bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiac baroreflex sensitivity and heart rate variability are lower in humans with high affinity hemoglobin compared to typical affinity hemoglobin
Authors: Pruter Wyatt W. , Klassen Stephen A. , Dominelli Paolo B. , Wiggins Chad C. , Senefeld Jonathon W. , Roy Tuhin K. , Joyner Michael J. , Baker Sarah E. 
Published: May 2022

BackgroundHumans with high O2 affinity hemoglobin (HAH) have a markedly lower partial pressure of O2at which 50% of hemoglobin is saturated (P50) and a leftward shift of the oxy‐hemoglobin dissociation curve. Humans with HAH have attenuated heart rate responses during both acute and chronic hypoxic exposure relative to humans with typical P50. Despite the attenuated heart rate responses to hypoxia, there are typically no blood pressure differences found in humans with HAH relative to humans with typical P50. Due to the blunted heart rate and normal blood pressure responses to hypoxia in humans with HAH, this study aimed to investigate the impact of HAH on cardiac autonomic function during normoxia and hypoxia. We hypothesized that humans with HAH would have lower cardiac baroreflex sensitivity (cBRS) and heart rate variability (HRV) during normoxia and hypoxia relative to individuals with typical P50.MethodsNine humans with a HAH mutation (6 female, Age: 40±12yrs, P50: 16±1 mmHg) and 12 controls with typical affinity hemoglobin (6 female, Age: 40±10yrs, P50: 26±1 mmHg) laid supine for 10‐minutes prior to 20‐minutes of isocapnic hypoxia, titrated to reduce arterial O2 pressure to ~50 mmHg (Avg. FiO2 = 11.9±0.0%). Beat‐to‐beat arterial pressures (arterial catheter) and heart rate (electrocardiogram) were continuously recorded. Data were averaged in five‐minute segments starting with the last five minutes of supine normoxic rest. Spontaneous cBRS was quantified using the sequence method. HRV was measured in time and frequency domains. Standard deviation of the RR interval (SDRR) was calculated as the standard deviation of all RR intervals in a data segment. Low frequency (LF) HRV was calculated using Fast Fourier Transformation and assessed as absolute spectral intensity in the LF band (0.04‐0.15Hz).ResultsArterial oxygen (PaO2) and carbon dioxide (PaCO2) pressures were not different between humans with HAH and controls during normoxia or isocapnic hypoxia [PaO2: (HAH vs. Control): 48±3 vs. 47±2 mmHg, p=0.612; PaCO2: (HAH vs. Control): 40±3 vs. 39±1 mmHg, p=0.328] exposure. cBRS was lower in humans with HAH compared to controls in normoxia and throughout isocapnic hypoxia [normoxia (HAH vs. Control): 7±4 vs. 16±10 ms/mmHg; hypoxia minutes 15‐20 (HAH vs. Control): 4±3 vs. 14±11 ms/mmHg; Hb type, p=0.024]. Several metrics of HRV were lower in humans with HAH relative to control (SDRR: Hb type, p≤0.001; LF: Hb type, p=0.030) and HRV was blunted to a similar extent in both groups with hypoxia (SDRR: time effect, p=0.009).ConclusionThe findings of this study are twofold. Compared to controls, humans with HAH have: 1) attenuated cardiac baroreflex sensitivity and 2) lower heart rate variability in both normoxia and isocapnic hypoxia.
The Effect of Tauroursodeoxycholic Acid (TUDCA) Treatment on Pregnancy Outcomes and Uterine Artery Function in a Rat Model of Advanced Maternal Age
Authors: Pasha Mazhar , Kirschenman Raven , Wooldridge Amy , Spaans Floor , Cooke Christy‐ Lynn , Davidge Sandra T. 
Published: May 2022

IntroductionAdvanced maternal age (AMA; ≥35 years) increases the risk of pregnancy complications and adverse pregnancy outcomes such as fetal growth restriction. Endoplasmic reticulum (ER) and oxidative stress have been linked to vascular dysfunction (i.e. reduced nitric oxide [NO] & increased endothelin‐1 [ET‐1] levels) in aging. Tauroursodeoxycholic acid (TUDCA) is an ER and oxidative stress inhibitor and has been shown to improve embryo development in vitro. However, whether treatment with TUDCA can help improve uterine vascular function and pregnancy outcomes in AMA has not been investigated. We hypothesize that TUDCA treatment will improve pregnancy outcomes and vascular function in a rat model of AMA.MethodsYoung (4 months) and aged (9.5 months of age; ~35 years in humans) pregnant control or TUDCA‐treated rats were studied on gestational day 20 (term=22 days). Following euthanasia, pregnancy outcomes (litter size, resorption sites, fetal weight, and placental weight) were recorded, and main uterine arteries were isolated. Endothelium‐dependent vasorelaxation to methacholine (MCh) was assessed by wire myography in the presence/absence of pan NO synthase inhibitor (L‐NAME). In addition, big‐endothelin‐1 (bET‐1) vasoconstriction responses were evaluated, in the presence/absence of endothelin converting enzyme (ECE) inhibitor (CGS). Data summarized as maximum vasodilation response (Emax) and analyzed by two‐way ANOVA with Sidak’s post‐test, p<0.05 was considered significant.ResultsFetal body weights were reduced in AMA control rats compared to young dams (p<0.017), while TUDCA treatment tended to increase fetal body weight in AMA rats (p=0.067); TUDCA did not affect fetal body weight in the young dams. Placental weights, litter size and number of resorptions were similar in all the groups. The maximum relaxation (Emax) to MCh was impaired in the AMA dams compared to young dam (p=0.047), and this reduced relaxation was not evident in the TUDCA treated AMA dams. Ex vivo treatment with L‐ NAME showed an increased contribution of NO in young TUDCA treated rats (ΔEmax [differences in Emax]; p=0.043) compared to young control rats but not in AMA rats. Ex vivo treatment with CGS demonstrated reduced ECE conversion in young TUDCA treated rats (Emax; p<0.001), while CGS had no effect in the young control dams or both AMA groups.ConclusionOur study assessed TUDCA as an intervention to improve the pregnancy outcomes in a rat model of AMA. An increased fetal body weight suggests a beneficial effect of TUDCA in AMA pregnancies. However, contrary to our hypothesis, in young dams, TUDCA increased NO contribution and reduced ECE effect, but did not affect uterine artery function in AMA dams. Nevertheless, TUDCA has the potential to improve pregnancy outcomes in complicated pregnancies, but further studies are warranted.
Reversal chemotherapeutic resistance of triple‐negative breast cancer via functionally inhibiting RNA‐binding protein HuR
Authors: Wei Lanjing , Zhang Qi , Zhong Cuncong , Aubé Jeffrey , Welch Danny R. , Wu Xiaoqing , Xu Liang 
Published: May 2022

Chemotherapy remains the primary option for the systemic treatment of triple‐negative breast cancer (TNBC). However, chemoresistance frequently occurs with the conventional use of chemotherapeutic drugs, resulting in a poorer prognosis and a higher recurrence rate of TNBC than other subtypes of breast cancer. Therefore, overcoming chemoresistance is a critical challenge to conquer for the successful treatment of TNBC. The RNA‐binding protein Hu antigen R (HuR) is a posttranscriptional regulator. It can stabilize mRNA by binding to U‐ or AU‐rich elements (ARE) mainly in 3’ untranslated region (UTR) of mRNA and therefore upregulate the translation most of the time. The encoded proteins of HuR target mRNAs are implicated in multiple cancer hallmarks, including therapeutic resistance. The cytoplasmic accumulation of HuR is reported to contribute to chemoresistance in several types of cancer cells, and HuR inhibition sensitizes cells to chemodrugs. We hypothesize that inhibition of HuR function by disrupting its interaction with mRNA can accelerate the decay of target mRNA and thus reduce the translation level of proteins responsible for chemoresistance.Recently, our lab reported a small molecule HuR inhibitor, KH‐3, which potently inhibits HuR function by disrupting HuR‐mRNA interactions. In this study, we investigate the roles HuR played in the chemoresistance of TNBC and evaluate whether HuR inhibition by KH‐3 can enhances the chemotherapy efficacy. To determine whether HuR inhibition overcomes acquired chemoresistance of TNBC, two MDA‐MB‐231 cell sub‐lines resistant to docetaxel (231‐TR) or doxorubicin (231‐DR) were generated. Compared to the parental cell line, two sub‐lines exhibit similar sensitivity to KH‐3, and KH‐3 re‐sensitizes chemoresistant cells to docetaxel or doxorubicin in the MTT‐based cytotoxicity assay and the colony formation assay, indicating that HuR inhibition can overcome the acquired chemoresistance. The combination index suggests that the combination of KH‐3 with docetaxel or doxorubicin has a synergistic effect. The in vivo efficacy studies in both MDA‐MB‐231 and 231‐TR orthotopic xenograft mouse models confirm that KH‐3 synergizes docetaxel treatment. Mechanistically, several HuR direct target mRNAs implicated in chemoresistance were found upregulated in the resistant cells, which were reversed by KH‐3 treatment. The detailed molecular mechanisms of how KH‐3 sensitized TNBC cells to chemodrugs are being investigated. This research suggests that HuR inhibition is a promising strategy for overcoming chemoresistance in TNBC.
Effects of Various Body Positions on Arterial Stiffness as Assessed by Pulse Wave Velocity
Authors: Alhalimi Taha A. , Wang Tianyu , Meyer Michelle , Tanaka Hirofumi 
Published: May 2022

BackgroundStandard measurements of arterial stiffness via pulse wave velocity (PWV) are conducted with participants in the supine position. When participants cannot tolerate supine position for prolonged procedure time (e.g., low back pain), accommodations may be made to tilt the bed up or bend the knees (i.e., Fowler’s positions). Moreover, a new testing device (Vicorder) that uses neck oscillometric cuff requires upper body tilt to avoid jugular vein interference on the recorded carotid pulse. Accordingly, this study aimed to investigate the effect of varying body positions on arterial stiffness measured via PWV.METHODSA total of 70 adults (43 women) varying widely in age (19‐66 years old), race/ethnicity (41% non‐white), and medical conditions were studied. Both carotid‐femoral PWV (cfPWV) and brachial‐ankle PWV (baPWV) were measured using two different testing devices (Omron vp1000plus and Vicorder) with participants in the reference supine (0º) position, 10º, 20º, 30º, and 40º upper body tilted‐up positions with and without knee flexion. The presence of jugular vein interference was documented visually on the oscillometric arterial waveforms at each body angle.RESULTSBoth cfPWV and baPWV measured at 10º upper body tilt‐up position were not significantly different from those assessed at the reference supine (0º) position. Upper body angle of 20º or greater produced PWVs that were significantly and gradually elevated (p<0.01). The magnitude of elevations in cfPWV were 7% (95% CI [6‐11%]) at 20º and 15% (95% CI [11‐18%]) at 40º while the elevations in baPWV were 8% (95% CI [6‐10%]) at 10º and 33% (95% CI [30‐36%]) at 40º compared with the supine (0º) position. Knee flexion did not alter cfPWV compared with straight knees whereas knee flexion decreased baPWV at the same upper body angle (p<0.05). Jugular vein interference in the Vicorder device appeared on 78% of participants in the supine (0º) position and gradually decreased as the upper body angle increased, resulting in 7% of the participants at 30º angle. The appearance of Jugular vein contamination was not affected by knee flexion.CONCLUSIONArterial stiffness as assessed by cfPWV and baPWV increased gradually and significantly by the use of semi‐Fowler position of ≥20º whereas bending knees at each angle decreased baPWV, but did not appear to influence cfPWV. Our present findings highlight the difficulty in comparing two different devices that are supposed to reflect the same arterial property.
Silencing of NILCO by Small Interfering RNA Effects MDR1 in Colon Cancer Cells
Authors: Erkasap Nilufer , Gultekin Aysel , Ozyurt Rumeysa , Ozkurt Mete 
Published: May 2022

The aim of the study is to investigate the effect of silencing of NILCO by siRNA on the MDR1 gene, which plays a role in chemoresistance. Cells of the human colon cancer lines Caco‐2 and HT‐29 were cultured at 37˚C in DMEM supplemented with 5% FBS in a humid incubator with 5% CO2. Exponentially growing untreated Caco‐2 and HT‐29 cells were collected and plated (4 x 105/ well in 2 mL) 24 hours before transfection. Plated cells were treated with either double‐stranded siRNA targeting Notch1 mRNA, leptin mRNA, IL‐1 β mRNA, control siRNA, or Paclitaxel (PTX) alone, Notch1 siRNA+PTX, Leptin siRNA+PTX, IL‐1β siRNA+PTX. The siRNAs of Notch1, IL‐1β and Leptin, were applied to the cells at a final concentration of 30 nM, and the cells were transfected with siRNA for 48 hours. After transfection, 100 nM Paclitaxel chemotherapeutic agent for HT‐29 and 130 nM for Caco‐2 was applied to the cells. Cells were harvested for PCR analysis after treatment with PTX for 24 hours.According to our findings, MDR1 gene expression was significantly increased in the paclitaxel group compared to the control group (p<0.05). Silencing of Notch, leptin and IL‐1β decreased MDR1 gene expression compared with the control group, but it was not statistically significant. (p>0.05). However, our results indicated that Notch1 siRNA+PTX, IL‐1β siRNA+PTX and Leptin siRNA+PTX downregulated MDR gene expression in the Caco‐2 cell line compared with PTX alone treated group (p<0.01). In addition, MDR1 gene expression levels were significantly decreased in the Leptin siRNA+PTX and IL‐1β siRNA+PTX groups compared with PTX alone group in the HT‐29 cell line, but the decrease in the Notch1 siRNA+PTX group was not statistically significant. (p<0.01, p<0.05, p>0.05). In conclusion, knockdown of NILCO genes is effective in regulating MDR1 expression, which is a hallmark in chemoresistance.The present study was supported by Eskisehir Osmangazi University Scientific Research Projects (BAP) Coordination Unit (grant no. 202011D11).
Liraglutide as a Prophylactic Treatment for Sepsis Induced Lung Inflammation and Edema
Authors: Baer Brandon , Putz Nathan D. , Gibson Dustin , Toki Shinji , Peebles Stokes , Cahill Katherine N. , Bastarache Julie A. 
Published: May 2022

BackgroundThe severe lung dysfunction that characterizes acute respiratory distress syndrome is associated with excessive inflammation and edema. It occurs after an initiating insult to the lung, the most common of which being sepsis. As such, our research group has been investigating a glucagon‐like peptide‐1 (GLP‐1) receptor agonist, liraglutide, that inactivates NF‐κB, a transcription factor involved in the inflammatory response associated with sepsis.Hypothesisprophylactic treatment with liraglutide reduces lung inflammation and edema associated with a septic insult.MethodsWe pretreated C57/Bl6J mice two times a day with liraglutide (0.1mg/kg) or placebo (PBS) seven days prior to a two‐hit model of acute lung injury (cecal slurry induced polymicrobial abdominal sepsis and exposure to hyperoxia). To induce sepsis, an intraperitoneal injection of either 5% dextrose (control) or cecal slurry (2.4mg/g) was administered. Mice were then placed in a hyperoxia chamber (95%). At 6‐hours post cecal slurry injection mice were euthanized, a bronchoalveolar lavage (BAL) was performed, and lung tissue was collected. BAL was analyzed to measure protein content, leukocyte influx, and cell differentials. Wet‐dry ratios of lung tissue were also calculated.ResultsCompared to PBS and liraglutide treated sham mice, cecal slurry+hyperoxia caused an increase in markers of lung inflammation and edema. Septic mice pretreated with liraglutide had significantly decreased lung inflammation as measured the total number of inflammatory cells (2.2 vs 8.75 x 104 cells/ml; p<0.01; Figure 1) and neutrophils (0.33 vs 16.15 x 103 cells/ml; p<0.01) compared to untreated septic mice. Similarly, these septic mice also had significantly decreased lung edema as measured by wet‐dry ratios (4.15 vs 5.49; p<0.01) and protein content (285.52 vs 889.54 pg/ml; p<0.01).DiscussionThese results suggest that GLP‐1 receptor agonism attenuates sepsis and hyperoxia‐induced increases in lung inflammation and edema. Further, this data provides a strong rationale for additional studies, in other pre‐clinical models, to evaluate the potential of this receptor as a therapeutic target.
Biomarkers Indicative of Late Stage Alzheimer’s Disease Found in the Brain and Retina
Authors: Sein Than , Abram David , Bondarenko Vladimir 
Published: May 2022

PurposeAlzheimer’s Disease (AD) is a common neurological disorder affecting millionsof individuals worldwide, and therefore identification of retinal biomarkersfor a noninvasive diagnosis of the disease is critical to confirm the presence of this brain disorder.MethodsCryosections of brains and retinas from cadavers were analyzed. The structures of the brain specifically focused on were the prefrontal cortex (PFC), hippocampus, temporal lobe, visual cortex. Each tissue section was immunostained with antibodies against total tau (TT), phospho‐tau 181 (PT181), phospho‐tau 205 (PT205), and beta‐amyloid (BA). Every stained section was then microscopically analyzed to compare and contrast each marker using optical density (OD) measurements.Results2 cadavers without a history of neurodegenerative disease (1 male, 1 female) and 4 cadavers affected by AD (2 males, 2 females) were used. Retina samples of AD cadavers expressed a statistical significance increase in OD of the TT marker when compared to normal cadavers (AD = 0.37 OD ± 0.179, Normal = 0.01 OD ± 0.0049). In regards to the brain structures, only the TT markers in PFC were found to have statistical significant increases in OD value (AD = 0.28 OD ± 0.0621, Normal = 0.04 OD ± 0.0423). TT, PT181, PT205, and BA also expressed slight increases in OD in several brain structures of the AD cadavers but were not found to be statistically significant.ConclusionThere is a significant increase in the TT marker in the retina with similar findings in the PFC. This suggests that using TT as a marker in the PFC and retina has the highest potential to aid in diagnosing AD, with a possibility of studying the progression of AD through TT in different areas of the brain in future research.
Efficacy of Extracorporeal Shockwave Therapy on Knee Osteoarthritis Related Pain and Activities of Daily Living: A Systematic Literature Review
Authors: Baloy Rodiel Kirby L. , Campbell Eamon , Duong Allen 
Published: May 2022

PurposeExtracorporeal Shockwave Therapy (ESWT) is currently being marketed and advertised as a safe treatment alternative for various musculoskeletal conditions including osteoarthritis. There has been an increased interest in the use of ESWT as a noninvasive passive modality by physical therapists as an adjunct to holistic care. This literature review aims to look at the state of evidence among previous systematic reviews and randomized controlled trials examining the application of ESWT for pain and activities of daily living (ADL) outcomes for individuals with knee osteoarthritis (OA).MethodologySystematic literature searches for randomized controlled trials between 2010‐2021 were performed in the databases of PubMed, PEDro Database, Google Scholar, Cochrane Library, EBSCO between November 18 to December 8, 2021. A total of six randomized controlled trials (full text available, PEDro score > 6, and conducted in the past 11 years) with a total of 459 subjects met quality guidelines using the PEDro scale. There were 5 systematic reviews (full text available, inclusion criteria, pain and ADL outcome measures, and conducted in the past 11 years) with a total of 6922 subjects that met methodological guidelines.ResultsA total of 2682 articles were screened, and 6 studies with a total population of n = 459 were included in this review. With heterogeneity in frequency, dosage, and volume no meta‐analysis was conducted. There were statistically significant improvements reported in the use of ESWT in terms of pain and ADL outcomes associated with knee OA in 5 of the studies (n= 370). No clinically significant differences were found in the use of ESWT for knee OA related pain and ADL outcomes in 1 of the studies (n=89), and no studies found nil effects. The results suggest that in the management of symptoms related to knee OA, the use of ESWT has some effect on pain and activities of daily living outcomes.ConclusionsA review of current randomized controlled trials and systematic reviews presented some evidence for the use of ESWT in knee OA. While the use of ESWT may improve pain and ADL outcomes, further studies towards dosing and prescription is suggested.
Salivary Microbiota is Associated with Cannabis Use in Adolescents
Authors: Browning Brittney D. , Kirkland Anna , Liu Helen , Green ReJoyce , Ticer Taylor , Glover Janiece , Engevik Melinda , Squeglia Lindsay 
Published: May 2022

PurposeCannabis is now the second most commonly used substance during adolescence, with 35.7% of 18‐year‐olds reporting use in the past year and 6.4% reporting daily use. Accumulating evidence suggests that cannabis use affects the microbiome, however, this is still underexplored. Given that adolescence is a vital period of neural and microbial development, it is essential to investigate if cannabis use is associated with differences in microbiota as perturbations to microbial systems during this period of development may influence brain development.MethodsSaliva biospecimens were collected from adolescent (15‐19 years old) cannabis users (N=8) and control participants (N=9) in an ongoing clinical trial (K23 AA025399) at the Medical University of South Carolina. Bacterial quantification was performed by real‐time quantitative PCR (qPCR) using primers for representative oral phyla (Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria) and related species (Staphylococcus, Clostridium coccoides, Clostridium leptum, Lactobacillus, Escherichia coli, Bacteroides, and Prevotella). Standard t‐test was used to compare the relative abundances between the cannabis using group and control group. Correlations between levels of oral phyla and related species with cannabis use days reported on the Timeline Follow back (TLFB) and Cannabis Use Disorder Identification Test (CUDIT) scores were completed.ResultsAll saliva samples contained significant levels of bacterial gDNA (mean concentration: 96.9 ng/μl; ~10 ng/μl is sufficient). We observed significantly lower levels of Proteobacteria (p=0.031) and Bacteroides (p= 0.006) in the cannabis‐using group compared to the non‐cannabis‐using control group. Additionally, the number of cannabis use days reported on the TLFB and CUDIT scores were inversely correlated with Bacteroides levels (p= <0.001, p=0.011 respectively).ConclusionThese preliminary data suggest that cannabis use during adolescence may be associated with changes in the oral microbiota, specifically in Proteobacteria and Bacteroides. The lower abundance of Bacteroides in the cannabis using group is further strengthened by the inverse correlations between cannabis use days and CUDIT scores. Interestingly, Bacteroidesactively expresses GABA‐producing pathways, a type of inhibitory neurotransmitter pathway that studies have shown is inhibited by THC. In addition, ratios of Bacteroides from stool microbiota analyses have also been reported to be decreased in cannabis users. Therefore, saliva microbiota collection may serve as a favorable alternative to classic stool collection. Inclusion of more participants in future studies will allow for more power to detect microbial differences within adolescents who use cannabis.