MATRIN3 deficiency triggers autoinflammation via cGAS-STING activation.

Interferon-stimulated genes (ISGs) comprise a program of immune effectors important for host immune defense. When uncontrolled, ISGs play a central role in interferonopathies and other inflammatory diseases. The mechanisms responsible for turning on ISGs are not completely known. By investigating MATRIN3 (MATR3), a nuclear RNA-binding protein mutated in familial ALS, we found that perturbing MATR3 results in elevated expression of ISGs. Using an integrative approach, we elucidate a pathway that leads to activation of cGAS-STING. This outlines a plausible mechanism for pathogenesis in a subset of ALS, and suggests new diagnostic and therapeutic approaches for this fatal disease.

Distribution and expression of the aac(6')-Im (aacA16) aminoglycoside resistance gene.

BACKGROUND: The aac(6')-Im (aacA16) amikacin, netilmicin and tobramycin resistance gene cassette had been circulating globally undetected for many years in a sublineage of Acinetobacter baumannii global clone 2. OBJECTIVES: To identify sources for the aac(6')-Im fragment found in A. baumannii. METHODS: MinION long-read sequencing and Unicycler hybrid assemblies were used to determine the genetic context of the aac(6')-Im gene. Quantitative reverse transcriptase PCR was used to measure expression. RESULTS: Among >60 000 non-Acinetobacter draft genomes in the MRSN collection, the aac(6')-Im gene was detected in Pseudomonas putida and Enterobacter hormaechei isolates recovered from patients in Thailand between 2016 and 2019. Genomes of multiply resistant P. putida MRSN365855 and E. hormaechei MRSN791417 were completed. The class 1 integron containing the aac(6')-Im cassette was in the chromosome in MRSN365855, and in an HI2 plasmid in MRSN791417. However, MRSN791417 was amikacin susceptible and the gene was not expressed due to loss of the Pc promoter of the integron. Further examples of aac(6')-Im in plasmids from or the chromosome of various Gram-negative species were found in the GenBank nucleotide database. The aac(6')-Im context in integrons in pMRSN791417-8 and a Klebsiella plasmid pAMR200031 shared similarities with the aac(6')-Im region of AbGRI2-Im islands in A. baumannii. In other cases, the cassette array including the aac(6')-Im cassette was different. CONCLUSIONS: The aac(6')-Im gene is widespread, being found so far in several different species and in several different gene cassette arrays. The lack of amikacin resistance in E. hormaechei highlights the importance of correlating resistance gene content and antibiotic resistance phenotype.

Initiation and Carbene Induced Radical Chain Reactions in CH2F2 Pyrolysis.

High temperature dissociations of organic molecules typically involve a competition between radical and molecular processes. In this work, we use a modeling, experiment, theory (MET) framework to characterize the high temperature thermal dissociation of CH2F2, a flammable hydrofluorocarbon (HFC) that finds widespread use as a refrigerant. Initiation in CH2F2 proceeds via a molecular elimination channel; CH2F2 → CHF + HF. Here we show that the subsequent self-reactions of the singlet carbene, CHF, are fast multichannel processes and a facile source of radicals that initiate rapid chain propagation reactions. These have a marked influence on the decomposition kinetics of CH2F2. The inclusion of these reactions brings the simulations into better agreement with the present and literature experiments. Additionally, flame simulations indicate that inclusion of the CHF + CHF multichannel reaction leads to a noticeable enhancement in predictions of laminar flame speeds, a key parameter that is used to determine the flammability of a refrigerant.

Heat shock protein 72 supports extracellular matrix production in metastatic mammary tumors.

This study identified tumorigenic processes most dependent on murine HSP72 in the MMTV-PyMT mammary tumor model, which give rise to spontaneous mammary tumors that exhibit HSP72-dependent metastasis to the lung. RNA-seq expression profiling of Hspa1a/Hspa1b (Hsp72) WT and Hsp72-/- primary mammary tumors discovered significantly lower expression of genes encoding components of the extracellular matrix (ECM) in Hsp72 knockout mammary tumors compared to WT controls. In vitro studies found that genetic or chemical inhibition of HSP72 activity in cultured collagen-expressing human or murine cells also reduces mRNA and protein levels of COL1A1 and several other ECM-encoding genes. In search of a possible mechanistic basis for this relationship, we found HSP72 to support the activation of the TGF-ß - SMAD3 signaling pathway and evidence of SMAD3 and HSP72 co-precipitation, suggesting potential complex formation. Human COL1A1 mRNA expression was found to have prognostic value for HER2+ breast tumors over other breast cancer subtypes, suggesting a possible human disease context where targeting HSP72 may have a therapeutic rationale. Analysis of human HER2+ breast tumor gene expression data using a gene set comprising ECM- and protein folding-related genes as an input to the statistical learning algorithm, Galgo, found a subset of these genes that can collectively stratify patients by relapse-free survival, further suggesting a potential interplay between the ECM and protein-folding genes may contribute to tumor progression.

Automated interpretations of single-lead electrocardiograms predict incident atrial fibrillation: The VITAL-AF Trial.

BACKGROUND: Single-lead electrocardiograms (1L ECG) are increasingly used for atrial fibrillation (AF) detection. Automated 1L ECG interpretation may possess prognostic value for future AF among cases where screening does not result in a short-term AF diagnosis. OBJECTIVE: Investigate the association between automated 1L ECG interpretation and incident AF. METHODS: VITAL-AF was a randomized controlled trial investigating the effectiveness of screening for AF using 1L ECGs. For the present study, participants were divided into four groups based on automated classification of 1L ECGs. Patients with prevalent AF were excluded. Associations between groups and incident AF were assessed using Cox proportional hazards models adjusted for risk factors. The start of follow-up was defined as 60 days after the latest 1L ECG (as some individuals had numerous screening 1L ECGs). RESULTS: The study sample included: Never screened (n=16,306), Normal (n=10,914), Other (n=2,675), Possible AF (n=561). Possible AF had the highest AF incidence (5.91 per 100 person-years, 95% Confidence Interval [CI] 4.24-8.23). Possible AF was associated with greater hazard of incident AF compared to Normal (adjusted Hazard Ratio (2.48, 95% CI 1.66-3.71). Other was associated with greater hazard of incident AF when compared to Normal (1.41, 95% CI 1.04-1.90). CONCLUSIONS: In patients undergoing AF screening with 1L ECGs without prevalent AF or AF within 60 days of screening, presumptive positive and indeterminate 1L ECG interpretations were associated with future AF. Abnormal 1L ECGs may identify individuals at higher risk for future AF.

Placental senescence pathophysiology is shared between peripartum cardiomyopathy and preeclampsia in mouse and human.

Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought to contribute to both diseases, suggesting a common underlying pathophysiological process. However, what drives this process remains unclear. Using serum proteomics, we identified the senescence-associated secretory phenotype (SASP), a marker of cellular senescence associated with biological aging, as the most highly up-regulated pathway in young women with PPCM or preeclampsia. Placentas from women with preeclampsia displayed multiple markers of amplified senescence and tissue aging, as well as overall increased gene expression of 28 circulating proteins that contributed to SASP pathway enrichment in serum samples from patients with preeclampsia or PPCM. The most highly expressed placental SASP factor, activin A, was associated with cardiac dysfunction or heart failure severity in women with preeclampsia or PPCM. In a murine model of PPCM induced by cardiomyocyte-specific deletion of the gene encoding peroxisome proliferator-activated receptor γ coactivator-1α, inhibiting activin A signaling in the early postpartum period with a monoclonal antibody to the activin type II receptor improved heart function. In addition, attenuating placental senescence with the senolytic compound fisetin in late pregnancy improved cardiac function in these animals. These findings link senescence biology to cardiac dysfunction in pregnancy and help to elucidate the pathogenesis underlying cardiovascular diseases of pregnancy.

Improved Outcomes in Eosinophilic Esophagitis with Higher Medication Possession Ratio.

Eosinophilic esophagitis (EoE) disease activity can be caused by treatment non-adherence. Medication possession ratio (MPR) is an established metric of medication adherence. A higher MPR correlates with better outcomes in several chronic diseases, but MPR has not been investigated with respect to EoE. A retrospective cohort study was performed using an established EoE registry for the years 2005 to 2020. Treatment periods were identified, MPRs were calculated, and medical records were assessed for histologic remission (<15 eos/hpf), dysphagia, food impaction, stricture occurrence, and esophageal dilation that corresponded to each treatment period. In total, 275 treatment periods were included for analysis. The MPR in the histologic remission treatment period group was 0.91 (IQR 0.63-1) vs. 0.63 (IQR 0.31-0.95) for the non-remission treatment period group (p < 0.001). The optimal MPR cut-point for histologic remission was 0.7 (Sen 0.66, Spec 0.62, AUC 0.63). With MPRs ≥ 0.7, there were significantly increased odds of histologic remission (odds ratio 3.05, 95% confidence interval 1.79-5.30) and significantly decreased odds of dysphagia (OR 0.27, 95% CI 0.15-0.45), food impaction (OR 0.26, 95% CI 0.11-0.55), stricture occurrence (OR 0.52 95% CI 0.29-0.92), and esophageal dilation (OR 0.29, 95% CI 0.15-0.54). Assessing MPR before repeating an esophagogastroduodenoscopy may decrease unnecessary procedures in the clinical management of eosinophilic esophagitis.

A process model of parental executive functioning as a spillover mechanism linking interparental conflict and parenting difficulties across parenting domains.

There is a well-documented interdependency between destructive interparental conflict (IPC) and parenting difficulties (i.e., spillover effect), yet little is known about the mechanisms that "carry" spillover between IPC and parenting. Guided by a cascade model framework, the current study used a longitudinal, multimethod, multi-informant design to examine a process model of spillover that tested whether parental executive functioning (working memory, cognitive flexibility, inhibitory control) served as a mediator of the prospective associations between IPC and subsequent changes in parenting over a 2-year period. Mothers and fathers were separated into differentiated models and multiple domains of parenting were examined (i.e., authoritarian discipline and scaffolding behavior). Participants included 231 families (both mothers and fathers of preschoolers). Race was reported as White (62%), Black (21%), Mixed (8%), Asian (3%), or Other (6%) and 14% considered their ethnicity to be Hispanic/Latino. Median household income was $65,000. Results indicated that for fathers, IPC indirectly predicted domain-general parenting difficulties (increased authoritarian parenting and decreased scaffolding) via deficits in paternal cognitive flexibility (but not inhibitory control or working memory). In mothers, IPC directly predicted domain-specific parenting difficulties (decreased scaffolding only) that did not operate via maternal executive functions. Notably, these effects occurred over and above the influence of parental socioeconomic status. This study constitutes a first step toward documenting parental executive functioning as a mechanism underlying the spillover of IPC to the parent-child relationship. Family interventions intended to interrupt IPC spillover should emphasize father involvement and consider targeting parental executive functions as change mechanisms. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

TAD boundary deletion causes PITX2-related cardiac electrical and structural defects.

While 3D chromatin organization in topologically associating domains (TADs) and loops mediating regulatory element-promoter interactions is crucial for tissue-specific gene regulation, the extent of their involvement in human Mendelian disease is largely unknown. Here, we identify 7 families presenting a new cardiac entity associated with a heterozygous deletion of 2 CTCF binding sites on 4q25, inducing TAD fusion and chromatin conformation remodeling. The CTCF binding sites are located in a gene desert at 1 Mb from the Paired-like homeodomain transcription factor 2 gene (PITX2). By introducing the ortholog of the human deletion in the mouse genome, we recapitulate the patient phenotype and characterize an opposite dysregulation of PITX2 expression in the sinoatrial node (ectopic activation) and ventricle (reduction), respectively. Chromatin conformation assay performed in human induced pluripotent stem cell-derived cardiomyocytes harboring the minimal deletion identified in family#1 reveals a conformation remodeling and fusion of TADs. We conclude that TAD remodeling mediated by deletion of CTCF binding sites causes a new autosomal dominant Mendelian cardiac disorder.

Vertically inherited microbiota and environment modifying behaviours conceal genetic variation in dung beetle life history.

Diverse organisms actively manipulate their (sym)biotic and physical environment in ways that feed back on their own development. However, the degree to which these processes affect microevolution remains poorly understood. The gazelle dung beetle both physically modifies its ontogenetic environment and structures its biotic interactions through vertical symbiont transmission. By experimentally eliminating (i) physical environmental modifications and (ii) the vertical inheritance of microbes, we assess how environment modifying behaviour and microbiome transmission shape heritable variation and evolutionary potential. We found that depriving larvae of symbionts and environment modifying behaviours increased additive genetic variance and heritability for development time but not body size. This suggests that larvae's ability to manipulate their environment has the potential to modify heritable variation and to facilitate the accumulation of cryptic genetic variation. This cryptic variation may become released and selectable when organisms encounter environments that are less amenable to organismal manipulation or restructuring. Our findings also suggest that intact microbiomes, which are commonly thought to increase genetic variation of their hosts, may instead reduce and conceal heritable variation. More broadly, our findings highlight that the ability of organisms to actively manipulate their environment may affect the potential of populations to evolve when encountering novel, stressful conditions.

Hostile interparental conflict and parental discipline: Romantic attachment as a spillover mechanism.

This study examined parental romantic attachment security as a mediator of prospective associations between hostile interparental conflict and parental discipline (i.e., power-assertive, permissive, and inductive discipline) for mothers and fathers of young children. Furthermore, this study utilized a novel, automatic assessment of romantic attachment security in examining whether romantic attachment assessed at controlled (i.e., self-reported) and automatic (i.e., a rapid word-sorting task) levels of representation differentially serve as spillover mechanisms. Participants included 235 mothers (62% White), fathers (55% White), and a target child between the ages of 2 and 4 (Mage = 2.97; 55% girls) recruited from a moderate-sized metropolitan area in the Northeastern United States. Families were assessed annually across three waves of data collection. Results from autoregressive structural equation model analyses revealed that romantic attachment operated as spillover mechanism for mothers. In particular, hostile interparental conflict was associated with power-assertive discipline through changes in mothers' automatic romantic attachment security. We also found that hostile interparental conflict was associated with inductive discipline through changes in mothers' romantic attachment avoidance. Neither controlled nor automatic romantic attachment representations served as spillover mechanisms for fathers. Findings are discussed within family systems and attachment frameworks. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Permanent Pacemaker Implantation and Long-Term Outcomes of Patients Undergoing Concomitant Mitral and Tricuspid Valve Surgery.

BACKGROUND: Tricuspid valve annuloplasty (TA) during mitral valve repair (MVr) is associated with increased risk of permanent pacemaker (PPM) implantation, but the magnitude of risk and long-term clinical consequences have not been firmly established. OBJECTIVES: This study assesses the incidence rates of PPM implantation after isolated MVr and following MVr with TA as well as the associated long-term clinical consequences of PPM implantation. METHODS: State-mandated hospital discharge databases of New York and California were queried for patients undergoing MVr (isolated or with concomitant TA) between 2004 and 2019. Patients were stratified by whether or not they received a PPM within 90 days of index surgery. After weighting by propensity score, survival, heart failure hospitalizations (HFHs), endocarditis, stroke, and reoperation were compared between patients with or without PPM. RESULTS: A total of 32,736 patients underwent isolated MVr (n = 28,003) or MVr + TA (n = 4,733). Annual MVr + TA volumes increased throughout the study period (P < 0.001, trend), and PPM rates decreased (P < 0.001, trend). The incidence of PPM implantation <90 days after surgery was 7.7% for MVr and 14.0% for MVr + TA. In 90-day conditional landmark-weighted analyses, PPMs were associated with reduced long-term survival among MVr (HR: 1.96; 95% CI: 1.75-2.19; P < 0.001) and MVr + TA recipients (HR: 1.65; 95% CI: 1.28-2.14; P < 0.001). In both surgical groups, PPMs were also associated with an increased risk of HFH (HR: 1.56; 95% CI: 1.27-1.90; P < 0.001) and endocarditis (HR: 1.95; 95% CI: 1.52-2.51; P < 0.001), but not with stroke or reoperation. CONCLUSIONS: Compared to isolated MVr, adding TA to MVr was associated with a higher risk of 90-day PPM implantation. In both surgical groups, PPM implantation was associated with an increase in mortality, HFH, and endocarditis.

Advancing differential susceptibility research: Development and validation of the temperamental sensitivity Q-scale.

Temperamental sensitivity (TS), which is a correlated suite of traits reflecting a lower threshold of environmental stimulation and heightened responsivity to a range of environmental contexts, is an empirically documented susceptibility factor that increases children's plasticity to supportive and harsh family environments. To expand the limited options for assessing TS, this article tested the psychometric properties of a new Q-set measure (i.e., TS Q-scale) derived from the California Child Q-Set (CCQ-Set) and completed by experimenters. Participants in Study 1 consisted of 243 mothers, their partners, and their preschool children (Mage = 4.60 years; 56% girls; 54% Black or multiracial; 16% Latinx). For Study 2, participants included 201 mothers and their young children (Mage = 2.25 years; 44% girls; 63% Black or multiracial; 11% Latinx). Both longitudinal studies utilized multimethod, multiinformant measurement batteries. The TS Q-scale evidenced satisfactory internal consistencies across both studies. Support for the convergent and discriminant validity in Study 1 was evident in its large, unique, and significantly stronger association with a standard, more extensive, observational assessment of TS when compared with conventional dimensions of temperament. In each study, the TS Q-scale significantly moderated the association between family functioning and latent change analyses of children's functioning for most of the forms of child adjustment. Supporting its predictive validity as a differential susceptibility attribute, children with higher scores on the TS Q-scale exhibited substantially better functioning than their peers in supportive socialization contexts and considerably worse functioning in harsh rearing conditions. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Hemoadsorption: Consensus report of the 30th Acute Disease Quality Initiative workgroup.

Adsorption-based extracorporeal therapies have been subject to technical developments and clinical application for close to five decades. More recently, new technological developments in membrane and sorbent manipulation have made it possible to deliver more biocompatible extracorporeal adsorption therapies to patients with a variety of conditions. There are several key rationales based on physicochemical principles and clinical considerations that justify the application and investigation of such therapies as evidenced by multiple ex-vivo, experimental, and clinical observations. Accordingly, unspecific adsorptive extracorporeal therapies have now been applied to the treatment of a wide array of conditions from poisoning to drug overdoses, to inflammatory states and sepsis, and acute or chronic liver and kidney failure. In response to the rapidly expanding knowledge base and increased clinical evidence, we convened an Acute Disease Quality Initiative (ADQI) consensus conference dedicated to such treatment. The data show that hemoadsorption has clinically acceptable short-term biocompatibility and safety, technical feasibility, and experimental demonstration of specified target molecule removal. Pilot studies demonstrate potentially beneficial effects on physiology and larger studies of endotoxin-based hemoadsorption have identified possible target phenotypes for larger randomized controlled trials (RCTs). Moreover, in a variety of endogenous and exogenous intoxications, removal of target molecules has been confirmed in vivo. However, some studies have raised concerns about harm or failed to deliver benefits. Thus, despite many achievements, modern hemoadsorption remains a novel and experimental intervention with limited data, and a large research agenda.

Timing, incidence and management of delayed bleeding after partial nephrectomy in patients at risk for recurrent, bilateral, multifocal renal tumors.

INTRODUCTION: Delayed bleeding is a potentially serious complication after partial nephrectomy (PN), with reported rates of 1%-2%. Patients with multiple renal tumors, including those with hereditary forms of kidney cancer, are often managed with resection of multiple tumors in a single kidney which may increase the risk of delayed bleeding, though outcomes have not previously been reported specifically in this population. The objective of this study was to evaluate the incidence and timing of delayed bleeding as well as the impact of intervention on renal functional outcomes in a cohort primarily made up of patients at risk for bilateral, multifocal renal tumors. METHODS: A retrospective review of a prospectively maintained database of patients with known or suspected predisposition to bilateral, multifocal renal tumors who underwent PN from 2003 to 2023 was conducted. Patients who presented with delayed bleeding were identified. Patients with delayed bleeding were compared to those without. Comparative statistics and univariate logistic regression were used to determine potential risk factors for delayed bleeding. RESULTS: A total of 1256 PN were performed during the study period. Angiographic evidence of pseudoaneurysm, AV fistula and/or extravasation occurred in 24 cases (1.9%). Of these, 21 were symptomatic presenting with gross hematuria in 13 (54.2%), decreasing hemoglobin in 4(16.7%), flank pain in 2(8.3%), and mental status change in 2 (8.3%), while 3 patients were asymptomatic. Median number of resected tumors was 5 (IQR 2-8). All patients underwent angiogram with super-selective embolization. Median time to bleed event was 13.5 days (IQR 7-22). Factors associated with delayed bleeding included open approach (OR 2.2, IQR(1.06-5.46), P = 0.04 and left-sided surgery (OR 4.93, IQR(1.67-14.5), P = 0.004. Selective embolization had little impact on ultimate renal functional outcomes, with a median change of 11% from the baseline eGFR after partial nephrectomy and embolization. One patient required total nephrectomy for refractory bleeding after embolization. CONCLUSIONS: Delayed bleeding after PN in a cohort of patients with multifocal tumors is an infrequent event, with similar rates to single tumor series. Patients should be counseled regarding timing and symptoms of delayed bleeding and multidisciplinary management with interventional radiology is critical for timely diagnosis and treatment.

Impact of Tricuspid Regurgitation on Outcomes After Transcatheter Mitral Valve Replacement.

Development of functional tricuspid regurgitation (TR) because of chronic mitral disease and subsequent heart failure is common. However, the effect of TR on clinical outcomes after transcatheter mitral valve replacement (TMVR) remains unclear. We aimed to evaluate the impact of baseline TR on outcomes after TMVR. This was a single-center, retrospective analysis of patients who received valve-in-valve or valve-in-ring TMVR between 2012 and 2022. Patients were categorized into none/mild TR and moderate/severe TR based on baseline echocardiography. The primary outcome was 3 years all-cause death and the secondary outcomes were in-hospital events. Of the 135 patients who underwent TMVR, 64 (47%) exhibited none/mild TR at baseline, whereas 71 (53%) demonstrated moderate/severe TR. There were no significant differences in in-hospital events between the groups. At 3 years, the moderate/severe TR group exhibited a significantly increased risk of all-cause death (adjusted hazard ratio 3.37, 95% confidence interval 1.35 to 8.41, p = 0.009). When patients with baseline moderate/severe TR were stratified by echocardiography at 30 days into improved (36%) and nonimproved (64%) TR groups, although limited by small sample size, there was no significant difference in 3-year all-cause mortality (p = 0.48). In conclusion, this study investigating the impact of baseline TR on clinical outcomes revealed that moderate/severe TR is prevalent in those who underwent TMVR and is an independent predictor of 3-year all-cause mortality. Earlier mitral valve intervention before the development of significant TR may play a pivotal role in improving outcomes after TMVR.

Integrated visible-light polarization rotators and splitters for atomic quantum systems.

In this work, we design and experimentally demonstrate the first, to the best of our knowledge, integrated polarization splitters and rotators at blue wavelengths. We develop compact and efficient designs for both a polarization splitter and rotator at a 422-nm wavelength, an important laser-cooling transition for 88Sr+ ions. These devices are fabricated in a 200-mm wafer-scale process and experimentally demonstrated, resulting in a measured polarization-splitter transverse-electric thru-port coupling of 98.0% and transverse-magnetic tap-port coupling of 77.6% for a compact 16-µm-long device and a polarization-rotator conversion efficiency of 92.2% for a separate compact 111-µm-long device. This work paves the way for more sophisticated integrated control of trapped-ion and neutral-atom quantum systems.

The role of oxidative stress in blood-brain barrier disruption during ischemic stroke: Antioxidants in clinical trials.

Ischemic stroke is one of the leading causes of death and disability. Occlusion and reperfusion of cerebral blood vessels (i.e., ischemia/reperfusion (I/R) injury) generates reactive oxygen species (ROS) that contribute to brain cell death and dysfunction of the blood-brain barrier (BBB) via oxidative stress. BBB disruption influences the pathogenesis of ischemic stroke by contributing to cerebral edema, hemorrhagic transformation, and extravasation of circulating neurotoxic proteins. An improved understanding of mechanisms for ROS-associated alterations in BBB function during ischemia/reperfusion (I/R) injury can lead to improved treatment paradigms for ischemic stroke. Unfortunately, progress in developing ROS targeted therapeutics that are effective for stroke treatment has been slow. Here, we review how ROS are produced in response to I/R injury, their effects on BBB integrity (i.e., tight junction protein complexes, transporters), and the utilization of antioxidant treatments in ischemic stroke clinical trials. Overall, knowledge in this area provides a strong translational framework for discovery of novel drugs for stroke and/or improved strategies to mitigate I/R injury in stroke patients.