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DNA unwinding mechanism of a eukaryotic replicative CMG helicase
High-resolution structures have not been reported for replicative helicases at a replication fork at atomic resolution, a prerequisite to understanding the unwinding mechanism. The eukaryotic replicative CMG (Cdc45, Mcm2-7, GINS) helicase contains a Mcm2-7 motor ring, with the N-tier ring in front and the C-tier motor ring behind. The N-tier ring is structurally divided into a zinc finger (ZF) sub-ring followed by the oligosaccharide/oligonucleotide-binding (OB) fold ring. Here we report the cryo-EM structure of CMG on forked DNA at 3.9 Å, revealing that parental DNA enters the ZF sub-ring and strand separation occurs at the bottom of the ZF sub-ring, where the lagging strand is blocked and diverted sideways by OB hairpin-loops of Mcm3, Mcm4, Mcm6, and Mcm7. Thus, instead of employing a specific steric exclusion process, or even a separation pin, unwinding is achieved via a “dam-and-diversion tunnel” mechanism that does not require specific protein-DNA interaction. The C-tier motor ring contains spirally configured PS1 and H2I loops of Mcms 2, 3, 5, 6 that translocate on the spirally-configured leading strand, and thereby pull the preceding DNA segment through the diversion tunnel for strand separation.
The DNA duplex is known to be split apart in a steric exclusion manner during replication, but the specific mechanism has remained unclear. Here the authors present a cryo-EM structure of a eukaryotic replicative CMG helicase on forked DNA, revealing the mechanism of DNA unwinding.
Journal Article
Auto repair for dummies
A reference guide covering the many parts of a vehicle provides step-by-step instructions for automotive repair and maintenance, as well as a list of the ten most common problems.
Book
Long-Term Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children with Autism Spectrum Disorder
Objective:
A recent double-blind randomized placebo-controlled study demonstrated 3-month efficacy and safety of a novel pediatric-appropriate prolonged-release melatonin (PedPRM) for insomnia in children and adolescents with autism spectrum disorder (ASD) and neurogenetic disorders (NGD) with/without attention-deficit/hyperactivity disorder comorbidity. Long-term efficacy and safety of PedPRM treatment was studied.
Methods:
A prospective, open-label efficacy and safety follow-up of nightly 2, 5, or 10 mg PedPRM in subjects who completed the 13-week double-blind trial (51 PedPRM; 44 placebo). Measures included caregiver-reported Sleep and Nap Diary, Composite Sleep Disturbance Index (CSDI), caregiver's Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale, and quality of life (WHO-5 Well-Being Index).
Results:
Ninety-five subjects (74.7% males; mean [standard deviation] age, 9 [4.24]; range, 2–17.5 years) received PedPRM (2/5 mg) according to the double-blind phase dose, for 39 weeks with optional dose adjustment (2, 5, or 10 mg/day) after the first 13 weeks. After 52 weeks of continuous treatment (PedPRM-randomized group) subjects slept (mean [SE]) 62.08 (21.5) minutes longer (p = 0.007); fell asleep 48.6 (10.2) minutes faster (p < 0.001); had 89.1 (25.5) minutes longer uninterrupted sleep episodes (p = 0.001); 0.41 (0.12) less nightly awakenings (>50% decrease; p = 0.001); and better sleep quality (p < 0.001) compared with baseline. The placebo-randomized group also improved with PedPRM. Altogether, by the end of 39-week follow-up, regardless of randomization assignment, 55/72 (76%) of completers achieved overall improvement of ≥1 hour in total sleep time (TST), sleep latency or both, over baseline, with no evidence of decreased efficacy. In parallel, CSDI child sleep disturbance and caregivers' satisfaction of their child's sleep patterns (p < 0.001 for both), PSQI global (p < 0.001), and WHO-5 (p = 0.001) improved in statistically significant and clinically relevant manner (n = 72) compared with baseline. PedPRM was generally safe; most frequent treatment-related adverse events were fatigue (5.3%) and mood swings (3.2% of patients).
Conclusion:
PedPRM, an easily swallowed formulation shown to be efficacious versus placebo, is an efficacious and safe option for long-term treatment (up to 52 weeks reported here) of children with ASD and NGD who suffer from insomnia and subsequently improves caregivers' quality of life.
Journal Article
Upadacitinib Induction and Maintenance Therapy for Crohn’s Disease
Upadacitinib, an oral selective Janus kinase (JAK) inhibitor, is under investigation for the treatment of Crohn's disease.
In two phase 3 induction trials (U-EXCEL and U-EXCEED), we randomly assigned patients with moderate-to-severe Crohn's disease to receive 45 mg of upadacitinib or placebo (2:1 ratio) once daily for 12 weeks. Patients who had a clinical response to upadacitinib induction therapy were randomly assigned in the U-ENDURE maintenance trial to receive 15 mg of upadacitinib, 30 mg of upadacitinib, or placebo (1:1:1 ratio) once daily for 52 weeks. The primary end points for induction (week 12) and maintenance (week 52) were clinical remission (defined as a Crohn's Disease Activity Index score of <150 [range, 0 to 600, with higher scores indicating more severe disease activity]) and endoscopic response (defined as a decrease in the Simple Endoscopic Score for Crohn's Disease [SES-CD; range, 0 to 56, with higher scores indicating more severe disease] of >50% from baseline of the induction trial [or for patients with an SES-CD of 4 at baseline, a decrease of ≥2 points from baseline]).
A total of 526 patients underwent randomization in U-EXCEL, 495 in U-EXCEED, and 502 in U-ENDURE. A significantly higher percentage of patients who received 45-mg upadacitinib than those who received placebo had clinical remission (in U-EXCEL, 49.5% vs. 29.1%; in U-EXCEED, 38.9% vs. 21.1%) and an endoscopic response (in U-EXCEL, 45.5% vs. 13.1%; in U-EXCEED, 34.6% vs. 3.5%) (P<0.001 for all comparisons). At week 52 in U-ENDURE, a higher percentage of patients had clinical remission with 15-mg upadacitinib (37.3%) or 30-mg upadacitinib (47.6%) than with placebo (15.1%), and a higher percentage had an endoscopic response with 15-mg upadacitinib (27.6%) or 30-mg upadacitinib (40.1%) than with placebo (7.3%) (P<0.001 for all comparisons). Herpes zoster infections occurred more frequently in the 45-mg and 30-mg upadacitinib groups than in the respective placebo groups, and hepatic disorders and neutropenia were more frequent in the 30-mg upadacitinib group than in the other maintenance groups. Gastrointestinal perforations developed in 4 patients who received 45-mg upadacitinib and in 1 patient each who received 30-mg or 15-mg upadacitinib.
Upadacitinib induction and maintenance treatment was superior to placebo in patients with moderate-to-severe Crohn's disease. (Funded by AbbVie; U-EXCEL, U-EXCEED, and U-ENDURE ClinicalTrials.gov numbers, NCT03345849, NCT03345836, and NCT03345823.).
Journal Article
Depression prevention via digital cognitive behavioral therapy for insomnia: a randomized controlled trial
Insomnia is a common precursor to depression; yet, the potential for insomnia treatment to prevent depression has not been demonstrated. Cognitive behavioral therapy for insomnia (CBT-I) effectively reduces concurrent symptoms of insomnia and depression and can be delivered digitally (dCBT-I); however, it remains unclear whether treating insomnia leads to sustained reduction and prevention of depression. This randomized controlled trial examined the efficacy of dCBT-I in reducing and preventing depression over a 1-year follow-up period.
Patients with Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) insomnia disorder were randomly assigned to receive dCBT-I or an attentional control. The follow-up sample included 358 patients in the dCBT-I condition and 300 patients in the online sleep education condition. The primary outcome measure was relative rate ratios for depression at 1-year follow-up. Insomnia responses to treatment were also tested as predictors of incident depression at the 1-year follow-up.
At 1-year follow-up, depression severity continued to be significantly lower in the dCBT-I condition relative to control. In addition, the number of individuals who reported no depression at 1-year follow-up was 51% higher in the dCBT-I condition relative to control. In those with minimal to no depression at baseline, the incident rate of moderate-to-severe depression at 1-year follow-up was reduced by half in the dCBT-I condition relative to the control condition.
dCBT-I showed robust effects as an intervention that prevents depression. Future research should examine dose-response requirements and further characterize mechanisms of action of dCBT-I for depression prevention.
Sleep to Prevent Evolving Affective Disorders; NCT02988375.
Journal Article
Cognitive and behavioral therapy for insomnia increases the use of continuous positive airway pressure therapy in obstructive sleep apnea participants with comorbid insomnia: a randomized clinical trial
Abstract
Study Objectives
Insomnia and obstructive sleep apnea (OSA) commonly co-occur which makes OSA difficult to treat with continuous positive airway pressure (CPAP). We conducted a randomized controlled trial in participants with OSA and co-occurring insomnia to test the hypothesis that initial treatment with cognitive and behavioral therapy for insomnia (CBT-i), versus treatment as usual (TAU) would improve insomnia symptoms and increase subsequent acceptance and use of CPAP.
Methods
One hundred and forty-five participants with OSA (apnea-hypopnea index ≥ 15) and comorbid insomnia were randomized to either four sessions of CBT-i, or TAU, before commencing CPAP therapy until 6 months post-randomization. Primary between-group outcomes included objective average CPAP adherence and changes in objective sleep efficiency by 6 months. Secondary between-group outcomes included rates of immediate CPAP acceptance/rejection, and changes in; sleep parameters, insomnia severity, and daytime impairments by 6 months.
Results
Compared to TAU, participants in the CBT-i group had 61 min greater average nightly adherence to CPAP (95% confidence interval [CI] = 9 to 113; p = 0.023, d = 0.38) and higher initial CPAP treatment acceptance (99% vs. 89%; p = 0.034). The CBT-i group showed greater improvement of global insomnia severity, and dysfunctional sleep-related cognitions by 6 months (both: p < 0.001), and greater improvement in sleep impairment measures immediately following CBT-i. There were no between-group differences in sleep outcomes, or daytime impairments by 6 months.
Conclusions
In OSA participants with comorbid insomnia, CBT-i prior to initiating CPAP treatment improves CPAP use and insomnia symptoms compared to commencing CPAP without CBT-i. OSA patients should be evaluated for co-occurring insomnia and considered for CBT-i before commencing CPAP therapy.
Clinical Trial
Treating comorbid insomnia with obstructive sleep apnea (COMSIA) study: A new treatment strategy for patients with combined insomnia and sleep apnea, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=365184 Australian New Zealand Clinical Trials Registry: ACTRN12613001178730. Universal Trial Number: U1111-1149-4230.
Journal Article