Loss of epigenetic information as a cause of mammalian aging.

All living things experience an increase in entropy, manifested as a loss of genetic and epigenetic information. In yeast, epigenetic information is lost over time due to the relocalization of chromatin-modifying proteins to DNA breaks, causing cells to lose their identity, a hallmark of yeast aging. Using a system called "ICE" (inducible changes to the epigenome), we find that the act of faithful DNA repair advances aging at physiological, cognitive, and molecular levels, including erosion of the epigenetic landscape, cellular exdifferentiation, senescence, and advancement of the DNA methylation clock, which can be reversed by OSK-mediated rejuvenation. These data are consistent with the information theory of aging, which states that a loss of epigenetic information is a reversible cause of aging.

Upper Gastrointestinal Series in the Workup for Pediatric Gastrostomy Placement: Does it Delay Care?

INTRODUCTION: Upper gastrointestinal (UGI) series is often part of the workup prior to the placement of gastrostomy tubes in children. Prior studies have suggested UGI to be limited in utility and an extra financial burden. The goal of this study was to investigate the utility and cost of UGI studies. METHODS: A retrospective, case control study of patients aged < 18 y receiving gastrostomy tubes at a free-standing children's hospital between 2012 and 2017. Total costs were obtained from the Pediatric Health Information System. RESULTS: Six hundred eighty five patients underwent gastrostomy placement during the study period. UGI was obtained in 90.8% of patients; 23.6% of studies were abnormal. The most common abnormal findings were reflux (13.8%) and abnormal anatomy (5.8%). The median time to obtain a UGI was 0.82 d (interquartile range 0.22-1.05). Obtaining a UGI was associated with delayed care in 104 patients (15.2%). If a delay was encountered, median time was 2.47 d (interquartile range 1.86-2.99). Ladd's procedures were performed in 12 patients (1.7%) found to have malrotation on UGI. None of the 63 patients who did not undergo UGI required a Ladd's procedure. Patients that had a UGI did not experience an increase in overall length of stay (14.3 versus 15.6 d, excluding intensive care unit patients), operative time (34 versus 39 min), or a change in rate of operative complications (11.5% versus 14.3%). In addition, UGI did not have a significant impact on total adjusted costs ($49,844 versus $83,438 without UGI, P = 0.12) but did slightly increase total adjusted costs per day ($2212 versus $1999 without UGI, P = 0.01). CONCLUSIONS: UGI prior to gastrostomy placement in children rarely identified abnormal findings that changed the operative plan, was associated with delayed care in 15% of patients, and was associated with slightly increased costs per day. Further analyses to identify subsets of children that may benefit from routine UGI are warranted.

Transcutaneous contrast-enhanced ultrasound imaging of the posttraumatic spinal cord.

STUDY DESIGN: Experimental animal study. OBJECTIVE: The current study aims to test whether the blood flow within the contused spinal cord can be assessed in a rodent model via the acoustic window of the laminectomy utilizing transcutaneous ultrasound. SETTING: Department of Neurological Surgery, University of Washington, Seattle WA. METHODS: Long-Evans rats (n = 12) were subjected to a traumatic thoracic spinal cord injury (SCI). Three days and 10 weeks after injury, animals underwent imaging of the contused spinal cord using ultrafast contrast-enhanced ultrasound with a Vantage ultrasound research system in combination with a 15 MHz transducer. Lesion size and signal-to-noise ratios were estimated via transcutaneous, subcutaneous, or epidural ultrasound acquisition through the acoustic window created by the original laminectomy. RESULTS: Following laminectomy, transcutaneous and subcutaneous contrast-enhanced ultrasound imaging allowed for assessment of perfusion and vascular flow in the contused rodent spinal cord. An average loss of 7.2 dB from transcutaneous to subcutaneous and the loss of 5.1 dB from subcutaneous to epidural imaging in signal-to-noise ratio (SNR) was observed. The hypoperfused injury center was measured transcutaneously, subcutaneously and epidurally (5.78 ± 0.86, 5.91 ± 0.53, 5.65 ± 1.07 mm2) at 3 days post injury. The same animals were reimaged again at 10 weeks following SCI, and the area of hypoperfusion had decreased significantly compared with the 3-day measurements detected via transcutaneous, subcutaneous, and epidural imaging respectively (0.69 ± 0.05, 1.09 ± 0.11, 0.95 ± 0.11 mm2, p < 0.001). CONCLUSIONS: Transcutaneous ultrasound allows for measurements and longitudinal monitoring of local hemodynamic changes in a rodent SCI model.

An integrated action plan to fund and support drug development for Dup15q syndrome: a patient organization perspective.

Maternal 15q11.2-13.1 duplication syndrome, or Dup15q syndrome (Dup15q), is a rare neurodevelopmental disorder affecting as many as 1 in 5000 to 1 in 20,000 children worldwide. Autism and seizures are two of the most commonly observed phenotypes in Dup15q, with intellectual disability, hypotonia, gastrointestinal distress, and substantial fine and gross motor deficits also commonly reported. The community that is now known as the Dup15q Alliance started in 1994 as a small group of families raising children with chromosome 15q duplications. Originally named IsoDicentric 15 Exchange, Advocacy and Support (IDEAS), the group received official nonprofit organization status 10 years later and rebranded to its current name, Dup15q Alliance, shortly thereafter. Today, there are over 2200 families affiliated with Dup15q Alliance, with an average intake of 10 new families each month. Historically, Dup15q Alliance has provided the community with access to family and caregiver resources in addition to serving as a repository for basic educational information about Dup15q and research developments. The recent installation of a dedicated director of scientific and clinical initiatives alongside other infrastructural changes has now primed the Dup15q Alliance to expand its scientific footprint by funding cutting-edge research, supporting clinical sites and trials, and investing in novel therapeutics that have the potential to change the reality of a Dup15q syndrome diagnosis. To do this, we have developed the LEARN. TREAT. CURE. program to align initiatives, fast-track progress, and bring hope and reality into coexistence. Briefly, we seek to learn as much as we can about the syndrome through cutting-edge research, natural history studies, and patient registry utilization, identify and develop methods to treat the symptoms of our patient community, with the ultimate goal of developing a cure for the disease-causing symptoms of the syndrome.

A campaign to accelerate drug discovery in Dup15q Syndrome Patient advocacy groups aid in raising awareness and funding for specific disorders. Nearly three decades ago, Dup15q Alliance was founded by parents of individuals with maternal Duplication 15q Syndrome. This group has grown significantly and is now focused on funding programs to advance research. To do this, they have revised their infrastructure to include a part-time Director of Scientific and Clinical Initiatives and developed a fundraising campaign dedicated to scientific and clinical programming. They also emphasize collaboration and community engagement as key elements of the campaign.

Mechanisms, pathways and strategies for rejuvenation through epigenetic reprogramming.

Over the past decade, there has been a dramatic increase in efforts to ameliorate aging and the diseases it causes, with transient expression of nuclear reprogramming factors recently emerging as an intriguing approach. Expression of these factors, either systemically or in a tissue-specific manner, has been shown to combat age-related deterioration in mouse and human model systems at the cellular, tissue and organismal level. Here we discuss the current state of epigenetic rejuvenation strategies via partial reprogramming in both mouse and human models. For each classical reprogramming factor, we provide a brief description of its contribution to reprogramming and discuss additional factors or chemical strategies. We discuss what is known regarding chromatin remodeling and the molecular dynamics underlying rejuvenation, and, finally, we consider strategies to improve the practical uses of epigenetic reprogramming to treat aging and age-related diseases, focusing on the open questions and remaining challenges in this emerging field.

Chemically induced reprogramming to reverse cellular aging.

A hallmark of eukaryotic aging is a loss of epigenetic information, a process that can be reversed. We have previously shown that the ectopic induction of the Yamanaka factors OCT4, SOX2, and KLF4 (OSK) in mammals can restore youthful DNA methylation patterns, transcript profiles, and tissue function, without erasing cellular identity, a process that requires active DNA demethylation. To screen for molecules that reverse cellular aging and rejuvenate human cells without altering the genome, we developed high-throughput cell-based assays that distinguish young from old and senescent cells, including transcription-based aging clocks and a real-time nucleocytoplasmic compartmentalization (NCC) assay. We identify six chemical cocktails, which, in less than a week and without compromising cellular identity, restore a youthful genome-wide transcript profile and reverse transcriptomic age. Thus, rejuvenation by age reversal can be achieved, not only by genetic, but also chemical means.

The gender equity gap: A multistudy investigation of within-job inequality in equity-based awards.

Laws in many countries mandate paying men and women equally when in similar jobs. Such laws, coupled with considerable organizational efforts, lead some scholars to contend that within-job pay inequality is no longer a source of the gender pay gap. We argue important differences in a widely used form of pay heretofore overlooked in existing studies-equity-based awards (i.e., pay where the value is tied to the employing organization's stock, such as stock and stock options)-may cause underestimation of gender-based within-job pay inequality. Specifically, we theorize that because of differences in both why and how equity-based awards are distributed to employees compared to other forms of pay, a gender gap will exist in equity-based awards, with biased perceptions of retention driving the gap. Using a multimethod study with novel data from two technology organizations, archival data from publicly traded firms, and experimental data, we find consistent support for our hypotheses. Taken together, our results suggest that using equity-based awards as a means to retain employees, and the rationale and processes associated with distributing such pay, can result in gender-based within-job inequality. Thus, our study sheds light on a previously overlooked form of inequality in the workplace while offering implications for both theory and practice. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

High-Frequency Nonlinear Doppler Contrast-Enhanced Ultrasound Imaging of Blood Flow.

Current methods for in vivo microvascular imaging (<1 mm) are limited by the tradeoffs between the depth of penetration, resolution, and acquisition time. Ultrasound Doppler approaches combined at elevated frequencies (<7.5 MHz) are able to visualize smaller vasculature and, however, are still limited in the segmentation of lower velocity blood flow from moving tissue. Contrast-enhanced ultrasound (CEUS) has been successful in visualizing changes in microvascular flow at conventional diagnostic ultrasound imaging frequencies (<7.5 MHz). However, conventional CEUS approaches at elevated frequencies have met with limited success, due, in part, to the diminishing microbubble response with frequency. We apply a plane-wave acquisition combined with the non-linear Doppler processing of ultrasound contrast agents at 15 MHz to improve the resolution of microvascular blood flow while compensating for reduced microbubble response. This plane-wave Doppler approach of imaging ultrasound contrast agents also enables simultaneous detection and separation of blood flow in the microcirculation and higher velocity flow in the larger vasculature. We apply singular value decomposition filtering on the nonlinear Doppler signal to orthogonally separate the more stationary lower velocity flow in the microcirculation and higher velocity flow in the larger vasculature. This orthogonal separation was also utilized to improve time-intensity curve analysis of the microcirculation, by removing higher velocity flow corrupting bolus kinetics. We demonstrate the utility of this imaging approach in a rat spinal cord injury model, requiring submillimeter resolution.

Contrast-Enhanced Ultrasound for Assessment of Local Hemodynamic Changes Following a Rodent Contusion Spinal Cord Injury.

INTRODUCTION: Severe trauma to the spinal cord leads to a near complete loss of blood flow at the injury site along with significant hypoperfusion of adjacent tissues. Characterization and monitoring of local tissue hypoperfusion is currently not possible in clinical practice because available imaging techniques do not allow for assessment of blood flow with sufficient spatial and temporal resolutions. The objective of the current study was to determine whether ultrafast contrast-enhanced ultrasound (CEUS) imaging could be used to visualize and quantify acute hemodynamic changes in a rat traumatic spinal cord injury (SCI) model. MATERIALS AND METHODS: We used novel ultrasound acquisition and processing methods that allowed for measurements of local tissue perfusion as well as for assessment of structural and functional integrity of spinal vasculature. RESULTS: CEUS imaging showed that traumatic SCI results in (1) an area with significant loss of perfusion, which increased during the first hour after injury, (2) structural alterations of the spinal cord vasculature, and (3) significant slowing of arterial blood flow velocities around the injury epicenter. CONCLUSION: We conclude that CEUS has the spatial and temporal sensitivity and resolution to visualize local tissue perfusion and vessel architecture, which maybe useful clinically to determine injury extent and severity in patients with SCI.