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Glucose metabolism in the retina is carefully orchestrated, with glucose being delivered to photoreceptors from the choroidal circulation through the retinal pigmented epithelium (RPE). In photoreceptors, glucose is processed principally by aerobic glycolysis, from which the lactate byproduct is provided to the RPE and Müller glia for their energetic needs. In this study, we utilize a modified arrestin1 protein to enhance the glycolytic output of lactate from rod photoreceptors through disinhibition of enolase1 activity with the goal being to use this increased lactate production as a gene-agnostic approach to slowing retinal degeneration. Mouse arrestin1 with E362G/D363G amino acid substitutions (referred to as "ArrGG") was packaged into AAV and tested for safety and for efficacy in increasing retinal lactate production. Overexpression of ArrGG in C57BL/6J mice did not result in any detectable changes in either electroretinogram (ERG) function or photoreceptor survival as measured by outer nuclear layer (ONL) thickness. However, mouse retinas expressing ArrGG showed a ∼25% increase in the rate of lactate secretion. Therefore, AAV-ArrGG was delivered intravitreally to heterozygous P23H rhodopsin knockin mice (RhoP23H/+) to determine if enhancing glycolysis in photoreceptors can slow retinal degeneration in this animal model of retinitis pigmentosa. We found that the expression of ArrGG in these mice slowed the decline of both scotopic and photopic ERG function. Correspondingly, there was significant preservation of ONL thickness in RhoP23H/+ mice treated with ArrGG compared with controls. In conclusion, our studies show that expressing ArrGG in C57BL/6J mouse retina results in an increase in lactate production, consistent with an upregulation of glycolysis. In the P23H rhodopsin model of retinitis pigmentosa, the expression of ArrGG led to significant preservation of photoreceptor function and slowing of retinal degeneration. These findings suggest that enhancing glycolysis by targeting increased enolase1 activity with a modified arrestin1 in photoreceptors may offer a therapeutic approach to slowing retinal degeneration.

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Expression of mutant Ataxin-1 with an abnormally expanded polyglutamine domain is necessary for the onset and progression of spinocerebellar ataxia type 1 (SCA1). Understanding how Ataxin-1 expression is regulated in the human brain could inspire novel molecular therapies for this fatal, dominantly inherited neurodegenerative disease. Previous studies have shown that the ATXN1 3'UTR plays a key role in regulating the Ataxin-1 cellular pool via diverse post-transcriptional mechanisms. Here we show that elements within the ATXN1 5'UTR also participate in the regulation of Ataxin-1 expression. PCR and PacBio sequencing analysis of cDNA obtained from control and SCA1 human brain samples revealed the presence of three major, alternatively spliced ATXN1 5'UTR variants. In cell-based assays, fusion of these variants upstream of an EGFP reporter construct revealed significant and differential impacts on total EGFP protein output, uncovering a type of genetic rheostat-like function of the ATXN1 5'UTR. We identified ribosomal scanning of upstream AUG codons and increased transcript instability as potential mechanisms of regulation. Importantly, transcript-based analyses revealed significant differences in the expression pattern of ATXN1 5'UTR variants between control and SCA1 cerebellum. Together, the data presented here shed light into a previously unknown role for the ATXN1 5'UTR in the regulation of Ataxin-1 and provide new opportunities for the development of SCA1 therapeutics.

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Management of patients receiving anticoagulants is a major factor in achieving better outcomes. Anticoagulant therapy may need to be discontinued or rapidly reversed before urgent surgery or invasive procedures. In these situations, treatment with concentrated vitamin K, fresh frozen plasma, and/or clotting factors can achieve more rapid anticoagulant reversal than can drug discontinuation alone. Activated prothrombin complex concentrate is used to treat hemophiliac patients with acquired factor VIII inhibitors. Nonactivated prothrombin complex concentrates are used for anticoagulant reversal. The concentrates are effective within minutes of dosing, providing a nearly immediate decrease in the international normalized ratio. The concentrates are lyophilized powders that can be quickly reconstituted, do not require ABO blood typing before use, and contain 25 times the concentration of vitamin K-dependent clotting factors compared with fresh frozen plasma. Studies suggest that the concentrates are associated with better clinical end points than is fresh frozen plasma.

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Exposure to traumatic events happens at an alarming rate for children and adolescents in the United States. If left unaddressed, these youth have a high risk of growing up with additional health and mental health problems. In this article the authors review three key aspects of helping youth heal from the symptoms of experiencing a traumatic event; (1) recommended guidelines, (2) specific treatments, and (3) the Trauma-Informed Care Framework. Eleven recommendations from the American Academy of Child and Adolescent Psychiatry are discussed as they relate to effective practices in the treatment of trauma in children and adolescents. Trauma-focused cognitive behavioral therapy and child-parent psychotherapy are also explored as the two specific interventions that have the most empirical support for treatment in children and adolescents. Finally, the tenets of a Trauma-Informed Care Framework are presented along with a review of how well these have been applied in youth serving organizations.

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