bluuebunny/crossref_metadata_2025_split huggingface dataset:
Humanizing Science and Engineering to Reduce Health Care Delivery Inequalities
Authors: Cabrales Pedro , Jani Vivek 
Published: November 2023

We have developed an experiential learning program that integrates modern non‐invasive medical sensors with basic physiological principles, and modern medical practices in order to introduce the importance of understanding our own human physiology and its relationship to enriching human life and society. This experimental, multi‐disciplinary, experiential learning program introduces physiology to undergraduate students in science, technology, engineering, and math (STEM). The program allows students to learn physiology by applying science and engineering within the context of their bodily functions. This personalized program to learn physiology utilizes an engineering approach via dynamic models and modern sensors. Additionally, the experiential learning program integrates the social problems that influence modern healthcare, giving students a broader approach to not only basic physiological principles that affect health, life at extreme environments, and how modern medicine influences society. This program includes an outreach component targeted to high school students of the greater San Diego area, with the objetive of increase interest in physiology and STEM fields. Understanding physiological principles also allows students to learn the importance of both healthy living and healthcare, and their implications on both human life and society.Support or Funding InformationUCSD Frontiers of Innovation Scholars Program (FISP) Program
An Explanatory Computational Simulation of Contiguous Capillary Occlusion in Diabetic Retinopathy based on Patient‐derived Vasculature
Authors: Fu Xiao , Gens John Scott , Glazier James A. , Burns Stephen , Gast Thomas J. 
Published: November 2023

Early stages of diabetic retinopathy often feature contiguous areas of capillary occlusion in both perifoveal and peripheral areas. While leukocyte‐endothelium interactions appear to cause individual capillary occlusions, the underlying mechanisms by which multiple occlusions create large ischemic areas are not clear. To explain the observed pattern of contiguous capillary blockage seen in diabetics using fluorescein angiography, we developed a computational simulation based on a hypoxia‐driven vascular endothelial growth factor (VEGF)‐mediated adverse feedback mechanism. We constructed an in silico network of retinal capillaries in the perifovea (with an architecture derived from an actual human perifoveal arteriovenous sector capillary map obtained using adaptive‐optics scanning laser ophthalmoscopy (AOSLO) imaging) and in the retinal periphery. A hemodynamic model calculates blood flow rates in the simulated capillary network and submodels simulate advection, diffusion and metabolism of oxygen and synthesis, diffusion and decay of VEGF. Our main hypothesis is that hypoxic retinal tissue produces VEGF, which diffuses to adjacent capillaries and increases their probability of occlusion. Our simulations reproduce the experimentally observed pattern of contiguous areas of capillary occlusion. Furthermore, the simulated temporal evolution of blood flow agrees quantitatively with experiment, and the simulated venous oxygenation agrees qualitatively. We used multiple replica simulations to generate a vulnerability map for the capillary network, which showed that only a few capillary segments have a high probability of triggering large areas of derived occlusions. We then simulated the effects of specific patterns of pan‐retinal photocoagulation therapy using patterned alterations of tissue oxygen consumption to explore alternative therapeutic approaches to inhibiting progressive tissue ischemia. Future versions of this simulation framework may increase our ability to intervene early, using patient‐specific photocoagulation or anti‐VEGF treatments, to prevent large ischemic areas from developing and thereby prevent blindness from diabetic retinopathy.Support or Funding InformationThis work was sponsored by National Institutes of Health/National Institute of General Medical Sciences grants R01 GM076692, R01 GM077138, and U01 GM111243 and National Institutes of Health/National Eye Institute R01 EY024315. We have received support from the College of Arts and Sciences, the Office of the Vice President for Research under their IU Collaborative Research Grant Program at Indiana University, Bloomington.
Loss of Axin2 leads to Myxomatous Valve Disease
Authors: Hulin Alexia , Yutzey Katherine 
Published: November 2023

In the older population, myxomatous valve disease (MVD) is the second most common heart valve disease and the leading cause of mitral regurgitation. Myxomatous valves display thickened leaflets with glycosaminoglycan (GAG) accumulation and increased chondrogenic markers, such as Sox9 and aggrecan. Recent human microarray data suggest activation of Wnt/β‐catenin signaling in MVD. However, the role of Wnt/β‐catenin signaling in the pathogenesis of MVD is still poorly understood.To further investigate the role of Wnt/β‐catenin signaling, we analyzed heart valves from mice deficient in Axin2, a negative regulator of Wnt/β‐catenin signaling.Axin2 is expressed in endothelial and interstitial cells in adult heart valves as indicated by X‐gal staining of Axin2‐lacZ heterozygous mice. Homozygous loss of Axin2 (KO) does not impair early heart valve development. However, at birth and in adult mice, KO mice demonstrate thickened GAG‐rich aortic valves with increased cell proliferation and nuclear Sox9. At 4 months, focal aggrecan‐rich areas are observed along with increased TGF‐β and BMP signaling, as indicated by increased phosphorylation of Smad2/3 and Smad1/5/9 respectively. These features are consistent with human myxomatous mitral valves. Moreover, thickened aortic valves do not calcify as indicated by lack of alizarin red staining in 1 year old KO mice. Interestingly, melanocyte accumulation is also observed in thickened aortic valves, suggesting that Axin2 may influence neural crest cell contributions to heart valves. Ongoing in vivo and in vitro studies are investigating the specific functions of Axin2 in valve disease mechanisms.Altogether these data indicate a role for Axin2 in heart valve homeostasis and in myxomatous disease. In addition, the Axin2‐deficient mouse is a new model for myxomatous valve disease that will be used to decipher molecular pathway interactions and identify therapeutic targets in valve pathogenesis.
Bilateral Intra‐individual Comparison of Vascular Structure Following Eight Weeks of Unilateral Maximal Interval Handgrip Training in Post‐Menopausal Women
Authors: Bentley Danielle C , Thomas Scott G 
Published: November 2023

There is a growing body of literature, both primary and review, that supports the use of handgrip exercise training for resting blood pressure reduction. In further investigating the causative mechanisms responsible for this blood pressure improvement researchers have identified that handgrip exercise of sustained grip contractions held for upwards of two minutes can result in working‐limb specific improvements to both vascular structure and vascular function. Training with a more dynamic handgrip exercise protocol (32 × 5sec @ maximal force with 5sec of rest between sets) was therefore expected to produce more of a local vascular stimulus and potentially result in a greater influence on vascular measures. This research presents a component of an at‐home training study where post‐menopausal women completed unilateral maximal interval handgrip exercise. Bilateral vascular assessments were completed at the onset (week0), midway (week4), and the end (week8) of training. Based on previous research, it was hypothesized that working‐limb specific changes to carotid‐radial Pulse Wave Velocity (crPWV) would be presented while measures of Augmentation Index (AIx) would remain the same. Seventeen older (61.1±4.0yrs), women without hypertension (SBP: 127.5±13.6mmHg, DBP: 77.7±8.1mmHg) completed this eight‐week unilateral (non‐dominant, left for all) training study. Women self‐reported high at‐home exercise adherence (96.9%) over the full eight weeks. Although maximal interval handgrip exercise training resulted in significant reductions to resting systolic blood pressure at both week4 (−5.7±7.7mmHg, p<0.05) and week8 (−5.1±7.7mmHg, p<0.05), vascular measures remained unchanged. Specifically, crPWV was unchanged for both the working (7.2±0.7 to 7.2±1.0) and non‐working (7.3±0.6 to 7.2±0.6) limbs. Also AIx was unchanged for both the working (32.4±6.2 to 33.1±6.6) and nonworking (33.7±5.9 to 33.0±6.9) limbs. In conclusion, post‐menopausal women completing eight weeks of maximal interval handgrip exercise training reduce their resting systolic blood pressure in the absence of alterations to local vasculature, ultimately suggesting that other mechanistic avenues may be more influential. Future research should confirm this speculation using alternative assessments of the vasculature including flow mediated dilation and ultrasound imaging of the vascular wall.Support or Funding InformationCanadian Institutes of Health Research, CGS Doctoral Research Award
Morphological Analyses of the Arterial Supply to the Brain
Authors: Kyle Emily G M , Hachinski Vladimir , Ramsay David A , Rogers Kem A 
Published: November 2023

IntroductionStroke is one of the leading causes of mortality and morbidity in North America. Specifically, lacunar infarcts – occurring within deeper cortical regions of the brain – account for up to 25% of all stroke incidence. These regions of the brain are supplied by short penetrating arteries (SPAs) that arise perpendicularly from their main arterial supply, such as the lateral lenticulostriate arteries which supply part of the basal ganglia. The penetrating arteries travel only a short distance before their systolic pressure must be reduced to capillary pressure. In contrast, the long circumferential arteries (LCAs) that supply the superficial cerebral cortex have a long course and oblique branching pattern, which permits a more gradual reduction in intraluminal pressure as the capillary bed is approached. This study compares the morphological design of the short vessels and the longer circumferential vessels to determine whether their structure reflects their different vascular pressure dynamics.ObjectiveThe objective of this study is to quantitatively assess the morphology of the SPAs and LCAs.MethodsHistological sections from the cortex, mammillary bodies and brainstem were stained with Masson's trichrome and scanned with an Aperio ScanScope AT Turbo at 40x. Using Aperio ImageScope, four arterial measurements were obtained from an average of 40 vessels per section: thickness of the tunica adventitia; combined breadth of the tunica intima and media; luminal diameter; and the arterial luminal circumference.ResultsThe preliminary results indicate that, in general, arteries at the brain base and adjacent to the brainstem (i.e., the SPAs) have a thicker tunica adventitia and a wider lumen as compared to the LCAs that supply the cortex. The ratio of tunica adventitia: tunica intima + tunica media is approximately 1.6 times higher for the basilar and rhombencephalic SPAs than the cortical LCAs. The ratio of luminal diameter: tunica intima + media is approximately 1.5 times higher for SPAs as compared to LCAs.ConclusionWe have demonstrated a reliable quantitative method to assess cerebral arteries and have shown clear differences between the morphology of the SPAs and LCAs. This method is now being used to investigate age‐related arterial changes and the relationship between vessel morphology and various diseases, including hypertension and whether or not there are lacunar infarcts.
Dysregulation of miRNA regulatory networks by chronic ethanol consumption impairs liver regeneration
Authors: Parrish Austin , Juskeviciute Egle , Hoek Jan B. , Vadigepalli Rajanikanth 
Published: November 2023

microRNAs are a class of small, non‐coding RNAs ~21 nucleotides long that regulate numerous cellular processes in a post‐transcriptional manner. Previous research has identified several microRNAs of interest involved in liver regeneration and hepatocellular carcinoma, including miR‐21, which has been shown by our lab and others to be significantly upregulated following liver damage by 70% partial hepatectomy (PHx); miR‐21 is further increased in animals undergoing PHx following ethanol adaptation. Given that different microRNAs can regulate multiple targets in any given pathway, we sought to identify additional microRNAs involved in liver regeneration alongside miR‐21. In order to accomplish this, we knocked down miR‐21 in vivo using a locked nucleic acid (LNA) probe containing a complementary sequence to miR‐21. Whole liver tissue samples were collected from both control‐ and ethanol‐fed Sprague‐Dawley rats at baseline conditions and 24 hours post‐partial hepatectomy. These samples were analyzed for microRNA expression using the NanoString microRNA microarray platform. Analysis of the expression data reveals seven microRNAs that show differential expression in response to miR‐21 knockdown. Of these genes, three show positive correlations with miR‐21 expression while four are negatively correlated. Using target prediction software, we developed a network of putative microRNA‐gene interactions and compared the predicted targets to genes identified as differentially expressed based on Affymetrix microarray analysis. This network of putative targets identifies a number of genes that are potentially regulated by these differentially expressed microRNAs. Gene ontology and pathway analysis reveals that multiple predicted targets are involved in processes relating to cell cycle progression. In conclusion, these studies identified a set of candidate co‐regulatory microRNAs whose dysregulation by chronic ethanol consumption may lead to impaired liver regeneration.Support or Funding InformationResearch was supported by the National Institutes of Health grants from National Institute on Alcohol Abuse and Alcoholism R01 AA018873, R21 AA022417, and T32 AA007463.
Epigenetic silencing of microRNA‐34a in human cholangiocarcinoma cells via DNA methylation and EZH2: Impact on regulation of Notch pathway
Authors: Kwon Hyunjoo , Song Kyoungsub , Han Chang , Zhang Jinqing , Ungerleider Nathan , Yao Lu , Wu Tong 
Published: November 2023

Aberrant expression and regulation of microRNAs (miRNAs) have been found in multiple cancers and their dysregulation importantly contribute to the tumorigenic processes. Among these miRNAs, miRNA‐34a (miR‐34a) functions as a tumor suppressor and its dysregulation has been reported in several cancers. In this study, we investigated epigenetic regulation and biological function of miR‐34a in human cholangiocarcinoma cells. Our data indicate that miR‐ 34a expression is epigenetically silenced in human cholangiocarcinoma cells (CCLP1, SG231, Hucct1 and TFK1) compared to the nonmalignant biliary epithelial cells (H69). Treatment of human cholangiocarcinoma cells with the DNA methylation inhibitor, 5′aza‐2′deoxycytidine (5‐ Aza‐CdR), or the EZH2 (enhancer of zeste 2 polycomb repressive complex 2) inhibitor, GSK126, enhanced the expression of miR‐34a. In parallel, knockdown of EZH2 by shRNA also significantly decreased miR‐34a expression in human cholangiocarcinoma cells. We further showed that DNA methylation and EZH2‐mediated histone H3 lysine 27 trimethylation (H3K27Me3) repressed miR‐34a gene expression, as determined by methylation‐specific PCR and chromatin immunoprecipitation, respectively. Functional analyses revealed that miR‐34a mimic decreased cholangiocarcinoma cell proliferation, colony formation and migration, in vitro. Moreover, we identified Notch1, Notch2 and Jagged 1, which are the major receptors and ligands of the Notch pathway, as miR‐34a target genes in cholangiocarcinoma cells. Accordingly, forced overexpression of miR‐34a significantly decreased the expression of Notch1, Notch2 and Jagged1, as determined by Western blotting and qRT‐PCR analyses. Our results provide novel evidence that miR‐34a expression is epigenetically silenced by DNA methylation and EZH2 in human cholangiocarcinoma cells. Thus, epigenetic induction of miR‐34a or miR‐34a replacement therapy may represent a novel therapeutic approach for the treatment of cholangiocarcinoma.Support or Funding InformationNIH R01 CA1023252 and R56DK077776
Epidermal Growth Factor Receptor (EGFR) Signaling: A Double‐edged Sword in Acetaminophen‐induced Liver Injury and Regeneration
Authors: Bhushan Bharat , Borude Prachi , Manley Michael W. , Chavan Hemant , Xie Yuchao , Du Kuo , McGill Mitch , Lebofsky Margitta , Jaeschke Hartmut , Kasturi Partha , Apte Udayan 
Published: November 2023

Epidermal Growth Factor Receptor (EGFR) signaling is known to play a crucial role in hepatocyte proliferation, but its role in liver injury has not been demonstrated. Its role in acetaminophen (APAP)‐mediated acute liver injury and subsequent liver regeneration is completely unknown, which was investigated in this study. Remarkable activation of EGFR was noted as early as 30 min after APAP treatment in mice and it remained activated up to 24 hr. Activation of EGFR was strikingly increased at higher, non‐regenerating, dose of APAP. Treatment of mice with an EGFR inhibitor (EGFRI), Canertinib, 1 hr post‐APAP caused robust inhibition of EGFR activation, resulting in striking reduction in APAP‐induced liver injury. APAP‐protein adducts formation and glutathione depletion were not altered indicating APAP metabolic activation was not affected by EGFRI. Further, APAP‐mediated JNK activation (a key mediator of APAP toxicity) and its mitochondrial translocation were not altered by EGFRI. However, EGFRI treatment reduced APAP‐mediated mitochondrial translocation of activated EGFR, nitrotyrosine protein adduct formation in mitochondria and blocked release of endonucleases from mitochondria, which are responsible for DNA damage and necrosis. Further, bioenergetics analysis with Seahorse Technology showed that EGFRI treatment rescued APAP‐mediated decreased mitochondrial function as indicated by restored mitochondrial coupling and maximal respiration. Whereas, treatment with NAC 4 hr after APAP in mice did not show any protection, treatment with EGFRI, 4 hr post‐APAP, showed remarkable decrease in liver injury. Treatment with Phorone (a glutathione depletory agent), standalone, also caused robust EGFR activation, whereas, replenishment of glutathione by N‐acetyl cysteine (NAC) treatment, 1.5 hr after APAP in mice inhibited APAP‐mediated EGFR activation, suggesting role of glutathione depletion after APAP overdose in activation of EGFR. EGFR activation was also observed in primary human hepatocytes after APAP treatment, preceding elevation of toxicity markers. Interestingly, delayed treatment with EGFRI, 12 hr post‐APAP, did not alter peak injury but caused remarkable impairment of liver regeneration response resulting in sustained injury and decreased survival after APAP overdose in mice. Impairment of liver regeneration was due to inhibition cyclin D1 induction and phosphorylation of retinoblastoma protein. In conclusion, our study has revealed an extremely novel role of EGFR both in development of APAP injury and in stimulation of subsequent compensatory liver regeneration after APAP overdose.Support or Funding InformationThis project was supported by grants from the NCRR 5P20RR021940‐07, NIDDK R01DK098414, NIEHS T32 ES007079 and Liver Scholar Award (Udayan Apte) by AASLD/American Liver Foundation
Soy Protein Diet Preserves Skilled Ladder Rung Walking Performance after Stroke Better than Isoflavones Alone in Adult and Aged Male Rats
Authors: Cheatwood Joseph L , Wallace Douglas G , Butteiger Dustie N , Banz William J 
Published: November 2023

Stroke injuries can reduce the ability of patients to perform daily activities like walking, eating, dressing, and other basic functions. Dietary interventions represent potential strategies for reducing the impact of strokes in people identified as being at enhanced risk due to lifestyle, genetics, previous stroke, or other factors. We have previously shown that young animals fed a semi‐purified diet containing soy protein isolate (SPI) experienced less disability after stroke than rats fed a diet containing caseinate (CAS). We hypothesized that the isoflavones daidzein and genistein, the two most abundant phytoestrogens in SPI, were likely mediating the observed benefits. To test this hypothesis, we utilized the same two diets (SPI and CAS) along with a third diet consisting of CAS plus added purified isoflavones daidzein and genistein (CAS + ISO) to match the isoflavone content of the SPI diet. Adult and aged male Long Evans Hooded rats were fed a semi‐purified diet containing either 1) SPI, 2) CAS, or 3) CAS+ISO. After two weeks on diet, rats were introduced to the skilled ladder rung walking task and baseline performance was recorded. Rats then underwent permanent unilateral middle cerebral artery occlusion (MCAO) to induce a stroke lesion (Day 0). After stroke, rats were maintained on the same diet and performance on the skilled ladder rung walking task was repeated on Day +3. At three days after stroke, both adult and aged rats fed the soy protein‐based diet exhibited significantly fewer forelimb slips than rats fed the caseinate‐based diet (p<0.05). This represents a significant reduction in the degree of forelimb impairment in the SPI diet group compared to the CAS diet group. The CAS+ISO diet affected adult and aged rats differently. In adult rats, performance on the walking task (best to worst) was a follows: SPI > CAS+ISO > CAS, but CAS+ISO was not significantly different than SPI or CAS (p>0.05). However, in the aged rats, no benefit of isoflavones was detected, as CAS+ISO and CAS rats exhibited significantly more slips than the SPI rats (p<0.05), and were not different from each other. The current results extend our previous findings that diets containing SPI as the sole protein source provides some protection from neurological damage following stroke in adult and aged rats. Although a portion of the SPI‐mediated neuroprotection in adult rats may be due to isoflavones, the contribution of isoflavones to this neuroprotection may differ between younger and older animalsSupport or Funding InformationNCCIH R15‐RAT006593A; Diet provided by DuPont Nutrition & Health