Improving small interfering RNA (siRNA) efficacy in target cell populations remains a challenge to its clinical implementation. Here, we report a chemical modification, consisting of ...phosphorodithioate (PS2) and 2'-O-Methyl (2'-OMe) MePS2 on one nucleotide that significantly enhances potency and resistance to degradation for various siRNAs. We find enhanced potency stems from an unforeseen increase in siRNA loading to the RNA-induced silencing complex, likely due to the unique interaction mediated by 2'-OMe and PS2. We demonstrate the therapeutic utility of MePS2 siRNAs in chemoresistant ovarian cancer mouse models via targeting GRAM domain containing 1B (GRAMD1B), a protein involved in chemoresistance. GRAMD1B silencing is achieved in tumours following MePS2-modified siRNA treatment, leading to a synergistic anti-tumour effect in combination with paclitaxel. Given the previously limited success in enhancing siRNA potency with chemically modified siRNAs, our findings represent an important advance in siRNA design with the potential for application in numerous cancer types.
Abstract
We present the results of a search for core-collapse supernova neutrinos, using long-term KamLAND data from 2002 March 9 to 2020 April 25. We focus on the electron antineutrinos emitted from ...supernovae in the energy range of 1.8–111 MeV. Supernovae will make a neutrino event cluster with the duration of ∼10 s in the KamLAND data. We find no neutrino clusters and give the upper limit on the supernova rate to be 0.15 yr
−1
with a 90% confidence level. The detectable range, which corresponds to a >95% detection probability, is 40–59 kpc and 65–81 kpc for core-collapse supernovae and failed core-collapse supernovae, respectively. This paper proposes to convert the supernova rate obtained by the neutrino observation to the Galactic star formation rate. Assuming a modified Salpeter-type initial mass function, the upper limit on the Galactic star formation rate is <(17.5–22.7)
M
⊙
yr
−1
with a 90% confidence level.
The diagnostic rate for Mendelian diseases by exome sequencing (ES) is typically 20–40%. The low rate is partly because ES misses deep-intronic or synonymous variants leading to aberrant splicing. In ...this study, we aimed to apply RNA sequencing (RNA-seq) to efficiently detect the aberrant splicings and their related variants.
Aberrant splicing in biopsied muscles from six nemaline myopathy (NM) cases unresolved by ES were analyzed with RNA-seq. Variants related to detected aberrant splicing events were analyzed with Sanger sequencing. Detected variants were screened in NM patients unresolved by ES.
We identified a novel deep-intronic NEB pathogenic variant, c.1569+339A>G in one case, and another novel synonymous NEB pathogenic variant, c.24684G>C (p.Ser8228Ser) in three cases. The c.24684G>C variant was observed to be the most frequent among all NEB pathogenic variants in normal Japanese populations with a frequency of 1 in 178 (20 alleles in 3552 individuals), but was previously unrecognized. Expanded screening of the variant identified it in a further four previously unsolved nemaline myopathy cases.
These results indicated that RNA-seq may be able to solve a large proportion of previously undiagnosed muscle diseases.
Junctional ectopic tachycardia (JET) is a common arrhythmia after congenital heart disease surgery. There is variability in the choice of antiarrhythmic therapy, with amiodarone used commonly. ...Intravenous (IV) sotalol is a newly available agent that may be useful for JET.
The purpose of this study was to evaluate the safety and efficacy of IV sotalol for postoperative JET and compare outcomes with IV amiodarone.
This is a retrospective single-center study of all patients who received IV sotalol or IV amiodarone for postoperative JET at Texas Children's Hospital from December 15, 2015, to December 15, 2020. Data included antiarrhythmic efficacy, hemodynamics, and adverse effects. Successful JET control was defined as a decrease in JET rate to <170 beats/min (or decrease by >20%), or conversion to sinus rhythm, with persistent control over 24 hours without requiring alternative antiarrhythmics or mechanical support.
A total of 32 patients (median age 71 days; interquartile range 17-221 days) received IV amiodarone (n = 20 62%) or IV sotalol (n = 12 38%) for postoperative JET. Amiodarone was successful in treating JET in 75% of cases; sotalol was successful in 83%. The JET rate decreased faster over the first 90 minutes after a sotalol bolus (25 beats/min per hour) than after an amiodarone bolus (8 beats/min per hour) (P < .01); no heart rate difference was seen after 24 hours. Amiodarone infusion was discontinued early because of hypotension/bradycardia in 2 patients; this was not required in any patients receiving sotalol.
For children with postoperative JET, both IV sotalol and amiodarone are safe and efficacious. IV sotalol may lead to a faster improvement in heart rate.
Background: Nearly all epidemiologic studies examining the association between the risk of Parkinson’s disease (PD) and diet have focused on single foods and specific nutrients. However, ...epidemiologic evidence for the association of dietary pattern with PD, namely the measurement of overall diet by considering the cumulative effects of nutrients is extremely limited. We conducted a hospital‐based case–control study in Japan to examine the relationship between dietary patterns and the risk of PD.
Methods: Patients with PD diagnosed using the UK PD Society Brain Bank criteria (n = 249) and controls without neurodegenerative diseases (n = 368) were recruited. At the time of recruitment, dietary intake during the preceding 1 month was assessed using a validated, self‐administered diet history questionnaire. Dietary patterns from 33 predefined food groups (energy‐adjusted food g/day) were extracted by factor analysis.
Results: Three dietary patterns were identified: ‘Healthy’, ‘Western’ and ‘Light meal’ patterns. After adjustment for potential non‐dietary confounding factors, the Healthy pattern, characterized by a high intake of vegetables, seaweed, pulses, mushrooms, fruits and fish, was inversely associated with the risk of PD with a border‐line significance (P for trend = 0.06). Multivariate Odds ratio (95% confidence intervals) for PD in the highest quartile of the Healthy pattern was 0.54 (0.32–0.92) compared with the lowest quartile. No associations with PD were detected for the other two dietary patterns.
Conclusion: In this case–control study in Japan, a dietary pattern consisting of high intakes of vegetables, fruits and fish may be associated with a decreased risk of PD.
Abstract
The Super-Omega beamline at J-PARC Materials and Life Science Experimental Facility provides an intense pulsed slow positive muon beam. Combined with a muonium production target and laser ...light for muonium ionization, the pulsed ultra-slow muon facility has been developed. At the facility, a spectrometer for muon spin rotation measurements using ultra-slow muons is under commissioning. In this paper, we will report on the current status of the beam optics optimization of slow muon transport and ultra-slow muon extraction to improve the intensity and quality of the ultra-slow muon beam.
Toll-like receptors (TLR) recognize a variety of microbial products and activate defense responses. Pathogen sensing by TLR2/4 requires accessory molecules, whereas little is known about a molecule ...required for DNA recognition by TLR9. After endocytosis of microbes, microbial DNA is exposed and recognized by TLR9 in lysosomes. We here show that cathepsins, lysosomal cysteine proteases, are required for TLR9 responses. A cell line Ba/F3 was found to be defective in TLR9 responses despite enforced TLR9 expression. Functional cloning with Ba/F3 identified cathepsin B/L as a molecule required for TLR9 responses. The protease activity was essential for the complementing effect. TLR9 responses were also conferred by cathepsin S or F, but not by cathepsin H. TLR9-dependent B cell proliferation and CD86 upregulation were apparently downregulated by cathepsin B/L inhibitors. Cathepsin B inhibitor downregulated interaction of CpG-B with TLR9 in 293T cells. These results suggest roles for cathepsins in DNA recognition by TLR9.
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