009, the federal cigarette excise tax increased from 39 cents to $1.01 per pack. Methods. This study describes call volumes to 16 state quitlines, characteristics of callers and cessation outcomes before and after the tax. Results. Calls to the quitlines increased by 23.5% in 2009 and more whites, smokers ≥ 25 years of age, smokers of shorter duration, those with less education, and those who live with smokers called after (versus before) the tax. Quit rates at 7 months did not differ before versus after tax. Conclusions. Descriptive analyses revealed that the federal excise tax on cigarettes was associated with increased calls to quitlines but multivariate analyses revealed no difference in quit rates. However, more callers at the same quit rate indicates an increase in total number of successful quitters. If revenue obtained from increased taxation on cigarettes is put into cessation treatment, then it is likely future excise taxes would have an even greater effect

Race differences in predictors of weight gain among a community sample of smokers enrolled in a randomized controlled trial of a multiple behavior change intervention.

African Americans have disproportionate rates of post-cessation weight gain compared to non-Hispanic whites, but few studies have examined this weight gain in a multiracial sample of smokers receiving evidence-based treatment in a community setting. We examined race differences in short-term weight gain during an intervention to foster smoking cessation plus weight management. Data were drawn from the Best Quit Study, a randomized controlled trial conducted via telephone quitlines across the U.S. from 2013 to 2017. The trial tested the effects on cessation and weight gain prevention of adding a weight control intervention either simultaneously with or sequentially after smoking cessation treatment. African Americans (n = 665) and whites (n = 1723) self-reported smoking status and weight during ten intervention calls. Random effects longitudinal modeling was used to examine predictors of weight change over the intervention period (average 16 weeks). There was a significant race × treatment effect; in the simultaneous group, weight increased for African Americans at a faster rate compared to whites (b = 0.302, SE = 0.129, p \u3c 0.05), independent of smoking status, age, baseline obesity, and education. After stratifying the sample, the effect of treatment group differed by race. Education level attenuated the rate of weight gain for African Americans in the simultaneous group, but not for whites. African Americans receiving smoking and weight content simultaneously gained weight faster than whites in the same group; however, the weight gain was slower for African Americans with higher educational attainment. Future studies are needed to understand social factors associated with treatment receptivity that may influence weight among African American smokers

Turnover of variant surface glycoprotein in Trypanosoma brucei is a bimodal process

This work was supported by United States Public Health Service grant R01 AI035739 and funds from the Jacobs School of Medicine and Biomedical Sciences to J.D.B. and from United States Public Health Service grant 1S10OD021719-01A1 to the University of Georgia, which purchased the ImageStreamX Mk II. This work was also supported by the Wellcome Trust (grant 094476/Z/10/Z) for funding the purchase of the TripleTOF 5600 mass spectrometer at the BSRC Mass Spectrometry and Proteomics Facility.African trypanosomes utilize glycosylphosphatidylinositol (GPI)-anchored variant surface glycoprotein (VSG) to evade the host immune system. VSG turnover is thought to be mediated via cleavage of the GPI anchor by endogenous GPI-specific phospholipase C (GPI-PLC). However, GPI-PLC is topologically sequestered from VSG substrates in intact cells. Recently, A. J. Szempruch, S. E. Sykes, R. Kieft, L. Dennison, et al. (Cell 164:246-257, 2016, https://doi.org/10.1016/j.cell.2015.11.051) demonstrated the release of nanotubes that septate to form free VSG+ extracellular vesicles (EVs). Here, we evaluated the relative contributions of GPI hydrolysis and EV formation to VSG turnover in wild-type (WT) and GPI-PLC null cells. The turnover rate of VSG was consistent with prior measurements (half-life [t1/2] of ∼26 h) but dropped significantly in the absence of GPI-PLC (t1/2 of ∼36 h). Ectopic complementation restored normal turnover rates, confirming the role of GPI-PLC in turnover. However, physical characterization of shed VSG in WT cells indicated that at least 50% is released directly from cell membranes with intact GPI anchors. Shedding of EVs plays an insignificant role in total VSG turnover in both WT and null cells. In additional studies, GPI-PLC was found to have no role in biosynthetic and endocytic trafficking to the lysosome but did influence the rate of receptor-mediated endocytosis. These results indicate that VSG turnover is a bimodal process involving both direct shedding and GPI hydrolysis. IMPORTANCE African trypanosomes, the protozoan agent of human African trypanosomaisis, avoid the host immune system by switching expression of the variant surface glycoprotein (VSG). VSG is a long-lived protein that has long been thought to be turned over by hydrolysis of its glycolipid membrane anchor. Recent work demonstrating the shedding of VSG-containing extracellular vesicles has led us to reinvestigate the mode of VSG turnover. We found that VSG is shed in part by glycolipid hydrolysis but also in approximately equal part by direct shedding of protein with intact lipid anchors. Shedding of exocytic vesicles made a very minor contribution to overall VSG turnover. These results indicate that VSG turnover is a bimodal process and significantly alter our understanding of the "life cycle" of this critical virulence factor.Publisher PDFPeer reviewe

Endogenous Zinc in Neurological Diseases

The use of zinc in medicinal skin cream was mentioned in Egyptian papyri from 2000 BC (for example, the Smith Papyrus), and zinc has apparently been used fairly steadily throughout Roman and modern times (for example, as the American lotion named for its zinc ore, 'Calamine'). It is, therefore, somewhat ironic that zinc is a relatively late addition to the pantheon of signal ions in biology and medicine. However, the number of biological functions, health implications and pharmacological targets that are emerging for zinc indicate that it might turn out to be 'the calcium of the twenty-first century'. Here neurobiological roles of endogenous zinc is summarized

Peripheral Delivery of a CNS Targeted, Metalo-Protease Reduces Aβ Toxicity in a Mouse Model of Alzheimer's Disease

Alzheimer's disease (AD), an incurable, progressive neurodegenerative disorder, is the most common form of dementia. Therapeutic options have been elusive due to the inability to deliver proteins across the blood-brain barrier (BBB). In order to improve the therapeutic potential for AD, we utilized a promising new approach for delivery of proteins across the BBB. We generated a lentivirus vector expressing the amyloid β-degrading enzyme, neprilysin, fused to the ApoB transport domain and delivered this by intra-peritoneal injection to amyloid protein precursor (APP) transgenic model of AD. Treated mice had reduced levels of Aβ, reduced plaques and increased synaptic density in the CNS. Furthermore, mice treated with the neprilysin targeting the CNS had a reversal of memory deficits. Thus, the addition of the ApoB transport domain to the secreted neprilysin generated a non-invasive therapeutic approach that may be a potential treatment in patients with AD