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Harnessing the potential beneficial effects of kinase signalling through the generation of direct kinase activators remains an underexplored area of drug development1-5. This also applies to the PI3K signalling pathway, which has been extensively targeted by inhibitors for conditions with PI3K overactivation, such as cancer and immune dysregulation. Here we report the discovery of UCL-TRO-1938 (referred to as 1938 hereon), a small-molecule activator of the PI3K isoform, a crucial effector of growth factor signalling. 1938 allosterically activates PI3K through a distinct mechanism by enhancing multiple steps of the PI3K catalytic cycle and causes both local and global conformational changes in the PI3K structure. This compound is selective for PI3K over other PI3K isoforms and multiple protein and lipid kinases. It transiently activates PI3K signalling in all rodent and human cells tested, resulting in cellular responses such as proliferation and neurite outgrowth. In rodent models, acute treatment with 1938 provides cardioprotection from ischaemia-reperfusion injury and, after local administration, enhances nerve regeneration following nerve crush. This study identifies a chemical tool to directly probe the PI3K signalling pathway and a new approach to modulate PI3K activity, widening the therapeutic potential of targeting these enzymes through short-term activation for tissue protection and regeneration. Our findings illustrate the potential of activating kinases for therapeutic benefit, a currently largely untapped area of drug development.

Background: Thrombolytic therapy for acute ischemic stroke has been approached cautiously because there were high rates of intracerebral hemorrhage in early clinical trials. We performed a randomized, double-blind trial of intravenous recombinant tissue plasminogen activator (t-PA) for ischemic stroke after recent pilot studies suggested that t-PA was beneficial when treatment was begun within three hours of the onset of stroke.

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Methods: To study this question, we randomly assigned 2431 patients to one of four treatment strategies for reperfusion: streptokinase with subcutaneous heparin; streptokinase with intravenous heparin; accelerated-dose tissue plasminogen activator (t-PA) with intravenous heparin; or a combination of both activators plus intravenous heparin. Patients were also randomly assigned to cardiac angiography at one of four times after the initiation of thrombolytic therapy: 90 minutes, 180 minutes, 24 hours, or 5 to 7 days. The group that underwent angiography at 90 minutes underwent it again after 5 to 7 days.

Rationale: Intrapleural tissue plasminogen activator (tPA)/deoxyribonuclease (DNase) therapy for pleural infection given at the time of diagnosis has been shown to significantly improve radiological outcomes. Published cases are limited to only a single randomized controlled trial and a few case reports.

RNA polymerase II (RNA Pol II) transcription reconstituted from purified factors suggests pre-initiation complexes (PICs) can assemble by sequential incorporation of factors at the TATA box. However, these basal transcription reactions are generally independent of activators and co-activators. To study PIC assembly under more realistic conditions, we used single-molecule microscopy to visualize factor dynamics during activator-dependent reactions in nuclear extracts. Surprisingly, RNA Pol II, TFIIF, and TFIIE can pre-assemble on enhancer-bound activators before loading into PICs, and multiple RNA Pol II complexes can bind simultaneously to create a localized cluster. Unlike TFIIF and TFIIE, TFIIH binding is singular and dependent on the basal promoter. Activator-tethered factors exhibit dwell times on the order of seconds. In contrast, PICs can persist on the order of minutes in the absence of nucleotide triphosphates, although TFIIE remains unexpectedly dynamic even after TFIIH incorporation. Our kinetic measurements lead to a new branched model for activator-dependent PIC assembly.

Next to the Diversified technique, the Activator adjusting instrument is reported to be one of the more common therapeutic interventions used by chiropractors. According to the National Board of Chiropractic Examiners, about half of full-time American chiropractors have used the Activator Method in their practices. 1 National Board of Chiropractic Examiners. Job Analysis of Chiropractic 2005: A project report, survey analysis, and summary of the practice of chiropractic within the United States. Greeley, CO. January 2005. The Activator Method is also commonly used in Canada, Australia, and New Zealand. 2 Huggins T, Boras AL, Gleberzon BJ, et al. Clinical effectiveness of the activator adjusting instrument in the management of musculoskeletal disorders: a systematic review of the literature. Journal of the Canadian Chiropractic Association 2012;56(1):49-57.

Most human cells lack sufficient telomerase to maintain telomeres, hence these genetic elements shorten with time and stress, contributing to aging and disease. In January, 2007, a commercial health maintenance program, PattonProtocol-1, was launched that included a natural product-derived telomerase activator (TA-65, 10-50 mg daily), a comprehensive dietary supplement pack, and physician counseling/laboratory tests at baseline and every 3-6 months thereafter. We report here analysis of the first year of data focusing on the immune system. Low nanomolar levels of TA-65 moderately activated telomerase in human keratinocytes, fibroblasts, and immune cells in culture; similar plasma levels of TA-65 were achieved in pilot human pharmacokinetic studies with single 10- to 50-mg doses. The most striking in vivo effects were declines in the percent senescent cytotoxic (CD8(+)/CD28(-)) T cells (1.5, 4.4, 8.6, and 7.5% at 3, 6, 9, and 12 months, respectively; p = not significant [N.S.], 0.018, 0.0024, 0.0062) and natural killer cells at 6 and 12 months (p = 0.028 and 0.00013, respectively). Most of these decreases were seen in cytomegalovirus (CMV) seropositive subjects. In a subset of subjects, the distribution of telomere lengths in leukocytes at baseline and 12 months was measured. Although mean telomere length did not increase, there was a significant reduction in the percent short (

TA-65 is a dietary supplement based on an improved formulation of a small molecule telomerase activator that was discovered in a systematic screening of natural product extracts from traditional Chinese medicines. This study summarizes the findings on telomere length (TL) changes from a randomized, double blind, placebo controlled study of TA-65 over a 1 year period. The study was conducted on 117 relatively healthy cytomegalovirus-positive subjects aged 53-87 years old. Subjects taking the low dose of TA-65 (250 U) significantly increased TL over the 12 months period (530 180 bp; p = 0.005), whereas subjects in the placebo group significantly lost TL (290 100 bp; p = 0.01). The high dose of TA-65 (1000 U) showed a trend of improvements in TL compared with that of the placebo group; however, the improvements did not reach statistical significance. TL changes in the low-dose group were similar for both median and 20th percentile TLs. The findings suggest that TA-65 can lengthen telomeres in a statistically and possibly clinically significant manner.

Acute infantile GM2 activator deficiency is a neurodegenerative disorder in which infants, who are generally normal at birth, have progressive weakness and slowing of developmental progress between ages four and 12 months. An ensuing developmental plateau is followed by progressively rapid developmental regression. By the second year of life decerebrate posturing, difficulty in swallowing, and worsening seizures lead to an unresponsive vegetative state. Death usually occurs between ages two and three years.

The diagnosis of GM2 activator deficiency is established in a proband with suggestive findings of GM2 gangliosidosis, normal beta-hexosaminidase A (HEX A) enzyme activity levels, and biallelic pathogenic (or likely pathogenic) variants in GM2A identified by molecular genetic testing.

Treatment of manifestations: There is no cure for GM2 activator deficiency. Supportive care to provide adequate nutrition and hydration, manage infectious disease, protect the airway, and control seizures involves multidisciplinary care by specialists in relevant fields.

GM2 activator deficiency is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a GM2A pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants. Once the GM2A pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.

The diagnosis of GM2 activator deficiency is established in a proband with suggestive findings, normal beta-hexosaminidase A (HEX A) enzyme activity levels, and biallelic pathogenic (or likely pathogenic) variants in GM2A identified by molecular genetic testing (see Table 1).

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of GM2 activator deficiency overlaps with several biochemically related disorders (GM2 gangliosidoses), most infants with the findings described in Suggestive Findings are likely to be diagnosed using a multigene panel or genomic testing.

When the phenotypic and laboratory findings suggest the diagnosis of GM2 activator deficiency, molecular genetic testing approaches can include single-gene testing or use of a multigene panel. be457b7860

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