bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationships between body roundness with body fat and visceral adipose tissue emerging from a new geometrical model
Authors: Thomas Diana Maria , Bredlau Carl , Bosy‐Westphal Anja , Müller Manfred , Shen Wei , Gallagher Dympna , Maeda Yuna , McDougall Andrew , Peterson Courtney , Ravussin Eric , Heymsfield Steven B.
Published: June 2021

Objective

To develop a new geometrically meaningful index that combines height, waist circumference (WC), and hip circumference (HC) and relate this index to total and visceral body fat.

Design and Methods

Subject data were pooled from three databases that contained demographic, anthropometric, dual energy X‐ray absorptiometry (DXA) measured fat mass, and magnetic resonance imaging measured visceral adipose tissue (VAT) volume. Two elliptical models of the human body were developed. Body roundness was calculated from the model using eccentricity.

Results

A body roundness index (BRI) was derived to quantify the roundness of an individual's body shape in a height‐independent manner. Body roundness slightly improved predictions of % body fat and % VAT compared to the traditional metrics of body mass index (BMI), WC, or HC. On this basis, ranges of healthy body roundness were determined based on previously established age‐dependent population ranges of % body fat.

Conclusions

Body roundness index, a new shape measure, is a predictor of % body fat and % VAT and can be applied as a visual tool for health status evaluations.
O‐GlcNAc Signaling Regulates Cancer Metabolism
Authors: Hsieh‐Wilson Linda
Published: June 2021

Cancer cells must satisfy the metabolic demands of rapid cell growth within a continually changing microenvironment. The dynamic post‐translational modification O‐linked β‐N‐acetylglucosamine (O‐GlcNAc) couples nutrient sensing to the regulation of many important signaling pathways. We recently discovered that O‐GlcNAc also serves as a key regulator of cellular metabolism itself and reprograms metabolic flux toward proliferative, pro‐survival pathways. Glycosylation was dynamically induced at Ser529 of phosphofructokinase 1 (PFK1) under hypoxic conditions in rapidly dividing cancer cells. Glycosylation inhibited PFK1 activity and redirected glycolytic flux through the pentose phosphate pathway, thereby conferring a selective growth advantage to cancer cells. Blocking glycosylation of PFK1 at Ser529 reduced cancer cell proliferation in vitro and impaired tumor formation in vivo. Our studies reveal a novel mechanism for the regulation of metabolic pathways and suggest a new therapeutic approach to combat cancer.
Activation of RelA (p65), but not of p50 dimers of nuclear factor kappa B (NF‐κB) is decreased in impaired renal function
Authors: Faustmann Gernot , Roob Johannes M. , Gruber Hans‐Jürgen , Hafner‐Giessauf Hildegard , Grabher Johanna , Tiran Beate , Winklhofer‐Roob Brigitte M.
Published: June 2021

The NF‐κB signaling pathway plays a central role in chronic inflammation and is an important interface between inflammation and oxidative stress. The heterodimer RelA (p65) ‐ p50 is the most abundant transcription factor of the NF‐κB family. Decreased activation of RelA has been found in different pathologies. The purpose of this study of the BIOCLAIMS project was to investigate the activation of both the RelA and p50 dimers in individuals with different stages of renal function. Peripheral blood mononuclear cells (PBMC) were collected from 362 study subjects with glomerular filtration rate (GFR, MDRD) of 18–123 mL/min/1.73 m2. Activation of NF‐κB dimers containing RelA and p50 was determined using an ELISA‐based assay (TransAM, Active Motif). Linear regression analysis showed that activation of RelA‐containing NF‐κB dimers decreased significantly with decreasing GFR (r = 0.171, P = 0.001), while activation of p50‐containing NF‐κB dimers increased significantly with decreasing GFR (r = − 0.148, P = 0.005). Antioxidant status, including plasma concentrations of vitamin C, α‐ and γ‐tocopherol and β‐carotene did not explain NF‐κB activation beyond kidney function. To our knowledge this is the first report on differential effects of impaired renal function on RelA and p50 activation. The underlying mechanisms of these findings need to be further elucidated.

Grant Funding Source: Supported by European Commission, FP7, contract 244995, and Austrian Government (bmwf).
Development of model systems for analysis of effects of cell‐cell and cell‐microenvironment interactions on pH regulatory proteins in breast cancer
Authors: Andersen Anne Poder , Ronnov‐Jessen Lone , Hulikova Alzbeta , Swietach Pawel , Pedersen Stine Falsig
Published: June 2021

When studying cancer development it is essential to employ models that recapitulate the tumor microenvironment (TME). We recently showed that truncated ErbB2 (ΔNErbB2) increases acid extrusion via the Na+/H+ exchanger NHE1 and the Na+,HCO3− cotransporter NBCn1 and increases NBCn1 expression in MCF‐7 breast cancer cells. Further, NHE1 inhibition strongly sensitized ΔNErbB2‐expressing MCF‐7 cells to chemotherapy‐induced death. Here, we explore the impact of specific aspects of the TME on pH‐regulatory and survival/motility signaling. Employing MCF‐7 cells +/− inducible ΔNErbB2 expression we show that: (i) TME simulation (pHe 6.5, 1% O2, 7.5 mM lactate) strongly increases Akt‐ and ERK1/2 phosphorylation/activity; TME mimicking conditions has no additional effect on NBCn1 expression but further increases ERK1/2 activity in ΔNErbB2+ cells (ii) in 2D coculture with primary human breast fibroblasts, MCF‐7 cells upregulate the lactate‐H+ cotransporter MCT1 and the epithelial‐mesenchymal transition (EMT) marker α‐smooth muscle actin; (iii) in MCF‐7 spheroids NHE1 expression and ERM‐ and Akt (S473) phosphorylation are greatly reduced compared to 2D monoculture, and pERM and apparently also NBCn1 localize to the spheroid periphery. In conclusion, the TME profoundly impacts on pH regulatory ion transporters and survival/motility signaling in MCF‐7 breast cancer cell models.

Funding: Danish Cancer Society, Danish Research Council
Using a diet and drug combination treatment prior to pregnancy to improve maternal health in rats
Authors: Reimer Raylene Alison , Eslinger Amanda Jane
Published: June 2021

Maternal obesity, before and during pregnancy, can program obesity risk in offspring. Glucagon‐like peptide‐1 (GLP‐1) is a satiety hormone stimulated by the prebiotic fiber, oligofructose (OFS). GLP‐1 is protected against degradation by the diabetes drug, sitagliptin. Our objective was to determine if treating maternal obesity in the pre‐pregnancy period with OFS and sitagliptin is more effective at reducing adiposity and improving gut microbiota profiles than either alone. Obese female rats (n=52) were randomized to 1 of 4 treatments for 8wk: 1) AIN‐93M; 2) OFS; 3) AIN‐93M+Sitagliptin; 4) OFS+ Sitagliptin. Reference groups were: high fat, sucrose (HFS, obese control), lean control, and caloric restriction (matched weight to gp 4). Rats were mated following treatment. Results showed: 1) Consumption of the HFS diet throughout pregnancy and lactation deteriorated maternal health with significantly increased adiposity and impaired glucose tolerance (P<0.05). 2) Whereas pre‐treating obesity with OFS and sitagliptin reduced maternal weight gain during pregnancy, rats that were calorically restricted showed excessive gestational weight gain. 3) The beneficial effects of OFS consumption on bifidobacteria and C. leptum numbers persisted throughout pregnancy and lactation. The significance of this work lies in identification of novel obesity treatments that could be used prior to conception and reduce the transmission of obesity risk to offspring. Funded by CIHR.
Shear stress reversal amplifies arteriogenesis in the mouse ischemic hindlimb model and augments a pro‐arteriogenic ICAM‐1hi/KLF2hi endothelial phenotype
Authors: Heuslein Joshua L , Meisner Joshua K , Blackman Brett R , Price Richard J
Published: June 2021

Femoral artery occlusion in the mouse leads to increased flow across all collateral arteries with some collateral segments also experiencing a reversal of flow direction. We have recently shown that these “flow reversal” segments exhibit an amplified arteriogenesis response (i.e. 22% and 33% diameter increases in “flow reversed” over “non‐reversed” segments by days 3 and 7, respectively) and a 4‐fold increase in pericollateral CD45+cells (day 3). Thus, we hypothesize that these “flow reversed” collateral segments could provide clues for how to amplify arteriogenesis therapeutically. To this end, we studied the expression of markers of a pro‐arteriogenic endothelial phenotype in response to an in vitro shear stress protocol mimicking the in vivo hemodynamics. We observed rapid endothelial cell repolarization and 30% increases in KLF2 (regulator of pro‐arteriogenic eNOS), eNOS, and ICAM‐1 (pro‐arteriogenic regulator of monocyte adhesion) mRNA expression in reversed conditions compared to non‐reversed. These results are consistent with the hypothesis that, when coupled with increased shear stress magnitude, the reversal of shear stress direction leads to enhanced arteriogenesis by activating KLF2 and ICAM‐1. Sources of research support: NIH HL098632 and AHA10GRNT3490001.
Fine tuning of the inflammaotry response by human deneddylase‐1/SENP8
Authors: Ehrentraut Stefan Felix , Campbell Eric L , Glover Louise E , Bowers Brittelle , Bayless Amanda J , Kelly Caleb J , Kominsky Douglas J , Colgan Sean P
Published: June 2021

Recent work has revealed a central role for neddylation (conjugation of a Nedd8 moiety) to Cullin‐proteins in the induction of NFκB (via Cullin‐1) and HIF (via Cullin‐2). Here, we elucidate the role of the human deneddylase‐1 (also called SENP8) in inflammatory responses in vitro and in vivo. Human microvascular endothelial cells (HMEC‐1) and HMEC‐1 lacking SENP8 (via lentiviral knockdown) were exposed to LPS or TNF and harvested for analysis of Cullin neddylation, NFκB activation and HIF‐1α stabilization. HMEC‐1 exposure to LPS significantly induced the neddylation of Cullin‐1 and increased NFκB transactivation. These responses were lost in cells lacking SENP8. Further analysis revealed that HIF‐1α protein was stabilized by LPS exposure in wild‐type cells but not in SENP8 knockdown cells. HIF promoter activity was increased following LPS compared to untreated controls. Pharmacological targeting of neddylation (MLN4924) abrogated NF‐κB responses, induced HIF‐1α promoter activity and reduced secretion of TNF‐α‐elicited pro‐inflammatory cytokines. The neddylation inhibitor MLN4924 stabilized HIF and abrogated pro‐inflammatory responses to LPS exposure in vivo. In conclusion, SENP8 is a proximal regulator of Cullin neddylation and fine‐tunes the inflammatory response. Pharmacological inhibition of Cullin neddylation may provide a viable therapeutic opportunity.

Funding: German Research Fund (EH 371/1–1), NIH grants DK50189, DK96491 and HL60569.
Cloning and expression of cryptochrome proteins from Arabidopsis thaliana and sunflower
Authors: Dyer James H , Velez Julian , Gonzales Christian
Published: June 2021

Two cryptochrome proteins, CRY1 and CRY2, occur in plants and animals. CRY1 regulates the circadian clock in a light‐dependent fashion in insects and plants. Also in plants, blue light photoreception can be used to cue developmental signals. Despite much research on the topic, the specific way that the pterin and flavin chromophores function in these proteins in Arabidopsis thaliana and other plants is still poorly understood. The goal of this research was to clone and express the Arabidopsis and Sunflower CRY1 and CRY2 proteins in an E. coli expression system. Consensus sequence primers flanking the complete coding regions of the two cryptochromes were made based on known sequences of other dicot plant cryptochromes. These primers will be used in a 5′—and 3′—Rapid Amplification of cDNA Ends protocol, and the complete CRY sequences will cloned into a pBAD‐His vector and purified using Ni‐NTA affinity chromatography. Purified proteins will be used for structural and functional analysis.
The Sialyltransferase, ST3Gal4, Protects Against Pressure‐Induced Cardiac Hypertrophy
Authors: Bennett Eric S , Deng Wei , Qi Jianyong
Published: June 2021

There are more than 40 types of human congenital disorders of glycosylation (CDG) characterized by a relatively modest but variable reduction in glycoprotein glycosylation that leads to dramatic multi‐system effects, including cardiac dysfunction. Nearly all CDG patients suffer from reduced protein sialylation. We sought to question whether and how reduced sialylation contributes to the observed cardiac symptoms that include dilated or hypertrophic cardiomyopathies. Trans‐aortic constriction (TAC) of a sialyltransferase knockout strain, ST3Gal4, that produces glycoproteins with fewer sialic acids attached was used to question whether ST3Gal4 expression protected against heart failure. Post‐TAC hypertrophy was observed in all mice, but survival and cardiac function of the post‐TAC ST3Gal4−/− mice were significantly compromised compared to wild type (WT) animals. Survival at one week post‐TAC was ~50% of WT (WT, 74%; ST3Gal4−/−, 38%), with ejection fraction (EF) and fraction shortening (FS) severely reduced (WT to ST3Gal4−/− in %: EF, 54 ± 2 to 29 ± 4; FS, 28 ± 1 to 14 ± 2), and ventricles and myocytes were significantly larger than WT. The calcineurin signaling pathway was upregulated in the ST3Gal4−/− ventricle. Together, the data suggest that ST3Gal4 gene deletion results in reduced protection against pressure‐induced hypertrophy and heart failure, likely through increased calcineurin activity.
Cryptosporidium spp. infection in breastfeeding mothers and their HIV‐exposed or unexposed infants in a peri‐urban community in northwestern Tanzania
Authors: Pedersen Sarah H , Wilkinson Amanda L , Andreasen Aura , Kinung'hi Safari M , Urassa Mark , Mkwashapi Denna M , Todd Jim , Changalucha John , McDermid Joann M
Published: June 2021

Globally, Cryptosporidium spp. is the most common diarrhea‐causing protozoan infection among children at health facilities. Infection may be asymptomatic or may manifest as severe, chronic diarrhea especially in malnourished or HIV‐positive individuals. Long‐term physical and cognitive impairment has been associated with infection. The objective of this study was to determine the prevalence of Cryptosporidium spp. infection among mothers and children from birth to 6 months, and to understand how breastfeeding practices relate to infection. This prospective cohort of 100 mother/infant pairs was conducted at a peri‐urban health clinic in northwestern Tanzania and 38% of infants were HIV‐exposed. Feeding/health questionnaires, anthropometrics and stool samples were obtained at Month 1, 2, 3 after birth. Approximately 1/3 of mothers had evidence of Cryptosporidium spp. at each visit; while infant infections did not appear until Month 3 when 11% were positive. These results indicate that mothers and infants are living in a Cryptosporidium spp. environment; however, infants remain uninfected until at least 3 months. Infection timing may be due to maternal immunological protection provided in utero, in breast milk and/or because exclusive breastfeeding eliminates the opportunity for exposure to contaminated food or water. Our ongoing research is focused on identifying mechanisms of protection and risk.

Grant Funding Source: Cornell University Unrestricted Grant
Investigation of in vitro inhibition of cytochrome P450 1A subfamily enzymes (CYP1A1/2) by polyphenols from coffee
Authors: Bouskela Alice , de Oliveira Ana C.A.X. , Paumgartten Francisco , Farah Adriana
Published: June 2021

It is suggested that dietary polyphenols play a protective role in the development of chronic diseases. Chlorogenic acids, mainly 5‐ caffeoylquinic acid, are the most abundant polyphenols in coffee, a largely consumed drink worldwide. Despite recent advances in the elucidation of their metabolism, it is still unknown whether they are substrates for the liver enzyme cytochrome P450 system. Knowing that the CYP1A1/2 play an important role in the biotransformation of flavonoids and other polyphenols, the purpose of this study was to investigate the inhibitory effects of 5‐ caffeoylquinic acid and other hydroxycinnamates from coffee on the activity of CYP1A1/2 in rat liver microsomes. Additionally, daidzein, hesperetin, naringin, quercetin and resveratrol, representing the major classes of polyphenols in foods, were tested for comparison purposes. The effects of the tested substances on the activity of ethoxyresorufin‐O‐deethylase and methoxyresorufin‐O‐demethylase, used as markers of CYP1A1 and CYP1A2, respectively, were determined in hepatic microsomes from Wistar rats treated with β‐naphthoflavone. Results showed that coffee polyphenols did not inhibit CYP1A1/2, which suggests that these substances are not substrates for them. All other polyphenols tested, except for naringin, showed clear inhibition on CYP1A1/2. Quercetin inhibition was particulaly potent (IC50 = 2.73 and 6.90 μM for CYP1A1 and CYP1A2, respectively), comparable to α‐ naphthoflavone (control).
Endothelial calcium signaling during leukocyte transendothelial migration
Authors: Weber Evan , Han Fei , Muller William A.
Published: June 2021

Leukocyte transendothelial migration (TEM) is a critical step in the inflammatory cascade and is regulated by a multitude of cellular signals. Leukocyte/endothelial PECAM‐PECAM interactions, targeted recycling of the lateral border recycling compartment (LBRC), and a transient increase in endothelial cytosolic Ca2+ (↑[Ca2+]i) are required for TEM. However, the sequentiality and coordination of these events is not known. Live cell imaging of BAPTA‐treated endothelial cells indicates that ↑ [Ca2+]i is not required for leukocyte adhesion or locomotion to the endothelial junction, but TEM is inhibited. Furthermore, if PECAM‐PECAM interactions are blocked to inhibit TEM, leukocytes adhere and migrate on endothelial cells without inducing a significant ↑ [Ca2+]i. Stimulation of the receptor operated Ca2+ channel TRPC6 in endothelial cells with a selective TRPC6 agonist can overcome an anti‐PECAM blockade to restore targeted recycling and TEM, suggesting that TRPC6 is a/the Ca2+ channel mediating the ↑ [Ca2+]i that is required for TEM. In preliminary studies, endothelial TRPC6 knockdown inhibits TEM. Taken together, our findings demonstrate that ↑ [Ca2+]i is downstream of PECAM‐PECAM interactions and upstream of targeted recycling in the pathway that governs TEM. Supported by an AHA Pre‐Doctoral Fellowship to EW, an AHA Postdoctoral fellowship to FH and NIH R01 HL046849 and R37 HL064774.
Smooth Muscle K+ Channels and the Modulation of Conduction in Cerebral Arteries
Authors: Samson Nina , Starreveld Yves , Watson Tim , Welsh Donald
Published: June 2021

Blood flow control is dependent on the initiation of electrical signals and their conduction along the arterial wall. The distance electrical phenomena conduct is primarily governed by gap junctions and membrane resistivity. In this study we determined whether changes in ion channel activity alter membrane resistivity, limiting electrical conduction. Middle cerebral arteries from Syrian hamsters were isolated, cannulated and studied under the standard conduction protocol. A focal KCl stimulus elicited a constrictor response that conducted robustly along the arterial wall with a decay constant of 0.484±0.036 μm/100μm vessel length. Manipulating the activity of large‐conductance Ca2+‐activated or voltage‐dependent K+ channels did not produce significant changes in conduction decay. Blocking and/or activating ATP‐sensitive K+ channels also failed to modify the conducted response. In contrast, Ba2+ blockade of inwardly‐rectifying K+ (KIR) channels augmented conduction decay (1.452±0.22 μm/100μm length), an effect attributed to the selective loss of negative slope conductance. In addition, experiments performed for the first time on human cerebral arteries displayed a similar increase in conduction decay in response to KIR inhibition. This study demonstrates that selective smooth muscle K+ conductances can tune electrical communication by retaining appropriate biophysical properties.
CK1 regulates NMDA receptor activity through protein phosphatase‐1 in hypothalamic presympathetic neurons in hypertension
Authors: Li De‐Pei , Pan Hui‐Lin
Published: June 2021

Increased NMDA receptor (NMDAR) activity in hypothalamic paraventricular nucleus (PVN) contributes to high sympathetic outflow in hypertension. However, the mechanisms underlying augmented NMDAR activity remain unclear. Here, we determined whether casein kinase 1 (CK1) and protein phosphatase‐1 (PP1) are involved in the regulation of NMDAR activity in hypertension. We recorded evoked NMDAR‐ and AMPA receptor (AMPAR)‐ excitatory postsynaptic currents (EPSCs) and NMDAR currents elicited by puff NMDA in spinally projecting PVN neurons in spontaneously hypertensive rats (SHR) and Sprauge‐Dawley (SD) rats. The basal NMDAR‐EPSCs and puff NMDAR currents were significantly higher in SHR than in SD rats. Pretreatment with the CK1ε selective inhibitor PF4800567 or the PP1 inhibitor tautomycetin alone significantly increased the ratio of NMDAR‐EPSCs to AMPAR‐EPSCs and puff NMDAR currents of PVN neurons in SD rats. PF4800567 did not further increase the ratio of NMDAR‐EPSCs to AMPAR‐EPSCs and puff NMDAR currents caused by tautomycetin in SD rats. However, treatment with PF4800567 or tautomycetin had no effect on the ratio of NMDAR‐EPSCs to AMPAR‐EPSCs and puff NMDAR currents in SHR. These data suggest that CK1 regulates NMDAR activity through PP1 in hypothalamic presympathetic neurons and that diminished CK1 activity may contribute to augmented NMDAR function and hyperactivity of PVN neurons in hypertension.
Role of MEK and RSK in Blood Pressure Regulation
Authors: Wongk Titus J , Carmichael Chabrian S , Nguyen Jenny H , Andresen Bradley T
Published: June 2021

A current hypothesis underlying Angiotensin II (Ang II) and norepinephrine (NE) mediated hypertension is that the extracellular regulated kinase cascade (MEK and ERK) is involved in phosphorylation of the regulatory myosin light chain (rMLC). However, the signal transduction is not fully elucidated. We hypothesized that in renal microvascular smooth muscle cells (RμVSMCs) MEK/ERK‐mediated phosphorylation of rMLC is through p90RSK, and this pathway contributes to hypertension. We utilized standard and PhosTag Western blots to measure Ang II and NE‐mediated phosphorylation of ERK, RSK, and rMLC in RμVSMCs. Additionally, CI‐1040 and SL 0101–1, which inhibit MEK and RSK, respectively, were utilized to interrogate this pathway. Simultaneously, an in vivo study was conducted to analyze the anti‐hypertensive effects of the MEK inhibitor CI‐1040 via regular tail cuff measurements. Osmotic minipumps were implanted in mice, delivering 1.0 μg/kg/min Ang II and 5 μg/kg/min NE. Two weeks after insertion of the pumps the mice were gavaged daily with 100 mg/kg of CI‐1040 for an additional 2 weeks. The molecular data suggest that the MEK/ERK/RSK pathway is involved in phosphorylation of rMLC, but contrary to previous studies the preliminary in vivo component failed to show a significant effect of CI‐1040 on blood pressure. TJW and this study were supported by the APS STEP‐UP program.
Effect of gravidity on jump performance and muscle physiology in the American locust
Authors: Carroll John P. , Kirkton Scott D.
Published: June 2021

The effect of gravidity (or load) on jumping is not well documented. Lizards produced shorter jumps when a load equal to 30% of body mass was attached. However in Schistocerca americana grasshoppers, 20% heavier gravid females have the same jump distance as non‐gravid females. We tested the hypothesis that grasshoppers increase their jumping muscle contraction duration when gravid (or loaded). We examined the effect of added mass on jump performance by attaching weights (20% or 40% of body mass) to gravid females, non‐gravid females, and males. We used high‐speed video analysis to compare jump performance and electromyography to measure jumping muscle contraction times. Results indicate that muscle contraction duration increased 20% from non‐gravid to gravid females. When an additional weight equal to 20% of body mass was attached, muscle contraction duration increased by over 30% for all grasshoppers. Further loading (40% of body mass) caused muscle contraction duration to increase 130% from un‐loaded controls in both males and gravid females, but it increased over 200% in nongravid females. These results suggest muscle contraction duration is proportional to load. Increasing muscle contraction time would allow grasshoppers to store more energy in their catapult mechanism prior to jumping, thereby allowing gravid females to have the same jump distance as non‐gravid females.
Breathlessness descriptors differ during constant load cycling in obese women with vs. without dyspnea on exertion
Authors: Bernhardt Vipa , Lorenzo Santiago , Moran Raksa B. , Bassett J. Todd , Haller Sarah F. , Pineda Jessica N. , Babb Tony G.
Published: June 2021

During constant load exercise, some otherwise healthy obese women experience dyspnea on exertion (+DOE), while others do not (−DOE). We investigated how the subjective quality of respiratory sensations differed between these groups. 80 women were categorized based on their Ratings of Perceived Breathlessness (RPB, Borg 0–10 scale) after 6 minutes of 60 W cycling. 34 women rated RPB ≥ 4 (+DOE) (34 ± 7 yr, 36 ± 5 BMI) and 24 women rated RPB ≤ 2 (−DOE) (33 ± 8 yr, 37 ± 4 BMI). 22 women with RPB = 3 were excluded to better delineate the groups. After exercise, subjects were asked to pick three of fifteen statements that best described their respiratory sensations. Descriptor data were analyzed as frequency statistics and compared using Fisher's exact test. The top descriptors chosen by +DOE women were “Breathing is heavy” (53%, p < 0.05), ”Breathing requires work” (50%), and “Breathing requires effort” (38%); −DOE women selected “I am breathing more” (82%, p < 0.05), “Breathing is rapid” (38%), and “Breathing is shallow” (38%, p < 0.05) most often (p values depict those descriptors that were different between groups). Not only is the intensity of breathlessness significantly different between these groups, but also the qualitative aspects of their breathlessness. +DOE women may have an increased sensation of the work of breathing than − DOE women, which may be related to the elevated RPB.

NIH HL096782, King Charitable Foundation Trust.
The anatomy of popliteomeniscal fascicles by dissections and MRI studies and their clinical significance
Authors: Ghosh Tamojit
Published: June 2021

Summary of results

PMFs or popliteomeniscal fibres attach the popliteal tendon to the lateral meniscus of the knee around its posterior horn. Popliteomeniscal fascicles (PMFs) were examined in 16 human knees by MRI scans and by arthroscopy and were found to be oriented superoposteriorly ( sPMFs) and and anteroinferiorly ( iPMFs) forming 2 distinct types of PMFs. MRI found sPMFs ( iPMFs) to be of three distinct patterns – Type 1 – attached to the superior part of the lateral meniscus as a clear band, Type 2 – unclear band of fibres much as in Type 1, Type 3 ‐ no band seen. In dissections the sPMF pass from the superomedial aspect of the popliteal tendon to the posterolateral corner of the lateral meniscus while the iPMF connect the anterior edge of the popliteal tendon to the lateral edge of the lateral meniscus. Using MRI scan orientations and grossly coordinating them with dissections, sPMF form the roof of the popliteal hiatus while the iPMFs form the floor. The popliteofibular ligament is attached more distally than the PMFs to the musculotendinous junction of the popliteal tendon and posteriorly to the head of the fibular behind the attachment of the arcuate popliteal and fabellofibular ligaments

Summary of conclusions

Most cases studied were clinical and came to orthopedic OPDs with snapping or locking of the knee as complaints. Arthroscopy and MRI scans of these knees found mostly Type 2 and Type 3 PMFs. These thus are the abnormal PMFs contributing to lateral compartment knee pain, snapping knee or locking knee scenarios. The evolution of the popliteal tendon also explains the orientations of the PMFs, popliteofibular ligament, cyamella (popliteal sesamoid) and the arcuate and fabellopopliteal ligaments

Grant Funding Source: Ministry of Health
Does The Phosphomannomutase pmm1 Functionally Compensate for Decreased pmm2 Expression in a Zebrafish model for PMM2‐CDG?
Authors: Steet Richard Anthony , Cline Abigail , Gao Ningguo , Flanagan‐Steet Heather , Lehrman Mark
Published: June 2021

Congenital Disorders of Glycosylation (CDGs) are rare diseases characterized by wide spectrum clinical abnormalities and impaired glycosylation. The most common CDG subtype, PMM2‐CDG, results from mutations in PMM2, which encodes the phosphomannomutase (pmm) enzyme that converts mannose‐6‐P (M6P) to mannose‐1‐P (M1P). We previously reported (Cline et al. 2012) a morpholino‐based PMM2‐CDG zebrafish model that exhibits defects consistent with PMM2‐CDG patients, including craniofacial defects and altered motor neurogenesis. In this model, pmm enzymatic activity could not be reduced below 30% of control, suggesting a second enzyme activity. Global N‐linked glycosylation and lipid‐linked oligosaccharide (LLO) levels were reduced, and the LLO deficiency was attributed to LLO destruction by accumulating M6P, the PMM2 substrate. Importantly, suppression of the M6P synthesizing enzyme, mannose phosphate isomerase, in the pmm2 background normalized M6P levels, partially rescued craniofacial defects, and abrogated pmm2‐dependent LLO cleavage. Here we investigate the expression and functional relevance of pmm1, a second enzyme reported to have pmm enzymatic activity. Overexpression of Pmm1 in pmm2 morphants increased net pmm activity two‐fold. Pmm1 expression also normalized biochemical and phenotypic parameters of pmm2 morphants.
c‐Jun N‐Terminal Kinase 1 (JNK1) Is Required for Coordination of Netrin Signaling in Axon Guidance
Authors: Qu Chao , Li Weiquan , Shao Qiangqiang , Dwyer Trisha , Guan Kunliang , Liu Guofa
Published: June 2021

The JNK family of MAPKs is involved in a large variety of physiological and pathological processes in brain development, such as, neural survival, migration and polarity as well as axon regeneration. However, whether JNK activation is involved in axon guidance remains unknown. Here, we provide evidence indicating the JNK pathway is required for netrin signaling in the developing nervous system. Netrin‐1 increased JNK1 in the presence of DCC or DSCAM, and the expression of both of them further enhanced netrin‐1‐induced JNK1 activity in vitro. Inhibition of JNK signaling either by expression of dominant negative MKK4, a JNK upstream activator, or a JNK inhibitor, SP600125, blocked netrin‐1‐induced JNK1 activation in HEK293 cells. Combination of the anti‐DCC function‐blocking antibody with introduction of DSCAM shRNA in primary neurons totally abolished netrin‐1‐induced JNK activation, while knockdown of DSCAM partially inhibited netrin‐1 effect. In the developing spinal cord, phospho‐JNK was strongly expressed in commissural axons before and as they cross the floor plate, and netrin‐1 stimulation dramatically increased the level of endogenous phospho‐JNK in commissural axon growth cones. Knockdown of JNK1 in ovo caused defects in spinal cord commissural axon projection and pathfinding. Our study reveals that JNK1 is important in coordination of DCC and DSCAM in netrin‐mediated attractive signaling.
Rapamycin Attenuates Cardiac Expression of Anti‐inflammatory AT2R and Anti‐Apoptotic MCL1
Authors: Arnold Nicholas , Somashekara Divyashree , Gul Rukhsana , Speth Robert , Pulakat Lakshmidevi
Published: June 2021

Angiotensin II (Ang II) receptor AT2R is a member of the vasodilative/anti‐inflammatory branch of renin‐angiotensin system (RAS). However, mechanisms underlying regulation of AT2R expression in cardiomyocytes are not understood. To determine how vasodilative insulin (INS) and anti‐inflammatory drug rapamycin (Rap) modulate AT2R expression, we performed radioligand binding experiments with 125I‐CGP42112A, an AT2 specific ligand, on mouse atrial cardiomyocyte HL‐1 cells. INS (100nM, 12h) increased expression of functional AT2R that binds 125I‐CGP42112A by 2.2 fold (P<0.05). Co‐treatment with Rap (10nM) attenuated this effect. Our in silico and in vitro studies showed that the AT2R is a target for the diabetic marker microRNA miR‐29 family. Expression levels of miR‐29a, b and c in HL‐1 cells were suppressed by INS and elevated by Rap (~3 fold; P<0.05). Moreover, transfection of HL‐1 cells with miR‐29 mimics reduced 125I‐CGP42112A binding and suppressed insulin‐induced increases in AT2R protein (P<0.05). Immunoblotting showed that Rap also suppressed miR‐29 target Mcl‐1, an anti‐apoptotic gene that promotes cardiomyocyte survival following ischemia‐reperfusion. Collectively these data show for the first time that Rap, a widely used anti‐inflammatory drug, attenuates cardiac expression of AT2R and Mcl1 and up‐regulates miR‐29 family that may promote cardiac INS resistance.
Impact of including no beverage control in detecting statistical differences between a test beverage containing fiber and fiber free, isocaloric placebo beverage when measuring next meal energy intake and satiety perception in a randomized, controlled, crossover human study
Authors: Park Sonhee , Scott Robert , Re Roberta , Hull Sarah
Published: June 2021

Satiety effects of a beverage with partially hydrolyzed guar gum (PHGG: 3.7 g/330 ml; 7.4 g/d) were assessed in a randomized, controlled, crossover study. Two controls were used in this study: a PHGG free, isocaloric (Placebo) and a no‐beverage control (NBC) to examine the impact of NBC in detecting differences between PHGG and Placebo. Thirty‐two healthy subjects consumed 1st serving with the fixed breakfast and the 2nd as a mid‐morning snack drink for 2 wk (with a 2‐wk washout). Satiety was measured by Visual Analogue Scale (VAS) and next meal energy intake before and after the 2‐wk adaptation. Energy intake data were analyzed via paired T‐test and VAS scores using analysis of variance (ANOVA), modelfit via F‐test and stepwise multiple regression. NBC significantly reduced satiety perception and increased next meal intake than Placebo and PHGG. PHGG showed significantly higher satiety perception than Placebo. Additional statistical analysis was conducted, comparing 2 arms without NBC even if complete removal of the impact of NBC in the study design is impossible. In general, the p‐values were lower following the two arm analysis, increasing statistical significance of the satiety perception from PHGG compared to Placebo due to a reduction in “background noise” in the data by excluding NBC arm, but there was no major impact in detecting statistical differences between PHGG and Placebo. Funded by The Coca‐Cola Company.
Comparison of the effects of Chemical Composition, Processing and Food Form on the Satiety of Barley
Authors: Aldughpassi Ahmed , Wolever Thomas , Elsayed Abdelaal
Published: June 2021

Low glycemic index (GI) diets have been promoted for weight maintenance due to their effect on satiety. Barley, a low‐GI cereal has been suggested as a satiety inducing food. Recently a number of barley cultivars have been developed for consumer uses and it has been shown that differences in chemical composition, food processing and food‐form affect glycemic responses, but the effect on satiety is not known. To investigate these factors nine cultivars varying in the nature of starch and β‐glucan were studied in two experiments in separate groups of 10 subjects. Satiety was measured by visual analog scales over two hours, satiety area under curve (AUC) and satiety index (SI) were calculated. Experiment 1: seven cultivars were tested with one undergoing four levels of pearling ranging from Whole Grain (WG) to White Pearled (WP). There were no differences in satiety AUC among cultivars or compared to white bread (WB) (AUC WB = 4774 ± 478 mm vs. AUC highest cultivar = 7518 ± 564 mm, P = 0.45) nor differences in SI (P = 0.77). Similarly pearling did not have an effect on satiety (P = 0.99). Experiment 2: WG and WP of 2 cultivars varying in total fiber were made into wet pasta. Compared to WB, high fiber barley pasta had a higher satiety AUC (P = 0.007) but not the low fiber barley pasta (P = 0.33). In conclusion, Food form may affect satiety; however these results do not support the hypothesis that inducing satiety is part of glycemic‐index mechanism.

Grant Funding Source: CHIR
Association of Apop gene polymorphism with obesity related phenotypes in Japanese population
Authors: Okuno kumiko , Tsuji Kumiko , Yasuda Osamu , Masaki Shiho , Tanino Norikazu , Katsuya Tomohiro , Akasaka Hiroshi , Rakugi Hiromi , Fukuo Keisuke
Published: June 2021

Background

Previous gene polymorphism studies have suggested that proteins modulating mitochondrial function are implicated as diabetogenic candidates. Here, we show that the gene polymorphism of apoptogenic protein (Apop), a novel mitochondrial protein which nuclear‐encoded gene was up‐regulated in atherosclerotic lesions (J Biol Chem. 2006;281(33):23899–907), is associated with phenotypes related with obesity in Japanese population.

Methods

1,517 Japanese subjects (60.8% women) were genotyped using TaqMan PCR method for the rs12889403 SNP in the Apop gene. We measured anthropometric indexes such as blood pressure, waist circumference and BMI in these subjects and the association between the rs12889403 SNP and these measurements was analyzed in the cross‐sectional analysis.

Results

We found that subjects with carriers of the T allele had significantly higher BMI (p=0.004), waist circumference (p=0.016) and diastolic blood pressure (p=0.020) compared with subjects with non‐T carriers. Additionally, subjects with the T allele younger than 65 years‐old had significantly higher serum insulin levels (p=0.040) as well as BMI (<0.001) and waist circumference (p=0.020) compared with subjects with non‐T carriers.

Conclusions

We suggest that a SNP (rs12889403) within the Apop gene is associated with obesity‐related phenotypes in Japanese subjects.
Profiling di‐ and tri‐glyceride species in weight‐controlled mice may be associated with cancer preventive mechanism
Authors: Standard Joseph , Jiang Yu , Su Xiaoyu , Welti Ruth , Wang Weiqun
Published: June 2021

Weight control by dietary calorie restriction (DCR) or exercise has been shown to prevent cancer in a mouse skin cancer model. However, the mechanisms are not well defined. Lipidomics using electrospray ionization MS/MS system was employed in this study to profile triglyceride (TG) and diglyceride (DG) species in both murine skin and plasma samples. CD‐1 mice were randomly assigned into 4 groups: ad lib‐fed sedentary control, ad lib‐fed exercise (AE), exercise but pair‐fed at isocaloric diet of control (PE), and 20% DCR. After 10‐wks, body weight and body fat composition significantly decreased in the groups of DCR and PE but not AE when compared with the controls. DCR had the lowest levels of TG species for both plasma (16:0, 18:0, 18:1) and skin tissue (18:1, 18:3, 20:4). While DCR had the lowest amount of total DG for skin tissues, it was the richest in longer, polyunsaturated species (16:0/20:2, 16:0/20:4, 18:0/20:3, 18:1/20:4). PE had a lowering effect in TG species for both plasma and skin. PE was also the lowest in total plasma DG levels. DCR may have a stronger effect in lowering TG levels, but both forms of weight control were effective in reducing TG and DG levels. This new approach of profiling TG and DG species provides novel insight of information that may lead to understanding of weight control's mechanisms for cancer prevention (supported by NIH CA167678).
Effects of cayenne pepper on antioxidant enzyme activity in DSS treated rats fed an atherogenic diet
Authors: Baca Kyrie Lyle , Plumlee Deva , Hong Mee Young
Published: June 2021

There is a need in nutritional research to discover functional foods that may help to reduce the risk of chronic diseases, such as CVD, the number one cause of morbidity and mortality among all adults in the United States. We have previously shown that a cayenne pepper diet improves the lipid profile in atherogenic diet fed rats. The goal of this study is to determine the underlying mechanism of cayenne pepper on antioxidant enzyme activity in DSS treated rats fed an atherogenic diet.

Forty male weanling (21 days old) Sprague‐Dawley rats were divided evenly into four groups (10/group, total N=40) in a 2 (diet) × 2 (treatment) factorial design using an atherogenic diet with or without cayenne pepper (2.9%) for 30 days, and with or without 3% Dextran sodium sulfate (DSS) inflammation inducing agent for 24 hours. Cayenne pepper‐fed rats had significantly increased serum Superoxide dismutase (SOD) (P<0.001), CAT (P=0.034), GST (P<0.001), and GPX (P<0.001) activities. Total antioxidant capacity was greater in cayenne pepper groups (P=0.011). These findings support the use of cayenne pepper in increasing antioxidant enzyme activity to reduce the risk factors of CVD and associated comorbidities.

Supported by SDSU UGP and NUTR 302L class.
Development of a multimodal technology‐based coaching program for use in the GOG national diet and activity trial of ovarian cancer survivors
Authors: Marshel Larissa J. , Crane Tracy E. , Scott‐Fleming Colin A , Merchant Nirav C , Alberts David S , Thomson Cynthia A
Published: June 2021

Background

An estimated 22,420 women are diagnosed with ovarian cancer in the U.S. annually; survival after diagnosis is poor. Epidemiological association studies suggest that a plant‐rich, low‐fat diet and moderate physical activity may enhance survival. Previously, telephone‐based interventions have proven successful for health behavior change in breast cancer survivors. Efforts to design similar platforms with expanded technological approaches are needed to target cancer survivors.

Methods

A web‐based coaching and coordinating platform was developed for the trial to facilitate telephone‐based coaching for 1,070 participants and communication with their respective clinic sites (n=133+ nationally).

Results

The program uses Drupal software and interface with Twilio, email and forums. In addition to coaching capacity, the software hosts videos, call scheduling, coaching reference material access, and web‐forms. An estimated 400 participants are expected to enroll annually; survivors will complete a 24 month period of trial participation.

Conclusions

The LIvES web‐based coaching intervention represents a novel product for delivery and case management of a large‐scale technology based behavioral intervention.

Funding:

GOG, NOCC, Up the Volume and the U of A Canyon Ranch Center for Prevention & Health Promotion
Improvement of p‐cymene antinociceptive effect by inclusion in beta‐cyclodextrin
Authors: Junior Lucindo Jose Quintans , Quintans Jullyana SS , Menezes Paula P , Santos Marcio RV , Bonjardim Leonardo R , Araujo Adriano AS
Published: June 2021

We demonstrate analgesic‐like property of p‐cymene (PC), a monoterpene. However, short half‐life is a limitation for PC application. Several approaches have been used to improve monoterpenes pharmaceutical properties, including the employment of drug‐delivery systems. Here we used p‐cymene/β‐cyclodextrin (β‐CD) complex and p‐cymene (PC) isolated to evaluated if the complex formulation is able to improve the antinociceptive activity of this monoterpene. Experimental protocols were approved by the Animal Care and Use Committee at UFS/Brazil (CEPA#19/11). Male mice (26–30g) were pretreated with PC/β‐CD (40 mg/kg, p.o.), PC (40 mg/kg, p.o.) or vehicle (distilled water), 0.5h before acetic acid induced abdominal writhing test and antinociceptive effect was evaluated at time: 0.5, 1, 2, 4, 8, and 16 h after treatment. We evaluated analgesic‐like effect of PC/β‐CD and PC in hot‐plate test at the same time of writhing test. The data were analyzed by ANOVA (two‐way) followed by Tukey's test (p<0.05). Our results demonstrated that acute treatment with complex PC/β‐CD produced an antinocicepitve effect (p<0.01 or p<0.001) for 8 h followed while isolated PC produced same effect for 2h. Similar results was obtained in hot‐plate test, PC/β‐CD, all doses, significantly reduces (p<0.01 or p<0.001) nociceptive behavior for 8 h while isolated PC for 1h, only higher dose. Such results were unlikely to be provoked by motor abnormality. Our results provide evidence to propose that complex with β‐CD improved analgesic effect of p‐cymene.

Financial support:

FAPITEC/SE/Brazil and CNPq/Brazil.
Vasopressin affects renal tubular dynamics during hemorrhagic shock resuscitation
Authors: Uyehara Catherine FT , Sarkar Joy , Murata Lee‐Ann M , Sato Aileen K , Ichimura Wayne M , Hernandez Claudia A , Allen Christopher L
Published: June 2021

Novel roles of cardiovascular regulating hormones in severe hemorrhagic shock may be differentiated by their affect on renal function when used as pressor agents during resuscitation. We thus investigated whether vasopressin (VP), norepinephrine (NE), or phenylephrine (PE), differentially affect renal fluid handling when restoring mean arterial pressure (MAP) after acute rapid hemorrhage (34 ml/kg in 20 min) in anesthetized Yorkshire cross pigs (n=18, 31.4±0.4 kg body wt). A severe hypotensive state sustained for 1 hour was associated with a 77% drop in urine flow to 3.6±0.5 μl/kg/min. While glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) both decreased with shock, filtration fraction increased with hemorrhage coincident with elevated renin activity, indicating selective efferent arteriolar constriction by angiotensin. With resuscitation, MAP was equally restored by all pressor agents to 63±4 mm Hg, which resulted in restoration of urine flow, ERPF and GFR. VP caused a dramatic six‐fold increase in urine flow not seen with PE or NE, and thus not explained by a pure pressure‐related diuresis. Indeed, VP induced significantly higher osmotic clearance and fractional excretions of sodium, potassium, and urea that did not occur with PE or NE. Therefore VP appears to have a novel role of manipulating renal tubular dynamics in regulation of blood pressure in severe hemorrhagic shock.
Dissociation of vascular and natriuretic Ang1–7 actions in AngII hypertensive and normotensive rats
Authors: Kuczeriszka Marta , Prieto Minolfa C , Kompanowska‐Jezierska Elzbieta , Navar L Gabriel
Published: June 2021

Studies in models of Angiotensin II‐dependent hypertension have shown that kidney medullary ACE2 activity and Ang1–7 levels are reduced, suggesting there are reduced compensatory vasodilator and natriuretic Ang1–7 effects available to counterbalance the hypertension and reduced sodium excretion. To assess the possible contribution of the reduced Ang1–7 levels, Ang1–7 was administered i.v. to anaesthetized normal and chronic AngII‐infused rats (80ng/min) at doses estimated to re‐establish Ang1–7 levels. Ang1–7(110fmol/min)led to small but significant increases in arterial pressure in both groups(114±3 to 123±5 and 140±5 to 149±5 mmHg), and to decreases in total renal blood flow (7.5±0.9 to 6.4±1 and 9.5 ±1.3 to 8.4±1 ml/min, p<0.05), medullary blood flow decreased only in control rats (124±22 to 113±19 PU, p<0.05). Acute Ang1–7 infusions also caused significant increases in urine flow (5.1±1.1 to 10±1.6 and 5.2±0.9 to 15.6±9 μl/min) and sodium excretion (0.05±0.03 to 0.96±0.35 and 0.04±0.02 to 0.42±0.14 μmol/min) in both groups indicating a dissociation between the hemodynamic and excretory effects and supporting a direct action of Ang1–7 to inhibit tubular sodium reabsorption to the same extent in the normotensive and hypertensive rats.

Supported by Polish Ministry of Science and Higher Education and the Tulane COBRE P20RR17659