Radical reform is needed to combat power abuses in academia
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A reform of value-added taxes on foods can have health, environmental and economic benefits in Europe
Fiscal policies can provide important incentives for encouraging the dietary changes needed to achieve global policy targets. Across Europe, the foods relevant to health and the environment often incur reduced but non-zero value-added tax (VAT) rates at about half the maximum rates, which allows for providing both incentives and disincentives. Integrating economic, health and environmental modelling, we show that reforming VAT rates on foods, including increasing rates on meat and dairy, and reducing VAT rates on fruits and vegetables can improve diets and result in health, environmental and economic benefits in most European countries. The health improvements were primarily driven by reductions in VAT rates on fruits and vegetables, whereas most of the environmental and revenue benefits were driven by increased rates on meat and dairy. Our findings suggest that differentiating VAT rates based on health and environmental considerations can support changes towards healthier and more sustainable diets in Europe.
Biomimetic 1,2-amino migration via photoredox catalysis
Synthetic organic chemists continually draw inspiration from biocatalytic processes to innovate synthetic methodologies beyond existing catalytic platforms. Within this context, although 1,2-amino migration represents a viable biochemical process, it remains underutilized within the synthetic organic chemistry community. Here we present a biomimetic 1,2-amino migration accomplished through the synergistic combination of biocatalytic mechanism and photoredox catalysis. This platform enables the modular synthesis of γ-substituted β-amino acids by utilizing abundant α-amino-acid derivatives and readily available organic molecules as coupling partners. This mild method features excellent substrate and functionality compatibility, affording a diverse range of γ-substituted β-amino acids (more than 80 examples) without the need for laborious multistep synthesis. Mechanistic studies, supported by both experimental observations and theoretical analysis, indicate that the 1,2-amino migration mechanism involves radical addition to α-vinyl-aldimine ester, 3-exo–trig cyclization and a subsequent rearrangement process. We anticipate that this transformation will serve as a versatile platform for the highly efficient construction of unnatural γ-substituted β-amino acids.
Multiple DNA damages induced by water radiolysis demonstrated using a dynamic Monte Carlo code
Multiple DNA damage resulting from different nearby ionizations of water molecules is an important process of the initial step of radiobiological effects. Several important characteristics of the damaged DNA site such as the critical size and types of chemical lesions are not well-known. We investigated this long-term issue by developing a dynamic Monte Carlo code for the chemical process. The reaction probabilities and the spatial distribution of lesions were theoretically solved as a function of the spur radius and distance between DNA and the initial ionisation position. From our previous reported results, we suggest that a hydroxyl radical and a hydrated electron from a single spur can concomitantly react within a 10 base pairs DNA to induce a multiple DNA damage site comprising a DNA single-strand break and reductive nucleobase damage; however, the reaction probability is 0.4% or less. Once this combination arises, it may result in a DNA double-strand break (DSB). DSBs are difficult to repair, which may lead to cell death or misrepair, and could lead to point mutations in the genome.
Investigating dopaminergic abnormalities in schizophrenia and first-episode psychosis with normative modelling and multisite molecular neuroimaging
Molecular neuroimaging techniques, like PET and SPECT, offer invaluable insights into the brain’s in-vivo biology and its dysfunction in neuropsychiatric patients. However, the transition of molecular neuroimaging into diagnostics and precision medicine has been limited to a few clinical applications, hindered by issues like practical feasibility, high costs, and high between-subject heterogeneity of neuroimaging measures. In this study, we explore the use of normative modelling (NM) to identify individual patient alterations by describing the physiological variability of molecular functions. NM potentially addresses challenges such as small sample sizes and diverse acquisition protocols typical of molecular neuroimaging studies. We applied NM to two PET radiotracers targeting the dopaminergic system ([11C]-(+)-PHNO and [18F]FDOPA) to create a reference-cohort model of healthy controls. The models were subsequently utilized on different independent cohorts of patients with psychosis in different disease stages and treatment outcomes. Our results showed that patients with psychosis exhibited a higher degree of extreme deviations (~3-fold increase) than controls, although this pattern was heterogeneous, with minimal overlap of extreme deviations topology (max 20%). We also confirmed that striatal [18F]FDOPA signal, when referenced to a normative distribution, can predict treatment response (striatal AUC ROC: 0.77–0.83). In conclusion, our results indicate that normative modelling can be effectively applied to molecular neuroimaging after proper harmonization, enabling insights into disease mechanisms and advancing precision medicine. In addition, the method is valuable in understanding the heterogeneity of patient populations and can contribute to maximising cost efficiency in studies aimed at comparing cases and controls.
Breaking barriers: we need a multidisciplinary approach to tackle cancer drug resistance
Most cancer-related deaths result from drug-resistant disease(1,2). However, cancer drug resistance is not a primary focus in drug development. Effectively mitigating and treating drug-resistant cancer will require advancements in multiple fields, including early detection, drug discovery, and our fundamental understanding of cancer biology. Therefore, successfully tackling drug resistance requires an increasingly multidisciplinary approach. A recent workshop on cancer drug resistance, jointly organised by Cancer Research UK, the Rosetrees Trust, and the UKRI-funded Physics of Life Network, brought together experts in cell biology, physical sciences, computational biology, drug discovery, and clinicians to focus on these key challenges and devise interdisciplinary approaches to address them. In this perspective, we review the outcomes of the workshop and highlight unanswered research questions. We outline the emerging hallmarks of drug resistance and discuss lessons from the COVID-19 pandemic and antimicrobial resistance that could help accelerate information sharing and timely adoption of research discoveries into the clinic. We envisage that initiatives that drive greater interdisciplinarity will yield rich dividends in developing new ways to better detect, monitor, and treat drug resistance, thereby improving treatment outcomes for cancer patients.
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