Inflationary resolution of the initial singularity

We construct geodesically complete inflationary models, addressing and overcoming existing no-go theorems related to past eternal inflation. We show that a period of accelerated expansion is indispensable for achieving nontrivial, geodesically complete (Generalized) Friedmann-Robertson-Walker spacetimes. We show within the framework of General Relativity, the persistence of eternal inflation comes at the expense of violating the null energy condition.Comment: 4 pages, 2 figure

Modulation of Mitochondrial Bioenergetics in the Isolated Guinea Pig Beating Heart by Potassium and Lidocaine Cardioplegia: Implications for Cardioprotection

Mitochondria are damaged by cardiac ischemia/reperfusion (I/R) injury but can contribute to cardioprotection. We tested if hyperkalemic cardioplegia (CP) and lidocaine (LID) differently modulate mitochondrial (m) bioenergetics and protect hearts against I/R injury. Guinea pig hearts (n = 71) were perfused with Krebs Ringer\u27s solution before perfusion for 1 minute just before ischemia with either CP (16 mM K+) or LID (1 mM) or Krebs Ringer\u27s (control, 4 mM K+). The 1-minute perfusion period assured treatment during ischemia but not on reperfusion. Cardiac function, NADH, FAD, m[Ca2+], and superoxide (reactive oxygen species) were assessed at baseline, during the 1-minute perfusion, and continuously during I/R. During the brief perfusion before ischemia, CP and LID decreased reactive oxygen species and increased NADH without changing m[Ca2+]. Additionally, CP decreased FAD. During ischemia, NADH was higher and reactive oxygen species was lower after CP and LID, whereas m[Ca2+] was lower only after LID. On reperfusion, NADH and FAD were more normalized, and m[Ca2+] and reactive oxygen species remained lower after CP and LID. Better functional recovery and smaller infarct size after CP and LID were accompanied by better mitochondrial function. These results suggest that mitochondria may be implicated, directly or indirectly, in protection by CP and LID against I/R injury

Cardiac Specific Knockout of p53 Decreases ER Stress-Induced Mitochondrial Damage

Endoplasmic reticulum (ER) stress contributes to cardiovascular disease including heart failure. Interactions between the ER and mitochondria during ER stress can impair the mitochondrial respiratory chain and increase cell injury. p53 is a tumor suppressor protein that regulates apoptosis. p53 contributes to the regulation of mitochondrial and ER interactions, especially during the progression of ER stress. The knockout (KO) of p53 leads to decreased injury in hearts following ischemia-reperfusion. We asked if KO of p53 can protect mitochondria during the induction of ER stress and decrease cell injury. Floxed p53 mice were crossed with mice carrying an α-myosin heavy chain cre to generate cardiac specific p53 KO mice. Thapsigargin (THAP) was used to induce ER stress in wild type (WT) and p53 KO mice. Mice were euthanized after 48 h THAP treatment. Cardiac mitochondria were isolated for functional measurement. TUNEL staining was used to assess myocyte death. In WT mice, THAP treatment decreased the rate of oxidative phosphorylation using pyruvate + malate as complex I substrates compared to vehicle-treated control. Complex I activity was also decreased in the THAP-treated WT mice. The rate of oxidative phosphorylation and complex I activity were not altered in THAP-treated p53 KO mice. The content of pyruvate dehydrogenase (PDH) α1 subunit was decreased in THAP-treated WT mice but not in p53 KO mice. ER stress led to a release of cytochrome c and apoptosis inducing factor from mitochondria into cytosol in WT but not in KO mice. Knockout of p53 also preserved mitochondrial bcl-2 content in THAP-treated mice. In WT mice, THAP treatment markedly increased cell death compared to vehicle treated hearts. In contrast, cell injury was decreased in THAP-treated p53 KO mice compared to corresponding wild type. Thus, KO of p53 decreased cell injury by protecting mitochondria during the ER stress

Blockade of Electron Transport at the Onset of Reperfusion Decreases Cardiac Injury in Aged Hearts by Protecting the Inner Mitochondrial Membrane

Myocardial injury is increased in the aged heart following ischemia-reperfusion (ISC-REP) compared to adult hearts. Intervention at REP with ischemic postconditioning decreases injury in the adult heart by attenuating mitochondrial driven cell injury. Unfortunately, postconditioning is ineffective in aged hearts. Blockade of electron transport at the onset of REP with the reversible inhibitor amobarbital (AMO) decreases injury in adult hearts. We tested if AMO treatment at REP protects the aged heart via preservation of mitochondrial integrity. Buffer-perfused elderly Fischer 344 24 mo. rat hearts underwent 25 min global ISC and 30 min REP. AMO (2.5 mM) or vehicle was given for 3 min at the onset of REP. Subsarcolemmal (SSM) and interfibrillar (IFM) mitochondria were isolated after REP. Oxidative phosphorylation (OXPHOS) and mitochondrial inner membrane potential were measured. AMO treatment at REP decreased cardiac injury. Compared to untreated ISC-REP, AMO improved inner membrane potential in SSM and IFM during REP, indicating preserved inner membrane integrity. Thus, direct pharmacologic modulation of electron transport at REP protects mitochondria and decreases cardiac injury in the aged heart, even when signaling-induced pathways of postconditioning that are upstream of mitochondria are ineffective

Socioscientific modelling as an approach towards justice-centred science pedagogy

Justice-centred science pedagogy has been suggested as an effective framework for supporting teachers in bringing in culturally relevant pedagogy to their science classrooms; however, limited instructional tools exist that introduce social dimensions of science in ways teachers feel confident navigating. In this article, we add to the justice-centred science pedagogy framework by offering tools to make sense of science and social factors and introduce socioscientific modelling as an instructional strategy for attending to social dimensions of science in ways that align with justice-centred science pedagogy. Socioscientific modelling offers an inclusive, culturally responsive approach to education in science, technology, engineering, the arts and mathematics through welcoming students’ diverse repertoires of personal and community knowledge and linking disciplinary knowledge with social dimensions. In this way, students can come to view content knowledge as a tool for making sense of inequitable systems and societal injustices. Using data from an exploratory study conducted in summer 2022, we present emerging evidence of how this type of modelling has shown students to demonstrate profound insight into social justice science issues, construct understandings that are personally meaningful and engage in sophisticated reasoning. We conclude with future considerations for the field

1015-71 Lower Adenosine Levels During Early Ischemia: Cause of Increased Injury in the Aging Heart?

Myocardial injury following ischemia and reperfusion is increased in the aging heart, including in the aging 24 mo Fischer 344 rat (mean survival 29 mo) compared to the Fischer 344 adult (6 mo). Adenosine (ADO) has been increasingly appreciated as a cardioprotective agent in myocardial ischemia. We hypothesized that a potential mechanism of the increased injury in the aging heart is decreased production of ADO in response to ischemia. Isolated buffer perfused (glucose 5 mM — insulin 5 μ/1) hearts from aging and adult Fischer 344 rats were subjected to stop-flow ischemia for either 2, 5, 10, 15 or 25 min after a 15 min equilibration phase. ADO and hypoxanthine (HX) were measured by HPLC. Tissue total adenylates, ATP, glycogen and lactate were measured.IschemiaPre-ischemia2 min5 min10 min15 min25 min(n=5)(n=5)(n=5)(n=5)(n=5)(n=5)ADO 6 mo0.2±0.10.7±0.10.7±0.12.2±0.237±0.64.5±0.324 mo0.2±0.105±0.10.3±0.1*1.1±0.3*2.1±0.3*3.5±0.4HX 6 mo2.0±0.21.6±0.22.3±0.32.2±0.125±0.22.8±0.224mo1.9±0.21.4±0.11.4±0.2*2.1±0.22.2±0.83.5±0.3(Mean±SE, nmol/mg protein)*p<0.05 vs 6 moADO levels were 50% lower in the aging heart at 5 and 10 min, remained depressed at 15 min and had not fully equalized to adult levels by 25 min of ischemia. HX was decreased at 5 min, consistent with decreased ADO production at that time. The change in total adenylate pool was similar in both groups. The decrease in tissue glycogen and increase in lactate were similar during ischemia in both groups, suggesting comparable glycolytic activity. ATP levels were decreased in aging hearts at 5 min (11.1±2.3 vs 18.7±1.9 nmol/mg protein), but reached levels similar to adult hearts as ischemia progressed.Thus, decreased ADO levels during early ischemia may reflect reduced production of ADO in the aging heart, and increase the susceptibility of the aging heart to damage during ischemia and reperfusion

Calpain-Mediated Protein Targets in Cardiac Mitochondria Following Ischemia–Reperfusion

Calpain 1 and 2 (CPN1/2) are calcium-dependent cysteine proteases that exist in cytosol and mitochondria. Pharmacologic inhibition of CPN1/2 decreases cardiac injury during ischemia (ISC)–reperfusion (REP) by improving mitochondrial function. However, the protein targets of CPN1/2 activation during ISC–REP are unclear. CPN1/2 include a large subunit and a small regulatory subunit 1 (CPNS1). Genetic deletion of CPNS1 eliminates the activities of both CPN1 and CPN2. Conditional cardiomyocyte specific CPNS1 deletion mice were used in the present study to clarify the role of CPN1/2 activation in mitochondrial damage during ISC–REP with an emphasis on identifying the potential protein targets of CPN1/2. Isolated hearts from wild type (WT) or CPNS1 deletion mice underwent 25 min in vitro global ISC and 30 min REP. Deletion of CPNS1 led to decreased cytosolic and mitochondrial calpain 1 activation compared to WT. Cardiac injury was decreased in CPNS1 deletion mice following ISC–REP as shown by the decreased infarct size compared to WT. Compared to WT, mitochondrial function was improved in CPNS1 deletion mice following ischemia–reperfusion as shown by the improved oxidative phosphorylation and decreased susceptibility to mitochondrial permeability transition pore opening. H2O2 generation was also decreased in mitochondria from deletion mice following ISC–REP compared to WT. Deletion of CPNS1 also resulted in less cytochrome c and truncated apoptosis inducing factor (tAIF) release from mitochondria. Proteomic analysis of the isolated mitochondria showed that deletion of CPNS1 increased the content of proteins functioning in regulation of mitochondrial calcium homeostasis (paraplegin and sarcalumenin) and complex III activity. These results suggest that activation of CPN1 increases cardiac injury during ischemia–reperfusion by impairing mitochondrial function and triggering cytochrome c and tAIF release from mitochondria into cytosol