Impaired Nuclear Export of Polyglutamine-Expanded Androgen Receptor in Spinal and Bulbar Muscular Atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by polyglutamine (polyQ) expansion in the androgen receptor (AR). Prior studies have highlighted the importance of AR nuclear localization in SBMA pathogenesis; therefore, in this study, we sought to determine the role of AR nuclear export in the pathological manifestations of SBMA. We demonstrate here that the nuclear export of polyQ-expanded AR is impaired, even prior to the formation of intranuclear inclusions of aggregated AR. Additionally, we find that promoting AR export with an exogenous nuclear export signal substantially reduces its aggregation and blocks hormone-induced toxicity. Moreover, we show that these protective effects are conferred by destabilization of the mutant protein due to an increase in proteasomal degradation of the cytoplasmic AR. Despite a growing body of evidence that global disruption of nucleo/cytoplasmic transport occurs in ALS and HD, our data suggest that no such global disruption occurs in models of SBMA; rather, AR-specific mechanisms, including reduced phosphorylation at Serine 650, are likely responsible for the impaired nuclear export of polyQ-expanded AR

Contemporary transformations seen in the use of human rights

Human rights are increasingly described as in crisis. The rising populist tide that puts nation, religion, and race first poses new kinds of threats to human rights. But are human rights, underpinning the universal order of justice, really on the verge of disappearing

Cutting edge: circulating plasmablasts induce the differentiation of human T follicular helper cells via IL-6 production

B cells require CD4(+) T follicular helper (Tfh) cells to progress through the germinal center and provide protective Ab responses. In this article, we reveal a reciprocal interaction whereby circulating human plasmablasts are potent inducers of the Tfh cell-differentiation program, including the expression of their key transcription factor Bcl-6. The markedly increased propensity of plasmablasts, compared with naive B cells, to induce Tfh cell differentiation was due to their increased production of IL-6. Specific targeting of IL-6 using tocilizumab therapy in patients with rheumatoid arthritis led to a significant reduction in circulating Tfh cell numbers and IL-21 production, which was correlated with reduced plasmablast formation. Our data uncover a positive-feedback loop between circulating plasmablasts and Tfh cells that could sustain autoimmunity and spread Ab-driven inflammation to unaffected sites; this represents an important therapeutic target, as well as reveals a novel mechanism of action for tocilizumab

PENEGAKAN HUKUM TERHADAP PELAKU USAHA PARIWISATA ATAS PELANGGARAN PEMBAYARAN PAJAK DAN RETRIBUSI DAERAH BERDASARKAN PERATURAN DAERAH KOTA MANADO NOMOR 2 TAHUN 2015 TENTANG PENYELENGARAAAN KEPARIWISATAAN

e journal Fakultas Hukum Universitas Sam Ratulang

Treatment-resistant depression in adolescents: is the addition of cognitive behavioral therapy of benefit?

BACKGROUND: Many young people with major depression fail first-line treatments. Treatment-resistant depression has various definitions in the literature but typically assumes nonresponse to medication. In young people, cognitive behavioral therapy (CBT) is the recommended first-line intervention, thus the definition of treatment resistance should be expanded. Therefore, our aim was to synthesize the existing evidence of any interventions for treatment-resistant depression, broadly defined, in children and adolescents and to investigate the effectiveness of CBT in this context. METHODS: We used Cochrane Collaboration methodology, with electronic searches of Medline, PsycINFO, Embase, and the Cochrane Depression Anxiety and Neurosis Group trials registers. Only randomized controlled trials were included, and were assessed for risk of bias. Meta- analysis was undertaken where possible and appropriate. RESULTS: Of 953 articles retrieved, four trials were eligible for inclusion. For one study, only the trial registration document was available, because the study was never completed. All other studies were well conducted with a low risk of bias, although one study had a high dropout rate. Two studies assessed the effect of adding CBT to medication. While an assertive trial of antidepressants does appear to lead to benefit, when compared with placebo, there was no significant advantage, in either study, or in a meta-analysis of data from these trials, that clearly demonstrated an additional benefit of CBT. The third trial showed little advantage of a tricyclic antidepressant over placebo in the context of an inpatient admission. CONCLUSION: Few randomized controlled trials have investigated interventions for treatment-resistant depression in young people, and results from these show modest benefit from antidepressants with no additional benefit over medication from CBT. Overall, there is a lack of evidence about effective interventions to treat young people who have failed to respond to evidence-based interventions for depression. Research in this area is urgently required

Perancangan Film Dokumenter Berjudul Saya Pemulung

Masih banyaknya masyarakat yang memandang perempuan berbeda dengan pria menyebabkan wanita dianggap lemah. Budaya patriaki masih melekat pada masyarakat khususnya di Indonesia, padahal banyak perempuan yang lebih kuat dan hebat daripada pria. Film dokumenter dibuat untuk mengubah pola pikir lama masyarakat dengan menceritakan potret kehidupan seorang perempuan yang berjuang bekerja menjadi seorang pemulung untuk menghidupi keluarganya. Semoga dapat mengubah pandangan masyarakat dan menginspirasi perempuan-perempuan lain