MSAT boom joint testing and load absorber design

Through a series of component and system-level tests, the torque margin for the MSAT booms is being determined. The verification process has yielded a number of results and lessons that can be applied to many other types of deployable spacecraft mechanisms. The MSAT load absorber has proven to be an effective way to provide high energy dissipation using crushable honeycomb. Using two stages of crushable honeycomb and a fusible link, a complex crush load profile has been designed and implemented. The design features of the load absorber lend themselves to use in other spacecraft applications

Sexual reproduction is the null hypothesis for life cycles of rust fungi

Sexual reproduction, mutation, and reassortment of nuclei increase genotypic diversity in rust fungi. Sexual reproduction is inherent to rust fungi, coupled with their coevolved plant hosts in native pathosystems. Rust fungi are hypothesised to exchange nuclei by somatic hybridisation with an outcome of increased genotypic diversity, independent of sexual reproduction. We provide criteria to demonstrate whether somatic exchange has occurred, including knowledge of parental haplotypes and rejection of fertilisation in normal rust life cycles

Using Mendelian randomisation to identify opportunities for type 2 diabetes prevention by repurposing medications used for lipid management

Background: Maintaining a healthy lifestyle to reduce type 2 diabetes (T2D) risk is challenging and additional strategies for T2D prevention are needed. We evaluated several lipid control medications as potential therapeutic options for T2D prevention using tissue-specific predicted gene expression summary statistics in a two-sample Mendelian randomisation (MR) design. Methods: Large-scale European genome-wide summary statistics for lipids and T2D were leveraged in our multi-stage analysis to estimate changes in either lipid levels or T2D risk driven by tissue-specific predicted gene expression. We incorporated tissue-specific predicted gene expression summary statistics to proxy therapeutic effects of three lipid control medications [i.e., statins, icosapent ethyl (IPE), and proprotein convertase subtilisin/kexin type-9 inhibitors (PCSK-9i)] on T2D susceptibility using two-sample Mendelian randomisation (MR). Findings: IPE, as proxied via increased FADS1 expression, was predicted to lower triglycerides and was associated with a 53% reduced risk of T2D. Statins and PCSK-9i, as proxied by reduced HMGCR and PCSK9 expression, respectively, were predicted to lower LDL-C levels but were not associated with T2D susceptibility. Interpretation: Triglyceride lowering via IPE may reduce the risk of developing T2D in populations of European ancestry. However, experimental validation using animal models is needed to substantiate our results and to motivate randomized control trials (RCTs) for IPE as putative treatment for T2D prevention. Funding: Only summary statistics were used in this analysis. Funding information is detailed under Acknowledgments. © 2022Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination.

Abstract OBJECTIVE: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination. METHODS: We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients. RESULTS: The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10\u2009mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of 652 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077). CONCLUSION: Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation

Modulation of Serotonin Transporter Function during Fetal Development Causes Dilated Heart Cardiomyopathy and Lifelong Behavioral Abnormalities

BACKGROUND: Women are at great risk for mood and anxiety disorders during their childbearing years and may become pregnant while taking antidepressant drugs. In the treatment of depression and anxiety disorders, selective serotonin reuptake inhibitors (SSRIs) are the most frequently prescribed drugs, while it is largely unknown whether this medication affects the development of the central nervous system of the fetus. The possible effects are the product of placental transfer efficiency, time of administration and dose of the respective SSRI. METHODOLOGY/PRINCIPAL FINDINGS: In order to attain this information we have setup a study in which these parameters were measured and the consequences in terms of physiology and behavior are mapped. The placental transfer of fluoxetine and fluvoxamine, two commonly used SSRIs, was similar between mouse and human, indicating that the fetal exposure of these SSRIs in mice is comparable with the human situation. Fluvoxamine displayed a relatively low placental transfer, while fluoxetine showed a relatively high placental transfer. Using clinical doses of fluoxetine the mortality of the offspring increased dramatically, whereas the mortality was unaffected after fluvoxamine exposure. The majority of the fluoxetine-exposed offspring died postnatally of severe heart failure caused by dilated cardiomyopathy. Molecular analysis of fluoxetine-exposed offspring showed long-term alterations in serotonin transporter levels in the raphe nucleus. Furthermore, prenatal fluoxetine exposure resulted in depressive- and anxiety-related behavior in adult mice. In contrast, fluvoxamine-exposed mice did not show alterations in behavior and serotonin transporter levels. Decreasing the dose of fluoxetine resulted in higher survival rates and less dramatic effects on the long-term behavior in the offspring. CONCLUSIONS: These results indicate that prenatal fluoxetine exposure affects fetal development, resulting in cardiomyopathy and a higher vulnerability to affective disorders in a dose-dependent manner

Alternative splicing in a presenilin 2 variant associated with Alzheimer disease

Objective: Autosomal-dominant familial Alzheimer disease (AD) is caused by by variants in presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein (APP). Previously, we reported a rare PSEN2 frameshift variant in an early-onset AD case (PSEN2 p.K115Efs*11). In this study, we characterize a second family with the same variant and analyze cellular transcripts from both patient fibroblasts and brain lysates. Methods: We combined genomic, neuropathological, clinical, and molecular techniques to characterize the PSEN2 K115Efs*11 variant in two families. Results: Neuropathological and clinical evaluation confirmed the AD diagnosis in two individuals carrying the PSEN2 K115Efs*11 variant. A truncated transcript from the variant allele is detectable in patient fibroblasts while levels of wild-type PSEN2 transcript and protein are reduced compared to controls. Functional studies to assess biological consequences of the variant demonstrated that PSEN2 K115Efs*11 fibroblasts secrete less Aβ₁-₄₀ compared to controls, indicating abnormal γ-secretase activity. Analysis of PSEN2 transcript levels in brain tissue revealed alternatively spliced PSEN2 products in patient brain as well as in sporadic AD and age-matched control brain. Interpretation: These data suggest that PSEN2 K115Efs*11 is a likely pathogenic variant associated with AD. We uncovered novel PSEN2 alternative transcripts in addition to previously reported PSEN2 splice isoforms associated with sporadic AD. In the context of a frameshift, these alternative transcripts return to the canonical reading frame with potential to generate deleterious protein products. Our findings suggest novel potential mechanisms by which PSEN variants may influence AD pathogenesis, highlighting the complexity underlying genetic contribution to disease risk.Jacquelyn E. Braggin, Stephanie A. Bucks, Meredith M. Course, Carole L. Smith, Bryce Sopher, Leah Osnis, Kiel D. Shuey, Kimiko Domoto-Reilly, Christina Caso, Chizuru Kinoshita, Kathryn P. Scherpelz, Chloe Cross, Thomas Grabowski, Seyyed H.M. Nik, Morgan Newman, Gwenn A. Garden, James B. Leverenz, Debby Tsuang, Caitlin Latimer, Luis F. Gonzalez-Cuyar, Christopher Dirk Keene, Richard S. Morrison, Kristoffer Rhoads, Ellen M. Wijsman, Michael O. Dorschner, Michael Lardelli, Jessica E. Young, Paul N. Valdmanis, Thomas D. Bird, Suman Jayade

D1 Dopamine Receptor Signaling Is Modulated by the R7 RGS Protein EAT-16 and the R7 Binding Protein RSBP-1 in Caenoerhabditis elegans Motor Neurons

Dopamine signaling modulates voluntary movement and reward-driven behaviors by acting through G protein-coupled receptors in striatal neurons, and defects in dopamine signaling underlie Parkinson's disease and drug addiction. Despite the importance of understanding how dopamine modifies the activity of striatal neurons to control basal ganglia output, the molecular mechanisms that control dopamine signaling remain largely unclear. Dopamine signaling also controls locomotion behavior in Caenorhabditis elegans. To better understand how dopamine acts in the brain we performed a large-scale dsRNA interference screen in C. elegans for genes required for endogenous dopamine signaling and identified six genes (eat-16, rsbp-1, unc-43, flp-1, grk-1, and cat-1) required for dopamine-mediated behavior. We then used a combination of mutant analysis and cell-specific transgenic rescue experiments to investigate the functional interaction between the proteins encoded by two of these genes, eat-16 and rsbp-1, within single cell types and to examine their role in the modulation of dopamine receptor signaling. We found that EAT-16 and RSBP-1 act together to modulate dopamine signaling and that while they are coexpressed with both D1-like and D2-like dopamine receptors, they do not modulate D2 receptor signaling. Instead, EAT-16 and RSBP-1 act together to selectively inhibit D1 dopamine receptor signaling in cholinergic motor neurons to modulate locomotion behavior

Liposomes in Biology and Medicine

Drug delivery systems (DDS) have become important tools for the specific delivery of a large number of drug molecules. Since their discovery in the 1960s liposomes were recognized as models to study biological membranes and as versatile DDS of both hydrophilic and lipophilic molecules. Liposomes--nanosized unilamellar phospholipid bilayer vesicles--undoubtedly represent the most extensively studied and advanced drug delivery vehicles. After a long period of research and development efforts, liposome-formulated drugs have now entered the clinics to treat cancer and systemic or local fungal infections, mainly because they are biologically inert and biocompatible and practically do not cause unwanted toxic or antigenic reactions. A novel, up-coming and promising therapy approach for the treatment of solid tumors is the depletion of macrophages, particularly tumor associated macrophages with bisphosphonate-containing liposomes. In the advent of the use of genetic material as therapeutic molecules the development of delivery systems to target such novel drug molecules to cells or to target organs becomes increasingly important. Liposomes, in particular lipid-DNA complexes termed lipoplexes, compete successfully with viral gene transfection systems in this field of application. Future DDS will mostly be based on protein, peptide and DNA therapeutics and their next generation analogs and derivatives. Due to their versatility and vast body of known properties liposome-based formulations will continue to occupy a leading role among the large selection of emerging DDS