Advancing Open Science

Nucleotide substitutions are common in cancer cells, and they occur in both protein coding regions and non-coding regions (5′ and 3′ UTRs and introns). Although substitutions in non-coding regions have the potential to alter gene expression, it is the alteration of coding regions that affects protein function and has the most drastic effect on cellular transformation. Mutations in certain genes (e.g., TP53, KRAS) are common to nearly all cancers, but most cancers are characterized by specific gene mutation signatures. In this report, we investigated nucleotide substitution signatures in coding regions of the top 25 most frequently mutated genes in multiple human cancers. The goal was to examine whether unique nucleotide substitution biases are associated with various cancers. A pan-cancer analysis showed that the most altered nucleotide is guanine, which is biased towards G->A transitions. A per-cancer analysis identified ten cancers with biased substitutions in certain genes. Some of these biases were expected (e.g., KRAS in gastrointestinal cancers or JAK2 in blood cancers). Our analysis revealed biased signature substitutions in 17 genes, of which 14 were characterized as drivers and constituted a closely related set of cell cycle regulators. We conclude that nucleotide substitution biases contribute to specific alterations in cancer genes that produce cellular transformation. Principle component analysis of nucleotide substitutions shows that most cancers cluster together, meaning that they have similar nucleotide changes. However, certain cancers, most notably lung, pancreas, and blood cancers, can be differentiated from each other based on specific nucleotide signatures. Thus, nucleotide substitution patterns can be used to differentiate between some cancers.

In this study, the insert length, location within the coat protein-encoding gene, and sequence orientation of the target fragment were optimized to construct an efficient virus-induced gene silencing (VIGS) system in melon using a Begomovirus solanumdelhiense vector. Existing systems are mostly RNA viruses, requiring in vitro synthesis of viral strands that are prone to degradation, although they exhibit high infectivity and stability in cucurbit hosts and ease of manipulation. This vector was selected for its more stable genome structure and these advantages. The melon phytoene desaturase (CmPDS), a key gene of carotenoid biosynthesis, was selected as a reporter gene to evaluate the effects of the VIGS system. Our results revealed that the melon leaves in all the VIGS treatments exhibited a typical photobleaching phenotype at 21 days post-inoculation. Moreover, reverse transcription quantitative real-time PCR revealed a significant reduction in the mRNA levels of PDS in melon. The highest silencing efficiency (lowest PDS mRNA levels) was achieved by the VIGS vector harboring a 165 bp CmPDS fragment at the 3′ end of the AV1. These findings not only establish a more efficient VIGS protocol for melon but also provide a foundation for developing novel virus-based silencing tools applicable to functional genomics and cucurbit crop improvement, particularly for traits requiring precise gene expression modulation such as disease resistance and fruit quality.

Recently, studies have increasingly focused on neuropathological and molecular alterations that occur in the early stages of neurodegenerative diseases to understand the primary pathogenesis. This review provides an updated overview of the early pathological and molecular changes in multiple system atrophy (MSA), a neurodegenerative condition characterised by the degeneration of both the striatonigral and olivopontocerebellar systems. In advanced stages of MSA, abnormal α-synuclein accumulates in the cytoplasm and nuclei of oligodendrocytes and neurones. However, in addition to these established pathological hallmarks, previous analyses of preclinical MSA cases have revealed characteristic accumulations of abnormal α-synuclein within and adjacent to the nuclear membrane. Moreover, analyses of cerebrospinal fluid and plasma from patients with MSA within 3 years of disease onset have identified alterations in various proteins and microRNAs linked to neurodegeneration and neuroinflammation. Consistent with these findings, in vitro and in vivo models of early-stage MSA have demonstrated abnormalities in neurodegeneration, neuroinflammation, and mitochondrial function. Collectively, these observations highlight the primary pathogenesis of early-stage MSA.

Obesity is a multifaceted disease that significantly increases the risk of various chronic conditions. GLP-1R (co)-agonists first emerged as therapeutics for treatment of type 2 diabetes mellitus and have since become an established drug class for improving glycemic control. The interest in GLP-1 for obesity treatment has surged in 2015 after the approval of Saxenda^® (liraglutide). To date, GLP-1 analogs are primarily administered by s.c. injection, which poses a significant burden on patient compliance. To address this challenge, research has focused on oral delivery. This review provides a concise overview of the techniques explored to enhance the oral delivery of GLP-1 analogs for the treatment of obesity. Relevant strategies include the following: (1) the use of permeation enhancers to increase gastrointestinal absorption of peptides; (2) micro- and nanocarriers loaded with GLP-1, including targeted delivery systems and general techniques for active drug targeting; (3) GLP-1 gene delivery; and (4) advanced microbiome systems for GLP-1 delivery. The potential for misuse and side-effects of GLP-1 analogs are also discussed.

Ecosystem services provided by coastal and marine environments are increasingly recognised as of paramount importance for human wellbeing. To inform marine spatial planning and its implementation, as well as to manage conflicts between marine resource beneficiaries, we developed a comprehensive estimate of the economic value of the ecosystem services of Algoa Bay (AB) from 2000 to 2019. This is to assist in the development of effective policies concerning the management of marine resources. We quantified and assessed the monetary value by integrating 15 ecosystem services (ES) across five ecosystems using a range of economic valuation techniques and four scenarios. The scenarios differentiate between the local and global beneficiaries of the services and a conservative and alternative valuation estimate. These latter two valuation benefits are calculated using different sets of valuation estimates. We identified that onshore ecosystems, and recreation and tourism services, hold the most value. We estimated that the value grew from USD 613.4 million to USD 1695.9 million for local beneficiaries and from USD 1127.7 million to USD 2787.9 million for global beneficiaries between 2000 and 2019. The local values are roughly equivalent to the municipal budget, implying that the value of the ES is at least equal to that of the combined value of public service delivery. This highlights the significant economic contributions of marine and coastal ecosystems to local economies. This valuation provides a framework to make explicit the value that beneficiaries derive from marine ecosystems and provides a novel perspective on the valuation of ES in the coastal and marine ecosystems. This framework can be replicated elsewhere where there is a need to develop the ocean economy in an equitable and sustainable way.

This study investigated the relationship between maternal barium (Ba) exposure and the risk of miscarriage using metabolomics and machine learning. Analyses were performed on samples from 183 pregnant women from Nanjing: the concentration of Ba in whole blood was measured using inductively coupled plasma mass spectrometry (ICP-MS), and untargeted metabolomics was performed on decidual tissue using high-resolution accurate mass spectrometry (UHPLC-QExactive HF-X). A metabolome-wide association study (MWAS) and mediation interaction effect analysis (MITM) identified metabolites and pathways linked to Ba exposure and miscarriage risk. Among 523 detected metabolites, 19 metabolites and 5 pathways were significantly associated with both Ba exposure and miscarriage, particularly glycerophospholipid metabolism. The effect of Ba exposure on miscarriage risk was mediated by five metabolites, with cuminaldehyde showing the highest share of the total mediating effect (54.74%). These metabolites, including N-acetyl-L-methionine, 4-hydroxynonenal, DG(18:0/18:3(9Z,12Z,15Z)/0:0), 10-formyldihydrofolate, and eicosadienoic acid, were used as biomarkers in a predictive model. The XGBoost model achieved an optimal AUC of 0.90 (95%CI: 0.83–0.96). This study suggests that maternal Ba exposure increases miscarriage risk, potentially through disruptions in amino acid metabolism, oxidative stress, and lipid peroxidation, and highlights the potential of metabolite biomarkers for predicting adverse birth outcomes.

Background/Objectives: Functional continence and potency outcomes are paramount for the pentafecta of robotic-assisted laparoscopic radical prostatectomy (RARP). We describe a modified approach of the pubovesical complex (PVC)-sparing technique under hypothermia for better continence and potency preservation. Methods: This is a retrospective single-institution case series. Thirty-three PVC-sparing RARP procedures under hypothermia were performed in patients with clinically localized prostate cancer by the same experienced surgeon. The method includes four principles: (1) modified PVC-sparing technique, according to Richard Gaston et al., (2) the use of near-infrared fluorescence technology and indocyanine green to identify the benchmark artery of the neurovascular bundle and blood supply for the PVC, (3) accessory pudendal artery preservation, and (4) hypothermia to reduce tissue edema. Functional outcomes, including continence, potency, and other surgical findings, are presented. This is a feasibility case series, not a comparative or hypothesis-testing study. Results: This study enrolled 33 cases from 15 April 2020 to 31 December 2022. Four patients had positive surgical margins. The urinary continence rate was 100% after Foley removal at a mean of 6.6 days. The potency rate was 74% (17/23) at 6 months and 91.3% (21/23) at 12 months. The inclusion of a small sample of patients from a single hospital and the selection of patient conditions were the study limitations. Conclusions: The modified approach we described is technically feasible, and it can expedite the restoration of urinary function and potency preservation. No severe complications occurred, and patients achieved good oncological outcomes.

This study conducted a quasi-natural experiment on Chinese mutual funds that signed the United Nations Principles for Responsible Investment (UNPRI) to examine whether institutional investors’ ESG commitments reduce ESG rating disagreements among their portfolio firms. We find that firms held by UNPRI-signatory investors exhibit significantly less ESG rating disagreement than those held by non-UNPRI investors. We further demonstrate that this effect operates through two channels: improved ESG disclosure quality and increased external ESG attention. Corporate governance and industry ESG sensitivity positively moderates the relationship between institutional investors’ ESG commitments and ESG rating disagreement. Moreover, the mitigating effect is more pronounced for domestic rating agencies. This study not only provides evidence for the role of institutional investors in ESG development but also identifies potential pathways to reduce ESG rating discrepancies, offering insights into enhancing the reliability of ESG rating outcomes.