Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor-mediated disease.

Expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR) causes neuromuscular degeneration in individuals with spinobulbar muscular atrophy (SBMA). PolyQ AR has diminished transcriptional function and exhibits ligand-dependent proteotoxicity, features that have both been implicated in SBMA; however, the extent to which altered AR transcriptional function contributes to pathogenesis remains controversial. Here, we sought to dissociate effects of diminished AR function from polyQ-mediated proteotoxicity by enhancing the transcriptional activity of polyQ AR. To accomplish this, we bypassed the inhibitory effect of AR SUMOylation (where SUMO indicates small ubiquitin-like modifier) by mutating conserved lysines in the polyQ AR that are sites of SUMOylation. We determined that replacement of these residues by arginine enhances polyQ AR activity as a hormone-dependent transcriptional regulator. In a murine model, disruption of polyQ AR SUMOylation rescued exercise endurance and type I muscle fiber atrophy; it also prolonged survival. These changes occurred without overt alterations in polyQ AR expression or aggregation, revealing the favorable trophic support exerted by the ligand-activated receptor. Our findings demonstrate beneficial effects of enhancing the transcriptional function of the ligand-activated polyQ AR and indicate that the SUMOylation pathway may be a potential target for therapeutic intervention in SBMA

Formation and Evolution of the Disk System of the Milky Way: [alpha/Fe] Ratios and Kinematics of the SEGUE G-Dwarf Sample

We employ measurements of the [alpha/Fe] ratio derived from low-resolution (R~2000) spectra of 17,277 G-type dwarfs from the SEGUE survey to separate them into likely thin- and thick-disk subsamples. Both subsamples exhibit strong gradients of orbital rotational velocity with metallicity, of opposite signs, -20 to -30 km/s/dex for the thin-disk and +40 to +50 km/s/dex for the thick-disk population. The rotational velocity is uncorrelated with Galactocentric distance for the thin-disk subsample, and exhibits a small trend for the thick-disk subsample. The rotational velocity decreases with distance from the plane for both disk components, with similar slopes (-9.0 {\pm} 1.0 km/s/kpc). Thick-disk stars exhibit a strong trend of orbital eccentricity with metallicity (about -0.2/dex), while the eccentricity does not change with metallicity for the thin-disk subsample. The eccentricity is almost independent of Galactocentric radius for the thin-disk population, while a marginal gradient of the eccentricity with radius exists for the thick-disk population. Both subsamples possess similar positive gradients of eccentricity with distance from the Galactic plane. The shapes of the eccentricity distributions for the thin- and thick-disk populations are independent of distance from the plane, and include no significant numbers of stars with eccentricity above 0.6. Among several contemporary models of disk evolution we consider, radial migration appears to have played an important role in the evolution of the thin-disk population, but possibly less so for the thick disk, relative to the gas-rich merger or disk heating scenarios. We emphasize that more physically realistic models and simulations need to be constructed in order to carry out the detailed quantitative comparisons that our new data enable.Comment: Accepted for publication in ApJ, 18 pages, 12 figures, 2 tables, emulateapj forma

Muir-Torre Syndrome: The Importance of a Detailed Family History

Muir-Torre syndrome, a variant of Lynch syndrome or hereditary nonpolyposis colorectal cancer, is an autosomal dominant disease characterized by skin neoplasms (sebaceous or keratoacanthomas) and visceral malignancies. Due to the rarity of the syndrome there are no firm guidelines on how and when to test patients with its typical skin lesions. We describe a case that highlights the importance of a detailed family history

Altered Chromosomal Positioning, Compaction, and Gene Expression with a Lamin A/C Gene Mutation

Lamins A and C, encoded by the LMNA gene, are filamentous proteins that form the core scaffold of the nuclear lamina. Dominant LMNA gene mutations cause multiple human diseases including cardiac and skeletal myopathies. The nuclear lamina is thought to regulate gene expression by its direct interaction with chromatin. LMNA gene mutations may mediate disease by disrupting normal gene expression.To investigate the hypothesis that mutant lamin A/C changes the lamina's ability to interact with chromatin, we studied gene misexpression resulting from the cardiomyopathic LMNA E161K mutation and correlated this with changes in chromosome positioning. We identified clusters of misexpressed genes and examined the nuclear positioning of two such genomic clusters, each harboring genes relevant to striated muscle disease including LMO7 and MBNL2. Both gene clusters were found to be more centrally positioned in LMNA-mutant nuclei. Additionally, these loci were less compacted. In LMNA mutant heart and fibroblasts, we found that chromosome 13 had a disproportionately high fraction of misexpressed genes. Using three-dimensional fluorescence in situ hybridization we found that the entire territory of chromosome 13 was displaced towards the center of the nucleus in LMNA mutant fibroblasts. Additional cardiomyopathic LMNA gene mutations were also shown to have abnormal positioning of chromosome 13, although in the opposite direction.These data support a model in which LMNA mutations perturb the intranuclear positioning and compaction of chromosomal domains and provide a mechanism by which gene expression may be altered

Treatment for Mild Chronic Hypertension during Pregnancy.

BACKGROUND: The benefits and safety of the treatment of mild chronic hypertension (blood pressure, \u3c160/100 mm Hg) during pregnancy are uncertain. Data are needed on whether a strategy of targeting a blood pressure of less than 140/90 mm Hg reduces the incidence of adverse pregnancy outcomes without compromising fetal growth. METHODS: In this open-label, multicenter, randomized trial, we assigned pregnant women with mild chronic hypertension and singleton fetuses at a gestational age of less than 23 weeks to receive antihypertensive medications recommended for use in pregnancy (active-treatment group) or to receive no such treatment unless severe hypertension (systolic pressure, ≥160 mm Hg; or diastolic pressure, ≥105 mm Hg) developed (control group). The primary outcome was a composite of preeclampsia with severe features, medically indicated preterm birth at less than 35 weeks\u27 gestation, placental abruption, or fetal or neonatal death. The safety outcome was small-for-gestational-age birth weight below the 10th percentile for gestational age. Secondary outcomes included composites of serious neonatal or maternal complications, preeclampsia, and preterm birth. RESULTS: A total of 2408 women were enrolled in the trial. The incidence of a primary-outcome event was lower in the active-treatment group than in the control group (30.2% vs. 37.0%), for an adjusted risk ratio of 0.82 (95% confidence interval [CI], 0.74 to 0.92; P CONCLUSIONS: In pregnant women with mild chronic hypertension, a strategy of targeting a blood pressure of less than 140/90 mm Hg was associated with better pregnancy outcomes than a strategy of reserving treatment only for severe hypertension, with no increase in the risk of small-for-gestational-age birth weight. (Funded by the National Heart, Lung, and Blood Institute; CHAP ClinicalTrials.gov number, NCT02299414.)

Ginger inhibits cell growth and modulates angiogenic factors in ovarian cancer cells

<p>Abstract</p> <p>Background</p> <p>Ginger (<it>Zingiber officinale </it>Rosc) is a natural dietary component with antioxidant and anticarcinogenic properties. The ginger component [6]-gingerol has been shown to exert anti-inflammatory effects through mediation of NF-κB. NF-κB can be constitutively activated in epithelial ovarian cancer cells and may contribute towards increased transcription and translation of angiogenic factors. In the present study, we investigated the effect of ginger on tumor cell growth and modulation of angiogenic factors in ovarian cancer cells <it>in vitro</it>.</p> <p>Methods</p> <p>The effect of ginger and the major ginger components on cell growth was determined in a panel of epithelial ovarian cancer cell lines. Activation of NF-κB and and production of VEGF and IL-8 was determined in the presence or absence of ginger.</p> <p>Results</p> <p>Ginger treatment of cultured ovarian cancer cells induced profound growth inhibition in all cell lines tested. We found that <it>in vitro</it>, 6-shogaol is the most active of the individual ginger components tested. Ginger treatment resulted in inhibition of NF-kB activation as well as diminished secretion of VEGF and IL-8.</p> <p>Conclusion</p> <p>Ginger inhibits growth and modulates secretion of angiogenic factors in ovarian cancer cells. The use of dietary agents such as ginger may have potential in the treatment and prevention of ovarian cancer.</p

Highlights From the Annual Meeting of the American Epilepsy Society 2022

With more than 6000 attendees between in-person and virtual offerings, the American Epilepsy Society Meeting 2022 in Nashville, felt as busy as in prepandemic times. An ever-growing number of physicians, scientists, and allied health professionals gathered to learn a variety of topics about epilepsy. The program was carefully tailored to meet the needs of professionals with different interests and career stages. This article summarizes the different symposia presented at the meeting. Basic science lectures addressed the primary elements of seizure generation and pathophysiology of epilepsy in different disease states. Scientists congregated to learn about anti-seizure medications, mechanisms of action, and new tools to treat epilepsy including surgery and neurostimulation. Some symposia were also dedicated to discuss epilepsy comorbidities and practical issues regarding epilepsy care. An increasing number of patient advocates discussing their stories were intertwined within scientific activities. Many smaller group sessions targeted more specific topics to encourage member participation, including Special Interest Groups, Investigator, and Skills Workshops. Special lectures included the renown Hoyer and Lombroso, an ILAE/IBE joint session, a spotlight on the impact of Dobbs v. Jackson on reproductive health in epilepsy, and a joint session with the NAEC on coding and reimbursement policies. The hot topics symposium was focused on traumatic brain injury and post-traumatic epilepsy. A balanced collaboration with the industry allowed presentations of the latest pharmaceutical and engineering advances in satellite symposia

Instrumental methods and challenges in quantifying polybrominated diphenyl ethers in environmental extracts: a review

Increased interest in the fate, transport and toxicity of polybrominated diphenyl ethers (PBDEs) over the past few years has led to a variety of studies reporting different methods of analysis for these persistent organic pollutants. Because PBDEs encompass a range of vapor pressures, molecular weights and degrees of bromine substitution, various analytical methods can lead to discrimination of some PBDE congeners. Recent improvements in injection techniques and mass spectrometer ionization methods have led to a variety of options to determine PBDEs in environmental samples. The purpose of this paper is therefore to review the available literature describing the advantages and disadvantages in choosing an injection technique, gas chromatography column and detector. Additional discussion is given to the challenges in measuring PBDEs, including potential chromatographic interferences and the lack of commercial standards for higher brominated congeners, which provides difficulties in examining degradation and debromination of BDE congeners, particularly for BDE 209