Controlling the helicity of light by electrical magnetization switching.

Controlling the intensity of emitted light and charge current is the basis of transferring and processing information1. By contrast, robust information storage and magnetic random-access memories are implemented using the spin of the carrier and the associated magnetization in ferromagnets2. The missing link between the respective disciplines of photonics, electronics and spintronics is to modulate the circular polarization of the emitted light, rather than its intensity, by electrically controlled magnetization. Here we demonstrate that this missing link is established at room temperature and zero applied magnetic field in light-emitting diodes2-7, through the transfer of angular momentum between photons, electrons and ferromagnets. With spin-orbit torque8-11, a charge current generates also a spin current to electrically switch the magnetization. This switching determines the spin orientation of injected carriers into semiconductors, in which the transfer of angular momentum from the electron spin to photon controls the circular polarization of the emitted light2. The spin-photon conversion with the nonvolatile control of magnetization opens paths to seamlessly integrate information transfer, processing and storage. Our results provide substantial advances towards electrically controlled ultrafast modulation of circular polarization and spin injection with magnetization dynamics for the next-generation information and communication technology12, including space-light data transfer. The same operating principle in scaled-down structures or using two-dimensional materials will enable transformative opportunities for quantum information processing with spin-controlled single-photon sources, as well as for implementing spin-dependent time-resolved spectroscopies.

A metabolomics pipeline for the mechanistic interrogation of the gut microbiome.

Gut microorganisms modulate host phenotypes and are associated with numerous health effects in humans, ranging from host responses to cancer immunotherapy to metabolic disease and obesity. However, difficulty in accurate and high-throughput functional analysis of human gut microorganisms has hindered efforts to define mechanistic connections between individual microbial strains and host phenotypes. One key way in which the gut microbiome influences host physiology is through the production of small molecules1-3, yet progress in elucidating this chemical interplay has been hindered by limited tools calibrated to detect the products of anaerobic biochemistry in the gut. Here we construct a microbiome-focused, integrated mass-spectrometry pipeline to accelerate the identification of microbiota-dependent metabolites in diverse sample types. We report the metabolic profiles of 178 gut microorganism strains using our library of 833 metabolites. Using this metabolomics resource, we establish deviations in the relationships between phylogeny and metabolism, use machine learning to discover a previously undescribed type of metabolism in Bacteroides, and reveal candidate biochemical pathways using comparative genomics. Microbiota-dependent metabolites can be detected in diverse biological fluids from gnotobiotic and conventionally colonized mice and traced back to the corresponding metabolomic profiles of cultured bacteria. Collectively, our microbiome-focused metabolomics pipeline and interactive metabolomics profile explorer are a powerful tool for characterizing microorganisms and interactions between microorganisms and their host.

Correlative montage parallel array cryo-tomography for in situ structural cell biology.

Imaging large fields of view while preserving high-resolution structural information remains a challenge in low-dose cryo-electron tomography. Here we present robust tools for montage parallel array cryo-tomography (MPACT) tailored for vitrified specimens. The combination of correlative cryo-fluorescence microscopy, focused-ion-beam milling, substrate micropatterning, and MPACT supports studies that contextually define the three-dimensional architecture of cells. To further extend the flexibility of MPACT, tilt series may be processed in their entirety or as individual tiles suitable for sub-tomogram averaging, enabling efficient data processing and analysis.

Systems biology elucidates the distinctive metabolic niche filled by the human gut microbe Eggerthella lenta.

Human gut bacteria perform diverse metabolic functions with consequences for host health. The prevalent and disease-linked Actinobacterium Eggerthella lenta performs several unusual chemical transformations, but it does not metabolize sugars and its core growth strategy remains unclear. To obtain a comprehensive view of the metabolic network of E. lenta, we generated several complementary resources: defined culture media, metabolomics profiles of strain isolates, and a curated genome-scale metabolic reconstruction. Stable isotope-resolved metabolomics revealed that E. lenta uses acetate as a key carbon source while catabolizing arginine to generate ATP, traits which could be recapitulated in silico by our updated metabolic model. We compared these in vitro findings with metabolite shifts observed in E. lenta-colonized gnotobiotic mice, identifying shared signatures across environments and highlighting catabolism of the host signaling metabolite agmatine as an alternative energy pathway. Together, our results elucidate a distinctive metabolic niche filled by E. lenta in the gut ecosystem. Our culture media formulations, atlas of metabolomics data, and genome-scale metabolic reconstructions form a freely available collection of resources to support further study of the biology of this prevalent gut bacterium.

WeSA: a web server for improving analysis of affinity proteomics data.

Protein-protein interaction experiments still yield many false positive interactions. The socioaffinity metric can distinguish true protein-protein interactions from noise based on available data. Here, we present WeSA (Weighted SocioAffinity), which considers large datasets of interaction proteomics data (IntAct, BioGRID, the BioPlex) to score human protein interactions and, in a statistically robust way, flag those (even from a single experiment) that are likely to be false positives. ROC analysis (using CORUM-PDB positives and Negatome negatives) shows that WeSA improves over other measures of interaction confidence. WeSA shows consistently good results over all datasets (up to: AUC = 0.93 and at best threshold: TPR = 0.84, FPR = 0.11, Precision = 0.98). WeSA is freely available without login (wesa.russelllab.org). Users can submit their own data or look for organized information on human protein interactions using the web server. Users can either retrieve available information for a list of proteins of interest or calculate scores for new experiments. The server outputs either pre-computed or updated WeSA scores for the input enriched with information from databases. The summary is presented as a table and a network-based visualization allowing the user to remove those nodes/edges that the method considers spurious.

Myc-regulated miRNAs modulate p53 expression and impact animal survival under nutrient deprivation.

The conserved transcription factor Myc regulates cell growth, proliferation and apoptosis, and its deregulation has been associated with human pathologies. Although specific miRNAs have been identified as fundamental components of the Myc tumorigenic program, how Myc regulates miRNA biogenesis remains controversial. Here we showed that Myc functions as an important regulator of miRNA biogenesis in Drosophila by influencing both miRNA gene expression and processing. Through the analysis of ChIP-Seq datasets, we discovered that nearly 56% of Drosophila miRNA genes show dMyc binding, exhibiting either the canonical or non-canonical E-box sequences within the peak region. Consistently, reduction of dMyc levels resulted in widespread downregulation of miRNAs gene expression. dMyc also modulates miRNA processing and activity by controlling Drosha and AGO1 levels through direct transcriptional regulation. By using in vivo miRNA activity sensors we demonstrated that dMyc promotes miRNA-mediated silencing in different tissues, including the wing primordium and the fat body. We also showed that dMyc-dependent expression of miR-305 in the fat body modulates Dmp53 levels depending on nutrient availability, having a profound impact on the ability of the organism to respond to nutrient stress. Indeed, dMyc depletion in the fat body resulted in extended survival to nutrient deprivation which was reverted by expression of either miR-305 or a dominant negative version of Dmp53. Our study reveals a previously unrecognized function of dMyc as an important regulator of miRNA biogenesis and suggests that Myc-dependent expression of specific miRNAs may have important tissue-specific functions.

FOXO-mediated repression of Dicer1 regulates metabolism, stress resistance, and longevity in Drosophila.

The adipose tissue plays a crucial role in metabolism and physiology, affecting animal lifespan and susceptibility to disease. In this study, we present evidence that adipose Dicer1 (Dcr-1), a conserved type III endoribonuclease involved in miRNA processing, plays a crucial role in the regulation of metabolism, stress resistance, and longevity. Our results indicate that the expression of Dcr-1 in murine 3T3L1 adipocytes is responsive to changes in nutrient levels and is subject to tight regulation in the Drosophila fat body, analogous to human adipose and hepatic tissues, under various stress and physiological conditions such as starvation, oxidative stress, and aging. The specific depletion of Dcr-1 in the Drosophila fat body leads to changes in lipid metabolism, enhanced resistance to oxidative and nutritional stress, and is associated with a significant increase in lifespan. Moreover, we provide mechanistic evidence showing that the JNK-activated transcription factor FOXO binds to conserved DNA-binding sites in the dcr-1 promoter, directly repressing its expression in response to nutrient deprivation. Our findings emphasize the importance of FOXO in controlling nutrient responses in the fat body by suppressing Dcr-1 expression. This mechanism coupling nutrient status with miRNA biogenesis represents a novel and previously unappreciated function of the JNK-FOXO axis in physiological responses at the organismal level.

Tad and toxin-coregulated pilus structures reveal unexpected diversity in bacterial type IV pili.

Type IV pili (T4P) are ubiquitous in both bacteria and archaea. They are polymers of the major pilin protein, which has an extended and protruding N-terminal helix, α1, and a globular C-terminal domain. Cryo-EM structures have revealed key differences between the bacterial and archaeal T4P in their C-terminal domain structure and in the packing and continuity of α1. This segment forms a continuous α-helix in archaeal T4P but is partially melted in all published bacterial T4P structures due to a conserved helix breaking proline at position 22. The tad (tight adhesion) T4P are found in both bacteria and archaea and are thought to have been acquired by bacteria through horizontal transfer from archaea. Tad pilins are unique among the T4 pilins, being only 40 to 60 residues in length and entirely lacking a C-terminal domain. They also lack the Pro22 found in all high-resolution bacterial T4P structures. We show using cryo-EM that the bacterial tad pilus from Caulobacter crescentus is composed of continuous helical subunits that, like the archaeal pilins, lack the melted portion seen in other bacterial T4P and share the packing arrangement of the archaeal T4P. We further show that a bacterial T4P, the Vibrio cholerae toxin coregulated pilus, which lacks Pro22 but is not in the tad family, has a continuous N-terminal α-helix, yet its α1 s are arranged similar to those in other bacterial T4P. Our results highlight the role of Pro22 in helix melting and support an evolutionary relationship between tad and archaeal T4P.

Simulating molecular polaritons in the collective regime using few-molecule models.

The study of molecular polaritons beyond simple quantum emitter ensemble models (e.g., Tavis-Cummings) is challenging due to the large dimensionality of these systems and the complex interplay of molecular electronic and nuclear degrees of freedom. This complexity constrains existing models to either coarse-grain the rich physics and chemistry of the molecular degrees of freedom or artificially limit the description to a small number of molecules. In this work, we exploit permutational symmetries to drastically reduce the computational cost of ab initio quantum dynamics simulations for large N. Furthermore, we discover an emergent hierarchy of timescales present in these systems, that justifies the use of an effective single molecule to approximately capture the dynamics of the entire ensemble, an approximation that becomes exact as N → ∞. We also systematically derive finite N corrections to the dynamics and show that addition of k extra effective molecules is enough to account for phenomena whose rates scale as 𝒪(N-k). Based on this result, we discuss how to seamlessly modify existing single-molecule strong coupling models to describe the dynamics of the corresponding ensemble. We call this approach collective dynamics using truncated equations (CUT-E), benchmark it against well-known results of polariton relaxation rates, and apply it to describe a universal cavity-assisted energy funneling mechanism between different molecular species. Beyond being a computationally efficient tool, this formalism provides an intuitive picture for understanding the role of bright and dark states in chemical reactivity, necessary to generate robust strategies for polariton chemistry.

Radiation necrosis after radiation therapy treatment of brain metastases: A computational approach.

Metastasis is the process through which cancer cells break away from a primary tumor, travel through the blood or lymph system, and form new tumors in distant tissues. One of the preferred sites for metastatic dissemination is the brain, affecting more than 20% of all cancer patients. This figure is increasing steadily due to improvements in treatments of primary tumors. Stereotactic radiosurgery (SRS) is one of the main treatment options for patients with a small or moderate number of brain metastases (BMs). A frequent adverse event of SRS is radiation necrosis (RN), an inflammatory condition caused by late normal tissue cell death. A major diagnostic problem is that RNs are difficult to distinguish from BM recurrences, due to their similarities on standard magnetic resonance images (MRIs). However, this distinction is key to choosing the best therapeutic approach since RNs resolve often without further interventions, while relapsing BMs may require open brain surgery. Recent research has shown that RNs have a faster growth dynamics than recurrent BMs, providing a way to differentiate the two entities, but no mechanistic explanation has been provided for those observations. In this study, computational frameworks were developed based on mathematical models of increasing complexity, providing mechanistic explanations for the differential growth dynamics of BMs relapse versus RN events and explaining the observed clinical phenomenology. Simulated tumor relapses were found to have growth exponents substantially smaller than the group in which there was inflammation due to damage induced by SRS to normal brain tissue adjacent to the BMs, thus leading to RN. ROC curves with the synthetic data had an optimal threshold that maximized the sensitivity and specificity values for a growth exponent ß* = 1.05, very close to that observed in patient datasets.

Serum GFAP levels correlate with astrocyte reactivity, post-mortem brain atrophy and neurofibrillary tangles.

Glial fibrillary acidic protein (GFAP), a proxy of astrocyte reactivity, has been proposed as biomarker of Alzheimer's disease. However, there is limited information about the correlation between blood biomarkers and post-mortem neuropathology. In a single-centre prospective clinicopathological cohort of 139 dementia patients, for which the time-frame between GFAP level determination and neuropathological assessment was exceptionally short (on average 139 days), we analysed this biomarker, measured at three time points, in relation to proxies of disease progression such as cognitive decline and brain weight. Most importantly, we investigated the use of blood GFAP to detect the neuropathological hallmarks of Alzheimer's disease, while accounting for potential influences of the most frequent brain co-pathologies. The main findings demonstrated an association between serum GFAP level and post-mortem tau pathology (ß = 12.85; P < 0.001) that was independent of amyloid deposits (ß = 13.23; P = 0.02). A mediation analysis provided additional support for the role of astrocytic activation as a link between amyloid and tau pathology in Alzheimer's disease. Furthermore, a negative correlation was observed between pre-mortem serum GFAP and brain weight at post-mortem (r = -0.35; P < 0.001). This finding, together with evidence of a negative correlation with cognitive assessments (r = -0.27; P = 0.005), supports the role of GFAP as a biomarker for disease monitoring, even in the late phases of Alzheimer's disease. Moreover, the diagnostic performance of GFAP in advanced dementia patients was explored, and its discriminative power (area under the receiver operator characteristic curve at baseline = 0.91) in differentiating neuropathologically-confirmed Alzheimer's disease dementias from non-Alzheimer's disease dementias was determined, despite the challenging scenario of advanced age and frequent co-pathologies in these patients. Independently of Alzheimer's disease, serum GFAP levels were shown to be associated with two other pathologies targeting the temporal lobes-hippocampal sclerosis (ß = 3.64; P = 0.03) and argyrophilic grain disease (ß = -6.11; P = 0.02). Finally, serum GFAP levels were revealed to be correlated with astrocyte reactivity, using the brain GFAP-immunostained area as a proxy (ρ = 0.21; P = 0.02). Our results contribute to increasing evidence suggesting a role for blood GFAP as an Alzheimer's disease biomarker, and the findings offer mechanistic insights into the relationship between blood GFAP and Alzheimer's disease neuropathology, highlighting its ties with tau burden. Moreover, the data highlighting an independent association between serum GFAP levels and other neuropathological lesions provide information for clinicians to consider when interpreting test results. The longitudinal design and correlation with post-mortem data reinforce the robustness of our findings. However, studies correlating blood biomarkers and neuropathological assessments are still scant, and further research is needed to replicate and validate these results in diverse populations.

Forecasting the Incidence and Prevalence of Inflammatory Bowel Disease: A Canadian Nationwide Analysis.

INTRODUCTION: Canada has a high burden of inflammatory bowel disease (IBD). Historical trends of IBD incidence and prevalence were analyzed to forecast the Canadian burden over the next decade. METHODS: Population-based surveillance cohorts in 8 provinces derived from health administrative data assessed the national incidence (2007-2014) and prevalence (2002-2014) of IBD. Autoregressive integrated moving average models were used to forecast incidence and prevalence, stratified by age, with 95% prediction intervals (PI), to 2035. The average annual percentage change (AAPC) with 95% confidence interval (CI) was calculated for the forecasted incidence and prevalence. RESULTS: The national incidence of IBD is estimated to be 29.9 per 100,000 (95% PI 28.3-31.5) in 2023. With a stable AAPC of 0.36% (95% CI -0.05 to 0.72), the incidence of IBD is forecasted to be 31.2 per 100,000 (95% PI 28.1-34.3) in 2035. The incidence in pediatric patients (younger than 18 years) is increasing (AAPC 1.27%; 95% CI 0.82-1.67), but it is stable in adults (AAPC 0.26%; 95% CI -0.42 to 0.82). The prevalence of IBD in Canada was 843 per 100,000 (95% PI 716-735) in 2023 and is expected to steadily climb (AAPC 2.43%; 95% CI 2.32-2.54) to 1,098 per 100,000 (95% PI 1,068-1,127) by 2035. The highest prevalence is in seniors with IBD (1,174 per 100,000 in 2023; AAPC 2.78%; 95% CI 2.75-2.81). DISCUSSION: Over the next decade, the Canadian health care systems will contend with the juxtaposition of rising incidence of pediatric IBD and a rising prevalence of overall IBD driven by the aging population.

Nanorheology and Nanoindentation Revealed a Softening and an Increased Viscous Fluidity of Adherent Mammalian Cells upon Increasing the Frequency.

The nanomechanical response of a cell depends on the frequency at which the cell is probed. The components of the cell that contribute to this property and their interplay are not well understood. Here, two force microscopy methods are integrated to characterize the frequency and/or the velocity-dependent properties of living cells. It is shown on HeLa and fibroblasts, that cells soften and fluidize upon increasing the frequency or the velocity of the deformation. This property was independent of the type and values (25 or 1000 nm) of the deformation. At low frequencies (2-10 Hz) or velocities (1-10 µm s-1 ), the response is dominated by the mechanical properties of the cell surface. At higher frequencies (>10 Hz) or velocities (>10 µm s-1 ), the response is dominated by the hydrodynamic drag of the cytosol. Softening and fluidization does not seem to involve any structural remodeling. It reflects a redistribution of the applied stress between the solid and liquid-like elements of the cell as the frequency or the velocity is changed. The data indicates that the quasistatic mechanical properties of a cell featuring a cytoskeleton pathology might be mimicked by the response of a non-pathological cell which is probed at a high frequency.

A continuous flow bioreactor system for high-throughput hyperpolarized metabolic flux analysis.

Hyperpolarized carbon-13 labeled compounds are increasingly being used in medical MR imaging (MRI) and MR imaging (MRI) and spectroscopy (MRS) research, due to its ability to monitor tissue and cell metabolism in real-time. Although radiological biomarkers are increasingly being considered as clinical indicators, biopsies are still considered the gold standard for a large variety of indications. Bioreactor systems can play an important role in biopsy examinations because of their ability to provide a physiochemical environment that is conducive for therapeutic response monitoring ex vivo. We demonstrate here a proof-of-concept bioreactor and microcoil receive array setup that allows for ex vivo preservation and metabolic NMR spectroscopy on up to three biopsy samples simultaneously, creating an easy-to-use and robust way to simultaneously run multisample carbon-13 hyperpolarization experiments. Experiments using hyperpolarized [1-13C]pyruvate on ML-1 leukemic cells in the bioreactor setup were performed and the kinetic pyruvate-to-lactate rate constants ( k PL ) extracted. The coefficient of variation of the experimentally found k PL s for five repeated experiments was C V = 35 % . With this statistical power, treatment effects of 30%-40% change in lactate production could be easily differentiable with only a few hyperpolarization dissolutions on this setup. Furthermore, longitudinal experiments showed preservation of ML-1 cells in the bioreactor setup for at least 6 h. Rat brain tissue slices were also seen to be preserved within the bioreactor for at least 1 h. This validation serves as the basis for further optimization and upscaling of the setup, which undoubtedly has huge potential in high-throughput studies with various biomarkers and tissue types.

Ferrocenyl Dinuclear Gold(I) Complexes. Study of their Structural Features and the Influence of Bridging and Phosphane Ligands in a Catalytic Cyclization Reaction.

The combination of the ferrocene moiety with gold(I) catalysis remains a relatively unexplored field. In this article, we delve into the synthesis, characterization, and potential catalytic activity of four complexes utilizing both monodentate and bidentate ferrocenyl diphenylphosphane ligands (ppf and dppf), coordinated with two gold(I) metal centers, linked by either chloride or pentafluorophenylthiolate bridging ligands. This leads to the formation of cationic "self-activated" precatalysts capable of initiating the catalytic cycle without the need for external additives. The catalytic activity of these complexes was assessed through a model reaction in gold(I) catalysis, specifically the cyclization of a N-propargylbenzamide to produce an oxazole. In addition, we studied and compared the influence exerted by both the phosphane and the bridging ligand on the performance of these catalysts.

Ferrocenyl Dinuclear Gold(I) Complexes. Study of their Structural Features and the Influence of Bridging and Phosphane Ligands in a Catalytic Cyclization Reaction.

Invited for the cover of this issue are the groups of Raquel P. Herrera and M. Concepción Gimeno at the Instituto de Síntesis Química y Catálisis Homogénea (University of Zaragoza-CSIC). The image depicts the light of the full moon illuminating a bridge between the gold(I) metal centers. Two dragons, symbolizing the use of bridging ligands, confront each other to determine the ultimate victor. Read the full text of the article at 10.1002/chem.202303585.

The Potential of Self-Activating Au(I) Complexes in Gold Catalysis.

Gold catalysis has emerged as a groundbreaking field in synthetic chemistry, revolutionizing numerous organic transformations. Despite the significant achieved advancements, the mechanistic understanding behind many gold-catalyzed reactions remains elusive. This Concept article covers the so-called "self-activating" Au(I) complexes, sorting out their pivotal role in gold catalysis. We comment on how Au(I) complexes can undergo self-activation, triggering diverse catalytic transformations without the need for external additives. The most important examples reported so far that underlie the catalytic activity of these species are discussed. This intrinsic reactivity represents a paradigm shift in gold catalysis, offering new avenues for the design of efficient and sustainable catalytic systems. Furthermore, we explore the factors influencing the stability, reactivity, and selectivity of these Au(I) complexes, providing insights into their synthetic utility and potential applications in synthesis. This area of research not only advances our fundamental understanding of gold catalysis but also paves the way for the development of novel catalytic strategies with broad implications in organic synthesis and the chemical industry.

Glucose-lowering treatment pathways of individuals with chronic kidney disease and type 2 diabetes according to the Kidney Disease: Improving Global Outcomes 2012 risk classification.

AIMS: To describe treatment pathways for key glucose-lowering therapies in individuals with chronic kidney disease (CKD) and type 2 diabetes (T2D) using retrospective data from DISCOVER CKD (NCT04034992). METHODS: Data were extracted from the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics data (2008-2020) and the US integrated Limited Claims and Electronic Health Records Database (LCED; 2012-2019). Eligible individuals were aged ≥18 years with CKD, identified by two consecutive estimated glomerular filtration rate (eGFR) measures (15-<75 mL/min/1.73 m2 ; 90-730 days apart; index date was the second measurement) and T2D. Chronological treatment pathways for glucose-lowering therapies prescribed on or after CKD index to end of follow-up were computed. Median time and proportion of overall follow-up time on treatment were described for each therapy by database and by eGFR and urinary albumin-to-creatinine ratio (UACR) categories. RESULTS: Of 36,951 and 4339 eligible individuals in the CPRD and LCED, respectively, median baseline eGFR was 67.8 and 64.9 mL/min/1.73 m2 ; 64.2 and 63.9% received metformin prior to index; and median (interquartile range) time on metformin during follow-up was 917 (390-1671) and 454 (192-850) days (accounting for ~75% of follow-up time in both databases). The frequency of combination treatment increased over time. There were trends towards decreased metformin prescriptions with decreasing eGFR and increasing UACR within each eGFR category. CONCLUSIONS: Individuals with CKD and T2D had many combinations of therapies and substantial follow-up time on therapy. These results highlight opportunities for improved CKD management.

Tumor growth for remodeling process: A 2D approach.

This paper aims to present a comprehensive framework for coupling tumor-bone remodeling processes in a 2-dimensional geometry. This is achieved by introducing a bio-inspired damage that represents the growing tumor, which subsequently affects the main populations involved in the remodeling process, namely, osteoclasts, osteoblasts, and bone tissue. The model is constructed using a set of differential equations based on the Komarova's and Ayati's models, modified to incorporate the bio-inspired damage that may result in tumor mass formation. Three distinct models were developed. The first two models are based on the Komarova's governing equations, with one demonstrating an osteolytic behavior and the second one an osteoblastic model. The third model is a variation of Ayati's model, where the bio-inspired damage is induced through the paracrine and autocrine parameters, exhibiting an osteolytic behavior. The obtained results are consistent with existing literature, leading us to believe that our in-silico experiments will serve as a cornerstone for paving the way towards targeted interventions and personalized treatment strategies, ultimately improving the quality of life for those affected by these conditions.