Citations

Abstract Oligodendroglioma is a primary central nervous system tumor classified by the presence of isocitrate dehydrogenase (IDH) mutations and codeletion of 1p/19q. Here we describe the generation of an IDH-mutant 1p/19q-codeleted oligodendroglioma mouse model using in utero electroporation. We identified IDH1 R132H , PIK3CA E545K , Cic KO , Fubp1 KO and Cdkn2a KO as the optimal combination (termed Oligo Cdkn2a ) to drive fully penetrant tumors that histologically resemble human grade II/III IDH-mutant, 1p/19q-codeleted oligodendroglioma. Replacing Cdkn2a with Trp53 loss in this mouse model shifted tumor histology towards high grade astrocytoma. Oligo Cdkn2a tumors displayed metabolic and transcriptional changes associated with IDH and CIC mutations, and single cell sequencing identified a bias towards oligodendrocyte differentiation compared to an IDH wild-type glioblastoma mouse model. Oligo Cdkn2a tumors represent the first mouse model system to recapitulate the genetic, histological and transcriptional features of human IDH-mutant 1p/19q-codeleted oligodendrogliomas, offering a platform to further dissect tumor biology and test new therapeutic strategies.

Endothelin-1 (ET-1) has been linked to increased hypoxic sensitivity of the chemoreceptors and the development of cardiometabolic disease. Repeated hypoxic exposures [i.e., intermittent hypoxia (IH)] elicit increases in ET-1, muscle sympathetic nerve activity (MSNA), and blood pressure (BP). In this brief review, we summarize data from our group(s) which examined the effect of acute IH on MSNA, BP, and indices of adipose tissue lipolysis [i.e., free fatty acids (FFAs)], as well as the role of ET-1 in these responses. Herein, we show that acute ET receptor inhibition (oral bosentan) attenuates the rise in BP during hypoxia and the fall in BP during hyperoxia in healthy young men. Although the effect of IH on MSNA and BP was not attenuated following ET-receptor inhibition, IH increased plasma ET-1, epinephrine, and FFA concentrations. Notably, inhibition of ET-1 receptors with oral bosentan attenuated the IH-mediated rise in epinephrine and FFA. With these findings, we demonstrate a role for ET-1 in the maintenance of resting BP in young men, possibly through a chemoreceptor-mediated mechanism. We further speculate that the effect of ET-1 receptor inhibition on circulating FFA is secondary to its ability to reduce sympathoadrenal tone during IH exposure. Results highlighted in this review may serve as the basis for future work exploring ET-1 as a therapeutic target for cardiometabolic dysfunction associated with IH.

Lactococcosis has emerged as an economically and ecologically significant disease in aquatic animals worldwide. This study employed multilocus sequence typing (MLST) to investigate the genetic diversity of Lactococcus spp. strains from Brazilian fish species and evaluate their phylogenetic relationships with global isolates to elucidate potential epidemiological connections involving multiple host species and distinct geographic regions. A total of 55 isolates from different laboratories had their DNA extracted, followed by the amplification and sequencing of the internal fragments of seven housekeeping genes (als, atpA, tuf, gapC, gyrB, rpoC and galP). Sequence types (STs) and clonal complexes (CCs) were defined. An unrooted neighbor-joining phylogenetic tree was generated using allele profiles from this study and those previously reported from other aquatic animal species. The isolates comprised 29 STs (11 previously reported, 18 novel ones), which were grouped into species-specific CCs: CC5 (L. formosensis); CC4, CC17, CC62 (L. garvieae); CC24, CC29, CC97 (L. petauri). Considerable genetic divergence was observed, with L. formosensis and L. garvieae forming heterogeneous populations, while L. petauri was more homogeneous. These findings describe the MLST structure of the sampled isolates and should be interpreted as hypothesis-generating rather than population-level estimates of genotype prevalence. Phylogenetics confirmed groupings within the CCs and revealed additional phylogenetic clustering patterns. In conclusion, the Brazilian Lactococcus spp. strains analyzed in this study constitute a genetically diverse population based on their STs. MLST and phylogenetic analysis demonstrated genetic relatedness between the L. garvieae and L. formosensis isolates from this study and those from other aquatic animal species. In contrast, all the STs identified for L. petauri in this study were unrelated to the MLST lineages responsible for outbreaks in Brazilian Nile tilapia (Oreochromis niloticus) and North American rainbow trout (Oncorhynchus mykiss). This suggests that piscine L. petauri populations in the Americas evolved from distinct ancestral origins.

Introduction The WHO/UNICEF Nurturing Care Framework (NCF) features five domains necessary for child development—physical/mental health, responsive caregiving, adequate nutrition, security and safety and opportunities for early learning. We explored caregiver perspectives on the NCF in two African settings. Methods Between November 2023 and July 2024, 14 focus group discussions (FGDs) were conducted with caregivers living with and without HIV; eight with mothers in Gaborone, Botswana, and six with mothers and fathers in Nairobi, Kenya. FGDs were stratified by country, sex, HIV status and partnership status. Semi-structured interviews with interactive activities elicited caregiver perspectives on the NCF to identify the most ‘important’, ‘easiest’ and ‘challenging’ domains to fulfil. Thematic analyses identified key themes and compared perspectives. Results Our qualitative study included 101 caregivers, 55 from Kenya (30 mothers, 25 fathers) and 46 mothers from Botswana. Overall, caregivers identified physical/mental health as the ‘most important’ domain to fulfil for children and caregivers, noting how closely tied they were (“ If you have pain, that pain affects your child” ). The ‘most challenging’ domain was adequate nutrition in Botswana and security and safety in Kenya. The ‘easiest’ domains were responsive caregiving in Botswana and opportunities for early learning in Kenya. Kenyan caregivers noted that spiritual nourishment was also critical for well-being but missing from the NCF. Caregivers emphasised the importance of receiving social support with childcare. Caregivers living with HIV expressed similar views compared with caregivers without HIV, but mentioned that social isolation, stigma and treatment disruption impact their ability to provide adequate nurturing care. Conclusions Caregivers face unique parenting challenges depending on cultural environment. HIV disrupts caregivers’ health, which has important implications for raising children within families affected by HIV. Interventions that support caregivers’ abilities to fulfil all NCF domains and address challenges are essential to ensure children reach their developmental potential.

Abstract Hyperpolarized [1-¹³C]pyruvate MRI provides real-time, radiation-free insight into myocardial pyruvate metabolism and mitochondrial oxidative capacity, yet its utility in patients with severe multivessel coronary artery disease before and after surgical revascularization remains unknown. Here we show, in the first prospective study applying this technique to three-vessel disease, that serial imaging is feasible and safe with no serious adverse events in 22 injections. Healthy myocardium displayed a bicarbonate-to-total hyperpolarized carbon product ratio of 0.66 ± 0.13, indicating that the majority of pyruvate undergoes oxidation. Patients exhibited significantly lower ratios in the inferolateral segment (P = 0.03) with reciprocal increases in lactate, and global ratios correlated with left ventricular ejection fraction (r = 0.695, P = 0.006). Post-revascularization changes were heterogeneous across individuals. These findings establish hyperpolarized 13C MRI as a powerful tool for noninvasive assessment of myocardial metabolism in multivessel coronary artery disease and support its potential for longitudinal therapeutic monitoring.

Introduction: Menopausal hot flashes are defined as rapid, intense sweating and/or an intense feeling of warmth. Subjective recordings of menopausal hot flashes can be difficult to obtain due to inconvenience to the individual and poor recall. This calls for an improved method to quantify hot flashes that are less dependent on human interaction. The goal of this study was to determine if an ambulatory skin conductance hot flash monitor would detect menopausal hot flash occurrence and frequency to the same degree as those reported by study participants. Methods: Thirty-five peri- and postmenopausal females (age: 53±4 years) participated in this study. An ambulatory, noninvasive sternal skin conductance monitor was placed on each participant for a 24-hour recording period. The monitor recorded a hot flash when an increase of 0.2 micromhos was detected in the participant’s sweat level compared to their baseline (objective). Participants manually recorded perceived hot flash occurrence on the monitor (subjective). For analysis, a monitor recording with ≥20 consecutive hours of intact data was included. Hot flash frequency was defined as the number of hot flashes per recording period. A Mann-Whitney test was conducted to compare subjective and objective hot flash frequencies. Statistical analyses for agreement in hot flash occurrence (yes/no; Cohen’s Kappa) and frequency (Bland-Altman) were completed. Data are reported as mean±SD or median (IQR). Results: The average hot flash monitor recording consisted of 23.8±0.7 hours of data. Twenty-eight females reported at least one hot flash during their recording period (5 [3-9] subjective hot flashes) while 7 females did not report any hot flashes. The monitor detected at least one hot flash in 30 females (10 [5-21] objective hot flashes) and no hot flashes in 5 females. For 3 participants, both the subjective and objective reports showed zero hot flashes. There was a significant difference between the frequency of hot flashes reported by all participants (3 [1-8] subjective hot flashes) and those detected by the hot flash monitor (8 [4-19] objective hot flashes; p=0.006). There was no agreement between the subjective (self-report) and objective (monitor) assessments of hot flash occurrence (k= -0.1734). The Bland-Altman showed a mean bias of 7.1±8.6 towards objective hot flash frequency with limits of agreement of -9.8 to 23.9. Conclusion: The ambulatory sternal skin conductance monitor used in the current study showed no agreement in detecting menopausal hot flashes compared to self-reported hot flashes. Overall, the monitor substantially overestimated the frequency of menopausal hot flashes that participants reported. While further investigation might be needed to improve the monitor’s sensitivity for accurate hot flash detection, it is possible that the monitor may be detecting subclinical menopausal hot flashes that are less recognizable to the individual. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Introduction: Endothelial cell (EC) dysfunction, driven by comorbidities of heart failure with preserved ejection fraction (HFpEF), has emerged as a potential contributor to disease progression, yet the EC specific molecular mediators in HFpEF remain poorly defined. Purpose: To identify EC-specific molecular mediators that are involved in HFpEF and determine their functional roles in disease pathogenesis. Hypothesis: Based on omics analysis of a murine HFpEF model, we hypothesized that EC plasminogen activator inhibitor-1 (PAI-1) is a key mediator of HFpEF pathogenesis. Methods: Male RiboTagEC (Cdh5CreERT2+/Rpl22HA/+) mice were used in a HFpEF model induced by hypertensive/metabolic stresses (60% calories from lard and L-NAME 0.5 g/L in water) or administrated with normal water and diet as controls. Hearts and skeletal muscle were collected for both bulk RNA sequencing (Bulk-seq) and EC-specific translatome analysis using translating ribosome affinity purification assay followed by RNA-sequencing (TRAP-seq). The functional roles of EC PAI-1 were tested using male tamoxifen-inducible, endothelial specific PAI-1 knockout (Cdh5CreERT2+/PAI-1flox/flox, PAI-1iEC KO) and control mice (PAI-1flox/flox, PAI-1iEC+/+) subjected to HFpEF induction. Cardiac function was assessed by echocardiography, pressure–volume (PV) loop analysis, and treadmill exercise testing. Student’s t-test was used (p < 0.05). Results: Bulk-seq and EC-specific TRAP-seq identified PAI-1 as one of the most upregulated genes in both heart and skeletal muscle EC in HFpEF. Bulk-seq demonstrated a 2.5-fold change (FC, log 2 FC=1.35) increases in the heart and 12.2-fold increases (log 2 FC = 3.61) in the skeletal muscle. TRAP-seq showed a 1.75-fold change (log 2 FC=0.81) increases in the heart and 4.76-fold increases (log 2 FC = 2.25) in the skeletal muscle. These consistent findings led us to investigate the functional role of EC PAI-1 in the pathogenesis of HFpEF. With similar body weight (Control: 40±4 g, n=10; KO: 38±6 g, n=11; p=0.319) and ejection fraction (Control: 54±6 %, n=10; KO: 54±5 %, n=12; p=0.686), we found that PAI-1iEC KO mice exhibited improved diastolic function after 10 weeks of HFpEF induction. Specifically, echocardiography demonstrated a significant reduction in E/e′ in KO mice (Control: 27±4, n=10; KO: 24±3, n=12; p=0.018). PV analysis confirmed this improvement with lower end-diastolic pressure (Control: 19±2 mmHg, n=8; KO: 13±5 mmHg, n=10; p=0.009), reduced Tau (Control: 9.7±1.2 ms, n=8; KO: 8.6±1.0 ms, n=10; p=0.047), and a reduced EDPVR constant β (Control: 0.20±0.05, n=6; KO: 0.10±0.03, n=6; p=0.017). KO mice also exhibited improved treadmill running distance (Control: 179±35 m, n=10; KO: 214±40 m, n=12; p=0.043). Conclusion: Endothelial PAI-1 contributes to diastolic dysfunction and reduced exercise capacity in HFpEF. These findings highlight endothelial PAI-1 as a potential therapeutic target for HFpEF. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Background: Spontaneous coronary artery dissection (SCAD) is a common type of myocardial infarction in females under the age of 50 years, caused by sudden separation between the coronary arterial wall layers and/or hematoma. The SCAD patient population is mostly females (~80%) with few or no traditional cardiovascular disease risk factors (e.g., obesity, hypertension). Common triggers for SCAD include sympathoexcitatory stimuli, such as intense physical and emotional stress. This implicates the sympathetic nervous system in the pathophysiology of SCAD. Thus, we aimed to investigate sympathetic nervous system responses to mental stress in patients with a history of SCAD. We hypothesized that females with a history of SCAD exhibit a greater increase in muscle sympathetic nerve activity (MSNA) with acute exposure to mental stress compared to healthy females. Methods: Seven females with a history of SCAD (age: 48±9 yrs, BMI: 29±6 kg/m 2 ) and seven age- and BMI-matched healthy female controls (CON, age: 49±9 yrs, BMI: 26±6 kg/m 2 ) participated in the study (both p>0.05). MSNA was measured via peroneal microneurography during a 2-minute rest, a 5-minute Stroop Color Word Test aimed at inducing mental stress, and a 2-minute recovery. Heart rate (HR, 3-lead electrocardiography) and BP (finger photoplethysmography) were continuously recorded during each stage. Data are presented as an absolute change from rest (Δmean±SD). Two-way independent t-tests were used for statistical analyses. Results: Resting mean blood pressure (MBP, SCAD: 96±14 vs CON: 89±7 mmHg, p=0.27), heart rate (HR, SCAD: 56±11vs CON: 65±16 bpm, p=0.25), MSNA burst frequency (SCAD: 22±9 vs CON: 18±7 bursts/minute, p=0.40) and total MSNA (SCAD: 1135±471 vs CON: 951±245 au/min, p=0.41) were not different between the groups. During the Stroop Color Word Test, average changes in MBP (SCAD: Δ10±9 vs CON: Δ8±5 mmHg, p=0.67) and HR (SCAD: Δ11±7 vs CON: Δ14±5 bpm, p=0.35) were not different between the groups. Similarly, average changes in MBP (SCAD: Δ3±4 vs CON: Δ-2±5 mmHg, p=0.13) and HR (SCAD: Δ3±4 vs CON: Δ3±2 bpm, p=0.62) were not different during the recovery. Changes in MSNA burst frequency with the Stroop Color Word Test (SCAD: Δ1±7 vs CON: Δ6±7 bursts/minute, p=0.22) and recovery (SCAD: Δ0±5 vs CON: Δ4±4 bursts/minute, p=0.13) were not different between the groups. Total MSNA changes were also not different during the Stroop Color Word Test (SCAD: Δ267±335 vs CON: Δ606±432 au/min, p=0.15) and recovery (SCAD: Δ68±666 vs CON: Δ217±217 au/min, p=0.61) between the two groups. Conclusion: These preliminary data suggest that contrary to our hypothesis, sympathetic nervous system responses to acute mental stress exposure are not different between females with a history of SCAD and healthy females. Further investigation is needed to understand MSNA association with chronic stress exposure in females with a history of SCAD. Funding: NIH K23 HL155506 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.