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For decades, variability in clinical efficacy of the widely used inflammatory bowel disease (IBD) drug 5-aminosalicylic acid (5-ASA) has been attributed, in part, to its acetylation and inactivation by gut microbes. Identification of the responsible microbes and enzyme(s), however, has proved elusive. To uncover the source of this metabolism, we developed a multi-omics workflow combining gut microbiome metagenomics, metatranscriptomics and metabolomics from the longitudinal IBDMDB cohort of 132 controls and patients with IBD. This associated 12 previously uncharacterized microbial acetyltransferases with 5-ASA inactivation, belonging to two protein superfamilies: thiolases and acyl-CoA N -acyltransferases. In vitro characterization of representatives from both families confirmed the ability of these enzymes to acetylate 5-ASA. A cross-sectional analysis within the discovery cohort and subsequent prospective validation within the independent SPARC IBD cohort ( n  = 208) found three of these microbial thiolases and one acyl-CoA N -acyltransferase to be epidemiologically associated with an increased risk of treatment failure among 5-ASA users. Together, these data address a longstanding challenge in IBD management, outline a method for the discovery of previously uncharacterized gut microbial activities and advance the possibility of microbiome-based personalized medicine. A novel multi-omics workflow, combining gut microbiome metagenomics, metatranscriptomics and metabolomics, enabled the identification of the microbial pathways responsible for the degradation of the immunomodulatory drug 5-ASA in the gut of patients with inflammatory bowel disease.

Increased demand for clean energy solutions along the coast led to this research work, which will attempt to design a small wave energy conversion system to produce electricity from ocean surface motion. Literature on wave behavior, marine energy systems, and the coastal conditions in Tamil Nadu was reviewed initially to determine primary design considerations. On this basis, three wing configurations were designed to transform wave-induced motion into rotational energy. These configurations were analyzed using static structural analysis in ANSYS, considering stress distribution and deformations due to wave and hydrostatic pressure. The most efficient design was incorporated into a mechanical setup that transforms wave energy into rotary motion and then into electrical energy. To project real-world performance, the entire system was simulated and modelled in MATLAB Simulink so that voltage and current output can be predicted based on real ocean wave conditions. The simulation confirmed that the chosen design is mechanically sound and capable of generating detectable electric output, proving the viability of micro-scale wave energy harvesting for coastal applications.

The SARS-CoV-2 Omicron variant evades vaccine-induced immunity. While a booster dose of ancestral mRNA vaccines effectively elicits neutralizing antibodies against variants, its efficacy against Omicron in older adults, who are at the greatest risk of severe disease, is not fully elucidated. Here, we evaluate multiple longitudinal immunization regimens of mRNA BNT162b2 to assess the effects of a booster dose provided >8 months after the primary immunization series across the murine lifespan, including in aged 21-month-old mice. Boosting dramatically enhances humoral and cell-mediated responses with evidence of Omicron cross-recognition. Furthermore, while younger mice are protected without a booster dose, boosting provides sterilizing immunity against Omicron-induced lung infection in aged 21-month-old mice. Correlational analyses reveal that neutralizing activity against Omicron is strongly associated with protection. Overall, our findings indicate age-dependent vaccine efficacy and demonstrate the potential benefit of mRNA booster immunization to protect vulnerable older populations against SARS-CoV-2 variants. A longitudinal study in mice reveals that a booster dose of mRNA vaccine BNT162b2 enhances humoral and cell-mediated responses and provides sterilizing immunity against Omicron-induced lung infection in aged animals.

Lactate is abundant in rapidly dividing cells owing to the requirement for elevated glucose catabolism to support proliferation 1 – 6 . However, it is not known whether accumulated lactate affects the proliferative state. Here we use a systematic approach to determine lactate-dependent regulation of proteins across the human proteome. From these data, we identify a mechanism of cell cycle regulation whereby accumulated lactate remodels the anaphase promoting complex (APC/C). Remodelling of APC/C in this way is caused by direct inhibition of the SUMO protease SENP1 by lactate. We find that accumulated lactate binds and inhibits SENP1 by forming a complex with zinc in the SENP1 active site. SENP1 inhibition by lactate stabilizes SUMOylation of two residues on APC4, which drives UBE2C binding to APC/C. This direct regulation of APC/C by lactate stimulates timed degradation of cell cycle proteins, and efficient mitotic exit in proliferative human cells. This mechanism is initiated upon mitotic entry when lactate abundance reaches its apex. In this way, accumulation of lactate communicates the consequences of a nutrient-replete growth phase to stimulate timed opening of APC/C, cell division and proliferation. Conversely, persistent accumulation of lactate drives aberrant APC/C remodelling and can overcome anti-mitotic pharmacology via mitotic slippage. In sum, we define a biochemical mechanism through which lactate directly regulates protein function to control the cell cycle and proliferation. Discovery of a biochemical mechanism through which lactate binds and inhibits the SUMO protease SENP1, stimulating timed degradation of cell cycle proteins, and resulting in mitotic exit.

The purpose of this qualitative case study was to describe the strategies teachers chose to successfully differentiate for high achieving upper elementary mathematics students. The context of the study was mixed ability classes in international schools. The study used Vygotsky’s sociocultural learning theory as a theoretical framework to investigate teachers’ actions and decisions when planning and delivering instruction. The research questions that guided this study were: What strategies are teachers using to differentiate for high achieving mathematicians in mixed ability classes? Why do they choose these strategies? The use of the term high achieving is explored and defined within the context of the study and within the literature. In addition, characteristics of high achieving mathematics students are further explored. Studies have shown it is difficult to adjust instruction to challenge high achieving students in mixed ability classes. This study suggests that establishing a class environment based on sociocultural learning such as frequent teacher-student dialogue and questioning, collaborative learning, and frequent and varied formative assessment, allows for successful use of strategies to differentiate successfully for higher ability mathematics students. In addition, the study’s findings highlighted that characteristics such as efficacy, enjoyment, and subject confidence were common to teachers who differentiated instruction for high achieving mathematics students in the elementary school.

Identifying potent lead molecules for specific targets remains a major bottleneck in drug discovery. As structural information about proteins becomes increasingly available, ultra-large virtual screenings (ULVSs) which computationally evaluate billions of molecules offer a powerful way to accelerate early-stage drug discovery. Here, we introduce AdaptiveFlow, an open-source platform designed to make ULVSs more accessible, scalable, and efficient. AdaptiveFlow provides free access to a screening-ready version of the Enamine REAL Space (1), the largest library of ready-to-dock, drug-like molecules, containing 69 billion compounds that we prepared using the ligand preparation module of the platform. A key innovation of the platform is its use of a multi-dimensional grid of molecular properties, which helps researchers explore and prioritize chemical space more effectively and reduce the computational costs by a factor of approximately 1000. This grid forms the basis of a new method for identifying promising regions of chemical space, enabling systematic exploration and prioritization of compound libraries. An optional active learning component can further accelerate this process by adaptively steering the search toward molecules most likely to bind a given target. To support a broad range of applications, AdaptiveFlow is compatible with over 1,500 docking protocols. The platform achieves near-linear scaling on up to 5.6 million CPUs in the AWS Cloud, setting a new benchmark for large-scale cloud computing in drug discovery. Using this approach, we identified nanomolar inhibitors of two disease-relevant targets: ferroptosis suppressor protein 1 (FSP1) and poly(ADP-ribose) polymerase 1 (PARP-1) (2, 3). By leveraging newly solved crystal structures of FSP1 in complex with NAD , FAD, and coenzyme Q , we validated these hits experimentally and determined the co-crystal structures of FSP1 bound to small-molecule inhibitors, enabling insights into inhibitor binding mechanisms previously unknown. With its high scalability, flexibility, and open accessibility, AdaptiveFlow offers a powerful new resource for discovering and optimizing drug candidates at an unprecedented scale and speed.

Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models in mice. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training. From this data, we find that EGT accumulates in muscle mitochondria upon exercise training. Proteome-wide thermal stability studies identify 3-mercaptopyruvate sulfurtransferase (MPST) as a direct molecular target of EGT; EGT binds to and activates MPST, thereby boosting mitochondrial respiration and exercise training performance in mice. Together, these data identify the first physiologically relevant EGT target and establish the EGT-MPST axis as a molecular mechanism for regulating mitochondrial function and exercise performance.

The SARS-CoV-2 Omicron variant evades vaccine-induced immunity. While a booster dose of ancestral mRNA vaccines effectively elicits neutralizing antibodies against variants, its efficacy against Omicron in older adults, who are at the greatest risk of severe disease, is not fully elucidated. Here, we evaluated multiple longitudinal immunization regimens of mRNA BNT162b2 to assess the effects of a booster dose provided >8 months after the primary immunization series across the murine lifespan, including in extremely aged 21-month-old mice. Boosting dramatically enhanced humoral and cell-mediated responses with evidence of Omicron cross-recognition. Furthermore, while younger mice were protected without a booster dose, boosting provided sterilizing immunity against Omicron-induced lung infection in extremely aged mice. Correlational analyses revealed that neutralizing activity against Omicron was strongly associated with protection. Overall, our findings indicate age dependent vaccine efficacy and demonstrate the potential benefit of mRNA booster immunization to protect vulnerable older populations against SARS-CoV-2 variants.

Sleep fragmentation, particularly reduced and interrupted night sleep, impairs the quality of life of older people. Strikingly similar declines in sleep quality are seen during ageing in laboratory animals, including the fruit fly Drosophila. We investigated whether reduced activity of the nutrient- and stress-sensing insulin/insulin-like growth factor (IIS)/TOR signalling network, which ameliorates ageing in diverse organisms, could rescue the sleep fragmentation of ageing Drosophila. Lowered IIS/TOR network activity improved sleep quality, with increased night sleep and day activity and reduced sleep fragmentation. Reduced TOR activity, even when started for the first time late in life, improved sleep quality. The effects of reduced IIS/TOR network activity on day and night phenotypes were mediated through distinct mechanisms: Day activity was induced by adipokinetic hormone, dFOXO, and enhanced octopaminergic signalling. In contrast, night sleep duration and consolidation were dependent on reduced S6K and dopaminergic signalling. Our findings highlight the importance of different IIS/TOR components as potential therapeutic targets for pharmacological treatment of age-related sleep fragmentation in humans.

Temperature is one of the most relevant factors influencing the development of aquatic species, making it a key parameter to consider for aquaculture. Largemouth bass (LMB; Micropterus spp .) are highly relevant for human consumption and sport fishing, representing one of North America’s most important freshwater fisheries. Yet, questions remain on how LMB raised in recirculating aquaculture systems (RAS) respond to different temperatures. The main objective of this study was to determine the impact of thermal rearing conditions (21°C, 24°C, and 27°C) on gene expression of Florida and Northern LMB larvae at 8- and 28-days post hatch (DPH). Using de novo transcriptomes as a reference, our results suggest that gene expression differences for Florida LMB were mostly associated with temperature, while differences for Northern LMB were controlled by temperature and developmental stage. In general, both lineages showed activation of molecular pathways associated growth, such as development of muscle, nervous system, and vascular system. There were molecular signatures of stress with warming as well, including immune function, apoptosis, regulation of inflammation, and heat shock proteins. Florida LMB showed large differences between temperatures at both stages, while differences were much larger for Northern LMB at 28 DPH, specifically for individuals reared at 27°C. The results from this study are in line with previous phenotypic studies that indicated faster growth at warmer temperatures and better performance of Northern LMB raised in RAS. Overall, this study exemplifies how controlling developmental temperatures during the critical early life stages can be essential to guarantee the success of commercial hatchery production techniques.