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Fractures continue to be a global economic burden as there are currently no osteoanabolic drugs approved to accelerate fracture healing. In this study, we aimed to develop an osteoanabolic therapy which activates the Wnt/β-catenin pathway, a molecular driver of endochondral ossification. We hypothesize that using an mRNA-based therapeutic encoding β-catenin could promote cartilage to bone transformation formation by activating the canonical Wnt signaling pathway in chondrocytes. To optimize a delivery platform built on recent advancements in liposomal technologies, two FDA-approved ionizable phospholipids, DLin-MC3-DMA (MC3) and SM-102, were used to fabricate unique ionizable lipid nanoparticle (LNP) formulations and then tested for transfection efficacy both in vitro and in a murine tibia fracture model. Using firefly luciferase mRNA as a reporter gene to track and quantify transfection, SM-102 LNPs showed enhanced transfection efficacy in vitro and prolonged transfection, minimal fracture interference and no localized inflammatory response in vivo over MC3 LNPs. The generated β-cateninGOF mRNA encapsulated in SM-102 LNPs (SM-102-β-cateninGOF mRNA) showed bioactivity in vitro through upregulation of downstream canonical Wnt genes, axin2 and runx2. When testing SM-102-β-cateninGOF mRNA therapeutic in a murine tibia fracture model, histomorphometric analysis showed increased bone and decreased cartilage composition with the 45 μg concentration at 2 weeks post-fracture. μCT testing confirmed that SM-102-β-cateninGOF mRNA promoted bone formation in vivo, revealing significantly more bone volume over total volume in the 45 μg group. Thus, we generated a novel mRNA-based therapeutic encoding a β-catenin mRNA and optimized an SM-102-based LNP to maximize transfection efficacy with a localized delivery.

Chronic conditions associated with aging have proven difficult to prevent or treat. Senescence is a cell fate defined by loss of proliferative capacity and the development of a pro-inflammatory senescence-associated secretory phenotype comprised of cytokines/chemokines, proteases, and other factors that promotes age-related diseases. Specifically, an increase in senescent peripheral blood mononuclear cells (PBMCs), including T cells, is associated with conditions like frailty, rheumatoid arthritis, and bone loss. However, it is unknown if the percentage of senescent PBMCs associated with age-associated orthopedic decline could be used for potential diagnostic or prognostic use in orthopedics. Here, we report senescent cell detection using the fluorescent compound C12FDG to quantify PBMCs senescence across a large cohort of healthy and osteoarthritic patients. There is an increase in the percent of circulating C12FDG+ PBMCs that is commensurate with increases in age and senescence-related serum biomarkers. Interestingly, C12FDG+ PBMCs and T cells also were found to be elevated in patients with mild to moderate osteoarthritis, a progressive joint disease that is strongly associated with inflammation. The percent of C12FDG+ PBMCs and age-related serum biomarkers were decreased in a small subgroup of study participants taking the senolytic drug fisetin. These results demonstrate quantifiable measurements in a large group of participants that could create a composite score of healthy aging sensitive enough to detect changes following senolytic therapy and may predict age-related orthopedic decline. Detection of peripheral senescence in PBMCs and subsets using C12FDG may be clinically useful for quantifying cellular senescence and determining how and if it plays a pathological role in osteoarthritic progression.

INTRODUCTION: Though early hypotension after pediatric in-hospital cardiac arrest (IHCA) is associated with inferior outcomes, ideal post-arrest blood pressure (BP) targets have not been established. We aimed to leverage prospectively collected BP data to explore the association of post-arrest BP thresholds with outcomes. We hypothesized that post-arrest systolic and diastolic BP thresholds would be higher than the currently recommended post-cardiopulmonary resuscitation BP targets and would be associated with higher rates of survival to hospital discharge. METHODS: We performed a secondary analysis of prospectively collected BP data from the first 24 h following return of circulation from index IHCA events enrolled in the ICU-RESUScitation trial (NCT02837497). The lowest documented systolic BP (SBP) and diastolic BP (DBP) were percentile-adjusted for age, height and sex. Receiver operator characteristic curves and cubic spline analyses controlling for illness category and presence of pre-arrest hypotension were generated exploring the association of lowest post-arrest SBP and DBP with survival to hospital discharge and survival to hospital discharge with favorable neurologic outcome (Pediatric Cerebral Performance Category of 1-3 or no change from baseline). Optimal cutoffs for post-arrest BP thresholds were based on analysis of receiver operator characteristic curves and spline curves. Logistic regression models accounting for illness category and pre-arrest hypotension examined the associations of these thresholds with outcomes. RESULTS: Among 693 index events with 0-6 h post-arrest BP data, identified thresholds were: SBP > 10th percentile and DBP > 50th percentile for age, sex and height. Fifty-one percent (n = 352) of subjects had lowest SBP above threshold and 50% (n = 346) had lowest DBP above threshold. SBP and DBP above thresholds were each associated with survival to hospital discharge (SBP: aRR 1.21 [95% CI 1.10, 1.33]; DBP: aRR 1.23 [1.12, 1.34]) and survival to hospital discharge with favorable neurologic outcome (SBP: aRR 1.22 [1.10, 1.35]; DBP: aRR 1.27 [1.15, 1.40]) (all p  10th percentile for age and DBP > 50th percentile for age during the first 6 h post-arrest.

AIM: To evaluate associations between characteristics of simulated point-of-care cardiopulmonary resuscitation (CPR) training with simulated and actual intensive care unit (ICU) CPR performance, and with outcomes of children after in-hospital cardiac arrest. METHODS: This is a pre-specified secondary analysis of the ICU-RESUScitation Project; a prospective, multicentre cluster randomized interventional trial conducted in 18 ICUs from October 2016-March 2021. Point-of-care bedside simulations with real-time feedback to allow multidisciplinary ICU staff to practice CPR on a portable manikin were performed and quality metrics (rate, depth, release velocity, chest compression fraction) were recorded. Actual CPR performance was recorded for children 37 weeks post-conceptual age to 18 years who received chest compressions of any duration, and included intra-arrest haemodynamics and CPR mechanics. Outcomes included survival to hospital discharge with favourable neurologic status. RESULTS: Overall, 18,912 point-of-care simulations were included. Simulation characteristics associated with both simulation and actual performance included site, participant discipline, and timing of simulation training. Simulation characteristics were not associated with survival with favourable neurologic outcome. However, participants in the top 3 sites for improvement in survival with favourable neurologic outcome were more likely to have participated in a simulation in the past month, on a weekday day, to be nurses, and to achieve targeted depth of compression and chest compression fraction goals during simulations than the bottom 3 sites. CONCLUSIONS: Point-of-care simulation characteristics were associated with both simulated and actual CPR performance. More recent simulation, increased nursing participation, and simulation training during daytime hours may improve CPR performance.

BACKGROUND: Previous studies have identified pulmonary hypertension (PH) as a relatively common diagnosis in children with in-hospital cardiac arrest (IHCA), and preclinical laboratory studies have found poor outcomes and low systemic blood pressures during CPR for PH-associated cardiac arrest. The objective of this study was to determine the prevalence of PH among children with IHCA and the association between PH diagnosis and intra-arrest physiology and survival outcomes. METHODS: This was a prospectively designed secondary analysis of patients enrolled in the ICU-RESUS clinical trial (NCT02837497). The primary exposure was a pre-arrest diagnosis of PH. The primary survival outcome was survival to hospital discharge with favorable neurologic outcome (Pediatric Cerebral Performance Category score 1-3 or unchanged from baseline). The primary physiologic outcome was event-level average diastolic blood pressure (DBP) during CPR. RESULTS: Of 1276 patients with IHCAs during the study period, 1129 index IHCAs were enrolled; 184 (16.3%) had PH and 101/184 (54.9%) were receiving inhaled nitric oxide at the time of IHCA. Survival with favorable neurologic outcome was similar between patients with and without PH on univariate (48.9% vs. 54.4%; p = 0.17) and multivariate analyses (aOR 0.82 [95%CI: 0.56, 1.20]; p = 0.32). There were no significant differences in CPR event outcome or survival to hospital discharge. Average DBP, systolic BP, and end-tidal carbon dioxide during CPR were similar between groups. CONCLUSIONS: In this prospective study of pediatric IHCA, pre-existing PH was present in 16% of children. Pre-arrest PH diagnosis was not associated with statistically significant differences in survival outcomes or intra-arrest physiologic measures.

AIM: To evaluate associations between calcium administration and outcomes among children with in-hospital cardiac arrest and among specific subgroups in which calcium use is hypothesized to provide clinical benefit. METHODS: This is a secondary analysis of observational data collected prospectively as part of the ICU-RESUScitation project. Children 37 weeks post-conceptual age to 18 years who received chest compressions in one of 18 intensive care units from October 2016-March 2021 were eligible. Data included child and event characteristics, pre-arrest laboratory values, pre- and intra-arrest haemodynamics, and outcomes. Outcomes included sustained return of spontaneous circulation (ROSC), survival to hospital discharge, and survival to hospital discharge with favourable neurologic outcome. A propensity score weighted cohort was used to evaluate associations between calcium use and outcomes. Subgroups included neonates, and children with hyperkalaemia, sepsis, renal insufficiency, cardiac surgery with cardiopulmonary bypass, and calcium-avid cardiac diagnoses. RESULTS: Of 1,100 in-hospital cardiac arrests, median age was 0.63 years (IQR 0.19, 3.81); 450 (41%) received calcium. Among the weighted cohort, calcium use was not associated with sustained ROSC (aOR, 0.87; CI95 0.61-1.24; p = 0.445), but was associated with lower rates of both survival to hospital discharge (aOR, 0.68; CI95 0.52-0.89; p = 0.005) and survival with favourable neurologic outcome at hospital discharge (aOR, 0.75; CI95 0.57-0.98; p = 0.038). Among subgroups, calcium use was associated with lower rates of survival to hospital discharge in children with sepsis and renal insufficiency. CONCLUSIONS: Calcium use was common during paediatric in-hospital cardiac arrest and associated with worse outcomes at hospital discharge.

Cardiomyopathy is a progressive disease of the myocardium leading to impaired contractility. Genotoxic cancer therapies are known to be potent drivers of cardiomyopathy, whereas causes of spontaneous disease remain unclear. To test the hypothesis that endogenous genotoxic stress contributes to cardiomyopathy, we deleted the DNA repair gene Ercc1 specifically in striated muscle using a floxed allele of Ercc1 and mice expressing Cre under control of the muscle-specific creatinine kinase (Ckmm) promoter or depleted systemically (Ercc1-/D mice). Ckmm-Cre+/- ;Ercc1-/fl mice expired suddenly of heart disease by 7 months of age. As young adults, the hearts of Ckmm-Cre+/- ;Ercc1-/fl mice were structurally and functionally normal, but by 6-months-of-age, there was significant ventricular dilation, wall thinning, interstitial fibrosis, and systolic dysfunction indicative of dilated cardiomyopathy. Cardiac tissue from the tissue-specific or systemic model showed increased apoptosis and cardiac myocytes from Ckmm-Cre+/- ;Ercc1-/fl mice were hypersensitive to genotoxins, resulting in apoptosis. p53 levels and target gene expression, including several antioxidants, were increased in cardiac tissue from Ckmm-Cre+/- ;Ercc1-/fl and Ercc1-/D mice. Despite this, cardiac tissue from older mutant mice showed evidence of increased oxidative stress. Genetic or pharmacologic inhibition of p53 attenuated apoptosis and improved disease markers. Similarly, overexpression of mitochondrial-targeted catalase improved disease markers. Together, these data support the conclusion that DNA damage produced endogenously can drive cardiac disease and does so mechanistically via chronic activation of p53 and increased oxidative stress, driving cardiac myocyte apoptosis, dilated cardiomyopathy, and sudden death.

Introduction: Impaired fracture healing, specifically non-union, has been found to occur up to 14% in tibial shaft fractures. The current standard of care to treat non-union often requires additional surgeries which can result in long recovery times. Injectable-based therapies to accelerate fracture healing have the potential to mitigate the need for additional surgeries. Gene therapies have recently undergone significant advancements due to developments in nanotechnology, which improve mRNA stability while reducing immunogenicity. Methods: In this study, we tested the efficacy of mineral coated microparticles (MCM) and fluoride-doped MCM (FMCM) to effectively deliver firefly luciferase (FLuc) mRNA lipoplexes (LPX) to the fracture site. Here, adult mice underwent a tibia fracture and stabilization method and all treatments were locally injected into the fracture. Level of osteogenesis and amount of bone formation were assessed using gene expression and histomorphometry respectively. Localized and systemic inflammation were measured through gene expression, histopathology scoring and measuring C-reactive protein (CRP) in the serum. Lastly, daily IVIS images were taken to track and measure transfection over time. Results: MCM-LPX-FLuc and FMCM-LPX-FLuc were not found to cause any cytotoxic effects when tested in vitro. When measuring the osteogenic potential of each mineral composition, FMCM-LPX-FLuc trended higher in osteogenic markers through qRT-PCR than the other groups tested in a murine fracture and stabilization model. Despite FMCM-LPX-FLuc showing slightly elevated il-1β and il-4 levels in the fracture callus, inflammation scoring of the fracture callus did not result in any differences. Additionally, an acute systemic inflammatory response was not observed in any of the samples tested. The concentration of MCM-LPX-FLuc and FMCM-LPX-FLuc that was used in the murine fracture model did not stimulate bone when analyzed through stereological principles. Transfection efficacy and kinetics of delivery platforms revealed that FMCM-LPX-FLuc prolongs the luciferase signal both in vitro and in vivo. Discussion: These data together reveal that FMCM-LPX-FLuc could serve as a promising mRNA delivery platform for fracture healing applications.

OBJECTIVES: Arterial diastolic blood pressure (DBP) greater than 25 mm Hg in infants and greater than 30 mm Hg in children greater than 1 year old during cardiopulmonary resuscitation (CPR) was associated with survival to hospital discharge in one prospective study. We sought to validate these potential hemodynamic targets in a larger multicenter cohort. DESIGN: Prospective observational study. SETTING: Eighteen PICUs in the ICU-RESUScitation prospective trial from October 2016 to March 2020. PATIENTS: Children less than or equal to 18 years old with CPR greater than 30 seconds and invasive blood pressure (BP) monitoring during CPR. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Invasive BP waveform data and Utstein-style CPR data were collected, including prearrest patient characteristics, intra-arrest interventions, and outcomes. Primary outcome was survival to hospital discharge, and secondary outcomes were return of spontaneous circulation (ROSC) and survival to hospital discharge with favorable neurologic outcome. Multivariable Poisson regression models with robust error estimates evaluated the association of DBP greater than 25 mm Hg in infants and greater than 30 mm Hg in older children with these outcomes. Among 1,129 children with inhospital cardiac arrests, 413 had evaluable DBP data. Overall, 85.5% of the patients attained thresholds of mean DBP greater than or equal to 25 mm Hg in infants and greater than or equal to 30 mm Hg in older children. Initial return of circulation occurred in 91.5% and 25% by placement on extracorporeal membrane oxygenator. Survival to hospital discharge occurred in 58.6%, and survival with favorable neurologic outcome in 55.4% (i.e. 94.6% of survivors had favorable neurologic outcomes). Mean DBP greater than 25 mm Hg for infants and greater than 30 mm Hg for older children was significantly associated with survival to discharge (adjusted relative risk [aRR], 1.32; 1.01-1.74; p = 0.03) and ROSC (aRR, 1.49; 1.12-1.97; p = 0.002) but did not reach significance for survival to hospital discharge with favorable neurologic outcome (aRR, 1.30; 0.98-1.72; p = 0.051). CONCLUSIONS: These validation data demonstrate that achieving mean DBP during CPR greater than 25 mm Hg for infants and greater than 30 mm Hg for older children is associated with higher rates of survival to hospital discharge, providing potential targets for DBP during CPR.

Microproteins (MPs) are a potentially rich source of uncharacterized metabolic regulators. Here, we use ribosome profiling (Ribo-seq) to curate 3,877 unannotated MP-encoding small ORFs (smORFs) in primary brown, white, and beige mouse adipocytes. Of these, we validated 85 MPs by proteomics, including 33 circulating MPs in mouse plasma. Analyses of MP-encoding mRNAs under different physiological conditions (high-fat diet) revealed that numerous MPs are regulated in adipose tissue in vivo and are co-expressed with established metabolic genes. Furthermore, Ribo-seq provided evidence for the translation of Gm8773, which encodes a secreted MP that is homologous to human and chicken FAM237B. Gm8773 is highly expressed in the arcuate nucleus of the hypothalamus, and intracerebroventricular administration of recombinant mFAM237B showed orexigenic activity in obese mice. Together, these data highlight the value of this adipocyte MP database in identifying MPs with roles in fundamental metabolic and physiological processes such as feeding.

ObjectivesThe COVID-19 pandemic resulted in adaptations to pediatric resuscitation systems of care. The objective of this study was to determine the temporal association between the pandemic and pediatric in-hospital cardiac arrest (IHCA) process of care metrics, cardiopulmonary resuscitation (cardiopulmonary resuscitation) quality, and patient outcomes.DesignMulticenter retrospective analysis of a dataset comprising observations of IHCA outcomes pre pandemic (March 1, 2019 to February 29, 2020) versus pandemic (March 1, 2020 to February 28, 2021).SettingData source was the ICU-RESUScitation Project ("ICU-RESUS;" NCT028374497), a prospective, multicenter, cluster randomized interventional trial.PatientsChildren (≤ 18 yr) who received cardiopulmonary resuscitation while admitted to the ICU and were enrolled in ICU-RESUS.InterventionsNone.Measurements and main resultsAmong 429 IHCAs meeting inclusion criteria, occurrence during the pandemic period was associated with higher frequency of hypotension as the immediate cause of arrest. Cardiac arrest physiology, cardiopulmonary resuscitation quality metrics, and postarrest physiologic and quality of care metrics were similar between the two periods. Survival with favorable neurologic outcome (Pediatric Cerebral Performance Category score 1-3 or unchanged from baseline) occurred in 102 of 195 subjects (52%) during the pandemic compared with 140 of 234 (60%) pre pandemic ( p = 0.12). Among survivors, occurrence of IHCA during the pandemic period was associated with a greater increase in Functional Status Scale (FSS) (i.e., worsening) from baseline (1 [0-3] vs 0 [0-2]; p = 0.01). After adjustment for confounders, IHCA survival during the pandemic period was associated with a greater increase in FSS from baseline (+1.19 [95% CI, 0.35-2.04] FSS points; p = 0.006) and higher odds of a new FSS-defined morbidity (adjusted odds ratio, 1.88 [95% CI, 1.03-3.46]; p = 0.04).ConclusionsUsing the ICU-RESUS dataset, we found that relative to the year prior, pediatric IHCA during the first year of the COVID-19 pandemic was associated with greater worsening of functional status and higher odds of new functional morbidity among survivors.

OBJECTIVES: To evaluate associations between sodium bicarbonate use and outcomes during pediatric in-hospital cardiac arrest (p-IHCA). DESIGN: Prespecified secondary analysis of a prospective, multicenter cluster randomized interventional trial. SETTING: Eighteen participating ICUs of the ICU-RESUScitation Project (NCT02837497). PATIENTS: Children less than or equal to 18 years old and greater than or equal to 37 weeks post conceptual age who received chest compressions of any duration from October 2016 to March 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Child and event characteristics, prearrest laboratory values (2-6 hr prior to p-IHCA), pre- and intraarrest hemodynamics, and outcomes were collected. In a propensity score weighted cohort, the relationships between sodium bicarbonate use and outcomes were assessed. The primary outcome was survival to hospital discharge. Secondary outcomes included return of spontaneous circulation (ROSC) and survival to hospital discharge with favorable neurologic outcome. Of 1,100 index cardiopulmonary resuscitation events, median age was 0.63 years (interquartile range, 0.19-3.81 yr); 528 (48.0%) received sodium bicarbonate; 773 (70.3%) achieved ROSC; 642 (58.4%) survived to hospital discharge; and 596 (54.2%) survived to hospital discharge with favorable neurologic outcome. Among the weighted cohort, sodium bicarbonate use was associated with lower survival to hospital discharge rate (adjusted odds ratio [aOR], 0.7; 95% CI, 0.54-0.92; p = 0.01) and lower survival to hospital discharge with favorable neurologic outcome rate (aOR, 0.69; 95% CI, 0.53-0.91; p = 0.007). Sodium bicarbonate use was not associated with ROSC (aOR, 0.91; 95% CI, 0.62-1.34; p = 0.621). CONCLUSIONS: In this propensity weighted multicenter cohort study of p-IHCA, sodium bicarbonate use was common and associated with lower rates of survival to hospital discharge.

Background: Pediatric critical care physician attitudes about withdrawal of ventricular assist devices (VAD) and extracorporeal membrane oxygenation (ECMO) in cases of medical futility are poorly defined. Our aim was to define current attitudes regarding the withdrawal of these devices. Methods: IRB-approved, cross-sectional observational survey conducted among pediatric critical care attending physicians and fellow physicians in the United States between 2016 and 2017. Data was collected anonymously and statistically analyzed. Results: A total of 158 physicians responded with 67% being attending physicians. Compared to a VAD, a higher percentage had taken care of a patient on ECMO where the device was turned off because care was believed to be futile (99% vs. 84%), including currently (95% vs. 57%). Nearly all reported that it can be ethically permissible to withdraw support from a patient with a VAD and on ECMO (97% vs. 99%), but varied opinions existed as to who should ultimately make this decision if the patient/their family disagrees. More respondents agreed that a patient/their family should agree to withdrawal of VAD or ECMO support prior to initiation if futility is later determined (60% vs. 58%) and that protocols should be created for VAD and ECMO withdrawal (77% vs. 76%). Conclusion: Most pediatric critical care physicians felt that it can be ethically permissible to withdraw VAD and ECMO support. Our study indicates that pediatric VAD and ECMO withdrawal protocols are desired, but further investigation is needed to determine how to best design protocols that would incorporate multiple stakeholders.

ObjectivesSoluble receptor for advanced glycation end products is a known plasma marker of alveolar epithelial injury. However, RAGE is also expressed on cell types beyond the lung, and its activation leads to up-regulation of pro-inflammatory mediators. We sought to examine the relationship between plasma soluble receptor for advanced glycation end products and primary pulmonary dysfunction, extrapulmonary organ dysfunction, and mortality in pediatric acute respiratory distress syndrome patients at two early time points following acute respiratory distress syndrome diagnosis and compare these results to plasma surfactant protein-D, a marker of pure alveolar epithelial injury.DesignProspective observational study.SettingFive academic PICUs.PatientsTwo hundred fifty-eight pediatric patients 30 days to 18 years old meeting Berlin Criteria for acute respiratory distress syndrome.InterventionsNone.Measurements and main resultsPlasma was collected for soluble receptor for advanced glycation end products and surfactant protein-D measurements within 24 hours (day 1) and 48 to 72 hours (day 3) after acute respiratory distress syndrome diagnosis. Similar to surfactant protein-D, plasma soluble receptor for advanced glycation end products was associated with a higher oxygenation index (p < 0.01) and worse lung injury score (p < 0.001) at the time of acute respiratory distress syndrome diagnosis. However, unlike surfactant protein-D, plasma soluble receptor for advanced glycation end products was associated with worse extrapulmonary Pediatric Logistic Organ Dysfunction score during ICU stay (day 3; p < 0.01) and positively correlated with plasma levels of interleukin-6 (p < 0.01), tumor necrosis factor-α (p < 0.01), and angiopoietin-2 (p < 0.01). Among children with indirect lung injury, plasma soluble receptor for advanced glycation end products was associated with mortality independent of age, sex, race, cancer/bone marrow transplant, and Pediatric Risk of Mortality score (day 3; odds ratio, 3.14; 95% CI, 1.46-6.75; p < 0.01).ConclusionsUnlike surfactant protein-D, which is primarily localized to the alveolar epithelium plasma soluble receptor for advanced glycation end products is systemically expressed and correlates with markers of inflammation, extrapulmonary multiple organ dysfunction, and death in pediatric acute respiratory distress syndrome with indirect lung injury. This suggests that unlike surfactant protein-D, soluble receptor for advanced glycation end products is a multifaceted marker of alveolar injury and increased inflammation and that receptor for advanced glycation end products activation may contribute to the pathogenesis of multiple organ failure among children with indirect acute respiratory distress syndrome.

Axionlike particles (ALPs) are predicted in many extensions of the standard model, and their masses can naturally be well below the electroweak scale. In the presence of couplings to electroweak bosons, these particles could be emitted in flavor-changing B meson decays. We report herein a search for an ALP, a, in the reaction B^{±}→K^{±}a, a→γγ using data collected by the BABAR experiment at SLAC. No significant signal is observed, and 90% confidence level upper limits on the ALP coupling to electroweak bosons are derived as a function of ALP mass, improving current constraints by several orders of magnitude in the range 0.175  GeV

We report on the first search for electron-muon lepton flavor violation (LFV) in the decay of a b quark and b antiquark bound state. We look for the LFV decay ϒ(3S)→e^{±}μ^{∓} in a sample of 118 million ϒ(3S) mesons from 27  fb^{-1} of data collected with the BABAR detector at the SLAC PEP-II e^{+}e^{-} collider operating with a 10.36 GeV center-of-mass energy. No evidence for a signal is found, and we set a limit on the branching fraction B[ϒ(3S)→e^{±}μ^{∓}]80  TeV on the energy scale Λ_{NP} divided by the coupling-squared g_{NP}^{2} of relevant new physics (NP).

We study the processes e+e-→π+π-π0π0π0π0γ and π+π-π0π0π0ηγ in which an energetic photon is radiated from the initial state. The data were collected with the BABAR detector at the SLAC National Accelerator Laboratory. About 7300 and 870 events, respectively, are selected from a data sample corresponding to an integrated luminosity of 469 fb-1. The invariant mass of the hadronic final state defines the effective e+e- center-of-mass energy. The center-of-mass energies range from threshold to 4.5 GeV. From the mass spectra, the first ever measurements of the e+e-→π+π-π0π0π0π0 and the e+e-→π+π-π0π0π0η cross sections are performed. The contributions from ωπ0π0π0, ηπ+π-π0, ωη, and other intermediate states are presented. We observe the J/ψ and ψ(2S) in most of these final states and measure the corresponding branching fractions, many of them for the first time.

The process e+e-→π+π-π0γ is studied at a center-of-mass energy near the D(4S) resonance using a data sample of 469 fb-1 collected with the BABAR detector at the PEP-II collider. We have performed a precise measurement of the e+e-→π+π-π0 cross section in the center-of-mass energy range from 0.62 to 3.5 GeV. In the energy regions of the ω and φ resonances, the cross section is measured with a systematic uncertainty of 1.3%. The leading-order hadronic contribution to the muon magnetic anomaly calculated using the measured e+e-→π+π-π0 cross section from threshold to 2.0 GeV is (45.86±0.14±0.58)×10-10. From the fit to the measured 3π mass spectrum we have determined the resonance parameters Γ(ω→e+e-)B(ω→π+π-π0)=(0.5698±0.0031±0.0082) keV, Γ(φ→e+e-)B(φ→π+π-π0)=(0.1841±0.0021±0.0080) keV, and B(ρ→3π)=(0.88±0.23±0.30)×10-4. The significance of the ρ→3π signal is greater than 6σ. For the J/ψ resonance we have measured the product Γ(J/ψ→e+e-)B(J/ψ→3π)=(0.1248±0.0019±0.0026) keV.

Food legumes are crucial for all agriculture-related societal challenges, including climate change mitigation, agrobiodiversity conservation, sustainable agriculture, food security and human health. The transition to plant-based diets, largely based on food legumes, could present major opportunities for adaptation and mitigation, generating significant co-benefits for human health. The characterization, maintenance and exploitation of food-legume genetic resources, to date largely unexploited, form the core development of both sustainable agriculture and a healthy food system. INCREASE will implement, on chickpea (Cicer arietinum), common bean (Phaseolus vulgaris), lentil (Lens culinaris) and lupin (Lupinus albus and L. mutabilis), a new approach to conserve, manage and characterize genetic resources. Intelligent Collections, consisting of nested core collections composed of single-seed descent-purified accessions (i.e., inbred lines), will be developed, exploiting germplasm available both from genebanks and on-farm and subjected to different levels of genotypic and phenotypic characterization. Phenotyping and gene discovery activities will meet, via a participatory approach, the needs of various actors, including breeders, scientists, farmers and agri-food and non-food industries, exploiting also the power of massive metabolomics and transcriptomics and of artificial intelligence and smart tools. Moreover, INCREASE will test, with a citizen science experiment, an innovative system of conservation and use of genetic resources based on a decentralized approach for data management and dynamic conservation. By promoting the use of food legumes, improving their quality, adaptation and yield and boosting the competitiveness of the agriculture and food sector, the INCREASE strategy will have a major impact on economy and society and represents a case study of integrative and participatory approaches towards conservation and exploitation of crop genetic resources.

We study the processes , , and using a data sample of recorded with the BABAR detector operating at the SLAC PEP-II asymmetric-energy collider at center-of-mass energies at and near the (, 3, 4) resonances. This is the first observation of the decay and we measure the branching fraction . Significant interference is observed between and the nonresonant two-photon process . A Dalitz plot analysis is performed of decays to , , and . Combined with our previous analysis of , we measure the parameters and the ratio between its and couplings. The decay is dominated by the resonance, also observed in radiative decays. A new resonance is observed in the channel. We also compare decays to and final states in association with scalar mesons as they relate to the identification of the scalar glueball.

We study the processes e+e-→2(π+π-)π0π0π0γ and 2(π+π-)π0π0ηγ in which an energetic photon is radiated from the initial state. The data were collected with the BABAR detector at SLAC. About 14 000 and 4700 events, respectively, are selected from a data sample corresponding to an integrated luminosity of 469 fb-1. The invariant mass of the hadronic final state defines the effective e+e- center-of-mass energy. The center-of-mass energies range from threshold to 4.5 GeV. From the mass spectra, the first ever measurements of the e+e-→2(π+π-)π0π0π0 and the e+e-→2(π+π-)π0π0η cross sections are performed. The contributions from ωπ+π-π0π0, η2(π+π-), and other intermediate states are presented. We observe the J/ψ and ψ(2S) in most of these final states and measure the corresponding branching fractions, many of them for the first time.

We study the processes e+e-→2(π+π-)π0π0π0γ and 2(π+π-)π0π0ηγ in which an energetic photon is radiated from the initial state. The data were collected with the BABAR detector at SLAC. About 14 000 and 4700 events, respectively, are selected from a data sample corresponding to an integrated luminosity of 469 fb-1. The invariant mass of the hadronic final state defines the effective e+e- center-of-mass energy. The center-of-mass energies range from threshold to 4.5 GeV. From the mass spectra, the first ever measurements of the e+e-→2(π+π-)π0π0π0 and the e+e-→2(π+π-)π0π0η cross sections are performed. The contributions from ωπ+π-π0π0, η2(π+π-), and other intermediate states are presented. We observe the J/ψ and ψ(2S) in most of these final states and measure the corresponding branching fractions, many of them for the first time.

Many scenarios of physics beyond the standard model predict the existence of new gauge singlets, which might be substantially lighter than the weak scale. The experimental constraints on additional scalars with masses in the MeV to GeV range could be significantly weakened if they interact predominantly with leptons rather than quarks. At an e^{+}e^{-} collider, such a leptophilic scalar (ϕ_{L}) would be produced predominantly through radiation from a τ lepton. We report herein a search for e^{+}e^{-}→τ^{+}τ^{-}ϕ_{L}, ϕ_{L}→ℓ^{+}ℓ^{-} (ℓ=e, μ) using data collected by the BABAR experiment at SLAC. No significant signal is observed, and we set limits on the ϕ_{L} coupling to leptons in the range 0.04

Many scenarios of physics beyond the standard model predict the existence of new gauge singlets, which might be substantially lighter than the weak scale. The experimental constraints on additional scalars with masses in the MeV to GeV range could be significantly weakened if they interact predominantly with leptons rather than quarks. At an e^{+}e^{-} collider, such a leptophilic scalar (ϕ_{L}) would be produced predominantly through radiation from a τ lepton. We report herein a search for e^{+}e^{-}→τ^{+}τ^{-}ϕ_{L}, ϕ_{L}→ℓ^{+}ℓ^{-} (ℓ=e, μ) using data collected by the BABAR experiment at SLAC. No significant signal is observed, and we set limits on the ϕ_{L} coupling to leptons in the range 0.04

We present a search for seven lepton-flavor-violating neutral charm meson decays of the type D0→X0e±μ, where X0 represents a π0, KS0, K̄∗0, ρ0, φ, ω, or η meson. The analysis is based on 468 fb-1 of e+e- annihilation data collected at or close to the (4S) resonance with the BABAR detector at the SLAC National Accelerator Laboratory. No significant signals are observed, and we establish 90% confidence level upper limits on the branching fractions in the range (5.0-22.5)×10-7. The limits are between 1 and 2 orders of magnitude more stringent than previous measurements.

We present a search for seven lepton-flavor-violating neutral charm meson decays of the type D0→X0e±μ, where X0 represents a π0, KS0, K̄∗0, ρ0, φ, ω, or η meson. The analysis is based on 468 fb-1 of e+e- annihilation data collected at or close to the (4S) resonance with the BABAR detector at the SLAC National Accelerator Laboratory. No significant signals are observed, and we establish 90% confidence level upper limits on the branching fractions in the range (5.0-22.5)×10-7. The limits are between 1 and 2 orders of magnitude more stringent than previous measurements.

AimThe mathematical method used to calculate chest compression (CC) rate during cardiopulmonary resuscitation varies in the literature and across device manufacturers. The objective of this study was to determine the variability in calculated CC rates by applying four published methods to the same dataset.MethodsThis study was a secondary investigation of the first 200 pediatric cardiac arrest events with invasive arterial line waveform data in the ICU-RESUScitation Project (NCT02837497). Instantaneous CC rates were calculated during periods of uninterrupted CCs. The defined minimum interruption length affects rate calculation (e.g., if an interruption is defined as a break in CCs ≥ 2 s, the lowest possible calculated rate is 30 CCs/min). Average rates were calculated by four methods: 1) rate with an interruption defined as ≥ 1 s; 2) interruption ≥ 2 s; 3) interruption ≥ 3 s; 4) method #3 excluding top and bottom quartiles of calculated rates. American Heart Association Guideline-compliant rate was defined as 100-120 CCs/min. A clinically important change was defined as ±5 CCs/min. The percentage of events and epochs (30 s periods) that changed Guideline-compliant status was calculated.ResultsAcross calculation methods, mean CC rates (118.7-119.5/min) were similar. Comparing all methods, 14 events (7%) and 114 epochs (6%) changed Guideline-compliant status.ConclusionUsing four published methods for calculating CC rate, average rates were similar, but 7% of events changed Guideline-compliant status. These data suggest that a uniform calculation method (interruption ≥ 1 s) should be adopted to decrease variability in resuscitation science.

A study of the two-body decays B^{±}→X_{cc[over ¯]}K^{±}, where X_{cc[over ¯]} refers to one charmonium state, is reported by the BABAR Collaboration using a data sample of 424  fb^{-1}. The absolute determination of branching fractions for these decays are significantly improved compared to previous BABAR measurements. Evidence is found for the decay B^{+}→X(3872)K^{+} at the 3σ level. The absolute branching fraction B[B^{+}→X(3872)K^{+}]=[2.1±0.6(stat)±0.3(syst)]×10^{-4} is measured for the first time. It follows that B[X(3872)→J/ψπ^{+}π^{-}]=(4.1±1.3)%, supporting the hypothesis of a molecular component for this resonance.

A study of the two-body decays B^{±}→X_{cc[over ¯]}K^{±}, where X_{cc[over ¯]} refers to one charmonium state, is reported by the BABAR Collaboration using a data sample of 424  fb^{-1}. The absolute determination of branching fractions for these decays are significantly improved compared to previous BABAR measurements. Evidence is found for the decay B^{+}→X(3872)K^{+} at the 3σ level. The absolute branching fraction B[B^{+}→X(3872)K^{+}]=[2.1±0.6(stat)±0.3(syst)]×10^{-4} is measured for the first time. It follows that B[X(3872)→J/ψπ^{+}π^{-}]=(4.1±1.3)%, supporting the hypothesis of a molecular component for this resonance.

Using 0.8 x 10(6) D+ D- pairs collected with the CLEO-c detector at the psi(3770) resonance, we have searched for flavor-changing neutral current and lepton-number-violating decays of D+ mesons to final states with dielectrons. We find no indication of either, obtaining 90% confidence level upper limits of B(D+ --> pi+ e+ e-) < 7.4 x 10(-6), B(D+ --> pi- e+ d+) < 3.6 x 10(-6), B(D+ --> K+ e+ e-) < 6.2 x 10(-6), and B(D+ --> K- e+ e+) < 4.5 x 10(-6).

We present a search for nine lepton-number-violating and three lepton-flavor-violating neutral charm decays of the type D^{0}→h^{'-}h^{-}ℓ^{'+}ℓ^{+} and D^{0}→h^{'-}h^{+}ℓ^{'±}ℓ^{∓}, where h and h^{'} represent a K or π meson and ℓ and ℓ^{'} an electron or muon. The analysis is based on 468  fb^{-1} of e^{+}e^{-} annihilation data collected at or close to the ϒ(4S) resonance with the BABAR detector at the SLAC National Accelerator Laboratory. No significant signal is observed for any of the twelve modes, and we establish 90% confidence level upper limits on the branching fractions in the range (1.0-30.6)×10^{-7}. The limits are between 1 and 3 orders of magnitude more stringent than previous measurements.

We present a search for nine lepton-number-violating and three lepton-flavor-violating neutral charm decays of the type D^{0}→h^{'-}h^{-}ℓ^{'+}ℓ^{+} and D^{0}→h^{'-}h^{+}ℓ^{'±}ℓ^{∓}, where h and h^{'} represent a K or π meson and ℓ and ℓ^{'} an electron or muon. The analysis is based on 468  fb^{-1} of e^{+}e^{-} annihilation data collected at or close to the ϒ(4S) resonance with the BABAR detector at the SLAC National Accelerator Laboratory. No significant signal is observed for any of the twelve modes, and we establish 90% confidence level upper limits on the branching fractions in the range (1.0-30.6)×10^{-7}. The limits are between 1 and 3 orders of magnitude more stringent than previous measurements.

Using the initial-state radiation method, the e+e-→KSKL cross section from 1.98 to 2.54 GeV is measured in a data sample of 469 fb-1 collected with the BABAR detector. The results are used in conjunction with previous BABAR results for the e+e-→K+K-, e+e-→π+π-, e+e-→π+π-η, and e+e-→ωππ cross sections to investigate the nature of the resonance structure recently observed by the BESIII experiment in the e+e-→K+K- cross section.

We report on a precision measurement of the ratio R_{τμ}^{ϒ(3S)}=B(ϒ(3S)→τ^{+}τ^{-})/B(ϒ(3S)→μ^{+}μ^{-}) using data collected with the BABAR detector at the SLAC PEP-II e^{+}e^{-} collider. The measurement is based on a 28  fb^{-1} data sample collected at a center-of-mass energy of 10.355 GeV corresponding to a sample of 122 million ϒ(3S) mesons. The ratio is measured to be R_{τμ}^{ϒ(3S)}=0.966±0.008_{stat}±0.014_{syst} and is in agreement with the standard model prediction of 0.9948 within 2 standard deviations. The uncertainty in R_{τμ}^{ϒ(3S)} is almost an order of magnitude smaller than the only previous measurement.

Using the initial-state radiation method, the e+e-→KSKL cross section from 1.98 to 2.54 GeV is measured in a data sample of 469 fb-1 collected with the BABAR detector. The results are used in conjunction with previous BABAR results for the e+e-→K+K-, e+e-→π+π-, e+e-→π+π-η, and e+e-→ωππ cross sections to investigate the nature of the resonance structure recently observed by the BESIII experiment in the e+e-→K+K- cross section.

A search for the rare flavor-changing neutral current process B-→Λpνν using data from the BABAR experiment has been performed. A total of 424 fb-1 of e+e-collision data collected at the center-of-mass energy of the Ï'(4S) resonance is used in this study, corresponding to a sample of (471±3)×106 BB pairs. Signal B-→Λpνν candidates are identified by first fully reconstructing a B+ decay in one of many possible exclusive decays to hadronic final states, then examining detector activity that is not associated with this reconstructed B+ decay for evidence of a signal B-→Λpνν decay. The data yield is found to be consistent with the expected background contribution under a null signal hypothesis, resulting in an upper limit of B(B-→Λpνν)

A search for the rare flavor-changing neutral current process B-→Λpνν using data from the BABAR experiment has been performed. A total of 424 fb-1 of e+e-collision data collected at the center-of-mass energy of the Ï'(4S) resonance is used in this study, corresponding to a sample of (471±3)×106 BB pairs. Signal B-→Λpνν candidates are identified by first fully reconstructing a B+ decay in one of many possible exclusive decays to hadronic final states, then examining detector activity that is not associated with this reconstructed B+ decay for evidence of a signal B-→Λpνν decay. The data yield is found to be consistent with the expected background contribution under a null signal hypothesis, resulting in an upper limit of B(B-→Λpνν)

An angular analysis of the decay B[over ¯]→D^{*}ℓ^{-}ν[over ¯]_{ℓ}, ℓ∈{e,μ}, is reported using the full e^{+}e^{-} collision data set collected by the BABAR experiment at the ϒ(4S) resonance. One B meson from the ϒ(4S)→BB[over ¯] decay is fully reconstructed in a hadronic decay mode, which constrains the kinematics and provides a determination of the neutrino momentum vector. The kinematics of the semileptonic decay is described by the dilepton mass squared, q^{2}, and three angles. The first unbinned fit to the full four-dimensional decay rate in the standard model is performed in the so-called Boyd-Grinstein-Lebed approach, which employs a generic q^{2} parametrization of the underlying form factors based on crossing symmetry, analyticity, and QCD dispersion relations for the amplitudes. A fit using the more model-dependent Caprini-Lellouch-Neubert (CLN) approach is performed as well. Our form factor shapes show deviations from previous fits based on the CLN parametrization. The latest form factors also provide an updated prediction for the branching fraction ratio R(D^{*})≡B(B[over ¯]→D^{*}τ^{-}ν[over ¯]_{τ})/B(B[over ¯]→D^{*}ℓ^{-}ν[over ¯]_{ℓ})=0.253±0.005. Finally, using the well-measured branching fraction for the B[over ¯]→D^{*}ℓ^{-}ν[over ¯]_{ℓ} decay, a value of |V_{cb}|=(38.36±0.90)×10^{-3} is obtained that is consistent with the current world average for exclusive B[over ¯]→D^{(*)}ℓ^{-}ν[over ¯]_{ℓ} decays and remains in tension with the determination from inclusive semileptonic B decays to final states with charm.

An angular analysis of the decay B[over ¯]→D^{*}ℓ^{-}ν[over ¯]_{ℓ}, ℓ∈{e,μ}, is reported using the full e^{+}e^{-} collision data set collected by the BABAR experiment at the ϒ(4S) resonance. One B meson from the ϒ(4S)→BB[over ¯] decay is fully reconstructed in a hadronic decay mode, which constrains the kinematics and provides a determination of the neutrino momentum vector. The kinematics of the semileptonic decay is described by the dilepton mass squared, q^{2}, and three angles. The first unbinned fit to the full four-dimensional decay rate in the standard model is performed in the so-called Boyd-Grinstein-Lebed approach, which employs a generic q^{2} parametrization of the underlying form factors based on crossing symmetry, analyticity, and QCD dispersion relations for the amplitudes. A fit using the more model-dependent Caprini-Lellouch-Neubert (CLN) approach is performed as well. Our form factor shapes show deviations from previous fits based on the CLN parametrization. The latest form factors also provide an updated prediction for the branching fraction ratio R(D^{*})≡B(B[over ¯]→D^{*}τ^{-}ν[over ¯]_{τ})/B(B[over ¯]→D^{*}ℓ^{-}ν[over ¯]_{ℓ})=0.253±0.005. Finally, using the well-measured branching fraction for the B[over ¯]→D^{*}ℓ^{-}ν[over ¯]_{ℓ} decay, a value of |V_{cb}|=(38.36±0.90)×10^{-3} is obtained that is consistent with the current world average for exclusive B[over ¯]→D^{(*)}ℓ^{-}ν[over ¯]_{ℓ} decays and remains in tension with the determination from inclusive semileptonic B decays to final states with charm.

We report the observation of the rare charm decay D^{0}→K^{-}π^{+}e^{+}e^{-}, based on 468  fb^{-1} of e^{+}e^{-} annihilation data collected at or close to the center-of-mass energy of the ϒ(4S) resonance with the BABAR detector at the SLAC National Accelerator Laboratory. We find the branching fraction in the invariant mass range 0.675

We report the observation of the rare charm decay D^{0}→K^{-}π^{+}e^{+}e^{-}, based on 468  fb^{-1} of e^{+}e^{-} annihilation data collected at or close to the center-of-mass energy of the ϒ(4S) resonance with the BABAR detector at the SLAC National Accelerator Laboratory. We find the branching fraction in the invariant mass range 0.675

Recent investigations have suggested that the six-quark combination uuddss could be a deeply bound state (S) that has eluded detection so far, and a potential dark matter candidate. We report the first search for a stable, doubly strange six-quark state in ϒ→SΛ[over ¯]Λ[over ¯] decays based on a sample of 90×10^{6}ϒ(2S) and 110×10^{6}ϒ(3S) decays collected by the BABAR experiment. No signal is observed, and 90% confidence level limits on the combined ϒ(2S,3S)→SΛ[over ¯]Λ[over ¯] branching fraction in the range (1.2-1.4)×10^{-7} are derived for m_{S}

Recent investigations have suggested that the six-quark combination uuddss could be a deeply bound state (S) that has eluded detection so far, and a potential dark matter candidate. We report the first search for a stable, doubly strange six-quark state in ϒ→SΛ[over ¯]Λ[over ¯] decays based on a sample of 90×10^{6}ϒ(2S) and 110×10^{6}ϒ(3S) decays collected by the BABAR experiment. No signal is observed, and 90% confidence level limits on the combined ϒ(2S,3S)→SΛ[over ¯]Λ[over ¯] branching fraction in the range (1.2-1.4)×10^{-7} are derived for m_{S}

We study the process e+e-→e+e-η′ in the double-tag mode and measure for the first time the γ γ →η′ transition form factor Fη′(Q12,Q22) in the momentum-transfer range 2

We study the processes e+e-→π+π-π0π0π0γ and π+π-π0π0ηγ in which an energetic photon is radiated from the initial state. The data are collected with the BABAR detector at SLAC. About 14 000 and 4700 events, respectively, are selected from a data sample corresponding to an integrated luminosity of 469 fb-1. The invariant mass of the hadronic final state defines the effective e+e- center-of-mass energy. From the mass spectra, the first precise measurement of the e+e-→π+π-π0π0π0 cross section and the first measurement ever of the e+e-→π+π-π0π0η cross section are performed. The center-of-mass energies range from threshold to 4.35 GeV. The systematic uncertainty is typically between 10% and 13%. The contributions from ωπ0π0, ηπ+π-, and other intermediate states are presented. We observe the J/ψ and ψ(2S) in most of these final states and measure the corresponding branching fractions, many of them for the first time.

We study the process e+e-→e+e-η′ in the double-tag mode and measure for the first time the γ γ →η′ transition form factor Fη′(Q12,Q22) in the momentum-transfer range 2

We study the processes e+e-→π+π-π0π0π0γ and π+π-π0π0ηγ in which an energetic photon is radiated from the initial state. The data are collected with the BABAR detector at SLAC. About 14 000 and 4700 events, respectively, are selected from a data sample corresponding to an integrated luminosity of 469 fb-1. The invariant mass of the hadronic final state defines the effective e+e- center-of-mass energy. From the mass spectra, the first precise measurement of the e+e-→π+π-π0π0π0 cross section and the first measurement ever of the e+e-→π+π-π0π0η cross section are performed. The center-of-mass energies range from threshold to 4.35 GeV. The systematic uncertainty is typically between 10% and 13%. The contributions from ωπ0π0, ηπ+π-, and other intermediate states are presented. We observe the J/ψ and ψ(2S) in most of these final states and measure the corresponding branching fractions, many of them for the first time.

Menthol contributes to poor cessation rates among smokers, in part because menthol enhances nicotine reward and reinforcement. Mentholated tobacco products contain (-)-menthol and (+)-menthol, in varying proportions. We examined these two menthol stereoisomers for their ability to upregulate α4β2 nAChRs and to alter dopamine neuron firing frequency using long-term, low-dose (≤500 nm) exposure that is pharmacologically relevant to smoking. We found that (-)-menthol upregulates α4β2 nAChRs while (+)-menthol does not. We also found that (-)-menthol decreases dopamine neuron baseline firing and dopamine neuron excitability, while (+)-menthol exhibits no effect. We then examined both stereoisomers for their ability to inhibit α4β2 nAChR function at higher concentrations (>10 µm) using the Xenopus oocyte expression system. To probe for the potential binding site of menthol, we conducted flooding simulations and site-directed mutagenesis. We found that menthol likely binds to the 9´ position on the TM2 (transmembrane M2) helix. We found that menthol inhibition is dependent on the end-to-end distance of the side chain at the 9´ residue. Additionally, we have found that (-)-menthol is only modestly (∼25%) more potent than (+)-menthol at inhibiting wild-type α4β2 nAChRs and a series of L9´ mutant nAChRs. These data reveal that menthol exhibits a stereoselective effect on nAChRs and that the stereochemical effect is much greater for long-term, submicromolar exposure in mice than for acute, higher-level exposure. We hypothesize that of the two menthol stereoisomers, only (-)-menthol plays a role in enhancing nicotine reward through nAChRs on dopamine neurons.

Menthol contributes to poor cessation rates among smokers, in part because menthol enhances nicotine reward and reinforcement. Mentholated tobacco products contain (-)-menthol and (+)-menthol, in varying proportions. We examined these two menthol stereoisomers for their ability to upregulate α4β2 nAChRs and to alter dopamine neuron firing frequency using long-term, low-dose (≤500 nm) exposure that is pharmacologically relevant to smoking. We found that (-)-menthol upregulates α4β2 nAChRs while (+)-menthol does not. We also found that (-)-menthol decreases dopamine neuron baseline firing and dopamine neuron excitability, while (+)-menthol exhibits no effect. We then examined both stereoisomers for their ability to inhibit α4β2 nAChR function at higher concentrations (>10 µm) using the Xenopus oocyte expression system. To probe for the potential binding site of menthol, we conducted flooding simulations and site-directed mutagenesis. We found that menthol likely binds to the 9´ position on the TM2 (transmembrane M2) helix. We found that menthol inhibition is dependent on the end-to-end distance of the side chain at the 9´ residue. Additionally, we have found that (-)-menthol is only modestly (∼25%) more potent than (+)-menthol at inhibiting wild-type α4β2 nAChRs and a series of L9´ mutant nAChRs. These data reveal that menthol exhibits a stereoselective effect on nAChRs and that the stereochemical effect is much greater for long-term, submicromolar exposure in mice than for acute, higher-level exposure. We hypothesize that of the two menthol stereoisomers, only (-)-menthol plays a role in enhancing nicotine reward through nAChRs on dopamine neurons.

A search is presented for the four-body decay B0→ppp̄p̄ in a sample of 471 million BB̄ pairs collected with the BABAR detector, operated at the SLAC PEP-II asymmetric-energy e+e- collider. The center-of-mass energy is 10.58 GeV. From a fit to the distribution of the energy-substituted mass mES, the branching fraction B(B0→ppp̄p̄)=(1.1±0.5±0.2)×10-7 is extracted, where the first uncertainty is statistical and the second is systematic. The significance of the signal, including the systematic uncertainty, is 2.9 standard deviations. The upper limit on the branching fraction is determined to be 2.0×10-7 at 90% confidence level.