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The establishment of silent chromatin requires passage through S-phase, but not DNA replication per se. Nevertheless, many proteins that affect silencing are bona fide DNA replication factors. It is not clear if mutations in these replication factors affect silencing directly or indirectly via deregulation of S-phase or DNA replication. Consequently, the relationship between DNA replication and silencing remains an issue of debate. Here we analyze the effect of mutations in DNA replication factors (mcm5-461, mcm5-1, orc2-1, orc5-1, cdc45-1, cdc6-1, and cdc7-1) on the silencing of a group of reporter constructs, which contain different combinations of “natural” subtelomeric elements. We show that the mcm5-461, mcm5-1, and orc2-1 mutations affect silencing through subtelomeric ARS  consensus sequences (ACS), while cdc6-1 affects silencing independently of ACS. orc5-1, cdc45-1, and cdc7-1 affect silencing through ACS, but also show ACS-independent effects. We also demonstrate that isolated nontelomeric ACS do not recapitulate the same effects when inserted in the telomere. We propose a model that defines the modes of action of MCM5 and CDC6 in silencing.

The determination of Shiga toxin (ST) subtypes can be an important element in the risk characterization of foodborne ST-producing Escherichia coli (STEC) isolates for making risk management decisions. ST subtyping methods include PCR techniques based on electrophoretic or pyrosequencing analysis of amplicons and in silico techniques based on whole genome sequence analysis using algorithms that can be readily incorporated into bioinformatics analysis pipelines for characterization of isolates by their genetic composition. The choice of technique will depend on the performance characteristics of the method and an individual laboratory's access to specialized equipment or personnel. We developed two whole genome sequence-based ST subtyping tools: (i) an in silico PCR algorithm requiring genome assembly to replicate a reference PCR-based method developed by the Statens Serum Institut (SSI) and (ii) an assembly-independent routine in which raw sequencing results are mapped to a database of known ST subtype sequence variants (V-Typer). These tools were evaluated alongside the SSI reference PCR method and a recently described PCR-based pyrosequencing technique. The V-Typer method results corresponded closely with the reference method in the analysis of 67 STEC cultures obtained from a World Health Organization National Reference Laboratory. In contrast, the in silico PCR method failed to detect ST subtypes in several cases, a result which we attribute to assembly-induced errors typically encountered with repetitive gene sequences. The V-Typer can be readily integrated into bioinformatics protocols used in the identification and characterization of foodborne STEC isolates.

ABSTRACTUsing a combination of Illumina paired-end sequencing, Pacific Biosciences RS II sequencing, and OpGen Argus whole-genome optical mapping, we report here the first complete genome sequence of Yersinia massiliensis. The completed genome consists of a 4.99-Mb chromosome, a 121-kb megaplasmid, and a 57-kb plasmid.

Among women with advanced ovarian cancer with a BRCA mutation who had a response after platinum-based therapy, the median progression-free survival was approximately 3 years longer with the use of olaparib maintenance therapy for 2 years than with placebo.

The persistence of CAR T cells and antigen escape remain major barriers to durable therapeutic success in hematologic malignancies. Our study integrates AI-guided design with targeted protein degradation to overcome these challenges. Utilizing an in-silico library of CAR constructs followed by an in vitro screening, we developed a predictive model, CARMSeD, which forecasts constructs prone to self-activation and dysfunction. Optimized bispecific CD20/CD19 CAR T cells demonstrate superior persistence and anti-tumor efficacy. To further improve durability, the platform incorporates a PROTAC-based module that selectively degrades AKT3, promoting FOXO4-driven mitochondrial fitness, central memory differentiation, and reduced mTOR signaling. We extended this strategy to develop a trispecific CAR T platform co-expressing a secretable CD3/CD22 bispecific engager, achieving potent tumor eradication even in CD19/CD20-negative malignancies demonstrates efficacy across patient-derived leukemia samples and solid tumor models. Together, our study introduces a next-generation AI-guided CAR T strategy that integrates structure-based optimization and intracellular modulation to improve persistence, broaden antigen coverage, and ensure durable therapeutic efficacy. Durable, multi-antigen CAR T responses in B-cell malignancies are in need. The authors here demonstrate that AI-guided CAR designs combined with targeted pathway modulation enhance persistence, prevent antigen escape, and improve anti-tumor efficacy.

Bread wheat germplasm is accessed from the International Maize and Wheat Improvement Centre (CIMMYT) and the International Centre for Agricultural Research in the Dry Areas (ICARDA) by Australian wheat breeders and researchers through the CIMMYT Australia ICARDA Germplasm Evaluation (CAIGE) program. The CAIGE program coordinates the selection, importation, quarantine, dissemination, and evaluation of the imported bread wheat germplasm and the management of associated data and information. This paper describes the CAIGE model and assesses both the genetic and economic impacts of these materials on the Australian wheat industry after commercialisation of wheat breeding in the early 21st century and the establishment of CAIGE. The CAIGE concept was validated using data collected and analysed from multi-environment trials between 2017 and 2020. The impact of cultivars with and without CAIGE contribution to pedigree on yield was estimated using production-by-variety statistics. Net gain in yield, estimated as the yield difference between CAIGE and Non-CAIGE varieties, was multiplied by the percentage contribution to pedigree to estimate the additional yield. The CAIGE bread wheat program identified diverse, high-yielding, and disease-resistant germplasm and significantly improved the capture and dissemination of information. The benefit-cost ratio, calculated as the sum of benefits divided by investments, indicated that, for every dollar invested in CAIGE, a further $20 was generated in benefits. The internal rate of return was estimated at 163% and the modified rate at 18%. The benefits of these international materials to Australian wheat breeding remained significant.

In the phase 3 SOLO1 trial, maintenance olaparib provided a significant progression-free survival benefit versus placebo in patients with newly diagnosed, advanced ovarian cancer and a BRCA mutation in response after platinum-based chemotherapy. We analysed health-related quality of life (HRQOL) and patient-centred outcomes in SOLO1, and the effect of radiological disease progression on health status. SOLO1 is a randomised, double-blind, international trial done in 118 centres and 15 countries. Eligible patients were aged 18 years or older; had an Eastern Cooperative Oncology Group performance status score of 0–1; had newly diagnosed, advanced, high-grade serous or endometrioid ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with a BRCA mutation; and were in clinical complete or partial response to platinum-based chemotherapy. Patients were randomly assigned (2:1) to either 300 mg olaparib tablets or placebo twice per day using an interactive voice and web response system and were treated for up to 2 years. Treatment assignment was masked for patients and for clinicians giving the interventions, and those collecting and analysing the data. Randomisation was stratified by response to platinum-based chemotherapy (clinical complete or partial response). HRQOL was a secondary endpoint and the prespecified primary HRQOL endpoint was the change from baseline in the Functional Assessment of Cancer Therapy–Ovarian Cancer Trial Outcome Index (TOI) score for the first 24 months. TOI scores range from 0 to 100 (higher scores indicated better HRQOL), with a clinically meaningful difference defined as a difference of at least 10 points. Prespecified exploratory endpoints were quality-adjusted progression-free survival and time without significant symptoms of toxicity (TWiST). HRQOL endpoints were analysed in all randomly assigned patients. The trial is ongoing but closed to new participants. This trial is registered with ClinicalTrials.gov, NCT01844986. Between Sept 3, 2013, and March 6, 2015, 1084 patients were enrolled. 693 patients were ineligible, leaving 391 eligible patients who were randomly assigned to olaparib (n=260) or placebo (n=131; one placebo patient withdrew before receiving any study treatment), with a median duration of follow-up of 40·7 months (IQR 34·9–42·9) for olaparib and 41·2 months (32·2–41·6) for placebo. There was no clinically meaningful change in TOI score at 24 months within or between the olaparib and placebo groups (adjusted mean change in score from baseline over 24 months was 0·30 points [95% CI −0·72 to 1·32] in the olaparib group vs 3·30 points [1·84 to 4·76] in the placebo group; between-group difference of −3·00, 95% CI −4·78 to −1·22; p=0·0010). Mean quality-adjusted progression-free survival (olaparib 29·75 months [95% CI 28·20–31·63] vs placebo 17·58 [15·05–20·18]; difference 12·17 months [95% CI 9·07–15·11], p<0·0001) and the mean duration of TWiST (olaparib 33·15 months [95% CI 30·82–35·49] vs placebo 20·24 months [17·36–23·11]; difference 12·92 months [95% CI 9·30–16·54]; p<0·0001) were significantly longer with olaparib than with placebo. The substantial progression-free survival benefit provided by maintenance olaparib in the newly diagnosed setting was achieved with no detrimental effect on patients' HRQOL and was supported by clinically meaningful quality-adjusted progression-free survival and TWiST benefits with maintenance olaparib versus placebo. AstraZeneca and Merck Sharp & Dohme.

Little is known about the proportion of hospitals in the United States that offer clinical trial enrollment opportunities and how patient outcomes differ between hospitals that do and do not participate in clinical trials. In the nationwide Chest Pain–MI registry, we described the proportion of hospitals that enrolled patients with acute myocardial infarction (MI) in clinical trials from 2009 to 2014. Hospital-level adherence to every eligible MI performance measure was compared between hospitals that did and did not enroll patients in clinical trials. Using linked Medicare data, we also compared 1-year major adverse cardiovascular events (MACE: death, MI, heart failure, or stroke) among patients ≥65 years old treated at trial versus nontrial hospitals. Among 766 hospitals, 430 (56.1%) enrolled ≥1 MI patient in a clinical trial during the study period, but the proportion of hospitals enrolling patients in clinical trials declined from 36.8% in 2009 to 26.6% in 2014. Complete adherence to performance measures was delivered to a greater proportion of patients at trial hospitals than nontrial hospitals (72.6% vs 64.9%, P < .001; adjusted OR 1.07, 95% CI 1.03-1.12). One-year MACE rates were also lower for trial hospitals (adjusted HR 0.96, 95% CI 0.93-0.99). Hospitals are becoming less likely to engage in clinical trials for patients with MI. Patients admitted to hospitals that participated in clinical trials more often received guideline-adherent care and had better long-term outcomes.