Engineering peptide-polymer hybrids for targeted repair and protection of cervical lesions

By 2060, nearly 100 million people in the U.S. will be over age 65 years. One-third of these older adults will have root caries, and nearly 80% will have dental erosion. These conditions can cause pain and loss of tooth structure that interfere with eating, speaking, sleeping, and quality of life. Current treatments for root caries and dental erosion have produced unreliable results. For example, the glass-ionomer-cement or composite-resin restorations used to treat these lesions have annual failure rates of 44% and 17%, respectively. These limitations and the pressing need to treat these conditions in the aging population are driving a focus on microinvasive strategies, such as sealants and varnishes. Sealants can inhibit caries on coronal surfaces, but they are ineffective for root caries. For healthy, functionally independent elders, chlorhexidine varnish applied every 3 months inhibits root caries, but this bitter-tasting varnish stains the teeth. Fluoride gel inhibits root caries, but requires prescriptions and daily use, which may not be feasible for some older patients. Silver diamine fluoride can both arrest and inhibit root caries but stains the treated tooth surface black. The limitations of current approaches and high prevalence of root caries and dental erosion in the aging population create an urgent need for microinvasive therapies that can: (a) remineralize damaged dentin; (b) inhibit bacterial activity; and (c) provide durable protection for the root surface. Since cavitated and non-cavitated root lesions are difficult to distinguish, optimal approaches will treat both. This review will explore the multi-factorial elements that contribute to root surface lesions and discuss a multi-pronged strategy to both repair and protect root surfaces. The strategy integrates engineered peptides, novel polymer chemistry, multi-scale structure/property characterization and predictive modeling to develop a durable, microinvasive treatment for root surface lesions

Sub-electron noise charge-coupled devices

A charge coupled device designed for celestial spectroscopy has achieved readout noise as low as 0.6 electrons rms. A nondestructive output circuit was operated in a special manner to read a single pixel multiple times. Off-chip electronics averaged the multiple values, reducing the random noise by the square root of the number of readouts. Charge capacity was measured to be 500,000 electrons. The device format is 1600 pixels horizontal by 64 pixels vertical. Pixel size is 28 microns square. Two output circuits are located at opposite ends of the 1600 bit CCD register. The device was thinned and operated backside illuminated at -110 degrees C. Output circuit design, layout, and operation are described. Presented data includes the photon transfer curve, noise histograms, and bar-target images down to 3 electrons signal. The test electronics are described, and future improvements are discussed

New advancements in charge-coupled device technology: sub-electron noise and 4096x4096 pixel CCDs

This paper reports on two new advancements in CCD technology. The first area of development has produced a special purpose CCD designed for ultra low-signal level imaging and spectroscopy applications that require sub-electron read noise floors. A nondestructive output circuit operating near its 1/f noise regime is clocked in a special manner to read a single pixel multiple times. Off-chip electronics average the multiple values, reducing the random noise by the square-root of the number of samples taken. Noise floors below 0.5 electrons rms are reported. The second development involves the design and performance of a high resolution imager of 4096 x 4096 pixels, the largest CCD manufactured in terms of pixel count. The device utilizes a 7.5-micron pixel fabricated with three-level poly-silicon to achieve high yield

Sub-electron noise charge-coupled devices

A charge coupled device designed for celestial spectroscopy has achieved readout noise as low as 0.6 electrons rms. A nondestructive output circuit was operated in a special manner to read a single pixel multiple times. Off-chip electronics averaged the multiple values, reducing the random noise by the square root of the number of readouts. Charge capacity was measured to be 500,000 electrons. The device format is 1600 pixels horizontal by 64 pixels vertical. Pixel size is 28 microns square. Two output circuits are located at opposite ends of the 1600 bit CCD register. The device was thinned and operated backside illuminated at -110 degrees C. Output circuit design, layout, and operation are described. Presented data includes the photon transfer curve, noise histograms, and bar-target images down to 3 electrons signal. The test electronics are described, and future improvements are discussed

New advancements in charge-coupled device technology: sub-electron noise and 4096x4096 pixel CCDs

This paper reports on two new advancements in CCD technology. The first area of development has produced a special purpose CCD designed for ultra low-signal level imaging and spectroscopy applications that require sub-electron read noise floors. A nondestructive output circuit operating near its 1/f noise regime is clocked in a special manner to read a single pixel multiple times. Off-chip electronics average the multiple values, reducing the random noise by the square-root of the number of samples taken. Noise floors below 0.5 electrons rms are reported. The second development involves the design and performance of a high resolution imager of 4096 x 4096 pixels, the largest CCD manufactured in terms of pixel count. The device utilizes a 7.5-micron pixel fabricated with three-level poly-silicon to achieve high yield

Organization Theory in Business and Management History: Present Status and Future Prospects

Copyright © The President and Fellows of Harvard College 2017. A common lament is that business history has been marginalized within mainstream business and management research. We propose that the remedy lies in part with more extensive engagement with organization theory. We illustrate our argument by exploring the potentialities for business history of three cognitive frameworks: institutional entrepreneurship, evolutionary theory, and Bourdieusian social theory. Exhibiting a higher level of theoretical fluency might enable business historians to accrue scholarly capital within the business and management field by producing theoretically informed historical discourse, demonstrating the potential of business history to extend theory, generate constructs, and elucidate complexities in unfolding relationships, situations, and events

Etiology of Severe Non-malaria Febrile Illness in Northern Tanzania: A Prospective Cohort Study.

The syndrome of fever is a commonly presenting complaint among persons seeking healthcare in low-resource areas, yet the public health community has not approached fever in a comprehensive manner. In many areas, malaria is over-diagnosed, and patients without malaria have poor outcomes. We prospectively studied a cohort of 870 pediatric and adult febrile admissions to two hospitals in northern Tanzania over the period of one year using conventional standard diagnostic tests to establish fever etiology. Malaria was the clinical diagnosis for 528 (60.7%), but was the actual cause of fever in only 14 (1.6%). By contrast, bacterial, mycobacterial, and fungal bloodstream infections accounted for 85 (9.8%), 14 (1.6%), and 25 (2.9%) febrile admissions, respectively. Acute bacterial zoonoses were identified among 118 (26.2%) of febrile admissions; 16 (13.6%) had brucellosis, 40 (33.9%) leptospirosis, 24 (20.3%) had Q fever, 36 (30.5%) had spotted fever group rickettsioses, and 2 (1.8%) had typhus group rickettsioses. In addition, 55 (7.9%) participants had a confirmed acute arbovirus infection, all due to chikungunya. No patient had a bacterial zoonosis or an arbovirus infection included in the admission differential diagnosis. Malaria was uncommon and over-diagnosed, whereas invasive infections were underappreciated. Bacterial zoonoses and arbovirus infections were highly prevalent yet overlooked. An integrated approach to the syndrome of fever in resource-limited areas is needed to improve patient outcomes and to rationally target disease control efforts

Metabolic phenotype of methylmalonic acidemia in mice and humans: the role of skeletal muscle

<p>Abstract</p> <p>Background</p> <p>Mutations in methylmalonyl-CoA mutase cause methylmalonic acidemia, a common organic aciduria. Current treatment regimens rely on dietary management and, in severely affected patients, liver or combined liver-kidney transplantation. For undetermined reasons, transplantation does not correct the biochemical phenotype.</p> <p>Methods</p> <p>To study the metabolic disturbances seen in this disorder, we have created a murine model with a null allele at the methylmalonyl-CoA mutase locus and correlated the results observed in the knock-out mice to patient data. To gain insight into the origin and magnitude of methylmalonic acid (MMA) production in humans with methylmalonyl-CoA mutase deficiency, we evaluated two methylmalonic acidemia patients who had received different variants of combined liver-kidney transplants, one with a complete liver replacement-kidney transplant and the other with an auxiliary liver graft-kidney transplant, and compared their metabolite production to four untransplanted patients with intact renal function.</p> <p>Results</p> <p>Enzymatic, Western and Northern analyses demonstrated that the targeted allele was null and correctable by lentiviral complementation. Metabolite studies defined the magnitude and tempo of plasma MMA concentrations in the mice. Before a fatal metabolic crisis developed in the first 24–48 hours, the methylmalonic acid content per gram wet-weight was massively elevated in the skeletal muscle as well as the kidneys, liver and brain. Near the end of life, extreme elevations in tissue MMA were present primarily in the liver. The transplant patients studied when well and on dietary therapy, displayed massive elevations of MMA in the plasma and urine, comparable to the levels seen in the untransplanted patients with similar enzymatic phenotypes and dietary regimens.</p> <p>Conclusion</p> <p>The combined observations from the murine metabolite studies and patient investigations indicate that during homeostasis, a large portion of circulating MMA has an extra-heptorenal origin and likely derives from the skeletal muscle. Our studies suggest that modulating skeletal muscle metabolism may represent a strategy to increase metabolic capacity in methylmalonic acidemia as well as other organic acidurias. This mouse model will be useful for further investigations exploring disease mechanisms and therapeutic interventions in methylmalonic acidemia, a devastating disorder of intermediary metabolism.</p