A method for the direct measurement of electronic site populations in a molecular aggregate using two-dimensional electronic-vibrational spectroscopy

Two dimensional electronic spectroscopy has proved to be a valuable experimental technique to reveal electronic excitation dynamics in photosynthetic pigment-protein complexes, nanoscale semiconductors, organic photovoltaic materials, and many other types of systems. It does not, however, provide direct information concerning the spatial structure and dynamics of excitons. 2D infrared spectroscopy has become a widely used tool for studying structural dynamics but is incapable of directly providing information concerning electronic excited states. 2D electronic-vibrational (2DEV) spectroscopy provides a link between these domains, directly connecting the electronic excitation with the vibrational structure of the system under study. In this work, we derive response functions for the 2DEV spectrum of a molecular dimer and propose a method by which 2DEV spectra could be used to directly measure the electronic site populations as a function of time following the initial electronic excitation. We present results from the response function simulations which show that our proposed approach is substantially valid. This method provides, to our knowledge, the first direct experimental method for measuring the electronic excited state dynamics in the spatial domain, on the molecular scale

Diurnal fuel moisture content variations of live and dead Calluna vegetation in a temperate peatland

The increasing frequency and severity of UK wildfires, attributed in part to the effects of climate change, highlights the critical role of fuel moisture content (FMC) of live and dead vegetation in shaping wildfire behaviour. However, current models used to assess wildfire danger do not perform well in shrub-type fuels such as Calluna vulgaris, requiring in part an improved understanding of fuel moisture dynamics on diurnal and seasonal scales. To this end, 554 samples of upper live Calluna canopy, live Calluna stems, upper dead Calluna canopy, dead Calluna stems, moss, litter and organic layer (top 5 cm of organic material above mineral soil) were sampled hourly between 10:00 and 18:00 on seven days from March-August. Using a novel statistical method for investigating diurnal patterns, we found distinctive diurnal and seasonal trends in FMC for all fuel layers. Notably, significant diurnal patterns were evident in dead Calluna across nearly all sampled months, while diurnal trends in live Calluna canopy were pronounced in March, June, and August, coinciding with the peak occurrence of UK wildfires. In addition, the moisture content of moss and litter was found to fluctuate above and below their relative ignition thresholds throughout the day on some sampling days. These findings underscore the impact of diurnal FMC variations on wildfire danger during early spring and late summer in Calluna dominated peatlands and the need to consider such fluctuations in management and fire suppression strategies

A national-scale sampled temperate fuel moisture database

Fuel moisture content (FMC) is important for the ignitability, behaviour and severity of wildfires. Understanding the drivers of FMC and its spatial and temporal variability can help us develop fuel moisture models and inform assessments of wildfire behaviour and danger. Here we present the first United Kingdom (UK) national-scale temperate FMC dataset of 8,057 samples of eighteen different fuel constituents collected across 58 sampling sites between 2021–2023. We sampled fuels across emerging fire-prone ecosystems in the UK across three studies: (1) UK-wide longer-term sampling characterising the spatio-temporal drivers of FMC; (2) landscape-scale measurement through the North Yorkshire Moors to investigate landscape-driven variability in FMC; (3) plot-scale intensive sampling in the West Midlands to quantify diurnal patterns and among-sampler variability in fuel measurements. This database addresses a global fuel moisture measurement gap within traditionally non-fire prone regions. The database will advance our understanding of temperate fuel moisture dynamics and forms a fundamental contribution towards the development of a fire danger rating system for traditionally non-fire prone regions such as the UK

Confinement of Therapeutic Enzymes in Selectively Permeable Polymer Vesicles by Polymerization-Induced Self-Assembly (PISA) Reduces Antibody Binding and Proteolytic Susceptibility

Covalent PEGylation of biologics has been widely employed to reduce immunogenicity, while improving stability and half-life in vivo. This approach requires covalent protein modification, creating a new entity. An alternative approach is stabilization by encapsulation into polymersomes; however this typically requires multiple steps, and the segregation requires the vesicles to be permeable to retain function. Herein, we demonstrate the one-pot synthesis of therapeutic enzyme-loaded vesicles with size-selective permeability using polymerization-induced self-assembly (PISA) enabling the encapsulated enzyme to function from within a confined domain. This strategy increased the proteolytic stability and reduced antibody recognition compared to the free protein or a PEGylated conjugate, thereby reducing potential dose frequency and the risk of immune response. Finally, the efficacy of encapsulated l-asparaginase (clinically used for leukemia treatment) against a cancer line was demonstrated, and its biodistribution and circulation behavior in vivo was compared to the free enzyme, highlighting this methodology as an attractive alternative to the covalent PEGylation of enzymes

Breaking the cycle: reversal of flux in the tricarboxylic acid cycle by dimethyl fumarate

Objective To infer molecular effectors of therapeutic effects and adverse events for dimethyl fumarate (DMF) in relapsing-remitting MS patients (RRMS) using untargeted plasma metabolomics. Methods Plasma from 27 RRMS patients was collected at baseline and six-weeks after initiating DMF. Patients were separated into discovery (n=15) and validation cohorts (n=12). Ten healthy controls were also recruited. Metabolomic profiling using ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS) was performed on the discovery cohort and healthy controls at Metabolon Inc. (Durham, NC). UPLC-MS was performed on the validation cohort at the National Phenome Centre (London, UK). Plasma neurofilament concentration (pNfL) was assayed using the Simoa platform (Quanterix, Lexington, MA). Time course and cross-sectional analyses were performed to identify pharmacodynamic changes in the metabolome secondary to DMF and relate these to adverse events. Results In the discovery cohort, tricarboxylic acid (TCA) cycle intermediates fumarate and succinate and TCA cycle metabolites succinyl-carnitine and methyl succinyl-carnitine increased 6-weeks following treatment (q < 0.05). Methyl succinyl carnitine increased in the validation cohort (q < 0.05). These changes were not observed in the control population. Increased succinyl-carnitine and methyl succinyl-carnitine were associated with adverse events from DMF (flushing, abdominal symptoms). pNfL concentration was higher in RRMS patients than controls and reduced over 15-months treatment. Conclusion TCA cycle intermediates and metabolites are increased in RRMS patients treated with DMF. The results suggest reversal of flux through the succinate dehydrogenase complex. The contribution of succinyl-carnitine ester agonism at hydroxylic acid receptor-2 to both therapeutic effects and adverse events requires investigation

Apobec1 complementation factor overexpression promotes hepatic steatosis, fibrosis, and hepatocellular cancer

The RNA-binding protein Apobec1 complementation factor (A1CF) regulates posttranscriptional ApoB mRNA editing, but the range of RNA targets and the long-term effect of altered A1CF expression on liver function are unknown. Here we studied hepatocyte-specific A1cf-transgenic (A1cf+/Tg), A1cf+/Tg Apobec1-/-, and A1cf-/- mice fed chow or high-fat/high-fructose diets using RNA-Seq, RNA CLIP-Seq, and tissue microarrays from human hepatocellular cancer (HCC). A1cf+/Tg mice exhibited increased hepatic proliferation and steatosis, with increased lipogenic gene expression (Mogat1, Mogat2, Cidea, Cd36) associated with shifts in polysomal RNA distribution. Aged A1cf+/Tg mice developed spontaneous fibrosis, dysplasia, and HCC, and this development was accelerated on a high-fat/high-fructose diet and was independent of Apobec1. RNA-Seq revealed increased expression of mRNAs involved in oxidative stress (Gstm3, Gpx3, Cbr3), inflammatory response (Il19, Cxcl14, Tnfα, Ly6c), extracellular matrix organization (Mmp2, Col1a1, Col4a1), and proliferation (Kif20a, Mcm2, Mcm4, Mcm6), and a subset of mRNAs (including Sox4, Sox9, Cdh1) were identified in RNA CLIP-Seq. Increased A1CF expression in human HCC correlated with advanced fibrosis and with reduced survival in a subset with nonalcoholic fatty liver disease. In conclusion, we show that hepatic A1CF overexpression selectively alters polysomal distribution and mRNA expression, promoting lipogenic, proliferative, and inflammatory pathways leading to HCC

Observation of electronic excitation transfer through light harvesting complex II using two-dimensional electronic–vibrational spectroscopy

Light Harvesting Complex II (LHCII) serves a central role in light harvesting for oxygenic photosynthesis, and is arguably the most important photosynthetic antenna complex. In this work, we present two-dimensional electronic-vibrational (2DEV) spectra of LHCII isolated from spinach, demonstrating the possibility of using this technique to track the transfer of electronic excitation energy between specific pigments within the complex. We assign the spectral bands via comparison with the 2DEV spectra of the isolated chromophores, chlorophyll a and b, and present evidence that excitation energy between the pigments of the complex are observed in these spectra. Finally, we analyze the essential components of the 2DEV spectra using singular value decomposition, which makes it possible to reveal the relaxation pathways within this complex

Shigella sonnei genome sequencing and phylogenetic analysis indicate recent global dissemination from Europe

Shigella are human-adapted Escherichia coli that have gained the ability to invade the human gut mucosa and cause dysentery1,2, spreading efficiently via low-dose fecal-oral transmission3,4. Historically, S. sonnei has been predominantly responsible for dysentery in developed countries, but is now emerging as a problem in the developing world, apparently replacing the more diverse S. flexneri in areas undergoing economic development and improvements in water quality4-6. Classical approaches have shown S. sonnei is genetically conserved and clonal7. We report here whole-genome sequencing of 132 globally-distributed isolates. Our phylogenetic analysis shows that the current S. sonnei population descends from a common ancestor that existed less than 500 years ago and has diversified into several distinct lineages with unique characteristics. Our analysis suggests the majority of this diversification occurred in Europe, followed by more recent establishment of local pathogen populations in other continents predominantly due to the pandemic spread of a single, rapidly-evolving, multidrug resistant lineage

Evidence that a Panel of Neurodegeneration Biomarkers Predicts Vasospasm, Infarction, and Outcome in Aneurysmal Subarachnoid Hemorrhage

Biomarkers for neurodegeneration could be early prognostic measures of brain damage and dysfunction in aneurysmal subarachnoid hemorrhage (aSAH) with clinical and medical applications. Recently, we developed a new panel of neurodegeneration biomarkers, and report here on their relationships with pathophysiological complications and outcomes following severe aSAH. Fourteen patients provided serial cerebrospinal fluid samples for up to 10 days and were evaluated by ultrasonography, angiography, magnetic resonance imaging, and clinical examination. Functional outcomes were assessed at hospital discharge and 6–9 months thereafter. Eight biomarkers for acute brain damage were quantified: calpain-derived α-spectrin N- and C-terminal fragments (CCSntf and CCSctf), hypophosphorylated neurofilament H