Daytime colour preference in Drosophila depends on the circadian clock and TRP channels.

Light discrimination according to colour can confer survival advantages by guiding animals towards food and shelter and away from potentially harmful situations1,2. Such colour-dependent behaviour can be learned or innate. Data on innate colour preference in mammals remain controversial3 and there are limited data for simpler organisms4-7. Here we show that, when given a choice among blue, green and dim light, fruit flies exhibit an unexpectedly complex pattern of colour preference that changes according to the time of day. Flies show a strong preference for green in the early morning and late afternoon, a reduced green preference at midday and a robust avoidance of blue throughout the day. Genetic manipulations reveal that the peaks in green preference require rhodopsin-based visual photoreceptors and are controlled by the circadian clock. The midday reduction in green preference in favour of dim light depends on the transient receptor potential (TRP) channels dTRPA1 and Pyrexia, and is also timed by the clock. By contrast, avoidance of blue light is primarily mediated by multidendritic neurons, requires rhodopsin 7 and the TRP channel Painless, and is independent of the clock. Our findings show that several TRP channels are involved in colour-driven behaviour in Drosophila, and reveal distinct pathways of innate colour preference that coordinate the behavioural dynamics of flies in ambient light.

Enhanced mucosal antibody- and T-cell responses against SARS-CoV-2 after heterologous intramuscular mRNA prime/intranasal protein boost vaccination with a combination adjuvant.

Current COVID-19 mRNA vaccines delivered intramuscularly (IM) induce effective systemic immunity, but with suboptimal immunity at mucosal sites, limiting their ability to impart sterilizing immunity. There is strong interest in rerouting immune responses induced in the periphery by parenteral vaccination to the portal entry site of respiratory viruses, such as SARS-CoV-2, by mucosal vaccination. We previously demonstrated the combination adjuvant, NE/IVT, consisting of a nanoemulsion (NE) and an RNA-based RIG-I agonist (IVT) induces potent systemic and mucosal immune responses in protein-based SARS-CoV-2 vaccines administered intranasally (IN). Herein, we demonstrate priming IM with mRNA followed by heterologous IN boosting with NE/IVT adjuvanted recombinant antigen induces strong mucosal and systemic antibody responses and enhances antigen-specific T cell responses in mucosa-draining lymph nodes compared to IM/IM and IN/IN prime/boost regimens. While all regimens induced cross-neutralizing antibodies against divergent variants and sterilizing immunity in the lungs of challenged mice, mucosal vaccination, either as homologous prime/boost or heterologous IN boost after IM mRNA prime was required to impart sterilizing immunity in the upper respiratory tract. Our data demonstrate the benefit of hybrid regimens whereby strong immune responses primed via IM vaccination are rerouted by IN vaccination to mucosal sites to provide optimal protection to SARS-CoV-2.

The Nitrile Bis-Thiol Bioconjugation Reaction.

Electron-poor aryl nitriles are promising reagents for bioconjugation due to their high electrophilicity and selectivity for reaction with thiols, albeit generally in a reversible manner. A transient species has previously been observed in such reactions, involving the addition of two thiols to the nitrile functional group, forming a tetrahedral amino dithioacetal (ADTA). In this work, the reaction of heteroaryl nitriles with bis-thiols is explored in an attempt to generate stable ADTAs, which could facilitate new bioconjugation protocols. By use of a 1,2-dithiol, or the incorporation of an electrophilic trap into the aryl nitrile design, the formation of stable products is achieved. The resultant "nitrile bis-thiol" (NBT) reaction is then explored in the context of protein modification, specifically to carry out antibody conjugation. By addition of these nitriles to the reduced disulfide bond of an antibody fragment, it is shown that, depending on the reagent design, cysteine-to-lysine transfer or disulfide bridged NBT products can be generated. Both represent site-selective conjugates and are shown to be stable when challenged with glutathione under physiological conditions and upon incubation in serum. Furthermore, the NBT reaction is tested in the more challenging context of a full antibody, and all four disulfide bonds are effectively modified by these new one-carbon bridging reagents. Overall, this reaction of heteroaryl-nitriles with bis-thiols is shown to be highly efficient and versatile, of tunable reversibility, and offers enticing prospects as a new addition to the toolbox of biocompatible "click"-type reactions.

An Albumin-Holliday Junction Biomolecular Modular Design for Programmable Multifunctionality and Prolonged Circulation.

Combinatorial properties such as long-circulation and site- and cell-specific engagement need to be built into the design of advanced drug delivery systems to maximize drug payload efficacy. This work introduces a four-stranded oligonucleotide Holliday Junction (HJ) motif bearing functional moieties covalently conjugated to recombinant human albumin (rHA) to give a "plug-and-play" rHA-HJ multifunctional biomolecular assembly with extended circulation. Electrophoretic gel-shift assays show successful functionalization and purity of the individual high-performance liquid chromatography-purified modules as well as efficient assembly of the rHA-HJ construct. Inclusion of an epidermal growth factor receptor (EGFR)-targeting nanobody module facilitates specific binding to EGFR-expressing cells resulting in approximately 150-fold increased fluorescence intensity determined by flow cytometric analysis compared to assemblies absent of nanobody inclusion. A cellular recycling assay demonstrated retained albumin-neonatal Fc receptor (FcRn) binding affinity and accompanying FcRn-driven cellular recycling. This translated to a 4-fold circulatory half-life extension (2.2 and 0.55 h, for the rHA-HJ and HJ, respectively) in a double transgenic humanized FcRn/albumin mouse. This work introduces a novel biomolecular albumin-nucleic acid construct with extended circulatory half-life and programmable multifunctionality due to its modular design.

A Toolkit for Delirium Identification and Promoting Partnerships Between Carers and Nurses: A Pilot Pre-Post Feasibility Study.

BACKGROUND: Delirium is frightening for people experiencing it and their carers, and it is the most common hospital-acquired complication worldwide. Delirium is associated with higher rates of morbidity, mortality, residential care home admission, dementia, and carer stress and burden, yet strategies to embed the prevention and management of delirium as part of standard hospital care remain challenging. Carers are well placed to recognize subtle changes indicative of delirium, and partner with nurses in the prevention and management of delirium. OBJECTIVE: To evaluate a Prevention & Early Delirium Identification Carer Toolkit (PREDICT), to support partnerships between carers and nurses to prevent and manage delirium. DESIGN: A pre-post-test intervention and observation study. MAIN MEASURES: Changes in carer knowledge of delirium; beliefs about their role in partnering with nurses and intended and actual use of PREDICT; carer burden and psychological distress. Secondary measures were rates of delirium. PARTICIPANTS: Participants were carers of Indigenous patients aged 45 years and older and non-Indigenous patients aged 65 years and older. INTERVENTION: Nurses implemented PREDICT, with a view to provide carers with information about delirium and strategies to address caregiving stress and burden. KEY RESULTS: Participants included 25 carers (43% response rate) (n = 17, 68% female) aged 29-88 (M = 65, SD = 17.7 years). Carer delirium knowledge increased significantly from pre-to-post intervention (p = < .001; CI 2.07-4.73). Carers' intent and actual use of PREDICT was (n = 18, 72%; and n = 17, 68%). Carer burden and psychological distress did not significantly change. The incidence of delirium in the intervention ward although not significant, decreased, indicating opportunity for scaling up. CONCLUSION: The prevention and management of delirium are imperative for safe and quality care for patients, carers, and staff. Further comprehensive and in-depth research is required to better understand underlying mechanisms of change and explore facets of nursing practice influenced by this innovative approach.

Creation of Polymer Datasets with Targeted Backbones for Screening of High-Performance Membranes for Gas Separation.

A simple approach was developed to computationally construct a polymer dataset by combining simplified molecular-input line-entry system (SMILES) strings of a targeted polymer backbone and a variety of molecular fragments. This method was used to create 14 polymer datasets by combining seven polymer backbones and molecules from two large molecular datasets (MOSES and QM9). Polymer backbones that were studied include four polydimethylsiloxane (PDMS) based backbones, poly(ethylene oxide) (PEO), poly(allyl glycidyl ether) (PAGE), and polyphosphazene (PPZ). The generated polymer datasets can be used for various cheminformatics tasks, including high-throughput screening for gas permeability and selectivity. This study utilized machine learning (ML) models to screen the polymers for CO2/CH4 and CO2/N2 gas separation using membranes. Several polymers of interest were identified. The results highlight that employing an ML model fitted to polymer selectivities leads to higher accuracy in predicting polymer selectivity compared to using the ratio of predicted permeabilities.

Building common understanding: seeking consensus and defining social prescribing across contexts - a collective commentary on a Delphi study.

Social prescribing has become a global phenomenon. A Delphi study was recently conducted with 48 social prescribing experts from 26 countries to establish global agreement on the definition of social prescribing. We reflect on the use and utility of the outputs of this work, and where we go from here.

Physical Determinants of Sprint and Long Jump Performance in Male Youth Track-and-Field Athletes With Differing Maturity Statuses.

PURPOSE: This study examined the physical determinants of 60-m sprint and long jump (LJ) performance and differences between maturity groups in physical characteristics in young male track-and-field athletes. METHODS: Competition results, countermovement jump, isometric leg press, 10-5 repeated jump test, and 50-m sprint were collected over 3 seasons for 54 male athletes (age 13 [1] y; stature 160.0 [8.9] cm; body mass, 48.0 [9.8] kg; percentage predicted adult height 92.2% [5.5%]) grouped by maturity status: approaching- (n = 16), circa- (n = 19), and post-peak height velocity (PHV) (n = 19). RESULTS: There were significant between-group differences in 60 m, LJ, and all physical testing variables (P < .001, g = 0.88-5.44) when comparing the approaching- and circa-PHV groups with the post-PHV group. Significant differences were identified between the approaching- and circa-PHV groups in 40-m (P = .033, g = 0.89), 50-m (P = .024, g = 1.64), and 60-m (P < .001, g = 0.89) sprint times. Countermovement jump and 50-m sprint variables were consistently important for projection of 60 m and LJ performance across the valid multivariate models. CONCLUSIONS: Large differences in performance across maturity groups highlight the importance of understanding athletes' maturity status to accurately interpret performance. Several physical performance variables were important for projecting competition 60 m and LJ performance.

Optimization of treatment workflow for 0.35T MR-Linac system.

PURPOSE: This study presents a novel and comprehensive framework for evaluating magnetic resonance guided radiotherapy (MRgRT) workflow by integrating the Failure Modes and Effects Analysis (FMEA) approach with Time-Driven Activity-Based Costing (TDABC). We assess the workflow for safety, quality, and economic implications, providing a holistic understanding of the MRgRT implementation. The aim is to offer valuable insights to healthcare practitioners and administrators, facilitating informed decision-making regarding the 0.35T MRIdian MR-Linac system's clinical workflow. METHODS: For FMEA, a multidisciplinary team followed the TG-100 methodology to assess the MRgRT workflow's potential failure modes. Following the mitigation of primary failure modes and workflow optimization, a treatment process was established for TDABC analysis. The TDABC was applied to both MRgRT and computed tomography guided RT (CTgRT) for typical five-fraction stereotactic body RT (SBRT) treatments, assessing total workflow and costs associated between the two treatment workflows. RESULTS: A total of 279 failure modes were identified, with 31 categorized as high-risk, 55 as medium-risk, and the rest as low-risk. The top 20% risk priority numbers (RPN) were determined for each radiation oncology care team member. Total MRgRT and CTgRT costs were assessed. Implementing technological advancements, such as real-time multi leaf collimator (MLC) tracking with volumetric modulated arc therapy (VMAT), auto-segmentation, and increasing the Linac dose rate, led to significant cost savings for MRgRT. CONCLUSION: In this study, we integrated FMEA with TDABC to comprehensively evaluate the workflow and the associated costs of MRgRT compared to conventional CTgRT for five-fraction SBRT treatments. FMEA analysis identified critical failure modes, offering insights to enhance patient safety. TDABC analysis revealed that while MRgRT provides unique advantages, it may involve higher costs. Our findings underscore the importance of exploring cost-effective strategies and key technological advancements to ensure the widespread adoption and financial sustainability of MRgRT in clinical practice.

Trifunctional Dibromomaleimide Reagents Built Around A Lysine Scaffold Deliver Site-selective Dual-modality Antibody Conjugation.

We describe the synthesis and application of a selection of trifunctional reagents for the dual-modality modification of native, solvent accessible disulfide bonds in trastuzumab. The reagents were developed from the dibromomaleimide (DBM) platform with two orthogonal clickable functional groups built around a lysine core. We also describe the development of an aryl diselenide additive which enables antibody disulfide reduction in 4 minutes and a rapid overall reduction-bridging-double click sequence.

Availability of palliative parenteral nutrition to patients with advanced cancer: A national survey of service provision.

BACKGROUND: Patients with advanced malignancy who are unable to meet their nutritional requirements orally or enterally as a result of intestinal failure may be considered for parenteral nutrition support. Current UK guidance recommends that patients with a 3-month prognosis and good performance status (i.e., Karnofsky performance status >50) should be considered for this intervention at home (termed Home Parenteral Nutrition; HPN). However, HPN is a nationally commissioned service by National Health Service (NHS) England and Improvement that can only be initiated at specific NHS centres and so may not be easily accessed by patients outside of these centres. This survey aimed to identify current clinical practice across UK hospitals about how palliative parenteral nutrition is initiated. METHODS: Clinical staff associated with Nutrition Support Teams at NHS Organisations within the UK were invited to complete an electronically administered survey of national clinical practice through advertisements posted on relevant professional interest groups. RESULTS: Sixty clinicians responded to the survey administered between September and November 2020. The majority of respondents responded positively that decisions made to initiate palliative parenteral nutrition were conducted in alignment with current national guidance in relation to decision-making and formulation of parenteral nutrition. Variation was observed in relation to the provision of advance care planning in relation to nutrition support prior to discharge, as well as the consideration of venting gastrostomy placement in patients with malignant bowel obstruction unsuitable for surgical intervention. CONCLUSIONS: Adherence to current national guidance in relation to the provision of palliative parenteral nutrition is variable for some aspects of care. Further work is required particularly in relation to maximising the opportunity for the provision of advance care planning prior to discharge in this patient cohort.

The unfulfilled potential of mucosal immunization.

Recent events involving the global coronavirus pandemic have focused attention on vaccination strategies. Although tremendous advances have been made in subcutaneous and intramuscular vaccines during this time, one area that has lagged in implementation is mucosal immunization. Mucosal immunization provides several potential advantages over subcutaneous and intramuscular routes, including protection from localized infection at the site of entry, clearance of organisms on mucosal surfaces, induction of long-term immunity through establishment of central and tissue-resident memory cells, and the ability to shape regulatory responses. Despite these advantages, significant barriers remain to achieving effective mucosal immunization. The epithelium itself provides many obstacles to immunization, and the activation of immune recognition and effector pathways that leads to mucosal immunity has been difficult to achieve. This review will highlight the potential advantages of mucosal immunity, define the barriers to mucosal immunization, examine the immune mechanisms that need to be activated on mucosal surfaces, and finally address recent developments in methods for mucosal vaccination that have shown promise in generating immunity on mucosal surfaces in human trials.

Safety of peanut (Arachis hypogaea) allergen powder-dnfp in children and teenagers with peanut allergy: Pooled summary of phase 3 and extension trials.

BACKGROUND: Peanut (Arachis hypogaea) allergen powder-dnfp (PTAH; previously known as AR101) is a daily oral immunotherapy approved to mitigate allergic reactions after accidental peanut exposure in peanut-allergic individuals aged 4-17 years. OBJECTIVE: We sought to comprehensively summarize the PTAH safety profile for up to ∼2 years of treatment. METHODS: Safety and adverse event (AE) data from participants aged 4-17 years from 3 controlled, phase 3 and 2 open-label extension trials were pooled and assessed. RESULTS: Of the 944 individuals receiving ≥1 PTAH dose, median exposure was ∼49 weeks; most participants experienced ≥1 treatment-related AE (TRAE; n = 853; 90.4%). A total of 829 participants experienced TRAEs with a maximum severity of mild (497, 52.6%) or moderate (332, 35.2%); 24 participants (2.5%) experienced TRAEs graded as severe. Overall, 80 participants (9.5%) discontinued as a result of AEs; most experienced gastrointestinal symptoms and discontinued during the first 6 months. When adjusted for exposure, AEs and TRAEs occurred at a rate of 76.4 and 58.7 events per participant-year of exposure (PYE), respectively, during updosing; AEs and TRAEs decreased to 23.0 and 14.2, respectively, during 300 mg maintenance. Overall, exposure-adjusted rates of systemic allergic reactions were 0.12 events/PYE (mild), 0.11 events/PYE (moderate), and 0.01 events/PYE (severe [anaphylaxis]). CONCLUSION: The safety profile of PTAH was consistent across trials, manageable, and improved over time. AEs were predominantly mild to moderate, and all grades declined in frequency with continued treatment. These data can be used to facilitate shared decision-making discussions with patients and families considering treatment with PTAH.

GC-MS Techniques Investigating Potential Biomarkers of Dying in the Last Weeks with Lung Cancer.

Predicting when a patient with advanced cancer is dying is a challenge and currently no prognostic test is available. We hypothesised that a dying process from cancer is associated with metabolic changes and specifically with changes in volatile organic compounds (VOCs). We analysed urine from patients with lung cancer in the last weeks of life by headspace gas chromatography mass spectrometry. Urine was acidified or alkalinised before analysis. VOC changes in the last weeks of life were identified using univariate, multivariate and linear regression analysis; 12 VOCs increased (11 from the acid dataset, 2 from the alkali dataset) and 25 VOCs decreased (23 from the acid dataset and 3 from the alkali dataset). A Cox Lasso prediction model using 8 VOCs predicted dying with an AUC of 0.77, 0.78 and 0.85 at 30, 20 and 10 days and stratified patients into a low (median 10 days), medium (median 50 days) or high risk of survival. Our data supports the hypothesis there are specific metabolic changes associated with the dying. The VOCs identified are potential biomarkers of dying in lung cancer and could be used as a tool to provide additional prognostic information to inform expert clinician judgement and subsequent decision making.

Fluorescence Switching for Temperature Sensing in Water.

A water-soluble thermochromic molecular switch with spectrally resolved fluorescence in its two interconvertible states can be assembled in three synthetic steps by integrating a fluorescent coumarin chromophore, a hydrophilic oligo(ethylene glycol) chain, and a switchable oxazole heterocycle in the same covalent skeleton. Measurements of its two emissions in separate detection channels of a fluorescence microscope permit the noninvasive and ratiometric sensing of temperature at the micrometer level with millisecond response in aqueous solutions and within hydrogel matrices. The ratiometric optical output of this fluorescent molecular switch overcomes the limitations of single-wavelength fluorescent probes and enables noninvasive temperature mapping at length scales that are not accessible to conventional thermometers based on physical contact.

Albumin Biomolecular Drug Designs Stabilized through Improved Thiol Conjugation and a Modular Locked Nucleic Acid Functionalized Assembly.

Albumin-nucleic acid biomolecular drug designs offer modular multifunctionalization and extended circulatory half-life. However, stability issues associated with conventional DNA nucleotides and maleimide bioconjugation chemistries limit the clinical potential. This work aims to improve the stability of this thiol conjugation and nucleic acid assembly by employing a fast-hydrolyzing monobromomaleimide (MBM) linker and nuclease-resistant nucleotide analogues, respectively. The biomolecular constructs were formed by site-selective conjugation of a 12-mer oligonucleotide to cysteine 34 (Cys34) of recombinant human albumin (rHA), followed by annealing of functionalized complementary strands bearing either a fluorophore or the cytotoxic drug monomethyl auristatin E (MMAE). Formation of conjugates and assemblies was confirmed by gel shift analysis and mass spectrometry, followed by investigation of serum stability, neonatal Fc receptor (FcRn)-mediated cellular recycling, and cancer cell killing. The MBM linker afforded rapid conjugation to rHA and remained stable during hydrolysis. The albumin-nucleic acid biomolecular assembly composed of stabilized oligonucleotides exhibited high serum stability and retained FcRn engagement mediating FcRn-mediated cellular recycling. The MMAE-containing assembly exhibited cytotoxicity in the human MIA PaCa-2 pancreatic cancer cell line with an IC50 of 342 nM, triggered by drug release from breakdown of an acid-labile linker. In summary, this work presents rHA-nucleic acid module-based assemblies with improved stability and retained module functionality that further promotes the drug delivery potential of this biomolecular platform.

Reliability, Validity, and Performance Characteristics of Elite Adolescent Athletes at Different Stages of Maturity in the 10 to 5 Repeated Jump Test.

PURPOSE: To examine the reliability, validity, and performance characteristics of the 10 to 5 repeated jump test (10-5 RJT) in adolescent male athletes. The 10-5 RJT has been shown to be a valid and reliable test of reactive strength index (RSI) in older adolescents (age 17-19 y), but less is known in younger adolescent athletes at different stages of maturity. METHODS: Athletes (age 11-17 y) completed the 10-5 RJT on 2 days, 1 week apart, to examine the reliability (n = 41), validity (n = 18) of the test. Athletes were classified as pre, circa, or post peak height velocity (PHV) height velocity using maturity offset to examine the effect of maturation status on RSI, flight time (FT), ground contact time (GCT), and jump height (JH) (n = 68) using a cross-sectional design. RESULTS: Paired samples t tests showed no significant differences (P ≥ .05), and Bland-Altman analysis showed no bias and close limits of agreement for RSI, JH, FT, and GCT between the contact mat and force plate. Interday reliability was rated excellent for RSI (intraclass correlation coefficient = .91) and good for GCT, FT, and JH (intraclass correlation coefficient = .81-.85). All variables had a coefficient of variation ≤ 10%. RSI increased across maturation groups, with significant differences between pre-PHV and post-PHV groups (P = .014, d = 1.00). CONCLUSION: The 10-5 RJT is a valid and reliable test for adolescent male athletes. Greater RSI with advancing maturity was primarily due to increased FT and JH, with GCT remaining similar.

COPD lung studies of Nrf2 expression and the effects of Nrf2 activators.

BACKGROUND: Nrf2 regulates cellular antioxidant defence in lung cells, including epithelial cells and alveolar macrophages (AM). The Nrf2/Keap-1 pathway can be modulated by activators with different modes of action; electrophilic compounds and protein-protein interaction (PPI) inhibitors. We assessed Nrf2 and Keap-1 protein and gene levels in COPD compared to controls and the effect of Nrf2 activators on COPD AM. METHODS: Lung resected tissue from non-smokers, smokers and COPD patients were analysed for epithelial and AM expression of Nrf2 and Keap-1 by imunoshistochemistry and by qPCR in isolated AM. AM were cultured with Nrf2 activators CDDO, C4X_6665, GSK7, MMF and Sulforaphane. Expression of Nrf2 target genes NQO1, HMOX1 SOD1 and TXNRD1 and NQO1 activity were assessed. RESULTS: Nrf2 and Keap-1 expression was not altered in the epithelium or AM of COPD patients compared to controls. NQO1 activity was downregulated, while NQO1, HMOX1, SOD1 and TXNRD1 gene expression increased in COPD patients. All Nrf2 activators increased NQO1 activity, and NQO1, HMOX1, SOD1 and TXNRD1 expression in AMs from both COPD and smokers. The potency of C4X_6665 on NQO1 activity and regulation of Nrf2 target gene expression was higher than other compounds. CONCLUSION: There is evidence of dysregulation of the Nrf2 signalling pathway in AM from COPD patients. The higher potency of the novel PPI Nrf2 compound C4X_6665 for inducing antioxidant activity and gene expression compared to electrophilic and other PPI Nrf2 activators highlights the therapeutic potential of this compound to address Nrf2 pathway dysregulation in COPD AM.

Juror decision-making regarding a defendant diagnosed with borderline personality disorder.

Stigma is an established consequence of the Borderline Personality Disorder (BPD) diagnosis. This diagnosis is subject to revision in the International Classification of Diseases-11th Revision (ICD-11). Using the legal issue of diminished responsibility, this study applied an experimental mock-jury methodology to explore the impact of diagnostic stigma of BPD on jury decision-making. Participants were allocated to one of two versions of a simplified fictitious homicide trial. The group whose defendant was described as having a 'severe personality disorder, borderline pattern' rated the defendant as more dangerous, and more in need of segregation and coercive treatment, than controls where the defendant was described as having a 'complex mental health problem'. Between-group differences in other measures, including the decision to agree a verdict of diminished responsibility, were not found. The ICD-11 'severe personality disorder, borderline pattern' diagnosis may adversely impact the attitudes of jurors considering the question of diminished responsibility.

Blocking the IL-1 receptor reduces cardiac transplant ischemia and reperfusion injury and mitigates CMV-accelerated chronic rejection.

Ischemia-reperfusion injury (IRI) is an important risk factor for accelerated cardiac allograft rejection and graft dysfunction . Utilizing a rat heart isogeneic transplant model, we identified inflammatory pathways involved in IRI in order to identify therapeutic targets involved in disease. Pathway analyses identified several relevant targets, including cytokine signaling by the IL-1 receptor (IL-1R) pathway and inflammasome activation. To investigate the role of IL-1R signaling pathways during IRI, we treated syngeneic cardiac transplant recipients at 1-hour posttransplant with Anakinra, a US Food and Drug Administration (FDA)-approved IL-1R antagonist; or parthenolide, a caspase-1 and nuclear factor kappa-light-chain-enhancer of activated B cells inhibitor that blocks IL-1ß maturation. Both Anakinra and parthenolide significantly reduced graft inflammation and cellular recruitment in the treated recipients relative to nontreated controls. Anakinra treatment administered at 1-hour posttransplant to recipients of cardiac allografts from CMV-infected donors significantly increased the time to rejection and reduced viral loads at rejection. Our results indicate that reducing IRI by blocking IL-1Rsignaling pathways with Anakinra or inflammasome activity with parthenolide provides a promising approach for extending survival of cardiac allografts from CMV-infected donors.