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Huntington's disease (HD) is a fatal neurodegenerative disease caused by an extended polyglutamine (polyQ) domain within the first exon of the huntingtin protein (htt). PolyQ expansion directly invokes the formation of a heterogenous mixture of toxic htt aggregates, including fibrils and oligomers. While htt is a cytosolic protein, it also associates with numerous membranous surfaces within the cell, leading to altered organelle morphology and dysfunction. Here, the impact of macromolecular crowding on htt aggregation in bulk solution and at solid/liquid or membrane/liquid interfaces was investigated. Dextran, Ficoll, and polyethylene glycol (PEG) were used as crowding agents. In bulk solution, crowding enhanced the heterogeneity of non-fibrillar aggregate species formed in a crowder dependent manner. However, crowding agents interfered with the deposition of htt fibrils on mica, suggesting that a crowded aqueous phase influences the interaction of htt with interfaces. By use of in situ atomic force microcopy (AFM), the aggregation of htt directly at mica and bilayer interfaces was tracked. The predominate aggregates type observed to form at the mica interface was fibrillar, but oligomeric aggregates of various stabilities were also observed. Crowding in the aqueous phase suppressed deposition and formation of htt aggregates on mica. In contrast, the addition of crowders enhanced deposition of htt aggregates onto supported total brain lipid extract (TBLE) bilayers. Different crowding agents led to distinct htt aggregates on supported bilayers with unique morphological impact on bilayer integrity. Collectively, these observations point to the complexity of htt aggregation at interfaces and that crowding in the aqueous phase profoundly influences this process.
Penile pain is one of the most stressful symptoms in men with Peyronie's disease (PD).
To evaluate the prevalence, clinical presentation and risk factors associated with penile pain in men with PD as well as to assess the psychosocial impact.
We revised our institution's database of men diagnosed with PD. The information collected included penile pain assessments, and the scores of the PD Questionnaire (PDQ), Self-Esteem and Relationship Questionnaire (SEAR) and Center for Epidemiologic Studies Depression Scale Questionnaire (CES-D). Descriptive and comparative statistics were used. Logistic regression analyses were performed to evaluate predictive factors associated with penile pain.
Penile pain descriptive assessment and factors associated with penile pain in men with PD. Comparison of SEAR, CES-D and PDQ domain scores of men with and without penile pain.
431 men with PD were included for this analysis with a mean age of 55.9 years. Penile pain was reported by 36.7%; 65.2% of those had painful ere It was more common in young men and was associated with physical and psychological bothers in this population. Flores JM, Salter CA, Nascimento B, et al. The Prevalence and Predictors of Penile Pain in Men with Peyronie's Disease. Sex Med 2021;9100398.
Vulvodynia is a difficult condition to treat due to both the uncertain etiology of the disorder and poorly available therapies. This difficulty leads to a disproportionately high prevalence and cost of treatment for this condition. Candida vulvovaginitis is a frequent co-present diagnosis in vulvodynia patients. Whether through treatment of co-present, candida vulvovaginitis or by systemic interaction, itraconazole has been proposed as a treatment for vulvodynia.
To describe objective change in vulvodynia pain in a cohort of patients treated with itraconazole.
This study was a retrospective cohort study comprised of women diagnosed with vulvodynia who were treated with itraconazole between January 1, 2011 and October 17, 2017. Patients had failed fluconazole treatment and had negative fungus cultures for >2 months before itraconazole treatment. All other vulvovaginal disorders were excluded.
The main outcome measure was the change in pain before and after treatment as measured by cotton swab testin0383.
Itraconazole therapy is associated with a significant reduction in vulvovaginal pain in patients with negative fungus cultures and no other identifiable disease in this pilot study. A randomized placebo-controlled trial is warranted. Rothenberger R, Jones W, MacNeill C. Itraconazole Improves Vulvodynia in Fungus Culture-Negative Patients Post Fluconazole Failure. J Sex Med 2021;9100383.TGFβ is crucial for the homeostasis of epithelial and neural tissues, wound repair, and regulating immune responses. Its dysregulation is associated with a vast number of diseases, of which modifying the tumor microenvironment is one of vital clinical interest. Despite various attempts, there is still no FDA-approved therapy to inhibit the TGFβ pathway. Major mainstream approaches involve impairment of the TGFβ pathway via inhibition of the TGFβRI kinase. With the purpose to identify non-receptor kinase-based inhibitors to impair TGFβ signaling, an in-house chemical library was enriched, through a computational study, to eliminate TGFβRI kinase activity. Selected compounds were screened against a cell line engineered with a firefly luciferase gene under TGFβ-Smad-dependent transcriptional control. Results indicated moderate potency for a molecule with phthalazine core against TGFβ-Smad signaling. A series of phthalazine compounds were synthesized and evaluated for potency. The most promising compound (10p) exhibited an IC50 of 0.11 ± 0.02 μM and was confirmed to be non-cytotoxic up to 12 μM, with a selectivity index of approximately 112-fold. Simultaneously, 10p was confirmed to reduce the Smad phosphorylation using Western blot without exhibiting inhibition on the TGFβRI enzyme. This study identified a novel small-molecule scaffold that targets the TGFβ pathway via a non-receptor-kinase mechanism.
Long noncoding RNAs (lncRNAs) have been reported to be associated with tumorigenesis and development of glioma. LINC00662 has been involved in the pathogenesis of various human cancers. SR59230A However, the mechanism underlying which LINC00662 exerts its role in glioma needs further exploration. In addition, regulation mechanism of LINC00662 expression in glioma remains unknown.
RT-qPCR was performed to evaluate the expression levels of LINC00662, miR-340-5p in glioma tissues and cell lines. The effect of LINC00662 and miR-340-5p in cell proliferation and invasion was assessed by Cell Counting Kit-8(CCK-8), clone colony formation and Transwell assay. Luciferase reporter assays and RNA immunoprecipitation assay validated the miR-340-5p-target relationships with LINC00662 or STAT3. CHIP-qPCR and Luciferase reporter assays were used to demonstrate the interaction between STAT3 and the promoter region of LINC00662. A tumor xenografts model was implemented to verify the effect of LINC00662 on glioma development in vivo.
