piRNAs and Aubergine cooperate with Wispy poly(A) polymerase to stabilize mRNAs in the germ plasm

Piwi-interacting RNAs (piRNAs) and PIWI proteins play a crucial role in germ cells by repressing transposable elements and regulating gene expression. In Drosophila, maternal piRNAs are loaded into the embryo mostly bound to the PIWI protein Aubergine (Aub). Aub targets maternal mRNAs through incomplete base-pairing with piRNAs and can induce their destabilization in the somatic part of the embryo. Paradoxically, these Aub-dependent unstable mRNAs encode germ cell determinants that are selectively stabilized in the germ plasm. Here we show that piRNAs and Aub actively protect germ cell mRNAs in the germ plasm. Aub directly interacts with the germline-specific poly(A) polymerase Wispy, thus leading to mRNA polyadenylation and stabilization in the germ plasm. These results reveal a role for piRNAs in mRNA stabilization and identify Aub as an interactor of Wispy for mRNA polyadenylation. They further highlight the role of Aub and piRNAs in embryonic patterning through two opposite functions

URGE-PD: A Multi-Site, Double-Blind, Randomized, Placebo-Controlled Trial of Solifenacin succinate (VESIcare®) for the Treatment of Overactive Bladder in Parkinson’s Disease

Objective: To evaluate the safety and efficacy of solifenacin succinate (VESIcare®) in Parkinson\u27s disease patients suffering from overactive bladder (OAB). Background: Urinary dysfunction is a commonly encountered non-motor feature in many idiopathic Parkinson\u27s disease (PD) patients. While antimuscarinic drugs are often used to treat urinary symptoms, there are no controlled trials to evaluate their efficacy in PD. Methods: This was a double-blind, randomized, placebo-controlled, 3-site study that evaluated the efficacy of solifenacin succinate (VESIcare®) in idiopathic PD patients with overactive bladder (OAB) defined as at least 8 voids per 24-hr period and at least daily urinary urgency. Patients were randomized to receive solifenacin succinate 5mg or placebo for 6 weeks, and were offered the option to increase the dose to 10mg daily based upon clinical need, or continue with 5 mg daily. The primary outcome was the change in mean number of micturitions per 24 hour period as recorded on a 3-day bladder diary 12 weeks after randomization; secondary objectives included the change in the mean number of urinary incontinence episodes, the mean number of nocturia episodes, urinary urgency as measured by the The Patient Perception of Intensity of Urgency Scale (PPIUS), and the mean change in Patient Perception of Bladder Condition (PBC/PPBC). The Unified Parkinson\u27s disease Rating Scale (UPDRS) was performed at each 6-week interval visit. Results: Twenty-eight patients enrolled in the study (60% men, mean age 67.04±7.88 years (range 52-79 years)); 3 patients discontinued the study due to side effects of constipation, xerostomia and urinary rentention that resolved upon medication discontinuation. At endpoint, the mean number of urinary incontinence episodes per 24 hour period decreased significantly in the solifenacin group compared to placebo (1.48 ± 2.56 to 0.30 ± 0.31 versus 1.78 ± 1.27 to 1.61 ± 1.40, p=0.01), at a mean dose of 6mg/day. There was a trend for improvement in the motor section of the UPDRS in the solifenacin group (9.89 ± 5.58 to 8.11 ± 5.37 versus 11.75 ± 4.58 to 11.75 ± 3.98, p=0.09). Conclusions: Use of solifenancin succinate (VESIcare®) led to a significant improvement in urinary incontinence in PD patients, and was generally well tolerated. Further studies are needed to evaluate treatment of urinary dysfunction in PD

An Open Label Study of Solifenacin Succinate (VESIcare®) for the Treatment of Overactive Bladder in Parkinson’s Disease

Objective: To evaluate the safety and efficacy of solifenacin succinate (VESIcare®) in Parkinson\u27s disease patients suffering from overactive bladder (OAB) in an open-label trial. Background: Urinary dysfunction is a commonly encountered non-motor feature in many idiopathic Parkinson\u27s disease (PD) patients. There are few controlled trials that have evaluated medical management of urinary dysfunction in PD. Methods: Following a double-blind, randomized, placebo-controlled trial that evaluated the efficacy of solifenacin succinate (VESIcare®) in 28 PD patients with OAB, patients were invited to participate in a 12 week open-label study. All patients were given 5 mg of solifenacin succinate for 4 weeks; patients were allowed to remain on this dose or increase to 10 mg for an additional 4 weeks. Patients could continue to remain on this current dose, or reduce by 1 dose level until study endpoint (week 12). The primary outcome measure was the change in mean number of micturitions per 24 hour period from baseline to endpoint between active and placebo groups; secondary objectives included the change in the mean number of urinary incontinence episodes, the mean number of nocturia episodes per 24 hour period, urinary urgency as measured by the symptom severity score on The Patient Perception of Intensity of Urgency Scale (PPIUS), and the mean change in Patient Perception of Bladder Condition (PBC/PPBC). Results: Seventeen patients enrolled in the study (mean age=67.71±7.06 years), and 16 completed it (1 withdrew due to constipation). The mean number of urinary incontinence episodes per 24 hour period decreased significantly (1.33 ± 1.54 to 0.52 ± 1.01, p = 0.03), as did the number of nocturia episodes per 24 hour period (8.88 ± 3.37 to 1.64 ± 1.09, p=0.001), at a mean dose of 7.81mg/day. There was a trend noted for improvement in the PPIUS (p=0.09) as well. Other measures showed improvement, although not significantly. Other side effects included xerostomia which resolved after treatment was discontinued. Conclusions: In this open-label trial, treatment with solifenancin succinate (VESIcare®) led to a significant improvement in urinary incontinence and nocturia in PD patients, and was generally well tolerated. Further larger studies are needed to evaluate treatments for urinary dysfunction in PD patients

Tropism of SARS-CoV-2 for Developing Human Cortical Astrocytes

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function of vital organ systems, with particularly severe impact on respiratory function. It proves fatal for one percent of those infected. Neurological symptoms, which range in severity, accompany a significant proportion of COVID-19 cases, indicating a potential vulnerability of neural cell types. To assess whether human cortical cells can be directly infected by SARS-CoV-2, we utilized primary human cortical tissue and stem cell-derived cortical organoids. We find significant and predominant infection in cortical astrocytes in both primary and organoid cultures, with minimal infection of other cortical populations. Infected astrocytes had a corresponding increase in reactivity characteristics, growth factor signaling, and cellular stress. Although human cortical cells, including astrocytes, have minimal ACE2 expression, we find high levels of alternative coronavirus receptors in infected astrocytes, including DPP4 and CD147. Inhibition of DPP4 reduced infection and decreased expression of the cell stress marker, ARCN1. We find tropism of SARS-CoV-2 for human astrocytes mediated by DPP4, resulting in reactive gliosis-type injury

The PIWI protein Aubergine recruits eIF3 to activate translation in the germ plasm

International audiencePiwi-interacting RNAs (piRNAs) and PIWI proteins are essential in germ cells to repress transposons and regulate mRNAs. In Drosophila, piRNAs bound to the PIWI protein Aubergine (Aub) are transferred maternally to the embryo and regulate maternal mRNA stability through two opposite roles. They target mRNAs by incomplete base pairing, leading to their destabilization in the soma and stabilization in the germ plasm. Here, we report a function of Aub in translation. Aub is required for translational activation of nanos mRNA, a key determinant of the germ plasm. Aub physically interacts with the poly(A)-binding protein (PABP) and the translation initiation factor eIF3. Polysome gradient profiling reveals the role of Aub at the initiation step of translation. In the germ plasm, PABP and eIF3d assemble in foci that surround Aub-containing germ granules, and Aub acts with eIF3d to promote nanos translation. These results identify translational activation as a new mode of mRNA regulation by Aub, highlighting the versatility of PIWI proteins in mRNA regulation

Randomized, Controlled Pilot Trial of Solifenacin Succinate for Overactive Bladder in Parkinson\u27s Disease

Objective: To evaluate the efficacy of solifenacin succinate in Parkinson\u27s disease (PD) patients suffering from overactive bladder (OAB). Background: Urinary dysfunction is a commonly encountered non-motor feature in PD that significantly impacts patient quality of life. Design/methods: This was a double-blind, randomized, placebo-controlled, 3-site study with an open label extension phase to determine the efficacy of solifenacin succinate in idiopathic PD patients with OAB. Patients were randomized to receive solifenacin succinate 5–10 mg daily or placebo for 12 weeks followed by an 8-week open label extension. The primary outcome measure was the change in the mean number of micturitions per 24 h period. Secondary outcome measures included the change in the mean number of urinary incontinence episodes and the mean number of nocturia episodes. Results: Twenty-three patients were randomized in the study. There was no significant improvement in the primary outcome measure in the double-blind phase, but there was an improvement in the number of micturitions per 24 h period in the solifenacin succinate group compared to placebo at a mean dose of 6 mg/day (p = 0.01). In the open label phase, the mean number of urinary incontinence episodes per 24 h period decreased (p = 0.03), as did the number of nocturia episodes per 24 h period (p = 0.01). Adverse events included constipation and xerostomia, which resolved after treatment was discontinued. Conclusions: In this pilot trial, solifenacin succinate treatment led to an improvement in urinary incontinence, despite persistence in other OAB symptoms

Tropism of SARS-CoV-2 for human cortical astrocytes.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function of vital organ systems, with particularly severe impact on respiratory function. Neurological symptoms, which range in severity, accompany as many as one-third of COVID-19 cases, indicating a potential vulnerability of neural cell types. To assess whether human cortical cells can be directly infected by SARS-CoV-2, we utilized stem-cell-derived cortical organoids as well as primary human cortical tissue, both from developmental and adult stages. We find significant and predominant infection in cortical astrocytes in both primary tissue and organoid cultures, with minimal infection of other cortical populations. Infected and bystander astrocytes have a corresponding increase in inflammatory gene expression, reactivity characteristics, increased cytokine and growth factor signaling, and cellular stress. Although human cortical cells, particularly astrocytes, have no observable ACE2 expression, we find high levels of coronavirus coreceptors in infected astrocytes, including CD147 and DPP4. Decreasing coreceptor abundance and activity reduces overall infection rate, and increasing expression is sufficient to promote infection. Thus, we find tropism of SARS-CoV-2 for human astrocytes resulting in inflammatory gliosis-type injury that is dependent on coronavirus coreceptors

Efficacy and safety of sparsentan versus irbesartan in patients with IgA nephropathy (PROTECT): 2-year results from a randomised, active-controlled, phase 3 trial

BackgroundSparsentan, a novel, non-immunosuppressive, single-molecule, dual endothelin angiotensin receptor antagonist, significantly reduced proteinuria versus irbesartan, an angiotensin II receptor blocker, at 36 weeks (primary endpoint) in patients with immunoglobulin A nephropathy in the phase 3 PROTECT trial's previously reported interim analysis. Here, we report kidney function and outcomes over 110 weeks from the double-blind final analysis.MethodsPROTECT, a double-blind, randomised, active-controlled, phase 3 study, was done across 134 clinical practice sites in 18 countries throughout the Americas, Asia, and Europe. Patients aged 18 years or older with biopsy-proven primary IgA nephropathy and proteinuria of at least 1·0 g per day despite maximised renin–angiotensin system inhibition for at least 12 weeks were randomly assigned (1:1) to receive sparsentan (target dose 400 mg oral sparsentan once daily) or irbesartan (target dose 300 mg oral irbesartan once daily) based on a permuted-block randomisation method. The primary endpoint was proteinuria change between treatment groups at 36 weeks. Secondary endpoints included rate of change (slope) of the estimated glomerular filtration rate (eGFR), changes in proteinuria, a composite of kidney failure (confirmed 40% eGFR reduction, end-stage kidney disease, or all-cause mortality), and safety and tolerability up to 110 weeks from randomisation. Secondary efficacy outcomes were assessed in the full analysis set and safety was assessed in the safety set, both of which were defined as all patients who were randomly assigned and received at least one dose of randomly assigned study drug. This trial is registered with ClinicalTrials.gov, NCT03762850.FindingsBetween Dec 20, 2018, and May 26, 2021, 203 patients were randomly assigned to the sparsentan group and 203 to the irbesartan group. One patient from each group did not receive the study drug and was excluded from the efficacy and safety analyses (282 [70%] of 404 included patients were male and 272 [67%] were White) . Patients in the sparsentan group had a slower rate of eGFR decline than those in the irbesartan group. eGFR chronic 2-year slope (weeks 6–110) was −2·7 mL/min per 1·73 m2 per year versus −3·8 mL/min per 1·73 m2 per year (difference 1·1 mL/min per 1·73 m2 per year, 95% CI 0·1 to 2·1; p=0·037); total 2-year slope (day 1–week 110) was −2·9 mL/min per 1·73 m2 per year versus −3·9 mL/min per 1·73 m2 per year (difference 1·0 mL/min per 1·73 m2 per year, 95% CI −0·03 to 1·94; p=0·058). The significant reduction in proteinuria at 36 weeks with sparsentan was maintained throughout the study period; at 110 weeks, proteinuria, as determined by the change from baseline in urine protein-to-creatinine ratio, was 40% lower in the sparsentan group than in the irbesartan group (−42·8%, 95% CI −49·8 to −35·0, with sparsentan versus −4·4%, −15·8 to 8·7, with irbesartan; geometric least-squares mean ratio 0·60, 95% CI 0·50 to 0·72). The composite kidney failure endpoint was reached by 18 (9%) of 202 patients in the sparsentan group versus 26 (13%) of 202 patients in the irbesartan group (relative risk 0·7, 95% CI 0·4 to 1·2). Treatment-emergent adverse events were well balanced between sparsentan and irbesartan, with no new safety signals.InterpretationOver 110 weeks, treatment with sparsentan versus maximally titrated irbesartan in patients with IgA nephropathy resulted in significant reductions in proteinuria and preservation of kidney function