bluuebunny/crossref_metadata_2025 huggingface dataset:
Physiological Basis For Novel Drug Hydrogen Sulfide‐Related Therapy Used To Treat Oxidative Stress In The Model Of Fructose‐Induced Injury
Authors: Zayachkivska Oksana , Pavlovskiy Yaroslav , Revenko Oleh , Yashchenko Antonina
Published: June 2021

Recent extensive research into accelerated aging and age‐related health problems confirmed the key role of metabolic dysfunction in multiple organ functions by overloaded fructose diet. Among important bioregulators of prostaglandin‐independent mechanisms of cytoprotection are sulfur compounds, and the key ones is Hydrogen Sulfide (H2S). However, it is little known about its physiological effects on fructose‐induced gastrointestinal mucosal (GIM) injury.

Aim

To test the hypothesis whether there is the interplay between H2S catalytic expression and age‐related GIM malfunction and oxidative stress with underlying high fructose diet (HFD), and evaluate effects of ATB 340 [4‐(5‐thioxo‐5H‐dithiol‐3‐yl)phenyl 2‐acetoxybenzoate].

Methods

Cystathionine‐γ‐lyase (CSE), cystathionine‐β‐synthase (CBS), and sulfite oxidase (SO) activities in GIM and oxidative stress indicators malonic dialdehyde (MDA) and carbonyl groups of oxide‐modified proteins (COMP) were estimated by standard biochemical methods in adult and old rats with standard diet (SD) and HFD, during stress exposure with vehicle and ATB 340 (17.5 mg/kg per 9 days per os) treatment. GIM injuries evaluated via histological damage index (DI). EC Approval: Committee on Bioethics of Lviv National Medical University protocol No 4, 23.04.2018.

Results

Oxidative stress was associated with increased MDA and COMP (р<0,05), and changes in CSE, CBS, fall of SO activities in older vs young rats, while HSD‐induced decline of GIM tolerance and indicators of oxidation were increased (р<0,05), coinciding with decreased SO (р<0,05) expression and DI value of GIM. Preprocessing ATB 340 reduces these description responses of serum MDA and COMP, DI values and increased SO activity (р<0,05) which may be aggravated stress tolerance.

Conclusions

Physiological basis of GIM injury during aging is associated with SO‐related mitochondrial dysfunction and increased MDA, COMP accumulations. ATB 340 ultimately improves the capacity of oxidative stress tolerance in hyperglycemia in older rats. These findings provide further insights into H2S‐mediated GIM protection and implicate the benefits of using H2S‐based therapies clinically for the treatment of age‐related changes and oxidative stress tolerance.

Support or Funding Information

We thank Prof. Natalia Zaichko (National Pirogov Memorial Medical University, Vinnytsia, Ukraine), Prof. J. Wallace (Antibes, Canada) for their support of our work.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Nanoformulation of bisphosphonates with a cationic peptide improves its activity against breast cancer cells
Authors: Fahmy Usama Ahmed , Ahmed Osama Abdulhakim , Alhakamy Nabil Abdulhafiz
Published: June 2021

Alendronate sodium (ALS) is one of the class bisphosphonates used to treat osteoporosis. Recent studies suggest that ALS may induce cell death and inhibit the proliferation of estrogen‐sensitive MCF‐7 breast cancer cells. The aim of this work is a combination of ALS and Trans‐activating regulatory protein (TAT) to potentiate ALS cytotoxicity against MCF‐7 breast cancer cells. ALS and TAT were prepared as nanostructured lipid carriers (NLCs). The formed NLCs were characterized for particle size and zeta potential. Cell viability was also carried out for the prepared NLCs. The results revealed that the prepared NLCs were spherical, with particle sizes of 285.2 ± 14.1 nm, with a polydispersity index of 0.51 and zeta potential of +21.1 ± 3.4 mV. The ALS %EE of the prepared NLCs was 12.2 ± 1.1%. ALS IC50 was decreased by about 30 % when compared with the raw drug. According to cell viability, The IC50 values for the treatments were as follows: ALS, 2.77 ± 0.36 μM; ALS‐TAT NLCs, 1.98 ± 0.17 μM; TAT, 1066.67 ± 21.22 μM and plain formula 10816.2 ± 112.32 μM. Which makes their combination with ALS a promising candidate for breast cancer therapy.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
CO2 expirograms during ERV expiration
Authors: Rueda Luis Antonio , Cruz Julio Cesar , Caucha Luis Jhony
Published: June 2021

Expired CO2 is usually recorded during normal breathing. There are few CO2 records beyond functional residual capacity (FRC) (Flores & Cruz. Chest 102:438‐443, 1992). However, the effect of apnea upon expired CO2 during the expiratory reserve volume (ERV) is not known. Thus, we are reporting CO2 expired curves (see figure of one subject) during ERV expiration, after holding the breath at FRC for several seconds (8s to 33s) which include the expiration time. Five subjects provided a written consent to this study, which was approved by the IRB of the University. The pattern of the curves shown was similar in all subjects to the one presented. Initial PCO2 values at 0s are the FRC end‐tidal values. The abrupt rise of CO2 corresponds to the elimination of CO2 from the dead space, followed by a waving alveolar plateau. The control curve agrees with Flores and Cruz (follows the model of West). With apnea, the expected increase in alveolar PCO2 is evident. After 8s the alveolar plateau starts to rise (positive slope) and becomes flat at 33s. Finally, the behavior of the curves, during the last 2s of expiration, suggests that the apex‐to‐base CO2 concentration difference is reversed. We must remember that the expirograms presented reflect the uneven emptying of parallel regions of the lung where the apical regions contribute more than the basal regions.

Supported in part by ONG ‐ Centro de Enseñanza Investigación y Servicios.
Allogeneic human mesenchymal stem cells for treatment of E. Coli endotoxin‐induced acute lung injury in an ex vivo perfused human lung
Authors: Lee Jae Woo , Gupta Naveen , Fang Xiaohui , Frank James A. , Briot Raphael , Matthay Michael A.
Published: June 2021

Recent studies have indicated that bone marrow derived mesenchymal stem cells (MSC) may have therapeutic applications in multiple clinical disorders. Currently, little is known regarding the effect of MSC in experimental models of acute lung injury (ALI) and pulmonary edema. We recently reported that intrapulmonary (via the trachea) treatment with MSC 4 h after endotoxin delivery to the lung improved survival and reduced the extent of pulmonary edema formation in endotoxin‐induced ALI in mice (J Immunol 2007). Here, we tested the therapeutic potential of human MSC to resolve pulmonary edema from ALI in an ex vivo perfused human lung preparation injured by E. Coli endotoxin. Intra‐bronchial instillation of endotoxin resulted in the loss of alveolar epithelial fluid transport measured as alveolar fluid clearance (AFC). Instillation of allogeneic human MSC or its conditioned medium given 1 h following endotoxin‐induced lung injury completely restored AFC. Using siRNA knockdown of potential paracrine soluble factors, we found that the secretion of keratinocyte growth factor (KGF) was essential for the restorative effect of MSC. In summary, the therapeutic effect of allogeneic human MSC on the resolution of endotoxin‐induced pulmonary edema in an ex vivo perfused human lung was mediated by the secretion of KGF. FAER & NHLBI HL093026, HL51854 and HL51856.
Quantitative responses of the mouse heart to pregnancy
Authors: Chung Eunhee , Leinwand Leslie A.
Published: June 2021

The heart changes its structure and function in response to various stimuli. Pathological stimuli initially activate an adaptive increase in mass, but may lead to heart failure. In contrast, cardiac hypertrophy induced by physiological stimuli, such as exercise, maintains or even enhances contractile function. A relatively under‐studied cardiac hypertrophic stimulus is pregnancy which is associated with altered estrogen levels and a prolonged cardiac volume overload. The objective of this study was to test the hypotheses that pregnancy could cause unique changes in function and signaling molecules compared to exiting other models of physiologic hypertrophy. Two‐to‐three month old virgin female C57/Bl6 mice were divided into non‐pregnant (NP), 10 to 13 days gestation (MP), and 18‐19 days gestation (LP). MP and LP have significant increases heart weight compared to NP. Fractional shortening (FS%) was significantly decreased in LP compared to NP and MP. We measured molecules in the PI3K pathway which have been implicated in exercise. The ratio of ph‐Akt to Akt and ph‐GSK3β to GSK3β were significantly increased in MP but returned to the NP level in LP. These results suggest that the PI3K pathway is activated in the early stage of pregnancy. We conclude that pregnancy‐induced cardiac hypertrophy is similar to but also distinct from exercise hypertrophy since systolic function (FS%) significantly decreased in LP.
A role of PFKFB3/iPFK2 in the regulation of neuronal glycolysis and food intake
Authors: Guo Xin , Li Honggui , Wu Chaodong
Published: June 2021

Glycolysis is crucial for hypothalamic neurons to sense glucose. However, the biochemical mechanism underlying the control of hypothalamic glycolysis is not well understood. Here we show that PFKFB3, a gene whose product controls glycolysis, is predominantly expressed in both mouse hypothalami and clonal hypothalamic neurons. In response to feeding, PFKFB3 expression is dramatically increased in mouse hypothalami. In addition, the increased PFKFB3 expression is accompanied by decreased phosphorylation of hypothalamic AMP‐activated protein kinase (AMPK), as well as decreased Agouti‐related protein (AgRP) expression and increased cocaine‐amphetamine‐related transcript (CART) expression. Similar results are observed in cultured hypothalamic neurons in response to glucose and insulin. Upon knockdown or overexpression of PFKFB3 in cultured hypothalamic neurons, glycolysis rates are altered, which in turn lead to changes in AMPK phosphorylation and neuropeptide expression. Furthermore, in hyperphagic mice, central overexpression of PFKFB3 causes a significant decrease in food intake, which contributes to a reduction in body weight. Taken together, our data suggest that PFKFB3 responds to feeding‐regulatory signals to govern hypothalamic glycolysis and in turn modulates AMPK phosphorylation and neuropeptide expression to regulate food intake.
The small intestinal lactase expression is reduced in the piglet with bowel inflammation
Authors: Lackeyram Dale , Archbold Tania , Mine Yoshinori , Fan Ming Z.
Published: June 2021

The effects of dextran sodium sulfate (DSS) induced bowel inflammation on jejunal lactase activity and expression were examined in 12 Yorkshire piglets at 5 d of age with body weight (BW) of 3 kg were fitted with ig catheters and divided into control (CON) and treatment groups (DSS). Both groups of pigs were infused with an equal volume of either saline or 1.25 g DSS/kg BW.d in saline, respectively, for 10 d. Lactase protein abundance was carried out by Western blotting and the mRNA abundance was measured by quantitative real time RT‐PCR. â‐actin was used as the housekeeping gene. DSS treatment decreased (P<0.05) jejunal lactase maximal specific activity (Vmax, µmol/mg protein.min) in the tissue homogenate (CON, 87.66±0.14 vs. DSS, 24.05±0.30) by 73%, cytosol (CON, 45.83±0.68 vs. DSS, 12.58±1.15) by 73% and apical membrane (CON, 422.67±3.29 vs. DSS, 92.22±2.42) by 78%, respectively, with orresponding decreases (P<0.05) of 26, 48, and 32% in the jejunal lactase protein abundance. The relative abundance of the jejunal lactase mRNA was lower by 25% in the DSS piglets. Bowel inflammation reduced the lactase activity in the small intestine by lowering its expression at the transcriptional and translational levels. Supported by AFMNet, OMAFRA and NSERC of Canada.
Carbon monoxide provides antioxidant protection in hepatic sinusoids during a remote inflammatory stress by reducing carbonylated MnSOD
Authors: James Megan L. , Dabkowski Erinne R. , Hollander John M. , Ripke Ingmar , Baumann Anja , Kothur Anand , Wunder Christian , Brock Robert W.
Published: June 2021

Although the anti‐inflammatory benefits of exogenous CO are well recognized, its antioxidant potential remains unknown. We examined the role of CO in regulating hepatic oxidant generation using bilateral hindlimb ischemia/reperfusion (I/R) as a model of systemic inflammation. Immediately following the onset of I/R, mice were treated with exogenous CO (methylene chloride or gaseous CO). Bilateral hindlimb I/R caused significant liver damage and lipid peroxidation. In vivo digital microscopy with the oxidant‐sensitive probe dihydrorhodamine confirmed the generation of hepatic oxidants. Treatment with CO significantly reduced all aspects of liver damage and oxidant formation. Due to its chemistry, CO is not likely a direct oxidant scavenger. Thus we investigated whether the antioxidant benefit of exogenous CO occurred via regulation of manganese superoxide dismutase (MnSOD) activity. As with direct I/R, MnSOD protein expression was unchanged yet its activity was diminished. Concomitant to this functional MnSOD demise was an increase in its carbonylation ‐ an inactivating oxidative protein modification. Treatment with CO reduced the carbonylation of MnSOD and restored its activity. These results suggest that exogenous CO indirectly reduces the hepatic oxidant stress that accompanies a remote inflammatory insult by diminishing MnSOD carbonylation, and thereby restoring MnSOD activity.
Abnormal autophagic response contributes to cardiac dysfunction in diabetic rat hearts following pressure overload
Authors: Marsh Susan A , Shan Dan , Dell'Italia Louis J , Chatham John C
Published: June 2021

Recent studies suggest that autophagy plays an important role in the response of the heart to increased stress including pressure overload hypertrophy. As diabetic patients exhibit a higher incidence of heart failure and mortality than non‐diabetics, particularly in the presence of hypertension, we hypothesized that this might be due to an abnormal autophagic response. Therefore, young male rats were divided into control (CON; 12% kcal fat/19% protein/69% carbohydrate), high fat diet (HF; 60/19/21%) and type 2 diabetic (DIA; high fat diet + low dose streptozotocin) groups for 8 weeks, followed by sham (SH) or pressure overload (PO) surgeries. Fasting glucose levels were elevated in DIA (10.8 ± 1.3 mmol/l) compared to CON (3.5 ± 0.1 mmol/l) and HF (3.9 ± 0.2 mmol/l); there were no differences between SH and PO. LV peak pressure was higher in all PO groups but end‐systolic wall stress was only elevated in DIA+PO (P<0.05). Hearts from DIA+SH exhibited a significantly higher number of apoptotic cells and this was enhanced in DIA+PO. Beclin‐1, a Bcl‐2 interacting protein which plays a critical role in regulating autophagy, was increased in response to PO in both CON and HF groups; however in the DIA+PO group Beclin‐1 levels were significantly lower than CON+PO group. These data suggest that an impaired autophagic response following pressure overload in diabetic hearts may promote increased cell death and cardiac dysfunction.
Pro‐inflammatory cytokines increase neuronal activity in the hypothalamic paraventricular nucleus and contribute to the pathogenesis of streptozotocin‐induced diabetes
Authors: Kang Yu‐Ming , Qin Da‐Nian , Elks Carrie , Francis Joseph
Published: June 2021

There is increased basal neuronal activity in the PVN in diabetic rats. In this study, we investigated the possible effects of pro‐inflammatory cytokines (PICs) on neuronal activity in the hypothalamic paraventricular nucleus (PVN) in streptozotocin‐induced diabetes. Sprague‐Dawley rats were injected with streptozotocin (STZ, 65 mg/kg, ip) to induce diabetes, and treated for 4 weeks with a continuous intracerebroventricular infusion of the cytokine blockers, pentoxifylline (PTX, 10µg/h) or etanercept (ETN, 5µg/h), or vehicle (artificial cerebrospinal fluid). There were higher plasma levels of glucose and PICs and lower insulin in plasma and pancreatic islets in the STZ‐induced diabetic rats compared to control rats. Diabetic rats had more PVN neurons expressing Fra‐like activity (indicating chronic neuronal activation), and more PVN neurons staining for TNF‐α and IL‐1β compared to the control rats. ICV treatments with PTX or ETN for 4 weeks reduced plasma levels of PICs in the STZ‐induced diabetic rats. Diabetic rats treated with ICV PTX or ETN for 4 weeks had fewer Fra‐like‐, TNF‐α‐ or IL‐1β‐positive cells in the PVN than vehicle‐treated diabetic rats. This study suggests that pro‐inflammatory cytokines increase neuronal activity in the PVN and contribute to the pathogenesis of streptozotocin‐induced diabetes. Supported by NIH HL‐080544.
Anti‐inflammatory effects of pyruvate‐enriched cardioplegia in pigs undergoing cardiopulmonary bypass
Authors: Mallet Robert T , Ryou Myoung‐Gwi , Flaherty Devin C , Hoxha Besim , Sun Jie , Bellard Monica , Hodge Lisa M , Olivencia‐Yurvati Albert H
Published: June 2021

Background

Reactive oxygen species produced during cardiopulmonary bypass (CPB) can elicit inflammation. Cardioplegia enriched with the intermediary metabolite pyruvate exerts antioxidant protection in myocardium of pigs subjected to CPB.

Hypothesis

Pyruvate‐fortified cardioplegia mitigates myocardial inflammation by increasing anti‐inflammatory cytokines, enhancing myocardial antioxidant defenses, and suppressing matrix metalloproteinase activity and neutrophil infiltration.

Methods

In situ swine hearts were arrested for 1 h with 4:1 blood:crystalloid cardioplegia, where the crystalloid component contained 188 mM glucose ± 24 mM pyruvate, then the hearts were reperfused and the pigs weaned from CPB. At 4 h post‐CPB, left ventricular myocardium was sampled for immunoblot analyses of the acute inflammation marker C‐reactive peptide (CRP), matrix metalloproteinase‐3 (MMP3) and tissue inhibitor of metalloproteinase‐2 (TIMP2), and to assess neutrophil infiltration by histology and myeloperoxidase activity.

Results

Myocardial CRP content increased over fivefold following CPB with control cardioplegia, but pyruvate cardioplegia prevented this increase. Circulating IL‐10 temporarily increased during and immediately after CPB; pyruvate cardioplegia provoked more sustained and robust enhancement of this anti‐inflammatory cytokine. CPB increased myocardial neutrophil infiltration and myeloperoxidase activity, but pyruvate‐fortified cardioplegia prevented these effects.

Conclusion

Pyruvate‐enriched cardioplegia suppresses CPB‐induced inflammation, an effect potentially mediated by anti‐inflammatory cytokines and TIMP‐2. Support: OHF 02‐18‐522
Short‐term insulin infusion alone has negative effect on skin protein mass in fasted pigs
Authors: Tuvdendorj Demidmaa , Børsheim Elisabet , Sharp Carwyn P , Zhang Xiaojun , Aarsland Asle , Herndorn David N , Chinkes David L , Wolfe Robert R
Published: June 2021

The effect of insulin (INS) on skin protein turnover (fractional synthesis and breakdown rates, FSR and FBR, respectively) in pigs is presented.

Methods

Pigs were divided into 4 groups: Control (CNT), Insulin (INS), Amino Acid (AA) and INS+AA. L‐[ring‐2H5]‐phenylalanine (Phe), INS and/or AAs were infused during the study. FBR was estimated from enrichment ratio of arterial Phe to intracellular free Phe.

Results

Plasma INS was increased in INS and INS+AA (p<0.05). Plasma glucose was constant in all groups. In INS group tissue intracellular branched and essential AA pools were lower than in other groups although did not reach statistical significance. The ratio of Phe inward transport to intracellular breakdown increased in AA (p<0.05) and INS+AA groups (p=0.05) compared to CNT. Hyperinsulinemia increased pig skin protein FSR and FBR, decreasing Net Balance (NB) (Table 1).

Conclusion

Ins infusion alone has a negative effect on protein mass in normal fasted pig skin because of insufficient AA availability.

Fundings: NIH AR0490380‐05, Shriners 8490.
EuroPhysiome, the Virtual Physiological Human toolkit, VPH Exemplar Projects, and the Renal Physiome
Authors: Thomas S. Randall
Published: June 2021

European Physiome activity is currently funded under the 7th Framework Program VPH call (Virtual Physiological Human), which supports more than a dozen targeted projects and also one Network of Excellence (NoE), whose mission is to coordinate these efforts, explore training possibilities, disseminate information about VPH resources and projects, and furnish a VPH ToolKit. I briefly summarize this activity and then focus on progress in the Renal Physiome, which is linked to the VPH NoE through the SAPHIR Exemplar Project treating blood pressure regulation in a Guyton‐inspired modular modeling environment. The Renal Physiome includes: (1) the Quantitative Kidney DataBase (QKDB) of experimental measurements and anatomical details, (2) links to other disciplines (incl. high‐throughput data) through common ontologies (e.g., FMA, GO...), (3) a library for models of channels and transporters expressed along the nephron, and (4) a repository of legacy models of kidney physiology at various scales (tubule transport, tubuloglomerular feedback, medullary models addressing the problem of urine concentration, etc.), with internet access through a KidneyGrid Portal (in collaboration with Univ. Melbourne).
Respiratory Syncytial Virus Inhibits Epithelial Na+ Currents by Upregulating iNOS
Authors: Song Weifeng , Liu Gang , Bosworth Charles , Walker John R , Lazrak Ahmed , Sullender Wayne M , Abraham Edward , Matalon Sadis
Published: June 2021

We have shown respiratory syncytial virus (RSV) infection of BALB/c mice resulted in a 40% reduction in Na+ driven alveolar fluid clearance (AFC), here we investigated the possible roles of iNOS and NO in this inhibition. H441 cells were infected with a GFP tagged RSV, whole‐cell and single channel Na+ currents were recorded 3 to 5 days after infection. RSV infection significantly decreased whole‐cell total and amiloride‐sensitive Na+ current in GFP (+) infected cells to 59% and 12% of those of the control uninfected cells; 4 pS ENaC single‐channel NPo was also decreased from 0.48 to 0.10. iNOS was significantly upregulated and nitrite concentration was 41% higher in RSV infected cells. Nuclear translocation of NF‐kB p65 subunit and NF‐kB activation were also upregulated. None of these effects were seen in cells exposed to UV‐inactivated RSV. Knock‐down of NF‐kB reversed the upregulation of iNOS, meanwhile inhibition of NO production with 1um 1400W partially restored amiloride‐sensitive currents in GFP (+) cells. These data indicate RSV infection inhibits Na+ currents via upregulation of iNOS and NO; provide new insight into the mechanisms of RSV induced decrease of AFC in vivo.
Depolarization is the trigger for PI3K/Akt activation and leads to ROS production in a model of pulmonary ischemia
Authors: Chatterjee Shampa , Hong NanKang , DeBolt Kris , Knihnicky Alexander , Sorokina Elena , Liu Weidong , Fisher Aron B.
Published: June 2021

We reported that ischemia or loss of shear in the lung endothelium causes endothelial plasma membrane depolarization (via KATP channel closure) that leads to NADPH oxidase activation and reactive oxygen species (ROS) production. Both high K+ induced depolarization and ischemia resulted in activation of PI3K; its inhibitor (wortmanin) prevented NADPH oxidase assembly and ROS production with ischemia. We used pulmonary microvascular endothelial cells, either wild type (WT), KATP−/−, gp91phox−/− or WT infected with dominant negative (DN) PI3K, and isolated Akt‐1 null lungs to study signal transduction with ischemia. Cells with DN PI3K and lungs with Akt1−/−, both showed the depolarization response but failed to show NADPH oxidase assembly and ROS generation. In WT cells, Akt activation (as monitored by the expression of p‐Akt) that was observed with ischemia was abolished in KATP−/− but not in gp91phox−/− cells. Blocking the ischemic depolarization by addition of cromakalim (KATP channel agonist) to gp91phox−/− cells prevented Akt phosphorylation. These results indicate that KATP induced depolarization leads to NADPH oxidase assembly and ROS generation and precedes PI3K/Akt activation. Thus, ROS which has hitherto been shown to activate PI3K/Akt in other systems lies downstream of PI3K/Akt in our model of pulmonary ischemia.
Long‐chain n‐3 fatty acids – New anabolic compounds improving protein metabolism
Authors: Thivierge M. Carole , Lévesque Janie , Julien Pierre , Couture Yvon , Davis Teresa A.
Published: June 2021

Previous animal studies demonstrated that chronic feeding of long‐chain n‐3 polyunsaturated fatty acids (LCn‐3PUFA) that modifies muscle membrane fatty acid composition promotes protein anabolism by blunting the age‐associated deterioration in insulin sensitivity. The current study assessed, as a proof of concept, the anabolic effects of LCn‐3PUFA‐rich menhaden oil in 78 male castrated pigs (20 kg initial body weight). Pigs were fed for 76 days diets containing 0, 3, or 4% menhaden oil using iso‐energetic oil substitutions in diets typical of swine production (6% fat matter). Performance and body composition were measured using ultrasound technology during growth at 55 and 85 kg according to a complete block design. Menhaden oil feeding linearly reduced feed intake with a decline from 2.58 to 2.51 kg/d (‐3%; P=0.04) at 85 kg body weight without altering body weight gain. Back fat thickness remained unchanged (11.16 mm) between treatments. The diameter of the longissimus dorsi was linearly increased as menhaden oil amount increased (50.0, 50.1, 51.8 mm; P=0.02). The results demonstrate for the first time that LCn‐3PUFA promote muscle protein accretion, this approach could be a novel intervention to ameliorate the age‐related loss of muscle mass in the human.
Ingestion of a high molecular weight modified waxy maize starch alters metabolic responses to prolonged exercise in trained cyclists
Authors: Roberts Michael , Lockwood Christopher , Dalbo Vincent James , Tucker Patrick , Frye Ashley , Polk Robert , Volek Jeff , Kerksick Chad
Published: June 2021

We examined whether ingestion of a modified waxy maize starch (WMS) designed to have a low glycemic impact would alter metabolic and hormonal responses to prolonged cycling compared to Maltodextrin. Ten male cyclists (n: 9, age: 30 2 y, weight: 79.2 2.1 kg, VO2peak: 4.7 0.1 L/min, training: 7.5 1.3 y) fasted for 12 h before cycling for 150 min @ 70% VO2peak. Before and after exercise, participants ingested 1g/kg of either WMS or Maltodextrin while providing blood and expired gas samples every 15 and 30 min, respectively, before, during, and following exercise. In a crossover fashion, identical testing was completed one week later. There was a rapid increase in blood glucose immediately after the ingestion of Maltodextrin pre‐ and post‐exercise, which was significantly attenuated by WMS (P < 0.05). In a similar manner, serum insulin levels were also significantly lower after ingestion of WMS (peak = 2.5 ìIU/ml) compared to Maltodextrin (peak = 20.3 ìIU/ml). WMS was associated with greater fat breakdown and oxidation during exercise and recovery as indicated by significantly increased serum non‐esterified fatty acids and glycerol levels and a trend for lower respiratory exchange ratios compared to Maltodextrin. Ingestion of a low glycemic modified waxy maize starch prior to prolonged submaximal cycling blunted the initial spike in blood glucose and insulin while enhancing breakdown and oxidation of fat.
Temporal effects of training on skeletal muscle angiogenic responses to acute exercise
Authors: Gutierrez‐Reed Navarre , Olfert I. Mark
Published: June 2021

Vascular endothelial growth factor (VEGF), matrix metalloproteinase (MMP)‐2 and MMP‐9 are important in extracellular matrix remodeling and skeletal muscle angiogenesis in response to exercise. We evaluated protein expression of VEGF, MMP‐2 and MMP‐9 in mouse gastrocnemius muscle following 0, 3, 5, 7, 14, and 28 (d)ays of voluntary wheel running (n=12 per group). Protein expression was evaluated at either rest (basal, n=6) or after a single 1‐hour treadmill running bout (25 m/min at 10‐degrees, n=6) in each group. Compared to untrained controls, basal VEGF levels were significantly decreased by 36% at 3d, increased by 31% at 7d, and again reduced by 48% at 28d (p<0.05 respectively). Basal MMP‐2 protein expression was only reduced at 3d (36%, p<0.05), while MMP‐9 protein levels were decreased by 43% at 5d, 43% at 7d, and 34% at 14d (p<0.05 respectively). Basal MMP‐9 was not significantly altered at either 3d or 28d. VEGF response to acute exercise was increased in by 61% in control (p<0.05), 33% at 3d (p<0.05), and, to a lesser extent, in 5d (29%, p=0.08) trained mice, but absent after 7d of training. Neither MMP‐2 nor MMP‐9 showed a significant protein response to acute exercise. These data show that the VEGF protein response to acute exercise is blunted after 7 days of training, at a time point when training‐induced capillary adaptation is expected.
A Three‐Year Anatomical Study of Lower Limb Length Discrepancy (LLLD) in an Urban Population Group
Authors: Jeanty Hamerton D , Weedon Jeremy , Marquez Samuel
Published: June 2021

LLLD patients as a group exhibit significantly poorer postoperative total hip/knee replacement outcomes with considerably more limping than preoperative patients with an anatomical LLLD; implicating compensatory mechanisms at play for the latter group. This three‐year study examines the frequency of LLLD and identifies the bony segments of the lower limb that contributes to the sample variance. 287 femora and tibial measures were taken from donor specimens at the SUNY Downstate Anatomy programs (males: n=37) and (females: n=35); examining side dominance and sex interaction effects.

Mixed Linear modeling was used to predict tibia and femur length; using gender side of body and their interaction as predictors. As expected there was a statistical significant difference between sexes for mean tibial length (F[1,70]=29.11, p<0.001). There was no difference found according to side of body (F[1,46]=0.25, p=0.622) and no sex interaction (F[1,46]=0.18, p=0.673). Similarly, a statistical difference between mean femur length by sex was revealed (F[1,70]=26.49, p<0.001) and a significant difference found in side of body (F[1,55]=5.84, p=0.019) but no sex interaction (F[1,55]=0.07, p=0.787). Results implicate the femora as the significant contributor to LLLD with the right femora being longer than the left in both males and females. Sex interaction effects did not contribute to this difference, appearing to be of similar extent in both sexes.

LLLD research continues to demonstrate the importance of accounting for asymmetric functionality in the preoperative evaluation for total hip/knee replacements. Our preliminary results may prove particularly useful in orthopedic surgery where a better understanding of LLLD would lead to improved outcomes in this unique patient demographic.
Cholesterol‐enriched diet induces endosome/lysosome dysfunction in a rabbit model of inclusion body myositis
Authors: Chen Xuesong , Wagener John F. , Ghribi Othman , Geiger Jonathan D.
Published: June 2021

Inclusion body myositis (IBM) is the most common myopathy in people over 50 years of age. The pathogenesis of IBM is poorly understood and no effective treatment is available. We have shown that rabbits fed a high cholesterol diet developed IBM‐like pathology, but the underlying mechanism is not clear. Recent studies indicate that vacuoles in human IBM muscle fiber are of endocytic origin and it is well known that the major source of cholesterol in skeletal muscle is via uptake through receptor‐mediated endocytosis. The present study tested the hypothesis that increased levels of cholesterol induce IBM‐like pathology by affecting endosomes/lysosomes. In rabbits fed a 2% cholesterol diet for 12 weeks we tested this hypothesis using immunostaining, immunoblotting and enzyme activity assays. We found that vacuoles induced by cholesterol‐enriched diet were enlarged endosomes/lysosomes; sites where free cholesterol accumulated. The cholesterol‐enriched diet also decreased the specific activities of three lysosomal enzymes. Moreover, the cholesterol‐enriched diet increased the accumulation of amyloid beta, phosphorylated tau and ubiquitin in endosomes/lysosomes. Our results indicate that cholesterol‐enriched diet induces IBM‐like pathology by disturbing endosome/lysosome function.

(Supported by P20RR17699 from the National Center for Research Resources, a component of the NIH)
Ozone Induces Nerve Growth Factor Expression in Tracheal Epithelial Cells in Early Postnatal Life
Authors: Carrell‐Jacks Lynnsey , Rogers‐Nieman Gabrielle , Dey Richard , Hunter Dawn
Published: June 2021

Nerve growth factor (NGF) is produced in the airway epithelium. The purpose of this study was to determine if ozone, a chemical irritant associated with air pollution, alters NGF message levels specifically in tracheal airway epithelial cells at early postnatal ages. Fisher‐344 rat pups were exposed to 2ppm ozone or filtered air for 3 hours on postnatal days (PD) 6, 15 or 21. Twelve hours after exposure, tracheal epithelial cells were isolated and treated in culture with IgG, resulting in an enriched population containing 96.04%±0.60% (n=3) epithelial cells and 3.97%±0.60% (n=3) immune cells. Total RNA was extracted and transcribed into cDNA. NGF mRNA expression was amplified using the real‐time PCR system and analyzed via the comparative threshold method and expressed relative to endogenous β‐actin. At PD 6, the relative NGF mRNA expression in ozone treated rats showed a significant 2‐fold increase in comparison to the air treated animals (p≤0.05, n=3 per group). At PD 15 (n=7 per group) and 21 (n=3 per group), there were no significant changes in NGF mRNA expression between ozone and air treated animals. Thus, the increase in NGF mRNA levels in response to ozone exposure seen at PD 6 was specifically from the tracheal epithelial cells and not immune cells in this cell population. The increase in NGF expression at PD 6 suggests increased sensitivity to ozone exposure compared to PD15 and 21.
ISOLATION AND CHARACTERIZATION OF BIORESPONSIVE RENAL CELLS FROM HUMAN AND LARGE MAMMAL WITH CHRONIC RENAL FAILURE
Authors: Presnell Sharon C , Bruce Andrew , Wallace Shay M , Choudhury Sumana , Kelley Russell W , Tatsumi Patricia , Werdin Eric , Rivera Elias , Merricks Elizabeth , Nichols Timothy C , Jennette J. Charles , Jayo Manuel J , Bertram Timothy A
Published: June 2021

Chronic kidney disease (CKD) is a global public health problem; U.S. patients on dialysis awaiting organ transplant more than doubled between 1991 and 2004. To avoid an immune response to implanted cells, functional autologous cells would be preferred components of regenerative medicine therapies for CKD; however, evidentiary support for autologous sourcing of therapeutically‐relevant cells from CKD patients and large animal models is lacking. Fresh kidney tissue (CKD and non‐CKD) was obtained from porcine and human subjects. CKD was confirmed by serology and histopathology. Tissue dissociation and cell isolation methods developed with non‐CKD tissue were employed to isolate and propagate cells from CKD tissue and yielded tubular cells and erythropoietin (EPO)‐expressing cells. Comparative in vitro studies demonstrated expression of megalin:cubilin and receptor‐mediated uptake of fluorescein‐conjugated albumin in tubular cell cultures from both CKD and non‐CKD tissues. Cells expressing erythropoietin (EPO) were present in both CKD and non‐CKD tissues and could be isolated and expanded with retention of oxygen‐responsive, HIF1‐alpha‐driven EPO expression. Taken together, these results suggest that autologous sourcing of at least two therapeutically‐relevant cell populations is feasible in advanced CKD.
TRO40303 attenuates oxidant‐induced mitochondrial dysfunction in cardiac myocytes
Authors: Ngoh Gladys Afor , Schaller Sophie A , Jones Steven P
Published: June 2021

Mitochondrial dysfunction figures prominently in post‐ischemic cardiac myocyte injury. A novel cytoprotective compound, TRO40303, can reduce infarct size following ischemia‐reperfusion injury in mice and prevent contractile dysfunction in vitro. To better understand how TRO40303 potentially mediates such protection from oxidative damage seen in ischemia‐reperfusion injury, we induced oxidative stress in neonatal rat cardiac myocytes (n>/=5/group) using hydrogen peroxide (100µmol/L) and assessed changes in intracellular calcium levels (via Rhod‐2AM and Fluo‐4AM), reactive oxygen species (ROS, via DCF), mitochondrial membrane potential (via TMRM), and mitochondrial permeability transition (mPT, via Calcein‐AM). H2O2 induced cytosolic and mitochondrial calcium overload, ROS production, loss of mitochondrial membrane potential, and mPT. BAPTA (50µmol/L), an intracellular calcium chelator, completely blocked oxidant‐induced calcium overload. NaCN (3mmol/L) significantly reduced ROS production implicating mitochondrial respiration as a primary source for ROS‐induced ROS production. Such oxidative damage was significantly attenuated by cyclosporin A (1µmol/L) and TRO40303 (3µmol/L). We conclude that TRO40303 may confer protection by attenuating calcium overload and ROS production, and subsequently, loss of mitochondrial membrane potential and mPT. Supported by TROPHOS SA.
The barrier functions of crude cervical mucus plugs against HIV-1 infection in the context of cell-free and cell-to-cell transmission
Authors: Mhlekude Baxolele , Lenman Annasara , Sidoyi Phikolomzi , Joseph Jim , Kruppa Jochen , Businge Charles Bitamazire , Mdaka Mana Lungisa , Konietschke Frank , Pich Andreas , Gerold Gisa , Goffinet Christine , Mall Anwar Suleman
Published: June 2021

Objective:

The cervical mucus plugs are enriched with proteins of known immunological functions. We aimed to characterize the anti-HIV-1 activity of the cervical mucus plugs against a panel of different HIV-1 strains in the contexts of cell-free and cell-associated virus.

Design:

A cohort of consenting HIV-1-negative and HIV-1-positive pregnant women in labour was recruited from Mthatha General Hospital in the Eastern Cape province of South Africa, from whom the cervical mucus plugs were collected in 6 M guanidinium chloride with protease inhibitors and transported to our laboratories at −80 °C.

Methods:

Samples were centrifuged to remove insoluble material and dialysed before freeze--drying and subjecting them to the cell viability assays. The antiviral activities of the samples were studied using luminometric reporter assays and flow cytometry. Time-of-addition and BlaM-Vpr virus-cell fusion assays were used to pin-point the antiviral mechanisms of the cervical mucus plugs, before proteomic profiling using liquid chromatography-tandem mass spectrometry.

Results:

The proteinaceous fraction of the cervical mucus plugs exhibited anti-HIV-1 activity with inter-individual variations and some degree of specificity among different HIV-1 strains. Cell-associated HIV-1 was less susceptible to inhibition by the potent samples whenever compared with the cell-free HIV-1. The samples with high antiviral potency exhibited a distinct proteomic profile when compared with the less potent samples.

Conclusion:

The crude cervical mucus plugs exhibit anti-HIV-1 activity, which is defined by a specific proteomic profile.
White Matter Disease—The True Source of Triphasic Waves?
Authors: Freund Brin , Kotchetkov Ivan S. , Kaplan Peter W.
Published: June 2021

Triphasic waves are EEG phenomena typically seen in patients with acute encephalopathy and have importance in diagnosis and prognosis in these cases. The underlying metabolic disturbances associated with their incidence have been described previously, but neuroimaging characteristics are not well delineated. There are a few small studies that define neuroimaging results in patients with triphasic waves. This review highlights the most common neuroimaging findings in these patients, including subcortical white matter disease, which itself may be a risk factor for triphasic waves.
Can We Distinguish Triphasic Waves From Other Generalized Periodic Discharges? Do We Need to?
Authors: Foreman Brandon
Published: June 2021

Triphasic waves are intuitively distinctive waveforms that fall under the umbrella of generalized periodic discharges. The ability to distinguish these waveforms consistently could be helpful if a specific underlying pathophysiology could be identified. However, scalp EEG and clinical observation have been limited in their ability to elucidate the underlying cortical physiology that leads to triphasic waves. Evidence from intracranial physiologic data and computational modeling suggest that these and other periodic discharges should be viewed not as strictly ictal nor non-ictal but rather on the spectrum between these two. Triphasic waves in particular appear to result from an abnormal balance between cortical excitation and synaptic transmission with input from functionally connected brain networks, such as the thalamocortical pathways involved in arousal. The practical implication of triphasic waves begins with acknowledgement of uncertainty and a rational approach should ask whether the pattern—or its treatment–might be creating harm.
Sepsis Subphenotyping Based on Organ Dysfunction Trajectory
Authors: Xu Zhenxing , Mao Chengsheng , Su Chang , Zhang Hao , Siempos Ilias , Torres Lisa K , Pan Di , Luo Yuan , Schenck Edward J , Wang Fei
Published: June 2021

Background

Sepsis is a heterogeneous syndrome, and the identification of clinical subphenotypes is essential. Although organ dysfunction is a defining element of sepsis, subphenotypes of differential trajectory are not well studied. We sought to identify distinct Sequential Organ Failure Assessment (SOFA) score trajectory-based subphenotypes in sepsis.

Methods

We created 72-hour SOFA score trajectories in patients with sepsis from four diverse intensive care unit (ICU) cohorts. We then used Dynamic Time Warping (DTW) to compute heterogeneous SOFA trajectory similarities and hierarchical agglomerative clustering (HAC) to identify trajectory-based subphenotypes. Patient characteristics were compared between subphenotypes and a random forest model was developed to predict subphenotype membership at 6 and 24 hours after being admitted to the ICU. The model was tested on three validation cohorts. Sensitivity analyses were performed with alternative clustering methodologies.

Results

A total of 4678, 3665, 12282, and 4804 unique sepsis patients were included in development and three validation cohorts, respectively. Four subphenotypes were identified in the development cohort: Rapidly Worsening (n=612, 13.1%), Delayed Worsening (n=960, 20.5%), Rapidly Improving (n=1932, 41.3%) and Delayed Improving (n=1174, 25.1%). Baseline characteristics, including the pattern of organ dysfunction varied between subphenotypes. Rapidly Worsening was defined by a higher comorbidity burden, acidosis, and visceral organ dysfunction. Rapidly Improving was defined by vasopressor use without acidosis. Outcomes differed across the subphenotypes, Rapidly Worsening had the highest in-hospital mortality (28.3%, p-value<0.001), despite a lower SOFA (mean: 4.5) at ICU admission compared to Rapidly Improving (mortality:5.5%, mean SOFA: 5.5). An overall prediction accuracy of 0.78 (95% CI, [0.77, 0.8]) was obtained at 6 hours after ICU admission, which increased to 0.87 (95% CI, [0.86, 0.88]) at 24 hours. Similar subphenotypes were replicated in three validation cohorts. The majority of patients with sepsis have an improving phenotype with a lower mortality risk, however they make up over 20% of all deaths due to their larger numbers.

Conclusions

Four novel, clinically-defined, trajectory-based sepsis subphenotypes were identified and validated. Identifying trajectory-based subphenotypes has immediate implications for the powering and predictive enrichment of clinical trials. Understanding the pathophysiology of these differential trajectories may reveal unanticipated therapeutic targets and identify more precise populations and endpoints for clinical trials.
Genetic overlap between multivariate measures of human functional brain connectivity and psychiatric disorders
Authors: Roelfs Daniel , van der Meer Dennis , Alnæs Dag , Frei Oleksandr , Shadrin Alexey A. , Loughnan Robert , Fan Chun Chieh , Dale Anders M. , Andreassen Ole A. , Westlye Lars T. , Kaufmann Tobias
Published: June 2021

Psychiatric disorders are complex, heritable, and highly polygenic. Supported by findings of abnormalities in functional magnetic resonance imaging (fMRI) based measures of brain connectivity, current theoretical and empirical accounts have conceptualized them as disorders of brain connectivity and dysfunctional integration of brain signaling, however, the extent to which these findings reflect common genetic factors remains unclear. Here, we performed a multivariate genome-wide association analysis of fMRI-based functional brain connectivity in a sample of 30,701 individuals from the UK Biobank and investigated the shared genetic determinants with eight major psychiatric disorders. The analysis revealed significant genetic overlap between functional brain connectivity and schizophrenia, bipolar disorder, attention-deficit hyperactivity disorder, autism spectrum disorder, anxiety, and major depression, adding further genetic support for the dysconnectivity hypothesis of psychiatric disorders and identifying potential genetic and functional targets for future studies.
A polygenic risk score predicts mosaic loss of chromosome Y in circulating blood cells
Authors: Riaz Moeen , Mattisson Jonas , Polekhina Galina , Bakshi Andrew , Halvardson Jonatan , Danielsson Marcus , Ameur Adam , McNeil John , Forsberg Lars A. , Lacaze Paul
Published: June 2021

Mosaic loss of Y chromosome (LOY) in leukocytes is associated with risk for death and disease in men. We investigated a polygenic risk score (PRS) for LOY comprising 156 previously associated germline variants, in 5131 men aged ≥70 years. Levels of LOY were estimated using microarrays and validated by whole genome sequencing. After adjusting for covariates, the PRS was a significant predictor of LOY (odds ratio 1.74). Men in the highest quintile of the PRS distribution had >5-fold higher risk of LOY than the lowest. A PRS for LOY could become a useful tool for risk prediction and targeted intervention.
Forecast verifications for the real COVID-19 pandemic dynamics in Qatar
Authors: Nesteruk Igor
Published: June 2021

The COVID-19 pandemic dynamics in Qatar in the second half of May and the first half of June 2021 was compared with the published results of SIR-simulations based on the data from the period April 25 - May 8, 2021. Forecast verification showed very good agreement with the real number of cases (which can exceed the laboratory-confirmed one more than 5 times). The positive effect of mass vaccination became visible in June 2021.
A physically plausible incidence rate for compartmental epidemiological models
Authors: Pitschel Thomas
Published: June 2021

Motivated by the recent trajectory of SARS-Cov-2 new infection incidences in Germany and other European countries, this note reconsiders the need to use a non-linear incidence rate function in deterministic compartmental models for current SARS-Cov-2 epidemic modelling. Employing a homogenous contact model, it derives such function systematically using stochastic arguments. The presented result, which is relevant to modelling of proliferation of arbitrary infectious diseases, integrates well with previous analyses, in particular closes an analytical “gap” mentioned in London and Yorke (1973) and complements the stability related work on incidence rate functions of the form βIpSq seen for example in Liu, Hethcote and Levin (1987).