Mechanism of age-dependent susceptibility and novel treatment strategy in glutaric acidemia type I

Glutaric acidemia type I (GA-I) is an inherited disorder of lysine and tryptophan metabolism presenting with striatal lesions anatomically and symptomatically similar to Huntington disease. Affected children commonly suffer acute brain injury in the context of a catabolic state associated with nonspecific illness. The mechanisms underlying injury and age-dependent susceptibility have been unknown, and lack of a diagnostic marker heralding brain injury has impeded intervention efforts. Using a mouse model of GA-I, we show that pathologic events began in the neuronal compartment while enhanced lysine accumulation in the immature brain allowed increased glutaric acid production resulting in age-dependent injury. Glutamate and GABA depletion correlated with brain glutaric acid accumulation and could be monitored in vivo by proton nuclear magnetic resonance (1H NMR) spectroscopy as a diagnostic marker. Blocking brain lysine uptake reduced glutaric acid levels and brain injury. These findings provide what we believe are new monitoring and treatment strategies that may translate for use in human GA-I

Uveitis Therapy With Shark Variable Novel Antigen Receptor Domains Targeting Tumor Necrosis Factor Alpha or Inducible T-Cell Costimulatory Ligand

Acknowledgments Supported by an unrestricted departmental grant from Research to Prevent Blindness (New York, NY), NEI K08EY023998 (KLP), P30-EY001730 (RVG; Bethesda, MD), by a grant from Elasmogen Limited (RVG), and with support from the Mark J. Daily, MD Research Fund (RVG, KLP).Peer reviewedPublisher PD

AAPM medical physics practice guideline 10.a.: Scope of practice for clinical medical physics.

The American Association of Physicists in Medicine (AAPM) is a nonprofit professional society whose primary purposes are to advance the science, education, and professional practice of medical physics. The AAPM has more than 8000 members and is the principal organization of medical physicists in the United States. The AAPM will periodically define new practice guidelines for medical physics practice to help advance the science of medical physics and to improve the quality of service to patients throughout the United States. Existing medical physics practice guidelines will be reviewed for the purpose of revision or renewal, as appropriate, on their fifth anniversary or sooner. Each medical physics practice guideline (MPPG) represents a policy statement by the AAPM, has undergone a thorough consensus process in which it has been subjected to extensive review, and requires the approval of the Professional Council. The medical physics practice guidelines recognize that the safe and effective use of diagnostic and therapeutic radiation requires specific training, skills, and techniques as described in each document. As the review of the previous version of AAPM Professional Policy (PP)-17 (Scope of Practice) progressed, the writing group focused on one of the main goals: to have this document accepted by regulatory and accrediting bodies. After much discussion, it was decided that this goal would be better served through a MPPG. To further advance this goal, the text was updated to reflect the rationale and processes by which the activities in the scope of practice were identified and categorized. Lastly, the AAPM Professional Council believes that this document has benefitted from public comment which is part of the MPPG process but not the AAPM Professional Policy approval process. The following terms are used in the AAPM's MPPGs: Must and Must Not: Used to indicate that adherence to the recommendation is considered necessary to conform to this practice guideline. Should and Should Not: Used to indicate a prudent practice to which exceptions may occasionally be made in appropriate circumstances

Coral macrobioerosion is accelerated by ocean acidification and nutrients

Author Posting. © The Author(s), 2014]. This is the author's version of the work. It is posted here by permission of Geological Society of America for personal use, not for redistribution. The definitive version was published in Geology 43 (2015): 7-10, doi: 10.1130/G36147.1.Coral reefs exist in a delicate balance between calcium carbonate (CaCO3) production and CaCO3 loss. Ocean acidification (OA), the CO2-driven decline in seawater pH and CaCO3 saturation state (Ω), threatens to tip this balance by decreasing calcification, and increasing erosion and dissolution. While multiple CO2 manipulation experiments show coral calcification declines under OA, the sensitivity of bioerosion to OA is less well understood. Previous work suggests that coral and coral reef bioerosion increase with decreasing seawater Ω. However, in the surface ocean, Ω and nutrient concentrations often covary, making their relative influence difficult to resolve. Here, we exploit unique natural gradients in Ω and nutrients across the Pacific basin to quantify the impact of these factors, together and independently, on macrobioerosion rates of coral skeletons. Using an automated program to quantify macrobioerosion in 3-D computerized tomography (CT) scans of coral cores, we show that macrobioerosion rates of live Porites colonies in both low-nutrient (oligotrophic) and high-nutrient (>1 µM nitrate) waters increase significantly as Ω decreases. However, the sensitivity of macrobioerosion to Ω is ten times greater under high-nutrient conditions. Our results demonstrate that OA (decreased Ω) alone can increase coral macrobioerosion rates, but the interaction of OA with local stressors exacerbates its impact, accelerating a shift toward net CaCO3 removal from coral reefs.This work was supported by NSF OCE 1041106 to A.L.C. and K.E.S., NSF OCE 1220529 to A.L.C., TNC award PNA/WHOI061810 to A.L.C., NSF Graduate Research Fellowships to T.M.D. and H.C.B., and a WHOI-OLI post-doctoral fellowship to K.E.S.2015-11-1

Defining Accelerometer Thresholds for Activity Intensities in Adolescent Girls

Purpose - To derive a regression equation that estimates metabolic equivalent (MET) from accelerometer counts, and to define thresholds of accelerometer counts that can be used to delineate sedentary, light, moderate, and vigorous activity. Methods - Seventy-four healthy 8th grade girls, age 13-14 yr, were recruited from urban areas of Baltimore, MD, Minneapolis/St. Paul, MN, and Columbia, SC, to participate in the study. Accelerometer and oxygen consumption (VO2) data for 10 activities that varied in intensity from sedentary (e.g., TV watching) to vigorous (e.g., running) were collected. While performing these activities, the girls wore two accelerometers, a heart rate monitor and a Cosmed K4b2 portable metabolic unit for measurement of VO2. A random-coefficients model was used to estimate the relationship between accelerometer counts and VO2. Activity thresholds were defined by minimizing the false positive and false negative classifications. Results - The activities provided a wide range in VO2 (3-36 mL·kg-1·min-1) with a correspondingly wide range in accelerometer counts (1-3928 counts·30 s-1). The regression line for MET score versus counts was MET=2.01+0.00171 (counts·30 s-1) (mixed model R2=0.84, SEE=1.36). A threshold of 1500 counts·30 s-1 defined the lower end of the moderate intensity (~4.6 METs) range of physical activity. That cutpoint distinguished between slow and brisk walking, and gave the lowest number of false positive and false negative classifications. The threshold ranges for sedentary, light, moderate, and vigorous physical activity were found to be 0-50, 51-1499, 1500-2600, and \u3e2600 counts·30 s-1, respectively. Conclusion - The developed equation and these activity thresholds can be used for prediction of MET score from accelerometer counts and participation in various intensities of physical activity in adolescent girls

The telomere of human chromosome 1p contains at least two independent autosomal dominant congenital cataract genes.

AIMS: Multiple genetic causes of congenital cataract have been identified, both as a component of syndromes and in families that present with isolated congenital cataract. Linkage analysis was used to map the genetic locus in a six generation Australian family presenting with total congenital cataract. METHODS: Microsatellite markers located across all known autosomal dominant congenital cataract loci were genotyped in all recruited family members of the Tasmanian family. Both two point and multipoint linkage analysis were used to assess each locus under an autosomal dominant model. RESULTS: Significant linkage was detected at the telomere of the p arm of chromosome 1, with a maximum two point LOD of 4.21 at marker D1S507, a maximum multipoint exact LOD of 5.44, and an estimated location score of 5.61 at marker D1S507. Haplotype analysis places the gene inside a critical region between D1S228 and D1S199, a distance of approximately 6 megabases. The candidate gene PAX7 residing within the critical interval was excluded by direct sequencing in affected individuals. CONCLUSION: This is the third report of congenital cataract linkage to 1ptel. The critical region as defined by the shared haplotype in this family is clearly centromeric from the Volkmann cataract locus identified through study of a Danish family, indicating that two genes causing autosomal dominant congenital cataract map to the telomeric region of chromosome 1p

Heterotrophy of oceanic particulate organic matter elevates net ecosystem calcification

Author Posting. © American Geophysical Union, 2019. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Geophysical Research Letters 46(16), (2019): 9851-9860, doi:10.1029/2019GL083726.Coral reef calcification is expected to decline due to climate change stressors such as ocean acidification and warming. Projections of future coral reef health are based on our understanding of the environmental drivers that affect calcification and dissolution. One such driver that may impact coral reef health is heterotrophy of oceanic‐sourced particulate organic matter, but its link to calcification has not been directly investigated in the field. In this study, we estimated net ecosystem calcification and oceanic particulate organic carbon (POCoc) uptake across the Kāne'ohe Bay barrier reef in Hawai'i. We show that higher rates of POCoc uptake correspond to greater net ecosystem calcification rates, even under low aragonite saturation states (Ωar). Hence, reductions in offshore productivity may negatively impact coral reefs by decreasing the food supply required to sustain calcification. Alternatively, coral reefs that receive ample inputs of POCoc may maintain higher calcification rates, despite a global decline in Ωar.Data needed for calculations are available in the supporting information. Additional data can be provided upon request directly from the corresponding author or accessed by links provided in the supporting information. The authors declare no competing financial interests. We thank Texas Sea Grant for providing partial funding for this project to A. Kealoha through the Grants‐In‐Aid of Graduate Research Program. We also thank the NOAA Nancy Foster Scholarship for PhD program funding to A. Kealoha and Texas A&M University for funds awarded to Shamberger that supported this work. This research was also supported by funding from National Science Foundation Grant OCE‐1538628 to Rappé. The Hawaii Institute of Marine Biology (particularly the Rappé Lab and Jason Jones), NOAA's Coral Reef Ecosystem Program, Connie Previti, Serena Smith, and Chris Maupin were instrumental in sample collection and data analysis.2020-02-2

Abelian Hidden Sectors at a GeV

We discuss mechanisms for naturally generating GeV-scale hidden sectors in the context of weak-scale supersymmetry. Such low mass scales can arise when hidden sectors are more weakly coupled to supersymmetry breaking than the visible sector, as happens when supersymmetry breaking is communicated to the visible sector by gauge interactions under which the hidden sector is uncharged, or if the hidden sector is sequestered from gravity-mediated supersymmetry breaking. We study these mechanisms in detail in the context of gauge and gaugino mediation, and present specific models of Abelian GeV-scale hidden sectors. In particular, we discuss kinetic mixing of a U(1)_x gauge force with hypercharge, singlets or bi-fundamentals which couple to both sectors, and additional loop effects. Finally, we investigate the possible relevance of such sectors for dark matter phenomenology, as well as for low- and high-energy collider searches.Comment: 43 pages, no figures; v2: to match JHEP versio