bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Lasting Effects of COVID‐19 on The Progression of Non‐Alcoholic Fatty Liver Disease
Authors: Backer‐Meurke Sean L. , Khanna Deepesh 
Published: May 2022

It is estimated that around 30% of the Western population has non‐alcoholic liver disease (NAFLD); a spectrum of pathology (not attributed to alcohol/substance intake) initiated by steatosis and progression towards inflammation and irreversible fibrosis (non‐alcoholic steatohepatitis, or NASH). With inflammation being a key component of the transition to NASH, it raises the question of whether the ongoing COVID‐19 pandemic, which has notoriously induced hyperinflammatory states, may influence the progression of NAFLD. Specifically, it remains unclear if potential chronic sequelae of COVID‐19 in recovered patients may increase predisposition for NASH. Since NASH maintains a high risk for hepatocellular carcinoma, liver failure, and need for liver transplant, potential additive effects of COVID‐19 could prove critical to study. Thus, the objective of this study was to conduct a literature review to examine if COVID‐19 could have chronic sequelae that affect the progression of NAFLD pathogenesis. It was hypothesized that severe cases of COVID‐19 could induce systemic inflammation, metabolic changes, and lasting gut microbiome alterations that lead to inflammatory and fibrotic changes of the liver, similar to those seen in NASH.A scoping review of literature was conducted utilizing the PubMed database. Studies that examined hepatobiliary pathology, gut microbiome, systemic inflammation, metabolic changes, drug‐induced liver injury, and hypoxia seen in COVID‐19 were included. Human studies of adult cohorts, animal models, and in vitro experiments were included. Genetic components of NAFLD were not examined. Exclusion criteria also encompassed any studies not referencing the hepatobiliary, GIT, portal system, or systemic circulation.Findings indicated a frequent trend of elevated liver enzymes, mild steatosis, Kupffer cell hyperplasia, and hepatobiliary congestion. It was found that direct cytopathic effects on hepatocytes was unlikely, but direct viral insult of cholangiocytes was a potential complication. High serum levels of IL‐1, TNF‐a, and MCP‐1, in COVID‐19 were found as potential risk factors for NASH development. Hypoxia, altered lipid metabolism, and iatrogenic drug‐induced liver injury were also proposed as potential precipitators of NASH development. Notably, lasting changes in gut microbiome were also frequently observed, and correlate closely with those seen in NASH.It was concluded that future research should target the gut microbiome, hyperinflammation, and hepatobiliary congestion as integral components of potentially accelerated NASH development NAFLD‐comorbid patients following COVID‐19 recovery.
Flavin binding affinity and initial kinetic characterization of DnmZ, a flavin‐dependent N‐oxygenase
Authors: Vaca Valerie , Huynh Katherine , Hinojosa Alejandra , Villanueva Molina Delmy , Palfey Bruce , Vey Jessica 
Published: May 2022

Doxorubicin is an anthracycline chemotherapeutic produced by Streptomyces peucetius. It is an effective chemotherapeutic but has severe side effects and high toxicity, and the details of its biosynthetic pathway are largely unknown. Baumycin is a derivatized form of doxorubicin with an additional seven‐carbon acetal moiety attached to the anthracycline backbone of the molecule. In this work, we report our progress on the characterization of DnmZ, a Class D flavin monooxygenase involved in formation of the baumycin acetal. DnmZ is a N‐oxygenase that oxidizes a sugar‐linked exocyclic amine, triggering a nonenzymatic retro oxime‐aldol cleavage of the hexose. We aim to characterize the kinetics of the DnmZ‐catalyzed reaction between flavin and oxygen using stopped flow spectrophotometry. Results from this research can aid in the development of derivatized anthracyclines and the understanding of the class of enzymes known as the class D flavin monooxygenases.Our transient‐state experiments confirm that DnmZ catalyzes the formation of the C4a‐(hydro)peroxyflavin intermediate (C4a‐OOH). We have identified the appropriate wavelengths to monitor to observe C4a‐OOH formation (378nm) and elimination (450 and 480 nm). With this information we have quantitated flavin binding and determined that DnmZ’s binding affinity for flavin is approximately 13 mM, which compares well with other Class D monooxygenases. Our preliminary results suggest that increasing pH speeds up C4a‐OOH elimination but has no effect on the intermediate’s formation. We are also investigating the effect of mutating active site residues on C4a‐OOH formation and elimination.
Chronic Unpredictable Stress Impairs the Reactivity of the Pudendal Artery and Corpus Cavernosum in Male Mice
Authors: Priviero Fernanda , Arishe Olufunke , Wilczynski Stephanie , Crockett Alexia , Hollis Fiona , Webb Clinton 
Published: May 2022

Erectile dysfunction (ED) can be associated with psychological disorders as well as vascular disorders. It is known that stress is associated with erectile dysfunction, however, it is not clear if psychological stressors could lead to a vascular and cavernosal dysfunction that could contribute to a vasculogenic erectile dysfunction. A recent study reported a positive correlation between hyperprolactinemia, stress and erectile dysfunction, and interestingly, prolactin was shown to decrease endothelium nitric oxide and endothelium‐ dependent vasorelaxation of aorta and coronary arteries. In this study, we aimed to evaluate the relaxation of the corpus cavernosum and pudendal artery of mice subject to chronic unpredictable stress (CUS). We hypothesize that CUS will lead to an impairment of the relaxation of the pudendal artery and corpus cavernosum leading to erectile dysfunction.MethodsMale C57Bl/6 mice were submitted to 28 days of chronic unpredictable stress (CUS). The pudendal artery and corpus cavernosum were removed and mounted in a myograph to evaluate reactivity. Tissues were kept in physiological salt solution at 37°C, constantly aerated with 95%O2/5%CO2 and concentration‐response curves to acetylcholine (ACh; 1 nM – 30 uM)) were obtained. Using non‐linear regression, we obtained the maximal response (Emax) and potency (pEC50) of ACh. Data are expressed as mean ± S.E.M. P<0.05 was considered statistically different.ResultsNeither the potency nor the maximal response to acetylcholine was changed in the pudendal artery of stressed animals (Fig. 1A) whereas in the corpus cavernosum, there was a significant decrease in the maximal relaxation induced by acetylcholine (control: 88 ± 4% vs stress: 75 ± 4%, n=7 each group; Fig. 1B).ConclusionOur findings demonstrate that CUS for 4 weeks impairs acetylcholine‐induced relaxation of the corpus cavernosum. This may contribute to the development of erectile dysfunction in stressed males.
PACER lncRNA Regulates COX‐2 Expression in Lung Cancer Cell Lines
Authors: Desind Samuel Z. , Iacona Joseph R. , Yu Christina Y. , Mitrofanova Antonina , Lutz Carol S. 
Published: May 2022

Long noncoding RNAs (lncRNAs) are known to regulate gene expression; however, in many cases, the mechanism of this regulation is unknown. One novel lncRNA relevant to inflammation and arachidonic acid (AA) metabolism is the p50‐associated COX‐2 extragenic RNA (PACER). We focused our research on the regulation of PACER in lung cancer. While the function of PACER is not entirely understood, PACER is known to play a role in inflammation‐associated conditions. Our data suggest that PACER is critically involved in COX‐2 transcription and dysregulation in lung cancer cells.Our analysis of The Cancer Genome Atlas (TCGA) expression data revealed that PACER expression is significantly higher in lung adenocarcinomas than normal lung tissues. Additionally, we discovered that elevated PACER expression strongly correlates with COX‐2 expression in lung adenocarcinoma patients. Specific siRNA‐mediated knockdown of PACER decreases COX‐2 expression indicating a direct relationship. Additionally, we show that PACER expression is induced upon treatment with proinflammatory cytokines to mimic inflammation. Treatment with prostaglandin E2 (PGE2) induces both PACER and COX‐2 expression, suggesting a PGE2‐mediated feedback loop. Inhibition of COX‐2 with celecoxib decreased PACER expression, confirming this self‐regulatory process. Significant overlap between the COX‐2 promotor and the PACER promotor led us to investigate their transcriptional regulatory mechanisms. Treatment with pharmacologic inhibitors of NF‐ϰB or AP‐1 showed a modest effect on both PACER and COX‐2 expression but did not eliminate expression. These data suggest that the regulation of expression of both PACER and COX‐2 is complex and intricately linked.
Irisin Improves Differentiation through Preserved Mitochondrial Function in Mouse C2C12 Skeletal Muscle Cells
Authors: Slate‐Romano John J. , Yano Naohiro , Kulthinee Supaporn , Wang Lijiang , Zhang Ling Zhang , Zhao Ting 
Published: May 2022

PURPOSEIn response to muscle contraction, irisin, a myokine released by skeletal muscle and white adipose tissue (WAT), is cleaved from the transmembrane protein fibronectin type III domain‐containing protein 5 (FNDC5) and has been shown to upregulate expression of uncoupling of protein 1 (UCP 1), inducing the browning of WAT. Prior research has demonstrated the protective role of irisin against insulin resistance, ischemic injury, and inflammation. We aimed to investigate the effects of Irisin on the differentiation of skeletal muscle myocytes.METHODSMouse C2C12 skeletal muscle cells were incubated in Dulbecco’s Modified Eagle Medium (DMEM) until cell confluency reached 60%. Once the plates reached 60% confluency, 2% Horse Serum was added to the medium to induce differentiation. The cells were incubated at 37 degrees C. and 5% CO2 for three days. Cells were then incubated in medium containing irisin at differing concentrations: 0 ng/mL, 10 ng/mL, and 20 ng/mL for an additional three days. Significance was established at p < 0.05. The number of myotubes were compared days three and six in each group. Immunofluorescent staining of actinin, myosin heavy chain, myocyte enhancing factor‐2C (MEF2C), and mitochondrial capture was performed for each group.RESULTSThe average number of myotubes per field for the no‐irisin group was 8.95 (+/‐ 7.85), compared to 13.6 myotubes (+/‐ 11.02 myotubes) in the 10 ng/mL irisin group and 30.5 myotubes (+/‐ 9.92 myotubes) in the 20 ng/mL irisin group. There was no statistical significance between the no‐irisin group and the 10 ng/mL group, however the number of myotubes in the 20 ng/mL group was statistically greater than both the no‐irisin group and the 10 ng/mL irisin group at p < 0.05.CONCLUSIONTreatment of C2C12 myocytes with irisin at 20 ng/mL concentration induced increased myotube differentiation. Irisin appears to play a significant role in muscle regeneration and growth.
The Role of Mitophagy in Quadriceps Atrophy after Non‐Invasive Anterior Cruciate Ligament Injury
Authors: Ahn Ahram , Davi Steven M. , White McKenzie S. , Lepley Lindsey K. , Kwon Oh Sung 
Published: May 2022

BACKGROUNDMany patients that suffer from anterior cruciate ligament (ACL) injury have persistent quadriceps atrophy even after considerable rehabilitation. Our previous finding has revealed that mitochondrial dysfunction and redox disturbances are causal events in the initiation of muscle atrophy and central to maintenance of a healthy mitochondria is the removal of damaged mitochondria through mitophagy. However, the extent to which mitophagy play a key role in quadriceps muscle atrophy after ACL injury has yet to be explored. If mitophagy is found to play a central role in directing muscle atrophy after ACL injury than it may be an attractive therapeutic target.PURPOSEUsing a pre‐clinical non‐invasive ACL injury model, our objective was to use a time course study to investigate the potential role of mitophagy in quadriceps muscle atrophy after ACL injury.METHODS48 Long Evans rats (n=8 per group; 4m/4f) underwent non‐invasive rupture of the right ACL and were euthanized at 7, 14, 28, 56 days post‐injury. 8 rats (4m/4f) served as healthy controls (HC). Mitophagy‐related cellular components of the vastus lateralis were analyzed by Western Blot analysis. One‐way ANOVAs with LSD post‐hoc were used to determine differences between groups (P < 0.05).RESULTSDynamin‐related protein 1 (DRP1), a protein regulating mitochondrial fission, was increased significantly at 56 days post‐injury [HC: n=8; 1.294 ± 0.364, 56D: n=7; 2.093 ± 1.519 (A.U), P<0.05]. Lysosomes are the terminal step in mitophagy and one of the lysosomal markers, Lysosomal‐associated membrane protein 1 (LAMP‐1) expression was significantly elevated at 56 days post‐injury [HC: n=8; 1.270 ± 0.840, 56D: n=8; 2.266 ± 1.137 (A.U), P<0.05]. Upstream autophagy marker, Beclin‐1 expression was also significantly increased at 56 days post‐injury (HC: n=8; 1.117 ± 0.339, 56D: n=6; 2.158 ± 1.274, P<0.05).CONCLUSIONCollectively, these results imply that long‐term ACL injury dysregulates mitochondrial quality control including key mitophagy markers, which contributes to ACL injury‐induced quadriceps atrophy. Therefore, targeting mitophagy may be the one of the potential therapeutic interventions to prevent muscle atrophy in patients with an ACL injury.
High Intensity Exercise Improves Cardiorespiratory Capacity in a Mouse Model of Hypertrophic Cardiomyopathy
Authors: Herrera Jonathan , Szczesniak Danielle , Szczesniak Kate , Goddard Rose‐Carmel , Yob Jaime , Day Sharlene 
Published: May 2022

IntroductionCardiorespiratory capacity (pVO2) is an important prognostic indicator in patients with HCM. Individuals with HCM that have a lower pVO2 possess a greater risk for heart failure (HF) and mortality. High intensity exercise (HIE) can increase pVO2 to a greater degree compared to other training modalities, including when used for cardiac rehabilitation for in cardiac disease states (e.g., HF and Cardiovascular disease). The effects of HIE on HCM, however, are largely unknown. Our study sought to evaluate the effects of High Intensity Interval Training (HIIT) on pVO2, as well as cardiac structural and functional parameters, in a preclinical mouse model of HCM.MethodsFemale and male C57BL/6J non‐transgenic nTG (n=27) and TG (n=32) mice were subjected to HIIT protocol that mirrored methods used clinically in cardiac rehabilitation. A single treadmill training session included 4‐4 minute high intensity intervals (~80% preVO2 max speed) interspersed by 5‐3 minute recovery intervals (~50% preVO2 max speed) for 31 total minutes. Exercise training sessions were repeated 3 times per week for 6 weeks. Pre and post pVO2 and murine echocardiography were measured and analyzed by a blinded technician.ResultsFollowing 6 weeks of the HIIT, nTG female (+13.5 mL/kg/min ± 3.6, p<0.01), nTG male (+13.5 mL/kg/min ± 3.6, p<0.01) and TG female (+7.06 ± 3.3 mL/kg/min, p<0.05) mice demonstrated an average increase in pVO2. A change in pVO2 observed in TG male mice did not reach statistical significance (+4.34 ± p=0.12). Sedentary female (‐15.9 mL/kg/min ± 3.3, p<0.001) and male (‐13.1 mL/kg/min ± 3.9, p<0.01) TG control mice experienced a significant decrease in pVO2 following the same period, while no change was observed in nTG sedentary controls. Independent of sex, nTG and TG HIIT mice had a significantly greater change in pVO2 compared to sedentary counterparts. HIIT training did not result in changes to the following echocardiography measures in either nTG or TG mice: LV mass, LA volume, cardiac output, or stroke volume.ConclusionOur results indicate that a translationally derived HIIT protocol improved cardiorespiratory capacity in a preclinical HCM mouse model, absent of adverse events or worsening of organ level disease pathology.
Effect of TTfields interference MARK2 on proliferation, migration and invasion of glioma cells
Authors: Duan Hubin , Hao Chunyan , Xue Wen , Li Mingli , Zhang Jinbao , Qiao Binjun , Chen Xianghui , Zheng Juan , Qiao* Xiaohong 
Published: May 2022

ObjectiveTo study the effect of tumor‐treating fields intervention on proliferation, migration and invasion of glioma cells by microtubule affinity regulated kinase 2 (MARK2).MethodsIn this study, a set of tumor treatment field device developed and improved by us was used to dynamically observe the mitosis of U251 glioma cells, as well as the effect of tumor treatment fields on the proliferation, migration and invasion of tumor cells. The changes in cell activity of tumor cells were evaluated by CCK‐8 and EdU experiments. The proliferation ability of tumor cells was evaluated by colony formation experiment, the invasion and migration ability of tumor cells was evaluated by scratch healing experiment and Transwell experiment, and cell apoptosis was measured by flow cytometry. Westem blot assay was used to compare the difference of MARK2 protein expression between tumor cells in tumor treatment fields intervention group and control group.Resultsthe results suggest that we developed a new device to dynamically observe the tumor cell mitosis, and also observed in tumor therapy fields affect tumor cell proliferation, migration and invasion, in addition to affect the mitosis, possibly by interfering with MARK2 expression, such as resist the tumor cell proliferation, migration, invasion, and promote the effect of tumor cell apoptosis.ConclusionTumor treatment fields may inhibit tumor proliferation, migration, invasion and promote tumor cell apoptosis by affecting mitosis and interfering MARK2 expression.
pQCT Analysis of Cortical Bone in Rats Exposed to High Levels of Cortisol in‐utero
Authors: Brown Sarah A. 
Published: May 2022

Unperturbed fetal development is essential for future health of an individual. Previous studies have linked diseases of aging to harmful alterations that happen during fetal development. Given the significant long‐term impact that intrauterine environment has on an individual's life, it was hypothesized that maternal stress during pregnancy will have negative effects on the offspring's bone density and cross‐sectional area. To test this, twenty‐eight female and seven male Wistar rats (Rattus norvegicus) were purchased and bred to produce 176 offspring. During pregnancy, dams were randomly divided into four groups (n=7, per group) and immobilization stress induced as follows; Group 1 (GW1): immobilization stress on days 1–7 of pregnancy, Group 2 (GW2): on days 8–14, Group 3 (GW3): on days 15–21, Group 4 (Controls): left undisturbed. Maternal cortisol hormone, food intake, and weight gain were monitored during pregnancy. Pups were raised under normal laboratory conditions and sacrificed at ages: 4, 8, 12, and 16 weeks to determine the effect of prenatal stress. At necropsy, the femur was removed and preserved for image analysis.Differences among groups were determined by T‐test or analysis of variance (ANOVA). P values ≤ 0.05 were considered significant. Cortisol hormone levels in controls were lower than those of stressed animals. Stressed dams consumed 12.5% less food per day compared to controls. Animals in GW1 and GW2 gained less weight during pregnancy but had larger litters than did GW3 or the control group. Offspring born to GW3 were heavier compared to all other groups. The femurs were scanned using the XCT Research SA+ peripheral Quantitative Computed Tomography (pQCT). Preliminary analysis of cortical bone shows the GW1 males as having a significantly lower cortical thickness compared to the controls at the age of 8, 12 and 16 weeks. The GW1 males also had a significantly lower periosteal perimeter and endosteal perimeter compared to controls at the age of 8 weeks. There was no significant difference in cortical thickness, periosteal perimeter and endosteal perimeter of females. This preliminary analysis shows that bone development in males was significantly impacted when fetuses in this study were exposed to high levels of cortisol in‐utero during the first week of gestation. Analysis of the remaining data is ongoing.
Inhibition of Hsp90 regulates fluconazole resistance in the pathogenic fungus Cryptococcus neoformans
Authors: Darrah Beka , Shah Dhriti , Chandrasekaran Srikripa 
Published: May 2022

Cryptococcus neoformans is an encapsulated yeast, found in the lungs of immunocompromised hosts. In the human host, Cryptococcusis subject to multiple forms of environmental stress, including heat stress. Heat shock protein 90 (Hsp90) is an essential protein that has been shown to protect fungal cells against extreme temperature in the human host and to assist in proper cell division. Hsp90 has also been implicated in resistance to the anti‐fungal drug fluconazole. To better characterize the role of Hsp90 in fluconazole resistance in Cryptococcuswe addressed two questions: 1. Does concomitant partial inhibition of Hsp90 and treatment with fluconazole lead to increased sensitivity to fluconazole and 2. Does prolonged partial inhibition of Hsp90 prior to treatment with fluconazole lead to subsequent increase in development of fluconazole resistance. Using growth assays, disk assays, and a standardized e‐test to determine the Minimum Inhibitory Concentration (MIC) of fluconazole, we found that indeed, pharmacological partial inhibition of Hsp90 with radicicol, concomitant with fluconazole treatment leads to increased sensitivity to fluconazole. However, initial pre‐treatment of Cryptococcuswith sub‐inhibitory concentration of radicicol followed by exposure to fluconazole leads to development of fluconazole resistant Cryptococcuscolonies. We characterized the resistant colonies, which show a lower MIC to fluconazole compared to cells that were never exposed to radicicol and fluconazole. Cells derived from the resistant colonies exhibit slower growth on drug‐free media, and lose resistance to the drug after passaging in drug‐free media.Based on the fact that resistance to fluconazole is lost when fluconazole is removed from the environment, we hypothesize that compromising Hsp90 function during the pre‐treatment with radicicol triggers aneuploidy in Cryptococcus neoformans. Furthermore, we hypothesize that the resistant colonies are aneuploids that possess an altered chromosome number to maintain drug resistance in response to an environmental insult, such as presence of fluconazole.