bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Sexually Dimorphic Hepatic Cycle of Very Low Density Lipoprotein Uptake and Assembly
Authors: Martini Tomaz , Gobet Cedric , Salati Andrea , Blanc Jerome , Mookhoek Aart , Knott Graham , Sordet-Dessimoz Jessica 
Published: May 2024

The liver shows striking sexual dimorphism, which is reflected in differences between women and men in pathologies inherently associated with hepatic function. Recent single-cell transcriptomes revealed spatiotemporal programmes of liver function on the sublobular scale. However, how sexual dimorphism affects this space-time logic remains poorly understood. To address this, we performed single-cell RNA-seq in the mouse liver, which allowed us to model how lobular position, circadian time and sex shape the transcriptome. We found that sex, space and time markedly influence xenobiotic detoxification and lipid processing, including lipoprotein metabolism. Crucially, the very low density lipoprotein receptor (VLDLR) is restricted to the pericentral zone, with significantly higher mRNA and protein levels in female mice. Using human samples, we were able to recapitulate both VLDLR's pericentral expression as well as higher mRNA and protein levels in premenopausal women compared to similarly aged men. In humans, we found that VLDLR expression depends not just on age but also body mass index. Conversely, several genes involved in VLDL assembly are periportally biased, and we corroborated periportal VLDL generation with electron microscopy, optimized for detecting low density lipid particles. Together, this suggests a hepatic cycle of periportal formation and pericentral uptake of VLDL. Crucially, these processes provide a new window into the sexual dimorphism characterizing differences in VLDL kinetics and atherosclerotic cardiovascular disease. The work was supported by a Swiss National Science Foundation grant. The authors declare no conflicting interests. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
OMICmAge: An integrative multi-omics approach to quantify biological age with electronic medical records
Authors: Dwaraka Varun , Chen Qingwen , Carreras-Gallo Natalia , Mendez Kevin , Chen Yulu , Begum Sofina , Kachroo Priyadarshini 
Published: May 2024

Biological aging is a multifactorial process involving complex interactions of cellular and biochemical processes that is reflected in omic profiles. Using common clinical laboratory measures in ~30,000 individuals from the MGB-Biobank with balanced sex representation, we developed a robust, predictive biological aging phenotype, EMRAge, that balances clinical biomarkers with overall mortality risk and can be broadly recapitulated across EMRs. We then applied elastic-net regression to model EMRAge with DNA-methylation (DNAm) and multiple omics, generating DNAmEMRAge and OMICmAge, respectively. Both biomarkers demonstrated strong associations with chronic diseases and mortality that outperform current biomarkers across our discovery (MGB-ABC, n=3,451) and validation (TruDiagnostic, n=12,666) cohorts. Furthermore, both DNAmEMRAge and OMICmAge exhibit greater accuracy (average ROC = 0.88) in predicting 5-year and 10-year mortality than current biological age predictors. Through the use of epigenetic biomarker proxies, OMICmAge has the unique advantage of expanding the predictive search space to include epigenomic, proteomic, metabolomic, and clinical data while distilling this in a measure with DNAm alone, providing opportunities to identify clinically-relevant interconnections central to the aging process. This work was funded in part by TruDiagnostic for data generation and manuscript writing. Efforts for RK, KM, YC, SB, and JALS are supported by R01HL123915 from the NIH/NHLBI; PK is supported by K99HL159234 from the NIH/NHLBI; RSK is supported by K01HL146980 from the NIH/NHLBI; SHC is supported by K01HL153941 from the NIH/NHLBI; YC and JAILS are supported by R01HL141826 from the NIH/NHLBI; AD is supported by K01HL130629 from the NIH/NHLBI; AD and JALS are supported by 1R01HL152244 from the NIH/NHLBI; MM and JALS are supported by R01HL155742 from the NIH/NHLBI; MM is supported by R01HL139634 from the NIH/NHLBI; JALS, STW, EWK are supported by the NIH U01HG008685; VNG is supported by NIH AG065403 and AG064223; CEW is supported by the JSPS KAKENHI Grant (JP19K21239), the Japanese Environment Research and Technology Development Fund (No. 5- 1752), JPJ SBP-1201854), HLF 20180290, HLF 20200693), and the Swedish Research Council (2016-02798); NJWR is supported by MR/Y010736/1 and IF\R1\231034; EM is supported by the NIH (ZICTR000410-03). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Loss of Acid Ceramidase in Myeloid Cells Impairs MHC II Expression on Dendritic Cells and Macrophages to Alleviate Chronic Colitis in IL10−/− Mice
Authors: Espinoza Keila , Marron Marilyn , Snider Justin , Snider Ashley 
Published: May 2024

Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the colon and drastically increases the risk in the development of colorectal cancer (CRC). Over expression of acid ceramidase (AC) resulting in accumulation of sphingosine-1-phosphate (S1P), which amplify inflammatory pathways, has been implicated in patients with IBD and CRC. The conditional loss of AC in myeloid cells (ACMYE) has demonstrated promise as a therapeutic target in an acute colitis model. We sought to expand the investigation of AC loss in a physiologically relevant model of IBD using IL-10 deficient mice. IL10−/− mice were crossed with AC conditional knockout mice where AC is deleted in myeloid cells to generate ACMYE/IL10−/−, with ACfl/fl/IL10−/− mice used as control. Male and female animals were collected at 8, 12, and 24 weeks of age and assessed for intestinal inflammation. Upon examination of basic parameters of colitis, ACMYE mice exhibited reduced body weight and enlarged spleens at 12 weeks of age. Histologic assessment revealed no difference between genotypes in colitis severity at 8 or 12 weeks of age. Flow cytometry analysis was utilized to define the role of AC in immune cell recruitment. ACMYE mice exhibit reduced MHC II surface expression on antigen presenting cells (APCs) as well as reductions in neutrophil activation markers in peripheral tissues and the colon at 8 weeks of age. Interestingly, at 12 weeks of age ACfl/fl mice demonstrate significant immunosuppression across various cell types in the colon compared to ACMYE mice, whose colonic immune cells demonstrate little change over time. Furthermore, CD8+ cytotoxic T cell populations were significantly elevated in peripheral tissues despite continued reductions of MHC II surface expression on APCs in ACMYE mice at 12 weeks of age. These data indicate that loss of AC may provide protection in early age while resulting in altered inflammation in later age; however, loss of AC may also disrupt MHC II expression as seen consistently in APCs, and may indicate interference with cell-to-cell cross talk. Realtime qPCR revealed that ACMYE mice exhibited significant ablation in the expression of several pro-inflammatory cytokines at 24 weeks of age. Together these data implicate AC as a potential therapeutic target in reducing inflammation in chronic IBD. This work is supported by the National Institute of Diabetes and Digestive and Kidney Diseases R01 DK132079 (AJS). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Selective Timing of Maternal Immune Activation Alters Developmental Milestones, Behavior, and Blood-Brain Barrier Integrity
Authors: Sheng Julietta A. , Tobet Stuart A. 
Published: May 2024

Background and Hypothesis: Maternal immune activation (MIA) has been associated with increased risk for neuropsychiatric disease. Fetal exposure to maternal infection activates different toll-like receptors (TLRs) to initiate innate inflammatory responses in mother and fetus. The goal of the current study is to determine sex-dependent aspects of MIA during mid-gestation on neurodevelopment. Methods: Timed-pregnant female mice were administered RQ (TLR7 agonist) or vehicle saline on embryonic day (E) 12.5. Maternal and fetal cytokines were measured to ensure infection of pregnant dam (E15). Offspring were assessed postnatally for developmental milestones and behavior. Adult offspring were perfused with fluorescein isothiocyanate (FITC; 100mg/mL) to visualize blood vessel integrity (FITC leakage; Frahm & Tobet, 2015). To determine neural molecular mechanisms for behavioral changes, sections through the paraventricular nucleus of the hypothalamus (PVN) of offspring were immunolabeled for Glial Fibrillary Acidic Protein (GFAP; astrocytic end feet), Desmin (pericytes) and IBA-1 (microglia). Results: Maternal cytokines IL-6 (p<0.05) and IL-10 (p<0.01) were higher while TNFα (p<0.01) and IL-17 were lower 3 days after RQ-exposure. In fetuses (E15), IL-6 (p<0.05) and IL-17 (p<0.0001) were greater, while IL-10 was higher only in males (p<0.001) exposed to maternal infection. RQ-exposed males also had reduced TNFα (p<0.05). Additionally, RQ-exposed offspring had lower body weights at birth and delayed eye openings. Females exposed to maternal RQ exhibited slower onset of puberty with delayed vaginal openings. On the behavioral side, juvenile and adult offspring of RQ injected moms exhibited less social-like behavior (p<0.001 for all groups) with lower hedonic-like behavior selectively in females (p<0.001). RQ-offspring further showed greater leakage in the PVN indicated by more FITC in the extravascular space (males p<0.001, females p<0.01). GFAP + (astrocytic end feet) coverage of FITC-labeled vessels was higher in the PVN selectively in RQ males (p<0.001). Desmin+ (pericyte) coverage was greater in the PVN of RQ males (p<0.01) and females (p<0.001). Finally, there was greater number of IBA-1+ cells in the adult offspring PVN of both sexes (p<0.01) after maternal injection of RQ. Conclusions: This study provides support for sex-dependent influences of fetal antecedents for altered brain development and behavioral outputs that could be indicative of increased susceptibility for adult disorders through immune mechanisms. Future studies will examine how timing of infection during gestation (mid vs. late) changes neurodevelopmental outputs in offspring. Supported by ORWH-NIMH U54 SCORE-MH118919. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Optogenetic stimulation of Phox2b-expressing neurons in the respiratory parafacial region rescue fentanyl-induced respiratory depression
Authors: Burgraff Nicholas , Moreira Thiago , Takakura Ana , Ramirez Jan Marino 
Published: May 2024

The primary cause of death from opioid overdose is opioid-induced respiratory depression (OIRD), which results in substantial suppression of respiratory rate, destabilization of breathing patterns, severe hypercapnia, and a heightened risk for life-threatening apnea. A crucial chemosensitive brainstem region, located in the rostral ventrolateral medullary reticular formation, contains a bilateral cluster of approximately 800 non-opioid receptor-expressing glutamatergic, non-catecholaminergic, Phox2b+ propriobulbar neurons. These neurons are stimulated by CO2 and acidification and play a vital role in regulating breathing to prevent respiratory acidosis. Under normal circumstances, opioid induced hypercapnia should stimulate these cells to restore ventilation and prevent disturbances in arterial blood gases. However, during OIRD, it remains unclear whether these neurons can effectively rescue breathing in the response to opioid induced hypercapnia. The present study aims to address this question by investigating whether the ability of these neurons to stimulate breathing is significantly altered during opioid-induced respiratory depression. Using optogenetic stimulation, we stimulated these Phox2b+ cells before and after fentanyl to test for whether their ability to stimulate ventilation is reduced during OIRD. As expected, fentanyl (500 μg/kg, ip) resulted in respiratory rate suppression and destabilization of breathing pattern. Before fentanyl administration optogenetic stimulation of Phox2b+ cells increased breathing activity in a pulse stimulation frequency dependent (5-20Hz) manner. Unexpectedly, following fentanyl administration, similar optogenetic stimulation of Phox2b+ cells resulted in a significantly greater frequency dependent (5-20Hz) increase in breathing activity compared to pre-fentanyl levels. Additionally, both hypercapnia (FiCO2 = 0.1) or hypoxia (FiO2 = = 0.1) produced an increase breathing activity in a similar manner in pre- and post-fentanyl conditions. The results suggest that fentanyl paradoxically increases the ability of Phox2b+ cells to stimulate breathing but shifts the steady-state relationship between ventilation and arterial blood gases, such that resting ventilation is reduced. FAPESP, NIH. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Deletion of the Aryl Hydrocarbon Receptor in Endothelial Cells Improves Ischemic Angiogenesis in Chronic Kidney Disease
Authors: Palzkill Victoria , Tan Jianna , Yang Qingping , Morcos Juliana , Laitano Orlando , Ryan Terence 
Published: May 2024

Background: Chronic kidney disease (CKD) is a strong yet underappreciated risk factor for peripheral arterial disease (PAD) that exacerbates disease progression and increases risk for limb amputation and cardiovascular mortality. An estimated 25-35% of CKD patients develop PAD, but mechanistic data linking these two pathologies is limited. Several tryptophan-derived uremic metabolites are retained in the blood and tissues as a consequence of CKD and are endogenous ligands of the aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor that has been shown to regulate angiogenesis. Hypothesis: We tested the hypothesis that endothelial cell-specific conditional deletion of the AHR would enhance ischemic limb outcomes in mice with CKD and femoral artery ligation (FAL). Methods: Twelve-week-old male and female endothelium-specific AHR knockout mice (AHRecKO) and AHR floxed mice (AHRfl/fl, Cre-negative control) were fed 0.2% adenine to induce CKD or casein control diet (n=10/group/sex) prior to undergoing FAL to induce limb ischemia. Laser Doppler flowmetry was used to measure limb perfusion. Isometric contraction of the tibialis anterior in-situ via nerve stimulus was performed to measure muscle function. Skeletal muscle mitochondrial respiratory function and H2O2 production were evaluated. Primary endothelial cells were isolated from male and female wildtype mice and treated with known AHR ligand indoxyl sulfate (IS) under hypoxic conditions to uncover sex-dependent differences in AHR activating potential. Results: In male mice with CKD, endothelium-specific ablation of the AHR resulted in significant increases in percentage of perfused capillaries within the ischemic limb (AHRecKO 73.41% ± 4.80% vs AHRfl/fl 64.75% ± 8.325%; p= 0.0074), improved laser Doppler perfusion recovery in the paw and gastrocnemius muscle, and larger myofiber cross-sectional area ( p=0.0258) compared to AHRfl/fl mice. However, these improvements did not translate to improved muscle contractile function. In contrast, deletion of the AHR in female mice with CKD had no significant impact on major outcome measures. Primary cells from male mice treated with IS had significantly higher expression of the AHR controlled gene Cyp1a1 ( p=0.026) compared to cells from female mice. Conclusion: Endothelium-specific deletion of the AHR improved ischemic angiogenesis in male, but not female, mice with CKD. These data reveal sex-dependent differences in AHR activating potential within endothelial cells that exist in the absence of sex hormones. This study was supported by National Institutes of Health (NIH) grant R01-HL149704 (T.E.R.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Association of Hypertensive Disorders of Pregnancy With Coronary Microvascular Dysfunction 8 to 10 Years After Delivery
Authors: Countouris Malamo E. , Catov Janet M. , Zhu Jianhui , de Jong Nikki , Brands Judith , Chen Xucai , Parks W. Tony , Berlacher Kathryn L. , Gandley Robin E. , Straub Adam C. , Villanueva Flordeliza S. 
Published: May 2024

BACKGROUND:
Hypertensive disorders of pregnancy (HDP) are associated with subsequent adverse cardiac remodeling and cardiovascular disease. The role of myocardial microvascular disease among individuals with HDP and left ventricular (LV) remodeling as a potential link to cardiovascular disease is unknown. We aimed to determine whether individuals with HDP history have coronary microvascular dysfunction measured by coronary flow reserve 8 to 10 years after delivery and whether microvascular dysfunction correlates with LV remodeling.

METHODS:
Individuals with pregnancies delivered from 2008 to 2010 underwent burst-replenishment myocardial contrast echocardiography (2017–2020) to quantify myocardial perfusion at rest and during dobutamine stress. Video intensity versus time data were used to derive β, the rate of rise of video intensity, a correlate for myocardial blood flow. Coronary flow reserve was calculated as the ratio of β at peak stress to β at rest, averaged across LV myocardial regions of interest.

RESULTS:

We studied 91 individuals (aged 38±6 and 9.1±0.9 years postdelivery) and 19 with a history of HDP. Individuals with coronary microvascular dysfunction (coronary flow reserve <2.0; n=13) had a higher proportion of HDP (46.2% versus 16.7%;
P
=0.026) and higher prepregnancy body mass index, baseline heart rate, and hemoglobin A1c compared with those without microvascular dysfunction. The association of coronary flow reserve and HDP was attenuated after adjusting for cardiometabolic factors (
P
=0.133). In exploratory subgroup analyses, individuals with both LV remodeling (relative wall thickness >0.42) and HDP (n=12) had the highest proportion of microvascular dysfunction (41.7% versus +HDP-LV remodeling [n=7] 14.3%; −HDP+LV remodeling [n=26] 7.7%;
P
=0.0498).

CONCLUSIONS:
In this small study, HDP history is associated with coronary microvascular dysfunction 1 decade after delivery, findings that may, in part, be driven by metabolic factors including obesity and diabetes. Microvascular dysfunction may contribute to cardiovascular disease among individuals with a history of HDP.
Clinical Value of Single-Projection Angiography–Derived FFR in Noninfarct-Related Artery
Authors: Kwon Woochan , Choi Ki Hong , Lee Seung Hun , Hong David , Shin Doosup , Kim Hyun Kuk , Park Keun Ho , Choo Eun Ho , Kim Chan Joon , Kim Min Chul , Hong Young Joon , Ahn Sung Gyun , Doh Joon-Hyung , Lee Sang Yeub , Park Sang Don , Lee Hyun-Jong , Kang Min Gyu , Koh Jin-Sin , Cho Yun-Kyeong , Nam Chang-Wook , Joh Hyun Sung , Kyu Park Taek , Yang Jeong Hoon , Song Young Bin , Choi Seung-Hyuk , Jeong Myung Ho , Gwon Hyeon-Cheol , Hahn Joo-Yong , Lee Joo Myung ,   the FRAME-AMI Investigators
Published: May 2024

BACKGROUND:
The Murray law–based quantitative flow ratio (μFR) is an emerging technique that requires only 1 projection of coronary angiography with similar accuracy to quantitative flow ratio (QFR). However, it has not been validated for the evaluation of noninfarct-related artery (non-IRA) in acute myocardial infarction (AMI) settings. Therefore, our study aimed to evaluate the diagnostic accuracy of μFR and the safety of deferring non-IRA lesions with μFR >0.80 in the setting of AMI.

METHODS:
μFR and QFR were analyzed for non-IRA lesions of patients with AMI enrolled in the FRAME-AMI trial (Fractional Flow Reserve Versus Angiography-Guided Strategy for Management of Non-Infarction Related Artery Stenosis in Patients With Acute Myocardial Infarction), consisting of fractional flow reserve (FFR)–guided percutaneous coronary intervention and angiography-guided percutaneous coronary intervention groups. The diagnostic accuracy of μFR was compared with QFR and FFR. Patients were classified by the non-IRA μFR value of 0.80 as a cutoff value. The primary outcome was a vessel-oriented composite outcome, a composite of cardiac death, non-IRA–related myocardial infarction, and non-IRA–related repeat revascularization.

RESULTS:

μFR and QFR analyses were feasible in 443 patients (552 lesions). μFR showed acceptable correlation with FFR (R=0.777;
P
<0.001), comparable C-index with QFR to predict FFR ≤0.80 (μFR versus QFR: 0.926 versus 0.961,
P
=0.070), and shorter total analysis time (mean, 32.7 versus 186.9 s;
P
<0.001). Non-IRA with μFR >0.80 and deferred percutaneous coronary intervention had a significantly lower risk of vessel-oriented composite outcome than non-IRA with performed percutaneous coronary intervention (3.4% versus 10.5%; hazard ratio, 0.37 [95% CI, 0.14–0.99];
P
=0.048).

CONCLUSIONS:
In patients with multivessel AMI, μFR of non-IRA showed acceptable diagnostic accuracy comparable to that of QFR to predict FFR ≤0.80. Deferred non-IRA with μFR >0.80 showed a lower risk of vessel-oriented composite outcome than revascularized non-IRA.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT02715518.
Deciphering Mean Flow–Eddy Interaction in Pacific–North American Teleconnection Linked to Storm Tracks at Subseasonal Time Scales
Authors: Liu Chen , Chen Lei , Liess Stefan 
Published: May 2024

Abstract
The features of large-scale atmospheric circulations, storm tracks, and the mean flow–eddy interaction during winter Pacific–North American (PNA) events are investigated using National Centers for Environmental Prediction–National Center for Atmospheric Research (NCEP–NCAR) reanalysis data at subseasonal time scales from 1979 to 2022. The day-to-day variations of storm-track activity and streamfunction reveal that storm-track activity varies along the evolution of mean flow. To better understand storm-track variability with the mean flow–eddy interaction, further exploration is made by analyzing local energy energetics. The changes in horizontal and vertical baroclinic energy conversions from background flow correspond to the storm-track anomalies over the North Pacific, indicating that the anomalies in storm tracks are due to the anomalous mean flow associated with PNA patterns impacting energy conversion through mean flow–eddy interaction. Eddy feedback driven by vorticity and heat fluxes is analyzed. This provides a concrete illustration of how eddy feedback serves as a positive factor for the upper-tropospheric circulation anomalies associated with the PNA pattern.

Significance Statement
The background flow plays a crucial role in governing storm-track dynamics. Our emphasis is on the Pacific storm tracks (PST) and their relation to Pacific–North American (PNA) patterns at subseasonal time scales. We unveil the relationship between anomalies of PST and PNA patterns using local energetics and eddy feedback on a day-by-day basis. It is noteworthy that the evolution of anomalous storm tracks during PNA events is the manifestation of mean flow–eddy interaction. Additionally, we provide detailed confirmation of the impact of anomalous storm tracks on large-scale anomalies associated with the PNA pattern.