Genetic Evidence for Single-Strand Lesions Initiating Nbs1-Dependent Homologous Recombination in Diversification of Ig V in Chicken B Lymphocytes

Homologous recombination (HR) is initiated by DNA double-strand breaks (DSB). However, it remains unclear whether single-strand lesions also initiate HR in genomic DNA. Chicken B lymphocytes diversify their Immunoglobulin (Ig) V genes through HR (Ig gene conversion) and non-templated hypermutation. Both types of Ig V diversification are initiated by AID-dependent abasic-site formation. Abasic sites stall replication, resulting in the formation of single-stranded gaps. These gaps can be filled by error-prone DNA polymerases, resulting in hypermutation. However, it is unclear whether these single-strand gaps can also initiate Ig gene conversion without being first converted to DSBs. The Mre11-Rad50-Nbs1 (MRN) complex, which produces 3′ single-strand overhangs, promotes the initiation of DSB-induced HR in yeast. We show that a DT40 line expressing only a truncated form of Nbs1 (Nbs1p70) exhibits defective HR-dependent DSB repair, and a significant reduction in the rate—though not the fidelity—of Ig gene conversion. Interestingly, this defective gene conversion was restored to wild type levels by overproduction of Escherichia coli SbcB, a 3′ to 5′ single-strand–specific exonuclease, without affecting DSB repair. Conversely, overexpression of chicken Exo1 increased the efficiency of DSB-induced gene-targeting more than 10-fold, with no effect on Ig gene conversion. These results suggest that Ig gene conversion may be initiated by single-strand gaps rather than by DSBs, and, like SbcB, the MRN complex in DT40 may convert AID-induced lesions into single-strand gaps suitable for triggering HR. In summary, Ig gene conversion and hypermutation may share a common substrate—single-stranded gaps. Genetic analysis of the two types of Ig V diversification in DT40 provides a unique opportunity to gain insight into the molecular mechanisms underlying the filling of gaps that arise as a consequence of replication blocks at abasic sites, by HR and error-prone polymerases

Effect of a stepwise lighting method termed “stage reduced lighting” using LED and metal halide fishing lamps in the Japanese common squid jigging fishery

Lighting systems combining light-emitting diodes (LEDs) and metal halide lamps (MHs) are expected to be energy-saving tools in Japan\u27s squid jigging fishery. Previous research has shown the need for light stronger than LEDs (9 kW) and 36 MHs (108 kW) to catch the Japanese common squid Todarodes pacificus. We tested a stepwise lighting method termed "stage reduced lighting" in the Tsushima Strait in January and February 2010 using nine fishing boats. LEDs (9 kW) and 50 MHs (150 kW) were lit for 3. 9 h on average, and then the number of MHs was reduced to either 30 or 36 until the end of fishing (7. 3 h on average). This method reduced fuel consumption by 22-25 % compared to the continuous use of all fishing lamps (159 kW). We carried out a catch analysis of nine experimental boats and 21 commercial boats during the experimental period. Generalized linear modeling analysis suggested that the squid catch can be explained by the illuminated fraction of the moon and monthly changes in squid abundance, and the lighting method. The stage reduced lighting using LEDs and MHs has the potential to reduce fuel consumption while maintaining the squid catch

Tongue Pressure in Healthy Populations:A Systematic Review and Meta-Analysis

OBJECTIVES Tongue pressure (TP) is used for the diagnosis of oral hypofunction, however, the impact of several variables on TP is unclear. Therefore, the current systematic review and meta-analysis aimed to analyze the variability in tongue-pressure among healthy individuals aged ≥60 years versus <60 years. Secondary outcomes were the influence of gender and the type of measuring device (Iowa Oral Performance Instrument (IOPI) vs. JMS tongue pressure measurement device (JMS)). METHODS PubMed and the Japanese database Ichu-Shi-Web were searched systematically by two independent reviewers for studies reporting TP values in healthy populations. Clinical studies published between 1959 and June 2020 with more than 10 participants, written in English, German, or Japanese were included. A random-effects meta-regression for aggregate-level data was applied (α<0.05). RESULTS Sixty-eight studies reported TP for a total of 13773 subjects aged <60 years (n=3265) and ≥60 years (n=10508). TP was significantly higher in subjects <60 years (estimated weighted mean (EWM)±standard error=51.9±1.28kPa; 95%CI=49.4-54.4) relative to those ≥60 (EWM=34.7±0.94kPa; 95%CI=32.8-36.5) (p< 0.001), men (EWM= 45.9±2.09kPa; 95%CI=41.8-50.0) relative to women (EWM=39.3±1.68kPa; 95%CI=36.0-42.6) (p=0.015), and when assessed with the IOPI (EWM=51.9±1.32kPa; 95%CI=49.3-54.5) compared to the JMS (EWM =33.5±0.63kPa; 95%CI=32.2-34.7) (p<0.001). In terms of gender, there was no significant difference in TP among subjects ≥60 years (p=0.282). However, in subjects younger than 60, a significant difference was observed (p=0.004). CONCLUSIONS Healthy populations aged <60 years showed significantly higher TP than those aged ≥60 years. TP values ascertained by the IOPI are significantly higher than those obtained with the JMS. (247 words)

Seizure control as a new metric in assessing efficacy of tumor treatment in low-grade glioma trials

Patients with low-grade glioma frequently have brain tumor-related epilepsy, which is more common than in patients with high-grade glioma. Treatment for tumor-associated epilepsy usually comprises a combination of surgery, anti-epileptic drugs (AEDs), chemotherapy, and radiotherapy. Response to tumor-directed treatment is measured primarily by overall survival and progression-free survival. However, seizure frequency has been observed to respond to tumor-directed treatment with chemotherapy or radiotherapy. A review of the current literature regarding seizure assessment for low-grade glioma patients reveals a heterogeneous manner in which seizure response has been reported. There is a need for a systematic approach to seizure assessment and its influence on health-related quality-of-life outcomes in patients enrolled in low-grade glioma therapeutic trials. In view of the need to have an adjunctive metric of tumor response in these patients, a method of seizure assessment as a metr

Vorasidenib in IDH1- or IDH2-Mutant Low-Grade Glioma

Background: Isocitrate dehydrogenase (IDH)-mutant grade 2 gliomas are malignant brain tumors that cause considerable disability and premature death. Vorasidenib, an oral brain-penetrant inhibitor of mutant IDH1 and IDH2 enzymes, showed preliminary activity in IDH-mutant gliomas. Methods: In a double-blind, phase 3 trial, we randomly assigned patients with residual or recurrent grade 2 IDH-mutant glioma who had undergone no previous treatment other than surgery to receive either oral vorasidenib (40 mg once daily) or matched placebo in 28-day cycles. The primary end point was imaging-based progression-free survival according to blinded assessment by an independent review committee. The key secondary end point was the time to the next anticancer intervention. Crossover to vorasidenib from placebo was permitted on confirmation of imaging-based disease progression. Safety was also assessed. Results: A total of 331 patients were assigned to receive vorasidenib (168 patients) or placebo (163 patients). At a median follow-up of 14.2 months, 226 patients (68.3%) were continuing to receive vorasidenib or placebo. Progression-free survival was significantly improved in the vorasidenib group as compared with the placebo group (median progression-free survival, 27.7 months vs. 11.1 months; hazard ratio for disease progression or death, 0.39; 95% confidence interval [CI], 0.27 to 0.56; P&lt;0.001). The time to the next intervention was significantly improved in the vorasidenib group as compared with the placebo group (hazard ratio, 0.26; 95% CI, 0.15 to 0.43; P&lt;0.001). Adverse events of grade 3 or higher occurred in 22.8% of the patients who received vorasidenib and in 13.5% of those who received placebo. An increased alanine aminotransferase level of grade 3 or higher occurred in 9.6% of the patients who received vorasidenib and in no patients who received placebo. Conclusions: In patients with grade 2 IDH-mutant glioma, vorasidenib significantly improved progression-free survival and delayed the time to the next intervention.</p