bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long Term Hypoxia Reduces Ca2+ Wave Function In Basilar Arterial Myocytes of Fetal and Adult Sheep
Authors: Reid Casey , Romero Monica , Francis Michael , Taylor Mark S , Longo Lawrence D , Hessinger David A , Wilson Sean M 
Published: June 2021

Ca2+ entry through L‐Type channels mediate contraction of basilar arterial myocytes and whole‐cell Ca2+ waveforms are thought to be integral to this process. Based on previous evidence, we hypothesize that modifications, due to both long term hypoxia (LTH) and ontogeny, will affect the influence of depolarization on intracellular Ca2+ waves. Specifically, fetal arteries will have reduced Ca2+ signals while LTH will further reduce depolarization induced Ca2+ responses. In order to test this hypothesis, we examined Ca2+ wave activity using confocal fluorescence imaging techniques on basilar arterial myocytes in an en face preparation of low and high altitude fetal (FN, FH) and adult (AN, AH) sheep, where sheep were placed at 3,801 m for >100 days. Ca2+ waves were evaluated with and without 30mM K (30K), which was used to depolarize the myocytes. LTH decreased the area under the curve (AUC) independent of animal age. These changes in AUC were due to a faster decay in the Ca2+ signal. Depolarization with 30K increased Ca2+ wave amplitude and duration in all groups except for AH. These observations illustrate that both altitude and ontogeny play important roles in affecting various aspects of the Ca2+ signals. This likely contributes to the changes in arterial contractility that were previously observed with ontogeny and LTH and potentially other mechanisms pertaining to cerebral blood flow.Support or Funding InformationSupport from NIH and NSF
Anti‐MBG antibodies attenuate MBG‐induced anti‐proliferative and anti‐angiogenic milieu in cytotrophoblast cell model
Authors: Afroze Syeda H , Larrick James W , Wright Susan C , Drever Nathan N , Allen Steven R , Sharma Vikram , Mendelsohn Andrew R , Wages John M , Zawieja David C , Kuehl Thomas J , Uddin Mohammad N 
Published: June 2021

Preeclampsia (PreE) is a hypertensive pregnancy disorder, which occurs in approximately 10% of all gestations. Recently, a digitalis‐like factor, marinobufagenin (MBG) has been implicated as a causative factor in preE. We demonstrated that MBG inhibits the proliferation, migration, and invasion of cytotrophoblast (CTB) cells. We have identified a novel human monoclonal antibody with higher specificity than Digibind for MBG. We assessed the attenuation of MBG‐induced CTBs dysfunction by three anti‐MBG antibodies: 206–208, H1L2, and 3e9.MethodsA panel of anti‐MBG antibodies with potential as human therapeutic agents was developed by Panorama Research, Inc.; Sunnyvale, CA (206–208, H1L2). H1L2 was a humanized version of previously described anti‐MBG murine antibody 3e9. 206–208 was identified in a human phage antibody library. Human CTBs were treated with DMSO (vehicle) or 0.1, 1, 10 or 100 nM of MBG for 48 h. Some cells were pretreated with 206–208, H1L2, or 3e9 for 2h, while others were co‐treated with these antibodies prior to MBG treatment. Culture media were collected for analysis of pro‐angiogenic and anti‐angiogenic factors. Cell viability was measured using a CellTiter Assay kit. Cell lysates were utilized to evaluate the expression of proliferating cell nuclear antigen (PCNA) and p38 MAPK phosphorylation by western blot. Levels of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), soluble fms‐like tyrosine kinase‐1 (sFlt‐1), and soluble endoglin (sEng) were measured in culture media using ELISA kits. Statistical comparisons were performed using analysis of variance with Duncan's post hoc test.ResultsMBG down‐regulated PCNA and up‐regulated p38 phosphorylation in CTBs treated with ≥1 nM MBG compared to basal (DMSO treatment) (*p < 0.05 for each). Secretion of sFlt‐1 and sEng were increased, while VEGF and PIGF were decreased in CTBs treated with ≥1.0 nM MBG (*p < 0.05 for each). Both anti‐MBG antibodies pretreatment and co‐treatment significantly up‐regulated PCNA and down‐regulated p38 phosphorylation, and corrected the angiogenic profile of CTBs (p < 0.05 for each). The anti‐proliferative and anti‐angiogenic effects of MBG were not due to a cytotoxic effect, as evaluated by a cell viability assay. MBG at 0.1 nM had no effect.ConclusionsWe found that all 3 anti‐MBG antibodies attenuate MBG‐induced anti‐proliferative and anti‐angiogenic milieu in cultured CTBs. Here we describe for the first time two fully human anti‐MBG antibodies, which can be targeted as therapeutic agents for the development of innovative treatment strategies for preE and potentially other disorders involving aberrant MBG signaling.Support or Funding InformationNIH Small Business Innovation Research (SBIR) : 1R43HD079238‐01
Angiotensin Receptor Blocker ameliorates hyperlipidemia and increases lipid utilization in a rat model of metabolic syndrome
Authors: Garcia Jose Antonio , Lee Andrew , Ortiz Rudy 
Published: June 2021

CD36 and lipoprotein lipase (LPL) are essential proteins involved in lipid mobilization and triglyceride storage in various cell types, including adipocytes. Accumulation of excess lipids in non‐adipose tissues leads to cell dysfunction, potentially cell death, and ultimately insulin resistance. Furthermore, activation of the renin‐angiotensin system (RAS) is implicated in the manifestation of metabolic syndrome, for which dyslipidemia is an associated factor. To address our hypothesis that blockade of the angiotensin II receptor (AT1) can improve lipid utilization, we measured body mass, retroperitoneal mass, adipose lipase activity, CD36 and LPL expression in five groups of rats; 1) Long‐Evans Tokushima Otsuka (LETO) normal diet (ND) (n=6), 2) Otsuka Long‐Evans Tokushima Fatty (OLETF) ND (n=8), 3) OLETF high‐fat diet (HFD, 62% fat in food) (n=8), 4) OLETF + angiotensin receptor blocker (ARB) (10 mg olmesartan/kg/d 6 wk) (n=8), and 5) OLETF HFD + ARB (n=7). Body mass increased 38% in OLETF relative to LETO; ARB decreased it by 20% relative to OLETF, and HFD+ARB decreased it by 37% relative to HFD. ARB decreased retroperitoneal fat 16% in relation to OLETF, and ARB+HFD decreased it 72% compared to HFD. CD36 decreased in response to a HFD and lipase activity increased with ARB treatment. Results suggest that AT1 activation increases lipid utilization, therefore, ameliorating the development of hyperlipidemia from a high fat diet.Support or Funding InformationUC Leadership and Excellence through Advanced Degrees (UC LEADS) United States Department of Agriculture (USDA)
Bone as a buffer: Consequences for vertebrate design and anaerobic physiological performance
Authors: Warren Dan 
Published: June 2021

Conventional wisdom usually states that mineralized tissues are primarily used by vertebrates as sites for respiratory and locomotory muscle attachment or for physical protection from predators. Often ignored is the role these tissues play in maintaining ionic and acid‐base homeostasis and how this might have shaped vertebrate evolution. We have argued that this latter function may have been important in shaping vertebrate design in early tetrapods, particularly the maintenance of dermal armor in early tetrapods, and is still important for anaerobic physiological performance in many extant vertebrates, especially in reptiles and amphibians. We use physiological, biomechanical, and mineralogical approaches to understand how vertebrate bone, especially that of turtles, interacts with and is affected by extreme deviations in acid‐base homeostasis. Our work, and that of others, has shown that the mineral composition of turtle bone can predict tolerance to extreme acidosis, and that the most derived of these vertebrates, the anoxia‐tolerant painted turtle, is able to utilize calcium and magnesium carbonates within its bone to prevent lethal decreases in body fluid pH in the face of a 180 mM lactic acid load, with minimal effect on whole‐bone material properties.Support or Funding InformationThis work is funded by a CAREER Award from the National Science Foundation.
Self‐Organizing Actomyosin Patterns on the Cell Cortex at Epithelial Cell‐Cell Junctions
Authors: Neufeld Zoltan 
Published: June 2021

The behavior of actomyosin critically determines morphologically distinct patterns of contractility found at the interface between adherent cells. One such pattern is found at the apical region (zonula adherens) of cell‐cell junctions in epithelia, where clusters of the adhesion molecule E‐cadherin concentrate in a static pattern. Meanwhile, E‐cadherin clusters throughout lateral cell‐cell contacts display dynamic movements in the plane of the junctions. To gain insight into the principles that determine the nature and organization of these dynamic structures, we analyze this behavior by modeling the 2D actomyosin cell cortex as an active fluid medium. The numerical simulations show that the stability of the actin filaments influences the spatial structure and dynamics of the system. We find that in addition to static Turing‐type patterns, persistent dynamic behavior occurs in a wide range of parameters. In the 2D model, mechanical stress‐dependent actin breakdown is shown to produce a continuously changing network of actin bridges, whereas with a constant breakdown rate, more isolated clusters of actomyosin tend to form. The model qualitatively reproduces the dynamic and stable patterns experimentally observed at the junctions between epithelial cells.Support or Funding InformationThis work was supported by the National Health and Medical Research Council of Australia (1037320, 1044041, and 1067405), the Australian Research Council (DP120104667 and FT130100659), and the Kids Cancer Project of the Oncology Research Foundation.
The Role of Cell Contractility in Epithelial Morphogenesis
Authors: Nelson Celeste M. , Varner Victor D. 
Published: June 2021

Cell‐generated mechanical forces drive many of the tissue movements and rearrangements that are required to transform simple populations of cells into the complex three‐dimensional geometries of mature organs. However, mechanical forces do not need to arise from active cellular movements. Here, I will describe recent studies that have illuminated the roles of passive mechanical forces resulting from mechanical instabilities between epithelial tissues and their surroundings. These mechanical instabilities cause essentially one‐dimensional epithelial tubes and two‐dimensional epithelial sheets to buckle or wrinkle into complex topologies containing loops, folds, and undulations in organs as diverse as the brain, the intestine, and the lung. Our work suggests a new class of tissue development ‐ buckling or wrinkling morphogenesis ‐ and that this morphogenetic mechanism may be broadly responsible for sculpting organ form. Harnassing these mechanical instabilities represents an intriguing strategy for engineering organs ex vivo.Support or Funding InformationThis work was supported by grants from the NIH (HL118532 and HL120142) and the NSF (CMMI‐1435853).
Green tea extract lowers NFκB‐mediated inflammation during nonalcoholic steatohepatitis in mice fed a high‐fat diet consistent with reduced Toll‐like receptor‐4 signaling
Authors: Li Jinhui , Chitchumroonchokchai Chureeporn , Kim Joshua B. , Moller Meredith V. , Bruno Richard S. 
Published: June 2021

Green tea extract (GTE) reduces NFκB‐mediated inflammation and oxidative stress during nonalcoholic steatohepatitis (NASH). We hypothesized that its antiinflammatory activities that limit oxidative stress and liver steatosis would be mediated in a Toll‐like receptor‐4 (TLR4)‐ dependent manner. Wild‐type (WT) and loss‐of‐function TLR4‐mutant (TLR4m) mice were fed a high‐fat diet containing 0 or 2% (w/w) powdered GTE for 8 wk before assessing hepatic steatosis, oxidative stress, and NFκB‐mediated inflammation. TLR4m mice had lower (P<0.05) body mass compared to WT mice, but similarly high adipose mass, whereas body mass and adiposity were lowered by GTE regardless of genotype. GTE in WT mice reduced hepatic TLR4 and MCP‐1 mRNA, and protein levels of the phosphorylated‐p65 NFκB subunit, which were also lowered in TLR4m mice regardless of GTE. Oxidized:reduced glutathione and malondialdehyde were lowered by GTE in WT mice and similarly lowered in TLR4m mice regardless of GTE. Relative to WT mice, histological evidence of liver steatosis, hepatic triglyceride, and serum alanine aminotransferase were also lowered in WT mice fed GTE and these were similarly lowered in TLR4m mice regardless of GTE. However, GTE lowered lipogenic gene expression regardless of genotype, but their expression in TLR4 controls was unaffected compared to WT controls. TLR4m mice had reduced insulin resistance compared to WT mice, but GTE in WT mice lowered it to a greater extent by more substantially reducing fasting glucose. These findings suggest that GTE limits NFκB‐mediated inflammatory responses leading to liver steatosis and oxidative stress during NASH, consistent with a mechanism of reduced pro‐inflammatory signaling through TLR4/NFκB.Support or Funding InformationSupported by USDA‐NIFA and Ohio Agricultural Research and Development Center
Controlling the Rate of Energy Transduction in a Protein System Through Coupling Pathway Redesign
Authors: Wilson Corey J. 
Published: June 2021

Protein mediated energy transduction reactions are fundamental life‐processes that can be leveraged to produce novel bio‐electronic devices and advance our understanding of complex phenomena such as photosynthesis and cellular respiration. Energy transduction typically involves two fundamental reactions, electron transfer (EleT) and energy transfer (EngT). Thus, our ability to control (re‐design) the properties that influence EleT and EngT are of critical importance. In this study we used computational protein design to alter the coupling matrix, followed by complementary and extensive experimental characterization to study the role of the intervening medium between the acceptor and donor species during EleT and EngT reactions using the model system Pseudomonas aeruginosa azurin.Support or Funding InformationThis work was supported by NSF Award 1507385, to CJW
Comparison of the Effects of a Sweetened Beverage Intervention on Self‐Selected Food Intake
Authors: Widaman Adrianne M. , Stanhope Kimber L. , Chen Guoxia X. , Medici Valentina M. , Bremer Andrew A. , Lee Vivian , Nunez Marinelle V. , Havel Peter J. , Keim Nancy L. 
Published: June 2021

Evidence suggests that the intake of added sugar increases the risk of chronic disease and should be targeted for reduction. It is unclear if all types of added sugar have equivalent effects on food intake. This prospective, blinded intervention study compared parallel groups consuming one of five types of beverage sweeteners: glucose (GLU), fructose (FRU), sucrose (SUC), high fructose corn syrup (HFCS) or aspartame (ASP). The beverages were provided at ~25% of estimated energy needs for weight maintenance for 2 weeks and consumed along with the subjects’ usual diets. Before (week 0) and at the end (week 2) of the intervention, subjects were admitted to a metabolic ward and as inpatients participated in a day‐long protocol designed to measure ad libitum food and beverage intake from buffets offered at breakfast, lunch, and dinner. One hundred and thirty men and women with an average age of 26.3 ± 6.3 y and a BMI of 25.3 ± 3.6 kg/m2 participated. The changes in food and beverage energy intake (week 2 – week 0) were analyzed using ANCOVA, adjusting for BMI, sex, and energy intake at week 0. Energy intake was significantly affected by sugar (p=0.0026, ANCOVA), with subjects consuming SUC (386 ± 96 kcal, p=0.0011, Tukeys) or HFCS (242 ± 89 kcal, p=0.022, Tukeys) significantly increasing their intake at 2 weeks compared with subjects consuming ASP (−169 ± 100 kcal) and compared with their week 0 intake (p=0.0001 and p=0.0072, respectively). Buffet energy intake did not change significantly for the groups consuming GLU (p=0.198), FRU (p=0.064), or ASP (p=0.096) between weeks 0 and 2. Further analysis of the influence of sex on buffet intake showed that the increases in energy intake at week 2 were mainly attributable to men. Men consuming SUC (580 ± 137 kcal, p=0.0072, Tukeys) or HFCS (426 ± 123 kcal, p=0.047, Tukeys) significantly increased their energy intake at 2 weeks compared with men consuming ASP (−176 ± 143 kcal). In contrast, for women, there were no differences among groups, or between week 0 and week 2 buffet energy intake, regardless of the sweetened beverage assigned. In conclusion, we found that compared with aspartame, the caloric sweeteners, HFCS and sucrose, commonly used to sweeten soft drinks and fruit drinks, increased total energy intake during a day‐long buffet protocol offered in a controlled research setting. The effect of these sweeteners was more pronounced in men.Support or Funding InformationSupported by NIH 1R01 HL09133, 1R01 HL107256, RR024146, and K12 HD051958, and USDA Project 2032‐51530‐022
SIRT5 in cancer metabolic reprogramming
Authors: Lombard David B , Park Jeongsoon , Kumar Surinder 
Published: June 2021

The sirtuins are a family of NAD+‐dependent protein deacylases that regulate metabolism and other diverse aspects of cell biology. Three sirtuins (SIRT3, SIRT4, and SIRT5) are present in the mitochondrial matrix. SIRT5 is an inefficient deacetylase, instead removing succinyl, malonyl, and glutaryl groups from lysines of its target proteins. To provide insight into SIRT5 functions, together with Dr. Yingming Zhao's group, we previously carried out proteomics profiling of the cellular succinylome (Park et al., Mol. Cell 2013). This revealed potential impacts of succinylation on enzymes involved in diverse aspects of mitochondrial metabolism. We tested the impact of SIRT5 on two substrates identified in our studies, Pyruvate Dehydrogenase Complex (PDC) and Succinate Dehydrogenase (SDH). SIRT5 inhibited biochemical activities of both complexes, and suppressed overall mitochondrial respiration in the presence of glucose, pyruvate, and succinate.Metabolism in tumor cells is “reprogrammed” to meet the anabolic demands of uncontrolled cellular proliferation. Reprogramming of mitochondrial metabolism represents a key element of this metabolic rewiring. PDC and SDH are both implicated in neoplasia and cancer cell metabolic reprogramming. In particular, activation of PDC activity in cancer cells reverts tumor cell metabolism, inhibits malignant behavior, and induces apoptosis in diverse cancer types. Given the role of SIRT5 in regulating PDC and SDH, we hypothesized that SIRT5 might play a role in metabolic reprogramming in cancer. Our progress in testing this idea will be discussed.Support or Funding InformationNIH R01GM101171 and UL1TR000433, DoD OC140123, the Glenn Foundation for Medical Research, the John S. and Suzanne C. Munn Cancer Fund of the University of Michigan Comprehensive Cancer Center, and the University of Michigan Department of Pathology.
Preoperative Considerations for Teenagers Undergoing Orthopaedic Surgery: VTE Prevention, Mental Health Assessment, Vaping, and Drug Addiction
Authors: Shore Benjamin J. , Flaugh Rachel , Shannon Brett A. , Curran Patrick , Hogue Grant 
Published: June 2021

Introduction:
Adolescents undergoing pediatric orthopaedic surgery typically experience an uncomplicated postoperative course. However, adolescence represents a unique transition period from pediatric to adult physiology. As a result, the astute pediatric orthopaedic surgeon will be aware of unique medical and social scenarios which are relevant to adolescents during the perioperative course including the risk of venous thromboembolism (VTE), prevalence of mental health conditions, and rising use of electronic cigarettes or “vaping” to consume nicotine and cannibas.

Discussion:
Adolescents are at a greater risk of VTE after pediatric orthopaedic surgery. In particular, adolescent females with a family history of blood clotting disorders and those with a change in mobility after surgery should be considered for prophylaxis. The prevalence of adolescent mental health conditions including anxiety, depression, and behavioral issues is increasing in the United States. Higher levels of preoperative anxiety and the presence of mental health pathology are associated with slower recovery, higher levels of postoperative pain, and the increased likelihood for chronic pain. Several quick screening instruments are available to assess adolescents for preoperative anxiety risk, including the Visual Analogue Scale for Anxiety or the Amsterdam Perioperative Anxiety Information Scale. Unfortunately, electronic cigarettes have become increasingly popular for the consumption of nicotine and cannabis among adolescents. Preoperative use of combustive cigarettes (nicotine/cannabis) represents perioperative risks for induction/anesthesia, postoperative pain, and analgesia requirements and issues with delayed wound and fracture healing.

Conclusions:
VTE, underlying mental health conditions, and usage of nicotine and cannabis are clear detriments to the recovery and healing of adolescent patients following orthopaedic surgery. Therefore, standardized screening for adolescents before orthopaedic surgery is indicated to identify perioperative risk factors which have negative impacts on functional outcomes.
Radius Shaft Fractures—What Alignment is Acceptable at What Age? Plates or Flexible Nails?
Authors: Ho Christine A. 
Published: June 2021

Introduction:
The transition from pediatric to adolescent fractures can lead to uncertainty on what level of surgical correction is warranted as remodeling is limited in these older patients.

Discussion:
Adolescent diaphyseal radial shaft fractures present several unique challenges; the radial bow must be restored to preserve forearm rotation and there are several clinical scenarios where plating, even in the skeletally immature child, is strongly recommended and will have more reliable results over flexible intramedullary nails. In addition, judging how much angulation, rotation, and displacement will remodel in the older child can be a challenging decision, even for experienced pediatric orthopaedists.

Conclusion:
This overview discusses parameters for acceptable alignment in these fractures, when surgical fixation should be considered, and circumstances where plating should be considered over flexible nails.