Feed aggregator

Chem Sci. 2025 May 5. doi: 10.1039/d5sc00903k. Online ahead of print.

ABSTRACT

The cell's ability to rapidly partition biomolecules into biomolecular condensates is linked to a diverse range of cellular functions. Understanding how the structural attributes of biomolecular condensates are linked with their biological roles can be facilitated by the development of synthetic condensate systems that can be manipulated in a controllable and predictable way. Here, we design and characterise a tuneable synthetic biomolecular condensate platform fusing modular consensus-designed tetratricopeptide repeat (CTPR) proteins to intrinsically-disordered domains. Trends between the CTPR structural attributes and condensate propensity were recapitulated across different experimental conditions and by in silico modelling, demonstrating that the CTPR domain can systematically affect the condensates in a predictable manner. Moreover, we show that incorporating short binding motifs into the CTPR domain results in specific target-protein recruitment into the condensates. Our model system can be rationally designed in a versatile manner to both tune condensate propensity and endow the condensates with new functions.

PMID:40375868 | PMC:PMC12076082 | DOI:10.1039/d5sc00903k

Protein Sci. 2025 Jun;34(6):e70150. doi: 10.1002/pro.70150.

ABSTRACT

Amyloid fibrils are ordered aggregates that are a pathological hallmark of many neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. The process of amyloid formation involves a complex cascade by which soluble monomeric protein converts to insoluble, ordered aggregates (amyloid fibrils). Although inhibiting the aggregation pathway is a key target for therapeutic development, the heterogeneous collection of aggregation-prone species formed in this process, including oligomers, protofibrils, and fibrils, represents other targets for modifying disease pathology. Developing molecules that can bind to amyloid fibrils and potentially disrupt the harmful interactions between the fibrils and the cellular components would be advantageous. Designing peptide modulators for α-synuclein aggregation is of great interest; however, effective inhibitory peptides are often hydrophobic and hence difficult to handle. Therefore, developing strategies to display these peptides in a soluble scaffold would be very beneficial. Here we demonstrate that the ultra-stable consensus-designed tetratricopeptide repeat (CTPR) protein scaffold can be grafted with "KLVFF" derived peptides previously identified to inhibit protein aggregation and interact with amyloid fibrils to produce proteins that bind along the surface of α-synuclein fibrils with micromolar affinity. Given the ability to insert hydrophobic peptides to produce soluble, CTPR-based binders, this method may prove beneficial in screening for peptide modulators of protein aggregation.

PMID:40371781 | DOI:10.1002/pro.70150

Protein Sci. 2025 Jun;34(6):e70150. doi: 10.1002/pro.70150.

ABSTRACT

Amyloid fibrils are ordered aggregates that are a pathological hallmark of many neurodegenerative disorders including Alzheimer's disease and Parkinson's disease. The process of amyloid formation involves a complex cascade by which soluble monomeric protein converts to insoluble, ordered aggregates (amyloid fibrils). Although inhibiting the aggregation pathway is a key target for therapeutic development, the heterogeneous collection of aggregation-prone species formed in this process, including oligomers, protofibrils, and fibrils, represents other targets for modifying disease pathology. Developing molecules that can bind to amyloid fibrils and potentially disrupt the harmful interactions between the fibrils and the cellular components would be advantageous. Designing peptide modulators for α-synuclein aggregation is of great interest; however, effective inhibitory peptides are often hydrophobic and hence difficult to handle. Therefore, developing strategies to display these peptides in a soluble scaffold would be very beneficial. Here we demonstrate that the ultra-stable consensus-designed tetratricopeptide repeat (CTPR) protein scaffold can be grafted with "KLVFF" derived peptides previously identified to inhibit protein aggregation and interact with amyloid fibrils to produce proteins that bind along the surface of α-synuclein fibrils with micromolar affinity. Given the ability to insert hydrophobic peptides to produce soluble, CTPR-based binders, this method may prove beneficial in screening for peptide modulators of protein aggregation.

PMID:40371781 | DOI:10.1002/pro.70150

J Am Chem Soc. 2025 May 12. doi: 10.1021/jacs.5c00567. Online ahead of print.

ABSTRACT

This study investigates the roles of ethylene and ethylidyne in the surface chemistry of N-methylaniline (NMA) on Pt(111). Using X-ray photoelectron spectroscopy, temperature-programmed desorption, and density functional theory calculations, we demonstrate that ethylidyne is not merely a passive spectator species but actively contributes to hydroamination. It facilitates C-N bond formation by transferring a methyl group to NMA, leading to the formation of N,N-dimethylaniline. Additionally, it stabilizes reaction intermediates and suppresses the decomposition of NMA. This works demonstrates, in contrast to the widely accepted notion, that ethylidyne is not just an inert spectator species; rather, it plays a dual role as both an active reaction partner and a stabilizer. In addition, the coadsorption of ethylene on an NMA-precovered surface shows a side reaction of ethylene with the decomposition products of NMA.

PMID:40353685 | DOI:10.1021/jacs.5c00567

Spec Care Dentist. 2025 May-Jun;45(3):e70041. doi: 10.1111/scd.70041.

ABSTRACT

INTRODUCTION: Poor oral health (OH) can led to severe general health issues, including respiratory infections and malnutrition, impacting the quality of life. In Malaysia, high prevalence of oral diseases including dental caries among individuals with disabilities (IWDs) has been reported, indicating a possible gap in the current system. This study aimed to analyze caries experience using DMFT index of IWDs in community-based rehabilitation (CBR) centers across Selangor, Malaysia.

METHODS: A CBR centers-based cross-sectional study was conducted on IWDs or CBR trainees in the period between August 2022 and December 2023. Recruitments of the study participants were done via census sampling method, involving all the trainees within the specific centers. Data collection was done using the World Health Organization oral health survey tool (WHO, 2013) and analyzed using SPSS 24.

RESULTS: Two hundred and twenty-six students with the age range of 2-47 years old were included in the study. Clinical examination of CBR trainees revealed (1) the mean DMFT scores were low for primary dentition (2.02), moderate for both mixed (3.86), and permanent dentitions (4.17); (2) prevalence of caries among those with primary, mixed, and permanent dentitions as 44.44%, 74.4%, and 74.80%, respectively.

CONCLUSIONS: Trainees with primary dentition had a low prevalence of dental caries and mean DMFT score, while those with mixed and permanent dentition exhibited moderate levels. A statistically significant association was observed between the total DMFT scores for participants with primary dentition with both gender and disability types.

PMID:40353331 | DOI:10.1111/scd.70041

Lancet Oncol. 2025 May 7:S1470-2045(25)00156-1. doi: 10.1016/S1470-2045(25)00156-1. Online ahead of print.

ABSTRACT

BACKGROUND: Carriers of BRCA1 and BRCA2 pathogenic variants are at elevated risk of developing breast and ovarian cancers. To mitigate ovarian cancer risk, bilateral salpingo-oophorectomy (BSO) is commonly recommended for unaffected carriers and those with personal breast cancer history. Assessing BSO's long-term health outcomes in carriers with previous breast cancer history is essential. This study aims to examine the association between BSO and long-term health outcomes in individuals carrying pathogenic variants in BRCA1 and BRCA2 and with personal history of breast cancer.

METHODS: Data from the National Cancer Registration Dataset (NCRD) were linked with data from genetic testing laboratories to identify carriers of BRCA1 and BRCA2 pathogenic variants affected by breast cancer using pseudonymised patient identifiers. Further linkage to the Hospital Episode Statistics-Admitted Patient Care (HES-APC) dataset identified patients who had undergone BSO. Women aged 20-75 years, with a diagnosis of breast cancer as their first primary malignancy in 1995-2019 were eligible. Long-term health outcomes were identified from HES-APC and NCRD. Missing data were imputed using multivariate imputations by chained equations. Multivariable Cox regression was used to examine the associations with mortality (all-cause mortality, breast cancer-specific mortality, and non-breast cancer-specific mortality), second non-breast cancer, cardiovascular diseases, ischaemic heart disease, cerebrovascular diseases, contralateral breast cancer, and depression. Analyses were adjusted for age at diagnosis, diagnosis year, ethnicity, deprivation index, tumour characteristics, Charlson comorbidity index, cancer treatment, and second cancer diagnosis before the start of follow-up.

FINDINGS: We included 1674 BRCA1, 1740 BRCA2, and nine BRCA1 and BRCA2 carriers who were diagnosed with breast cancer between 1995 and 2019, with median follow-up time of 5·5 years (IQR 3·4-8·2). The study population (n=3423) consisted of 3002 (88·7%) White, 170 (5·0%) Asian, 59 (1·7%) Black, 26 (0·8%) mixed, and 74 (2·2%) other ethnic groups, and 92 (2·7%) had missing ethnicity. The uptake of BSO was significantly lower among Black women (odds ratio [OR] vs White women 0·48, 95% CI 0·34-0·67), and Asian women (0·47, 0·27-0·82). BSO uptake was higher in women living in the least socioeconomically deprived areas (OR vs most deprived 1·38, 95% CI [1·10-1·72]). BSO was associated with a reduced risk of all-cause mortality for both BRCA1 and BRCA2 pathogenic variant carriers (HR 0·52, 95% CI 0·41-0·64) and reduced breast cancer-specific mortality (BRCA1: HR 0·62, 95% CI 0·42-0·92 and BRCA2: 0·48, 0·34-0·68). It was also associated with a reduced risk of second non-breast cancer in the combined BRCA1 and BRCA2 sample (HR 0·59, 95% CI 0·37-0·94). There BSO was not associated with increased risk of cardiovascular diseases (HR 0·73, 95% CI 0·53-1·01), ischaemic heart disease (1·04, 0·48-2·26), cerebrovascular disease (0·32, 0·11-0·90), non-breast cancer specific mortality (0·72, 0·45-1·16), contralateral breast cancer (1·18, 0·64-2·16), or depression (0·94, 0·62-1·42).

INTERPRETATION: The evidence supports offering BSO to BRCA1 and BRCA2 pathogenic variant carrriers with a personal history of breast cancer, as they appear to benefit from having the procedure, without evidence of an increased risk of adverse long-term health outcomes.

FUNDING: Cancer Research UK.

PMID:40347974 | DOI:10.1016/S1470-2045(25)00156-1