Hematologic Safety of Chronic Brain-Penetrating Erythropoietin Dosing in APP/PS1 Mice

Introduction: Low blood-brain barrier (BBB) penetration and hematopoietic side effects limit the therapeutic development of erythropoietin (EPO) for Alzheimer\u27s disease (AD). A fusion protein of EPO and a chimeric monoclonal antibody targeting the mouse transferrin receptor (cTfRMAb) has been engineered. The latter drives EPO into the brain via receptor-mediated transcytosis across the BBB and increases its peripheral clearance to reduce hematopoietic side effects of EPO. Our previous work shows the protective effects of this BBB-penetrating EPO in AD mice but hematologic effects have not been studied. Herein, we investigate the hematologic safety and therapeutic effects of chronic cTfRMAb-EPO dosing, in comparison to recombinant human EPO (rhu-EPO), in AD mice. Methods: Male APPswe PSEN1dE9 (APP/PS1) mice (9.5 months) were treated with saline (n = 11), and equimolar doses of cTfRMAb-EPO (3 mg/kg, n = 7), or rhu-EPO (0.6 mg/kg, n = 9) 2 days/week subcutaneously for 6 weeks, compared to saline-treated wild-type mice (n = 10). At 6 weeks, exploration and memory were assessed, and mice were sacrificed at 8 weeks. Spleens were weighed, and brains were evaluated for amyloid beta (Aβ) load and synaptophysin. Blood was collected at 4, 6 and 8 weeks for a complete blood count and white blood cells differential. Results: cTfRMAb-EPO transiently increased reticulocyte counts after 4 weeks, followed by normalization of reticulocytes at 6 and 8 weeks. rhu-EPO transiently increased red blood cell count, hemoglobin and hematocrit, and significantly decreased mean corpuscular volume and reticulocytes at 4 weeks, which remained low at 6 weeks. At 8 weeks, a significant decline in red blood cell indices was observed with rhu-EPO treatment. Exploration and cognitive deficits were significantly worse in APP/PS1-rhu-EPO mice. Both cTfRMAb-EPO and rhu-EPO decreased 6E10-positive brain Aβ load; however, cTfRMAb-EPO and not rhu-EPO selectively reduced brain Aβ1-42 and elevated synaptophysin expression. Discussion: Chronic treatment with cTfRMAb-EPO results in better hematologic safety, behavioral, and therapeutic indices compared with rhu-EPO, supporting the development of this BBB-penetrable EPO analog for AD. therapeutic indices compared with rhu-EPO, supporting the development of this BBB-penetrable EPO analog for AD

Robust estimation of microbial diversity in theory and in practice

Quantifying diversity is of central importance for the study of structure, function and evolution of microbial communities. The estimation of microbial diversity has received renewed attention with the advent of large-scale metagenomic studies. Here, we consider what the diversity observed in a sample tells us about the diversity of the community being sampled. First, we argue that one cannot reliably estimate the absolute and relative number of microbial species present in a community without making unsupported assumptions about species abundance distributions. The reason for this is that sample data do not contain information about the number of rare species in the tail of species abundance distributions. We illustrate the difficulty in comparing species richness estimates by applying Chao's estimator of species richness to a set of in silico communities: they are ranked incorrectly in the presence of large numbers of rare species. Next, we extend our analysis to a general family of diversity metrics ("Hill diversities"), and construct lower and upper estimates of diversity values consistent with the sample data. The theory generalizes Chao's estimator, which we retrieve as the lower estimate of species richness. We show that Shannon and Simpson diversity can be robustly estimated for the in silico communities. We analyze nine metagenomic data sets from a wide range of environments, and show that our findings are relevant for empirically-sampled communities. Hence, we recommend the use of Shannon and Simpson diversity rather than species richness in efforts to quantify and compare microbial diversity.Comment: To be published in The ISME Journal. Main text: 16 pages, 5 figures. Supplement: 16 pages, 4 figure

Direct evidence for cancer-cell-autonomous extracellular protein catabolism in pancreatic tumors

Mammalian tissues rely on a variety of nutrients to support their physiological functions. It is known that altered metabolism is involved in the pathogenesis of cancer, but which nutrients support the inappropriate growth of intact malignant tumors is incompletely understood. Amino acids are essential nutrients for many cancer cells that can be obtained through the scavenging and catabolism of extracellular protein via macropinocytosis. In particular, macropinocytosis can be a nutrient source for pancreatic cancer cells, but it is not fully understood how the tumor environment influences metabolic phenotypes and whether macropinocytosis supports the maintenance of amino acid levels within pancreatic tumors. Here we utilize miniaturized plasma exchange to deliver labeled albumin to tissues in live mice, and we demonstrate that breakdown of albumin contributes to the supply of free amino acids in pancreatic tumors. We also deliver albumin directly into tumors using an implantable microdevice, which was adapted and modified from ref. 9. Following implantation, we directly observe protein catabolism and macropinocytosis in situ by pancreatic cancer cells, but not by adjacent, non-cancerous pancreatic tissue. In addition, we find that intratumoral inhibition of macropinocytosis decreases amino acid levels. Taken together, these data suggest that pancreatic cancer cells consume extracellular protein, including albumin, and that this consumption serves as an important source of amino acids for pancreatic cancer cells in vivo.National Science Foundation (U.S.) (Grant T32GM007287)National Cancer Institute (U.S.) (Grant F30CA183474)National Institute of General Medical Sciences (U.S.) (Award T32GM007753)National Institutes of Health (U.S.) (Grant P30CA1405141)National Institutes of Health (U.S.) (Grant R01CA168653

The James Webb Space Telescope Mission: Optical Telescope Element Design, Development, and Performance

The James Webb Space Telescope (JWST) is a large, infrared space telescope that has recently started its science program which will enable breakthroughs in astrophysics and planetary science. Notably, JWST will provide the very first observations of the earliest luminous objects in the Universe and start a new era of exoplanet atmospheric characterization. This transformative science is enabled by a 6.6 m telescope that is passively cooled with a 5-layer sunshield. The primary mirror is comprised of 18 controllable, low areal density hexagonal segments, that were aligned and phased relative to each other in orbit using innovative image-based wavefront sensing and control algorithms. This revolutionary telescope took more than two decades to develop with a widely distributed team across engineering disciplines. We present an overview of the telescope requirements, architecture, development, superb on-orbit performance, and lessons learned. JWST successfully demonstrates a segmented aperture space telescope and establishes a path to building even larger space telescopes.Comment: accepted by PASP for JWST Overview Special Issue; 34 pages, 25 figure

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Effectiveness of manual physical therapy to the cervical spine in the management of lateral epicondylalgia: A retrospective analysis

Design: Retrospective ex-post facto design. Objectives: To retrospectively review the management of patients with lateral epicondylalgia, and to compare self-reported outcomes to assess the potential benefit of manual physical therapy to the cervical spine. Background: It has been postulated that dysfunction of the cervical spine may contribute to the symptoms associated with lateral epicondylalgia; however, the literature assessing the effectiveness of manual physical therapy to the cervicothoracic region in this patient population has been inconclusive. Documentation and analysis of outcomes of management strategies focusing on the cervical spine may lead to determining the most effective and efficient clinical practices. Methods and Measures: Of the 213 charts reviewed, 112 satisfied inclusion-exclusion criteria and were divided into 2 groups: those who received treatment solely directed at the elbow (local management [LM]), or those who received treatment directed at the elbow and cervical manual therapy (LM+C). Telephone follow-up interviews were used to determine the number of successful outcomes. Percentages of successful outcomes in each group were compared using chi-square analysis. An independent samples t test was used to compare the total number of visits per group. Results: Sixty-one of the 112 patients were in the LM group, while 51 received LM+C. Seventy five percent of the patients available for follow-up in the LM group and 80% in the LM+C group reported a successful outcome. Patients in the LM group received a greater number of visits (mean, 9.7; SD, 2.4) than patients in the LM+C group (mean, 5.6; SD, 1.7; P\u3c.01). Conclusions: The results of this retrospective review suggest that most patients had successful outcomes regardless of the inclusion of manual therapy interventions to the cervical spine. The LM+C group achieved the successful long-term outcome in significantly fewer visits

Psychometric Properties of the Neck Disability Index and Numeric Pain Rating Scale in Patients With Mechanical Neck Pain

Cleland JA, Childs JD, Whitman JM. Psychometric properties of the Neck Disability Index and numeric pain rating scale in patients with mechanical neck pain. Objective: To examine the psychometric properties including test-retest reliability, construct validity, and minimum levels of detectable and clinically important change for the Neck Disability Index (NDI) and the numeric rating scale (NRS) for pain in a cohort of patients with neck pain. Design: Single-group repeated-measures design. Setting: Outpatient physical therapy (PT) clinics. Participants: Patients (N=137) presenting to PT with a primary report of neck pain. Interventions: Not applicable. Main Outcome Measures: All patients completed the NDI and the NRS at the baseline examination and at a follow-up. At the time of the follow-up, all patients also completed the global rating of change, which was used to dichotomize patients as improved or stable. Baseline and follow-up scores were used to determine the test-retest reliability, construct validity, and minimal levels of detectable and clinically important change for both the NDI and NRS. Results: Test-retest reliability was calculated using an intraclass correlation coefficient (ICC) (NDI ICC=.50; 95% confidence interval [CI], .25-.67; NRS ICC=.76; 95% CI, .51-.87). The area under the curve was .83 (95% CI, .75-.90) for the NDI score and .85 (95% CI, .78-.93) for the NRS score for determining between stable and improved patients. Thresholds for the minimum clinically important difference (MCID) for the NDI were 19-percentage points and 1.3 for the NRS. Conclusions: Both the NDI and NRS exhibit fair to moderate test-retest reliability in patients with mechanical neck pain. Both instruments also showed adequate responsiveness in this patient population. However, the MCID required to be certain that the change in scores has surpassed a level that could be contributed to measurement error for the NDI was twice that which has previously been reported. Therefore the ongoing analyses of the properties of the NDI in a patient population with neck pain are warranted. © 2008 American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation