bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P214: Mechanotransduction And Uterine Blood Flow In Preeclampsia- The Role Of Piezo 1 Ion Channels.
Authors: Arishe Olufunke O , Dela Justina Vanessa , Priviero Fernanda B , Webb Clinton R
Published: September 2020

Background:
There is a large increase in uterine arterial blood flow during normal pregnancy. Structural and cellular adjustments occur in the uterine vasculature during pregnancy to accommodate this increased blood flow through a process is known as ‘vascular remodeling’. The etiology of preeclampsia involves aberrant placentation and vascular remodeling leading to reduced uteroplacental perfusion. However, the underlying source of the deficient vascular remodeling and the subsequent development of preeclampsia remains to be fully understood. Piezo 1 channels have been shown to be highly expressed in vascular smooth muscle cells of small-diameter arteries and play a role in the structural remodeling of the arteries. Studies have also shown that Piezo 1 is present in uterine arteries and it’s not exclusive to the endothelial cells.

Hypothesis:
This study tests the hypothesis that reduced Piezo 1 activity contributes to decreased uterine vascular relaxation in hypertensive pregnant rats.

Methods:
Hypertension was induced by treating the pregnant rats with synthetic CpG ODN (ODN 2395) via three intraperitoneal injections (100μg/rats) while the normotensive controls were treated with saline (vehicle) on the 14
th
, 17th and 18
th
days of pregnancy. Mean arterial pressure (MAP) was measured. In vitro vascular reactivity of uterine arterial (UA) ring segments were evaluated using isometric wire myograph system. Rings were pre-contracted with 3μM phenylephrine (PE), concentration responses of to Yoda1; a pharmacological agonist of Piezo 1 channel were compared. Statistical analysis was performed using nonlinear regression and Students’ t-test.

Results:
Our results show that MAP was greater in rats treated with ODN2395 vs untreated rats (112 ± 1 vs 90 ± 1
p
=0.0004). Concentration-dependent relaxation responses to Yoda1 were greater in UAs of untreated rats compared to those treated with ODN2395 (EC50 0.06571 ± 0.09781 vs. 0.5774 ± 0.1187
p
=0.0018).

Conclusion:
These results suggest that the reduced vasodilation in pregnancy-associated hypertension may be due to a reduced Piezo 1 channel activity.
Abstract P217: Phenotypic Difference Exist Between Bph/5 Offspring In A Sex-dependent Manner
Authors: Beckers Kalie , Gomes Viviane , Robillard Kat , Liu Chin-CHi , Johnston Andrea , Sones Jennifer L
Published: September 2020

Preeclampsia (PE) is a hypertensive disorder of pregnancy occurring in ~10% of women worldwide. Maternal obesity is a risk factor for PE and the effects on offspring are long-standing with increased incidence of cardiometabolic disease into adulthood. The maternal obesogenic environment may play a role in pregnancy outcomes and offspring in a sex-dependent manner; however, in the context of superimposed PE, it is not completely understood. Obese BPH/5 mice spontaneously exhibit late-gestational hypertension, fetal demise and growth restriction, and excessive gestational weight gain, similar to PE. We hypothesized that phenotypic differences exist between female and male BPH/5 offspring and maternal weight loss in BPH/5 during pregnancy would influence these phenotypic differences. Obese BPH/5 dams were calorie restricted via pair-feeding (PF) to match the food intake of C57 dams for the first 9 days of pregnancy. Offspring were fed an ad libitum (lib) diet until phenotypic analysis. Body weights (BW), visceral peri-gonadal and peri-renal white adipose tissue (WAT), hearts, and livers were recorded in BPH/5 and control C57 age-matched adult females and males born to ad lib fed and PF dams. Values are reported as mean ± standard error of the mean. As previously described, BPH/5 females born to ad lib fed dams are overweight with increased peri-renal and gonadal WAT, cardiomegaly, and hepatomegaly (1308 ±13.3 vs 979.9 ±82.3g in C57, p<0.05). BPH/5 male mice are underweight (23.8±1.6 vs C57: 27.9±1.6g) with increased peri-renal WAT (158± 23 vs C57: 53.25±10.3mg, p<0.05), and cardiomegaly (heart: BW 8.1±0.5 vs C57: 5.7±1.1, p<0.05). Without altering BPH/5 male or female offspring BW, peri-renal adiposity (males: 103.5±13mg, females: 73.2±10.3mg, p<0.05), cardiomegaly (males: 5.74±0.5, females: 6.03±0.4, p<0.05), and female hepatomegaly (1149.8 ±58.1mg, p<0.05) are significantly attenuated in PF BPH/5 dams. To conclude, reduction in the maternal obesogenic environment may play a role in BPH/5 sex-dependent phenotypic differences. Future investigations are necessary to understand the differences observed in BPH/5 male versus female mice into adulthood as well as the transgenerational impact of attenuated maternal obesity in pregnancy.
Abstract P218: Tumor Necrosis Factor Alpha Improves Placental Perfusion And Attenuates Intrauterine Growth Restriction In A Rodent Model Of Preeclampsia
Authors: Coats Laura E , Rawls Adam Z , Cockrell Kathy L , Chamoun Gabrielle M , Alexander Barbara T
Published: September 2020

Preeclampsia (
PE
) is not only detrimental to the mother and her fetus during pregnancy, but it is also associated with increased cardiovascular (
CV
) risk in the mother and her intrauterine growth restricted (
IUGR
) offspring in later life. Currently there are no known treatment options for PE beyond early delivery. Thus, there is a critical need to identify therapeutic treatments for PE. The inflammatory cytokine TNF-α is increased in women with PE. In the clinically relevant Reduced Uterine Perfusion Pressure (
RUPP
) model of PE in the rat, TNF-α is also increased and importantly, etanercept abolishes maternal hypertension. Etanercept is a soluble receptor that binds TNF-alpha to inhibit the inflammatory response. Although not yet prescribed for PE, etanercept is non-contraindicated during pregnancy. Therefore, this study tested the hypothesis that maternal administration of etanercept will mitigate IUGR in the RUPP model of PE and that improvement in fetal growth occurs in association with improved uteroplacental perfusion, placental morphology, and placental nutrient transporter protein expression. Sham or RUPP was performed at gestational day 14 (
G14
). Dams were administered vehicle or the TNF-α inhibitor (etanercept, 0.4 mg/kg, s.c.) at G18. At G20 uterine artery resistance index (
UARI
) was significantly increased in vehicle RUPP (0.69±0.02 mm/s) vs. vehicle Sham (0.60±0.02mm/s)(
p
<0.05), indicative of reduced uteroplacental perfusion, but UARI was no longer increased in treated RUPP (0.65±0.03 mm/s)(
p
<0.05). At G20, fetal weight was significantly reduced in vehicle RUPP (3.52g±0.10) vs. vehicle Sham (3.82 g±0.09)(
p
<0.05). Yet, fetal weight was significantly increased in treated RUPP (3.82g±0.12) vs. vehicle RUPP (
p
<0.05). Fetal brain weight did not differ in Sham or RUPP, regardless of maternal treatment. However, fetal liver weight was significantly increased in treated RUPP (0.29g ±0.02) vs. vehicle RUPP (0.24g±0.01)(
p
<0.05) suggesting attenuation of asymmetric growth restriction. These findings indicate that maternal administration of a TNF-α inhibitor during PE improves fetal growth in association with improved uteroplacental blood flow. Future studies are warranted to investigate the long-term benefit in IUGR offspring.
Abstract P219: Mice Exposed To Early Life Stress Have Impaired Autonomic Activity At Baseline And In Response To Acute Stress In Adulthood
Authors: Rhoads Megan K , McPherson Kasi C , Kemp Keri M , Becker Bryan , Colson Jackson , Meek Rachel E , Jin Chunhua , Johnson Alan K , Pollock David M , Pollock Jennifer
Published: September 2020

Early life stress (ELS) is an independent risk factor for the development of cardiovascular disease in adulthood in both humans and rodent models. Maternal separation and early weaning (MSEW), a model of ELS, produces mice with an increased risk of cardiovascular dysfunction in adulthood, despite resting blood pressures (BP), heart rates (HR), and body weights comparable to normally reared controls. Autonomic regulation of HR and BP is an important component of the homeostatic response to stress but has not been investigated in MSEW mice. We hypothesized that exposure to MSEW impairs autonomic function at baseline and in response to an acute psychosocial stressor in adult male mice. C57Bl/6J litters were randomly assigned to MSEW or normally reared control conditions. MSEW litters were separated from dams for 4 h on postnatal days (PDs) 2-5, 8 h on PDs 6-16, and weaned at PD 17. Control litters were undisturbed until weaning at PD 21. At 9 weeks old, telemeters were implanted in MSEW (n=16) and control mice (n=12). During cage switch stress (CSS), mice were moved to a soiled, unfamiliar cage for 4 h. HR, systolic BP (SBP), diastolic BP (DBP), and activity (monitored by telemetry) were similar between control and MSEW mice at baseline and during CSS (p>0.05, 2-way ANOVA). Spectral analysis of HR, SBP, and DBP indicated that HR variability (HRV) total power was lower in MSEW mice during the 12 h inactive period compared to controls (18.9±1.1 ms
2
vs. 27.5±3.1 ms
2
; p=0.0033, 2-way ANOVA) at baseline. HRV low frequency (LF) power was also lower during the 12 h inactive period in MSEW mice (4.2±0.4 ms
2
vs.6.6±0.9 ms
2
; p=0.009). At baseline, 12 h and 24 h DBP variability LF/high frequency (HF) ratio, normalized LF, and normalized HF power were lower in the MSEW group (p<0.05, all comparisons). During the final 90 minutes of CSS, MSEW mice had lower HRV total, LF, and HF power compared to controls (p<0.05); although HR, SBP, DBP, and activity remained similar between groups. These data suggest that MSEW mice have impaired autonomic control of HR and DBP and lack the ability to robustly respond and recover from an acute stressor. Reduced responsiveness of the autonomic nervous system may contribute to the increased risk of cardiovascular disease development in adult mice exposed to MSEW.
Abstract P222: Progesterone Induced Blocking Factor Decreases Hypertension, Mitochondrial Dysfunction And Reactive Oxygen Species In Response To Elevated Sflt-1 During Pregnancy
Authors: Deer Evangeline M , Comley Kyleigh , Cornelius Denise C , Jones Jalisa , Ibrahim Tarek , Vaka Ramana , Franks Michael , Amaral Lorena
Published: September 2020

Preeclampsia (PE) is characterized by new onset hypertension in association with placental ischemia, reduced fetal weight, elevated soluble fms-like tyrosine kinase-1 (sFlt-1) and placental mitochondrial (mt) dysfunction and oxidative stress (ROS). Infusion of sFlt-1 causes hypertension and other characteristics of PE in pregnant rodents. However a role for sFlt-1 in causing mt dysfunction and ROS is unknown. Progesterone induced blocking factor (PIBF), is a product of progesterone signaling which lowers inflammatory processes. We have shown that PIBF lowers blood pressure in a rat models of PE. This study was designed not only examine the role of mt ROS in sFlt-1 induced hypertension during pregnancy but to also examine the effect of PIBF to improve mt function and hypertension in response to elevated sFlt-1 during pregnancy. sFlt-1 was infused into normal pregnant (NP) Sprague-Dawley rats (3.7 μg·kg
–1
·day
–1
for 6 days, gestation days (GD) 13-19
)
in the presence or absence of PIBF (2.0 μg/mL) administered intraperitoneal on GD 15 to sFlt-1 induced hypertensive pregnant rats. Mean arterial blood pressure (MAP), placental and endothelial mt ROS and function were measured on GD 19. Infusion of sFlt-1 into NP rats increased MAP to 112
+
2 (n=11) compared with control NP rats 98
+
2 mmHg (n=15, p<0.05). Administration of PIBF reduced MAP to 100
+
1 mmHg in the presence of sFlt-1(n=5, p<0.05). Mt ROS in placenta was 108
+
6 in NP (n=4), 429
+
32 in NP+ sFlt-1(n=3) and reduced to 234
+
15 in NP+ sFlt-1+ PIBF (n=3). State 3 respiration, which is indicative of ATP production, was reduced in placentas of sFlt-1 infused rats versus NP, but was improved with PIBF. Moreover, sera from NP+sFlt-1 treated with PIBF attenuated endothelial cell mtROS ( 29
+
8 % gate) compared with sera from NP+sFlt-1 (54
+
15 % gate (n=4)). Our study indicates a role of sFlt-1 induced hypertension during pregnancy to reduce placental and endothelial cell mt function. Importantly, supplementation of PIBF improved mt function and ROS which was associated with improved blood pressure in sFlt-1 induced hypertensive pregnant rats indicating the efficacy of improved progesterone signaling as a potential therapeutic for PE.
Abstract P229: Site-1 Protease-derived Soluble (pro) Renin Receptor Mediates Aldosterone-induced Enac Activation In The Collecting Duct
Authors: Wang Fei , Luo Renfei , PENG KEXIN , Wu Peng , Liu Xiyang , Soodvilai Sunhapas , Wang Wen-Hui H , Yang Tianxin
Published: September 2020

We have previously shown that activation of (pro)renin receptor (PRR) induces epithelial Na
+
channel (ENaC) activity in cultured collecting duct cells. Here, we examined the role of soluble PRR (sPRR), generated by site-1 protease (S1P), a newly identified PRR cleavage protease, in ENaC regulation, and further tested its relevance to Aldo signaling. In cultured mpkCCD cells, administration of recombinant histidine-tagged sPRR (sPRR-His) at 10 nM for 24 h induced a significant increase in the amiloride-sensitive short-circuit current as assessed using the Ussing chamber technique (

I
eq

:
7.5 ± 0.7 μA/cm
2
in sPRR group vs. 3.5 ± 0.5 μA/cm
2
in vehicle group, n = 6, p < 0.01)
.
In primary cultured rat IMCD cells, the same sPRR-His treatment induced a 1.7 fold increase in protein expression of the α-subunit but not β- or γ-subunit of ENaC, in parallel with upregulation of mRNA expression as well as promoter activity of the α-subunit. The upregulation of α-ENaC transcription depended on β-catenin signaling. Consistent results obtained by epithelial volt ohmmeter measurement of equivalent current and Using chamber determination of short-circuit current showed that Aldo-induced ENaC activity was almost completely abolished by PF-429242 (PF), a S1P inhibitor, and the response was restored by supplement of sPRR-His (

I
eq

:
7.2 ± 0.7 μA/cm
2
in Aldo group vs. 5.0 ± 0.3 μA/cm
2
in Aldo/PF group vs. 6.8 ± 0.3 μA/cm
2
in Aldo/PF/sPRR-His group, n = 5, p < 0.05). Medium sPRR was elevated by Aldo and inhibited by PF. Male C57BL/6 mice were pretreated with PF (30 mg/kg/day) or vehicle via minipump, followed by 3 days of aldosterone (0.2 mg/kg/day via a second minipump). Amiloride-sensitive Na+ current in freshly isolated CCD as measured by using patch clamp lower in Aldo + PF group than in Aldo group. Together, these results support an essential role of S1P-derived sPRR in mediating Aldo-induced ENaC activation.
Abstract P230: Depletion Of Cyclic-gmp Levels And The Inhibition Of Cgks Activate P21
Cip1
/p27
Kip1
Pathways And Trigger High Blood Pressure With Renal Fibrosis And Dysfunction
Authors: Das Subhankar , Neelamegam Kandasamy , Peters Whitney N , Periyasamy Ramu , Pandey Kailash N
Published: September 2020

Targeted-deletion of
Npr1
gene (coding for guanylyl cyclase/natriuretic peptide receptor-A, GC-A/NPRA) exhibits hypertrophic and proliferative effects in target organs of
Npr
1 gene-knockout mice. Fibrosis and hypertrophy are regulated by p21
Cip1
and p27
Kip1
, cell-cycle regulatory proteins that inhibit target cyclin and cyclin-dependent kinase (cyclin-CDK) complex. We examined the activation of CDK blocker (p21
Cip1
/p27
Kip1
) in
Npr1
gene-knockout (0-copy;
Npr
1
-/-
) mice and guanylyl cyclase (GC) inhibitor, A71915-treated and cGMP-dependent protein kinase (cGK) inhibitor, Rp-8-Br-cGMPS (Rp)-treated wild-type 2-copy (
Npr
1
+/+
) and gene-duplicated 4-copy (
Npr
1
++/++
) mice. Blood pressure (BP) was significantly higher in 0-copy mice (138.6 ± 3.1 mmHg) and lower in 4-copy mice (86.0 ± 2.8 mmHg) than 2-copy mice (102.2 ± 1.7 mmHg). Treatment with A71915 and Rp showed significant changes in BP in 2-copy mice but caused only small increase in 4-copy mice. We found a significant decrease in renal cGMP levels with diminished cGK activity in 0-copy mice (p<0.0001) as well as A71915-treated (p<0.001) and Rp-treated (p<0.05) 2-copy and 4-copy mice as compared with controls animals. While significant activation of p-Erk1/2 (3-fold), p-p38MAPK (4-fold), p21
Cip1
(6-fold), and p27
Kip1
(5-fold) occurred in 0-copy, A71915-treated 2-copy, and A71915-treated 4-copy mice but Rp treatment caused minimal changes compared to control mice. There were significant increases in the proinflammatory cytokines, including TNF-α (6-fold), and IL-6 (3-fold) and profibrotic cytokine TGF-β1 (4-fold) in plasma and kidneys of 0-copy and A791915-treated 2-copy mice, but less in A71915-treated 4-copy mice than controls. Progressive renal pathology, including fibrosis, mesangial matrix expansion, tubular hypertrophy, and perivascular infiltration were significantly scored in 0-copy and A71915-treated 2-copy mice, but did so minimally in 4-copy mice compared with controls. The present results suggest that
Npr1
has a pivotal role in inhibiting the renal fibrosis and pathology and exerts renal protective effects through the cGMP/cGK axis by repressing the CDK inhibitors, p21
Cip1
and p27
Kip1
. This work was supported by NIH grant (HL062147).
Abstract P235: The Additive Genetic Association of Beta-2 Adrenergic Receptor and Serum-and-Glucocorticoid-Inducible Kinase 1 on Salt-Sensitive Hypertension
Authors: Yuan Yan Emily , Haas Andrea V , Yee Li En , Wong Yinhan , Williams Jonathan S , Adler Gail K , Williams Gordon H
Published: September 2020

Salt sensitivity of blood pressure (SSBP) is associated with increased cardiovascular morbidity. A diplotype on the beta 2 adrenergic receptor (β2AR) gene (rs1042713, rs1042714)—associated with increased aldosterone (ALDO)—and a polymorphism in the serum-and-glucocorticoid-inducible kinase 1 (SGK1) gene (rs2758151)—an ALDO target that increases sodium reabsorption—are each associated with SSBP. We hypothesized that SSBP will be increased in homozygotes for both β2AR and SGK1 (Combo) when compared to non-risk homozygotes and homozygotes in either gene alone.

The HyperPATH database includes individuals who completed 7 days of both restricted and liberal sodium diets to determine systolic SSBP. We conducted a gene association study in 329 individuals: 42 were homozygotes for Combo; 242 were homozygotes for β2AR or SGK1; and 45 were non-carriers.

Multivariate regression analyses (adjusted for age, sex, BMI, race, hypertension) found a significantly higher SSBP in the Combo homozygotes when compared to non-carriers and homozygotes for either β2AR or SGK1(p<0.001, 95% CI: 2.35, 7.56) (Figure 1). Serum ALDO levels were higher in Combo homozygotes than in the other groups (p=0.035, CI: 0.069,1.87). Additionally, analyses of either gene alone with SSBP (β2AR: p=0.056, CI: -0.038, 2.89; SGK1: p=0.003, CI: 0.87, 4.35) was less than what was observed in the Combo. In sum, Combo homozygotes for SGK1 and β2AR substantially increased the level of SSBP compared to that observed in risk allele homozygotes in each gene alone. Thus, hypertensive Combo homozygotes are likely candidates for mineralocorticoid receptor antagonist therapy—gene driven, personalized medicine.

Figure 1.
Abstract P241: Intermittent Fasting Lowers Blood Pressure In A Rat Model Of Hypertension By Modulating The Gut Microbiota
Authors: Shi Huanan , Abo-Hamzy Taylor , Bryan Robert M , Durgan David J
Published: September 2020

Studies have demonstrated that disruption of the gut microbiota, termed gut dysbiosis, plays a causal role in the development of hypertension (HT) in animal models and patients. Recent studies revealed that intermittent fasting alters the gut microbiota and the production of microbial metabolites. Thus, we hypothesized that every-other-day-fasting (EODF) would prevent elevations of blood pressure (BP) in spontaneously hypertensive stroke prone rat (SHRSP) by maintaining a healthy gut microbiota. Five-week old SHRSP rats and normotensive Wistar Kyoto (WKY) rats were randomized to be fed
ad lib
or on EODF for 10 weeks. BP was measured weekly, and cecal content and plasma were collected at the end of the study. To examine the roles of gut microbiota and microbial metabolites in hypertension, we performed whole-genome shotgun sequencing on cecal samples and non-targeted metabolomics on cecal contents and plasma. To examine the direct effects of the EODF altered microbiota on BP regulation and eliminate the confounding variable of fasting, pooled cecal contents of SHRSP and WKY animals fed
ad lib
or EODF were given to germ free (GF) rats by oral gavage. We found that ten-weeks EODF was able to prevent elevations of systolic BP (SBP) in SHRSP compared to
ad lib
fed SHRSP (~220 vs. ~170mmHg; n=6-8, p<0.05), and that germ free rats transplanted with SHRSP
ad lib
microbiota had a significantly higher SBP as compared to those transplanted with SHRSP EODF microbiota (~152 vs. ~140 mmHg; n=6-7, p<0.01), indicating that microbiota and their metabolites are accountable for the effects of EODF. Principle coordinate analysis showed that EODF significantly altered the overall composition of both WKY and SHRSP microbiota (WKY p<0.01, SHRSP p<0.009). Multi-omics analysis indicates distinct microbiome and metabolome in SHRSP compared to WKY, and significant alterations to each induced by EODF. These findings suggest that EODF is able to prevent hypertension in SHRSP, and this involves altering the gut microbiota and metabolome.
Abstract P242: Perivascular Adipose Tissue Regulates Endothelial Function And Glucose Disposal Via Leptin Control Of The 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 / NADPH Oxidase 1 Pathways
Authors: Atawia Reem T , Bruder-nascimento Thiago B , Horimatsu Tetsuo , Li Xueyi , Kennard Simone , CHEN Weiqin , Weintraub Neal L , Fulton David , Kim Ha Won W , Belin De Chantemele Eric J
Published: September 2020

Our group has previously reported that lack of adipose tissue (lipodystrophy) leads to glucose intolerance and impaired endothelial-dependent vasorelaxation (EDR) via reduced signaling of the adipokine, leptin in the endothelium. However, the identity of the adipose depot responsible for endothelial leptin signaling activation and the underlying mechanism remains ill-defined. Our new data indicate that the perivascular adipose tissue (PVAT) is an important source of leptin. Thus, we hypothesized that leptin specifically derived from PVAT restores EDR and glucose tolerance in a mouse model with global deficiency in adipose tissue (lipodystrophic, BSCL2
-/-
). Restoration of PVAT in BSCL2
-/-
mice corrected systemic glycemic status (GTT AUC, BSCL2
-/-
+ PVAT 635.3 ± 31.28 vs sham 741.6 ± 45.87, p<0.05). Moreover, PVAT transplantation restored EDR locally (abdominal aorta EDR AUC, BSCL2
-/-
+ PVAT 224.9 ± 23.97 vs 109 ± 19, P<0.05) but not systemically (thoracic aorta EDR AUC, BSCL2
-/-
+ PVAT 143.8 ± 22.29 vs sham 131.3 ± 11.54, P<0.05), indicating a distinctive paracrine role for PVAT-derived leptin in the vasculature. Concomitantly, we reported that inhibition of endothelial glycolysis, the main bioenergetic pathway of endothelial cells, via inhibition of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a major regulator of the glycolytic pathway, significantly improved endothelial function in both lipodystrophic mice and endothelial leptin receptor (LepR) deficient mice, as leptin does. Also, endothelial cells extracted from aortas of BSCL2
-/-
mice showed a trend towards an increase in PFKFB3 mRNA expression compared to WT mice. Moreover, we found that overexpression of PFKFB3 in aortic rings and endothelial cells impaired EDR and increased the ROS generating enzyme, Nox1 expression, respectively. Collectively, our results showed the critical role of PVAT-driven leptin and endothelial leptin receptor signaling in regulating systemic glucose disposal as well as endothelial function via a mechanism that potentially regulates endothelial glycolysis and oxidative stress-mediated via PFKFB3/NOX1.
Abstract P247: Gut Microbiota From A Rat Model Of Metabolic Syndrome Lowers Fitness Of High Exercise Capacity Rats (HCR/
Tol
) By Impairing Energy Homeostasis And Increasing Blood Pressure
Authors: Zhou Guannan , Yang Tao , Kumarasamy Sivarajan , Joe Bina , Koch Lauren G
Published: September 2020

Introduction:
Low exercise capacity is a strong predictor of cardiovascular disease and overall mortality. Previously we have shown that rats artificially selected for low intrinsic exercise capacity (LCR) have reduced longevity and develop features consistent with metabolic syndrome (MetS) compared to high intrinsic exercise capacity rats (HCR). Current knowledge suggests that gut microbiota is an important contributor for host fitness. Thus, we hypothesized that transferring gut microbiota from LCR rats into inbred high capacity runner (HCR
/Tol
) rats would increase risk factors for MetS, including high blood pressure (BP), gain in body weight (BW), and altered resting energy metabolism.

Methods:
Gut microbiota was depleted in male HCR/
Tol
rats (4 mo.) by an antibiotic cocktail given orally (50mg/kg of BW/day) for 5 days, followed by weekly fecal microbiota transfer (FMT) from male LCR or HCR rats (13 mo.) to generate HCR/
Tol
-LCR
FMT
(n = 5) or HCR/
Tol
-HCR
FMT
(n = 6) groups. BW was measured every 4 weeks. At week 11, whole body metabolism was measured by indirect calorimetry (Oxymax, Columbus Instruments). Respiratory Exchange Ratio (RER), Energy Expenditure (EE), glucose and fat oxidation were calculated from oxygen consumption and carbon dioxide release (VO
2
and VCO
2
). At week 12, BP was measured by tail-cuff method (Kent Scientific) and treadmill exercise test was done at week 13.

Results:
Compared to HCR/
Tol
-HCR
FMT
, HCR/
Tol
-LCR
FMT
showed a significant gain in BW (7.2% vs 1.9%, P<0.05), elevated systolic BP (147 vs 120 mmHg, P<0.0001), diastolic BP (112 vs 91 mmHg, P<0.01), and mean BP (123 vs 100 mmHg, P<0.001). BP changes in HCR/
Tol
-LCR
FMT
associated with 1) increased VO
2
(355 vs 320 ml/hr, P<0.05), 2) elevated VCO
2
(350 vs 298 ml/hr, P<0.01), 3) increased EE (1.8 vs 1.6 kcal/hr, P<0.01), 4) higher RER (0.96 vs 0.91, P<0.001), 5) higher glucose oxidation (1.36 vs 1.12 g/kg/hr, P<0.001) and 6) reduced fatty acid oxidation (0.09 vs 0.15 g/kg/hr, P<0.01) and a 23% lower exercise capacity.

Conclusions:
Gut microbiota from LCR rats strongly associated with poor health outcomes, notably elevated BP and impaired energy metabolism. These findings suggest that altered energy homeostasis by microbiota is mechanistically linked to host BP regulation within MetS.
Abstract P248: The Intake Of Dried Bonito Extract May Decrease Blood Pressure Through Antioxidant Effect In 2-kidney, 1-clip Renovascular Hypertensive Rats.
Authors: Maruyama Saki , Segawa Yukiko , Hashimoto Hiroko , Osera Tomoko , Kurihara Nobutaka
Published: September 2020

Objective:
Dried bonito is a processed marine product unique to Japan, and the hot water extracted product is widely used as soup stock. It has been reported that the dried bonito extract (DBE) has antioxidants. 2-kidney, 1-clip hypertensive (2K1C) rats is an experimental model of renovascular hypertension which is known to enhance the production of oxidative stress. Plasma thiobarbituric acid reactive substances (TBARS) level, a indicator for oxidative stress, was reported to increase in 2K1C rats when compared with sham operation (SHAM) rats. Moreover, previous studies have reported that intake of a few antioxidants ameliorate hypertension in 2K1C rats. Therefore, the intake of DBE may alleviate hypertension through antioxidant effect in 2K1C rats. To test the hypothesis, in the present study, we examined the effects of dietary intake of DBE intake on blood pressure (BP) of 2K1C rats. Additionally, to investigate the mechanism, we evaluated TBARS level in plasma in those rats.

Methods:
Male Sprague-Dawley rats (6 wks) were treated with SHAM or clipping the left renal artery (2K1C). After surgery, the rats started receiving a control diet (CTL), a diet with 5.0% (5 of 100, w/w) DBE for 6 consecutive weeks. Systolic BP (SBP) was measured by a tail-cuff method every week. At the end of the protocol, mean arterial pressure (MAP) was measured in each rat under anesthesia. Plasma lipid peroxide levels were determined by measuring TBARS using a colorimetric method. The TBARS level was determined by the absorbance at 532 nm.

Results:
Analysis of variance shows that SBP was significantly higher in 2K1C-CTL (152±4 mmHg) than SHAM-CTL (131±3 mmHg) through the experiment period (P<0.001), that SBP was lower in 2K1C-DBE (147±4 mmHg) than in 2K1C-CTL (P<0.05). At the end of the protocol, MAP showed the similar trend to SBP. TBARS level in 2K1C-CTL (1.06±0.03) was significantly higher than SHAM-CTL (1.00±0.03, P<0.05). Compared with 2K1C-CTL, a significant reduction in TBARS level was observed in 2K1C-DBE (0.96±0.11, P<0.05).

Conclusion:
The reduction of TBARS level may contribute to a mechanism by which DBE intake decreases BP in 2K1C rats.
Fragments of Fury? Lunacy, Agency, and Contestation in the Great Yarmouth Workhouse, 1890s–1900s
Authors: King Steven A. , Jones Peter
Published: September 2020

A methodological and philosophical focus on scandals has turned the workhouse that stands at the heart of popular and historiographical understandings of the English and Welsh New Poor Law (1834–1929) into a dark place of confinement and harsh treatment that the poor were largely powerless to resist. Yet viewed through the lens of interdisciplinary methods not often applied to the history of welfare—in particular, historical sociolinguistics and material-culture analysis—the pauper letters and “stitched” texts that have emerged from large-scale research projects reveal that inmates’ experience in the workhouse were not as dire, and their voices not as suppressed, as once supposed.
Unraveling the nomenclatural puzzle of the collared and white-lipped peccaries (Mammalia, Cetartiodactyla, Tayassuidae)
Authors: ACOSTA LUIS E. , GARBINO GUILHERME S. T. , GASPARINI GERMÁN M. , DUTRA RODRIGO PARISI
Published: September 2020

The nomenclatural history of the collared and white-lipped peccaries, two well-recognized taxonomic entities, has been confusing. From the 18th century to the beginning of the 20th century, several genera were created, most of them without an explicit designation of type species. Due to differing opinions as to whether the two species should be included in a single genus or, if separate genera were recognized, which generic name should be applied to each of the two taxa, the validity of generic and specific names oscillated until even recently. This paper aims to solve these nomenclatural issues by reviewing the different taxonomic arrangements of these two peccaries and applying appropriately the International Code on Zoological Nomenclature. We contend that the valid generic name for the white-lipped peccary is Tayassu Fischer, 1814 (type Sus pecari Link, 1795), while Dicotyles Cuvier, 1816 (type Dicotyles torquatus Cuvier, 1816) is the valid genus for the collared peccary, with Pecari Reichenbach, 1835 as its junior synonym.
The Southern Hemisphere Midlatitude Circulation Response to Rapid Adjustments and Sea Surface Temperature Driven Feedbacks
Authors: Wood T. , Maycock A. C. , Forster P. M. , Richardson T. B. , Andrews T. , Boucher O. , Myhre G. , Samset B. H. , Kirkevåg A. , Lamarque J.-F. , Mülmenstädt J. , Olivié D. , Takemura T. , Watson-Parris D.
Published: September 2020

Rapid adjustments—the response of meteorology to external forcing while sea surface temperatures (SST) and sea ice are held fixed—can affect the midlatitude circulation and contribute to long-term forced circulation responses in climate simulations. This study examines rapid adjustments in the Southern Hemisphere (SH) circulation using nine models from the Precipitation Driver and Response Model Intercomparison Project (PDRMIP), which perform fixed SST and coupled ocean experiments for five perturbations: a doubling of carbon dioxide (2xCO2), a tripling of methane (3xCH4), a fivefold increase in sulfate aerosol (5xSO4), a tenfold increase in black carbon aerosol (10xBC), and a 2% increase in solar constant (2%Sol). In the coupled experiments, the SH eddy-driven jet shifts poleward and strengthens for forcings that produce global warming (and vice versa for 5xSO4), with the strongest response found in austral summer. In austral winter, the responses project more strongly onto a change in jet strength. For 10xBC, which induces strong shortwave absorption, the multimodel mean (MMM) rapid adjustment in DJF jet latitude is ~75% of the change in the coupled simulations. For the other forcings, which induce larger SST changes, the effect of SST-mediated feedbacks on the SH circulation is larger than the rapid adjustment. Nevertheless, for these perturbations the magnitude of the MMM jet shift due to the rapid adjustment is still around 20%–30% of that in the coupled experiments. The results demonstrate the need to understand the mechanisms for rapid adjustments in the midlatitude circulation, in addition to the effect of changing SSTs.
Stress Reactivity: What Pushes Us Higher, Faster, and Longer—and Why It Matters
Authors: Kiecolt-Glaser Janice K. , Renna Megan E. , Shrout M. Rosie , Madison Annelise A.
Published: September 2020

Brief everyday stressors can provoke cardiovascular, hormonal, and immune changes, and the magnitude and duration of these responses can vary considerably. Acute responses to daily stressors can differ widely among individuals experiencing the same stressor, and these physiological responses may not align with stress appraisals. This review highlights individual and dyadic factors that may heighten and prolong stress reactivity, along with their implications for health. We discuss depression, rumination, early life adversity, and social evaluation as individual-level factors and interpersonal stress processes and relationship quality as dyadic-level factors that may influence physiological stress responses. Heightened and prolonged stress reactivity can provide a gateway to the physiological dysregulation that underlies depression and chronic disease, which themselves alter stress reactivity—a vicious cycle. Interventions that may dampen physiological stress reactivity include yoga, meditation, health behaviors (diet, exercise, and sleep), and cognitive behavior therapy.
Life is not chess: Towards a dynamic theory on altruism
Authors: Ahmed Zarak
Published: September 2020

Economic theory propagates a model of the human being commonly known as homoeconomicus; an individual with a rational orientation directed towards maximizing his/her preferences. However, our everyday lives involve many altruistic acts. These can range from small gestures of kindness such as holding a door open for another person, to heroic feats such as risking one's life to save a child from drowning. During our lives we also meet certain people that instantly induce our kindness. Our nicety in these moments is not based on a pursuit to optimize our material desires. Rather, we allow our feelings and intuitions to guide the course of our actions. How do we reconcile these experiences against the economic conception of human nature as inherently selfish? Addressing this contradiction, the paper will deconstruct the economic view and repositioning it as the product of an epistemological stance that distorts our view of altruism. An alternative model on altruism will then be developed by merging anthropological theories on value with insights from cultural psychology and grounded cognition. Through this process, a passage will be shown from static and universalizing perspective towards an emergent and dynamic theory on altruism.
Polarisation, accountability, and interstate conflict
Authors: Gallop Max , Greene Zachary
Published: September 2020

Voters constrain democratic leaders’ foreign policy decisions. Yet, studies show that elite polarisation restricts the choices available to voters, limiting their ability to punish or reward incumbent governments. Building on a comparative elections and accountability perspective, we hypothesise that the governing context moderates the effectiveness of domestic punishment and reward. The rise of elite polarisation in many democracies undermines voters’ ability to sanction leaders through elections. Linking data on international crises to domestic polarisation, we find that leaders are more likely to be involved in the initiation of inter-state disputes, resulting disputes will be more likely to result in prolonged conflict, and ultimately that foreign policy outcomes exhibit greater variance. Results from our analysis and extensive robustness checks demonstrate evidence that increased dispersion of preferences among key actors can lead to extreme and negative foreign policy outcomes as electoral mechanisms fail to reign in and hold governing parties to account.
Delusional content at initial presentation to a catchment-based early intervention service for psychosis
Authors: Lemonde Ann-Catherine , Joober Ridha , Malla Ashok , Iyer Srividya N. , Lepage Martin , Boksa Patricia , Shah Jai L.
Published: September 2020

Background

During a psychotic episode, patients frequently suffer from severe maladaptive beliefs known as delusions. Despite the abundant literature investigating the simple presence or absence of these beliefs, there exists little detailed knowledge regarding their actual content and severity at the onset of illness.

Aims

This study reports on delusions during the initiation of indicated treatment for first-episode psychosis (FEP).

Method

Data were systematically collected from a sample of 636 patients entering a catchment-based early intervention service for FEP. The average severity and frequency of each delusional theme at baseline was reported with the Scale for the Assessment of Positive Symptoms. Delusional severity (globally and per theme) was examined across a number of sociodemographic and clinical variables.

Results

Delusions were present in the vast majority of individuals experiencing onset of FEP (94%), with persecutory (77.7%) being the most common theme. Persecutory delusions remained consistent in severity across diagnoses, but were more severe with older age at onset of FEP. No meaningful differences in delusional severity were observed across gender, affective versus non-affective psychosis, or presence/absence of substance use disorder. Globally, delusion severity was associated with anxiety, but not depression. Delusions commonly referred to as passivity experiences were related to hallucinatory experiences.

Conclusions

This community sample offers a rare clinical lens into the severity and content of delusions in FEP. Although delusional severity was consistent across certain sociodemographic and clinical variables, this was not always the case. Future research should now consider the course of delusion themes over time.
Age Dependency of the Prognostic Impact of Tumor Genomics in Localized Resectable MYCN-Nonamplified Neuroblastomas. Report From the SIOPEN Biology Group on the LNESG Trials and a COG Validation Group
Authors: Ambros Inge M. , Tonini Gian-Paolo , Pötschger Ulrike , Gross Nicole , Mosseri Véronique , Beiske Klaus , Berbegall Ana P. , Bénard Jean , Bown Nick , Caron Huib , Combaret Valérie , Couturier Jerome , Defferrari Raffaella , Delattre Olivier , Jeison Marta , Kogner Per , Lunec John , Marques Barbara , Martinsson Tommy , Mazzocco Katia , Noguera Rosa , Schleiermacher Gudrun , Valent Alexander , Van Roy Nadine , Villamon Eva , Janousek Dasa , Pribill Ingrid , Glogova Evgenia , Attiyeh Edward F. , Hogarty Michael D. , Monclair Tom F. , Holmes Keith , Valteau-Couanet Dominique , Castel Victoria , Tweddle Deborah A. , Park Julie R. , Cohn Sue , Ladenstein Ruth , Beck-Popovic Maja , De Bernardi Bruno , Michon Jean , Pearson Andrew D. J. , Ambros Peter F.
Published: September 2020

PURPOSE

For localized, resectable neuroblastoma without MYCN amplification, surgery only is recommended even if incomplete. However, it is not known whether the genomic background of these tumors may influence outcome.

PATIENTS AND METHODS

Diagnostic samples were obtained from 317 tumors, International Neuroblastoma Staging System stages 1/2A/2B, from 3 cohorts: Localized Neuroblastoma European Study Group I/II and Children’s Oncology Group. Genomic data were analyzed using multi- and pangenomic techniques and fluorescence in-situ hybridization in 2 age groups (cutoff age, 18 months) and were quality controlled by the International Society of Pediatric Oncology European Neuroblastoma (SIOPEN) Biology Group.

RESULTS

Patients with stage 1 tumors had an excellent outcome (5-year event-free survival [EFS] ± standard deviation [SD], 95% ± 2%; 5-year overall survival [OS], 99% ± 1%). In contrast, patients with stage 2 tumors had a reduced EFS in both age groups (5-year EFS ± SD, 84% ± 3% in patients < 18 months of age and 75% ± 7% in patients ≥ 18 months of age). However, OS was significantly decreased only in the latter group (5-year OS ± SD in < 18months and ≥ 18months, 96% ± 2% and 81% ± 7%, respectively; P = .001). In < 18months, relapses occurred independent of segmental chromosome aberrations (SCAs); only 1p loss decreased EFS (5-year EFS ± SD in patients 1p loss and no 1p loss, 62% ± 13% and 87% ± 3%, respectively; P = .019) but not OS (5-year OS ± SD, 92% ± 8% and 97% ± 2%, respectively). In patients ≥ 18 months, only SCAs led to relapse and death, with 11q loss as the strongest marker (11q loss and no 11q loss: 5-year EFS ± SD, 48% ± 16% and 85% ± 7%, P = .033; 5-year OS ± SD, 46% ± 22% and 92% ± 6%, P = .038).

CONCLUSION

Genomic aberrations of resectable non– MYCN-amplified stage 2 neuroblastomas have a distinct age-dependent prognostic impact. Chromosome 1p loss is a risk factor for relapse but not for diminished OS in patients < 18 months, SCAs (especially 11q loss) are risk factors for reduced EFS and OS in those > 18months. In older patients with SCA, a randomized trial of postoperative chemotherapy compared with observation alone may be indicated.
Exercise Training Reduces Inflammation of Adipose Tissue in the Elderly: Cross-Sectional and Randomized Interventional Trial
Authors: Čížková Terezie , Štěpán Marek , Daďová Klára , Ondrůjová Barbora , Sontáková Lenka , Krauzová Eva , Matouš Miloš , Koc Michal , Gojda Jan , Kračmerová Jana , Štich Vladimír , Rossmeislová Lenka , Šiklová Michaela
Published: September 2020

Context

Metabolic disturbances and a pro-inflammatory state associated with aging and obesity may be mitigated by physical activity or nutrition interventions.

Objective

The aim of this study is to assess whether physical fitness/exercise training (ET) alleviates inflammation in adipose tissue (AT), particularly in combination with omega-3 supplementation, and whether changes in AT induced by ET can contribute to an improvement of insulin sensitivity and metabolic health in the elderly.

Design, Participants, Main Outcome Measures

The effect of physical fitness was determined in cross-sectional comparison of physically active/physically fit (trained) and sedentary/less physically fit (untrained) older women (71 ± 4 years, n = 48); and in double-blind randomized intervention by 4 months of ET with or without omega-3 (Calanus oil) supplementation (n = 55). Physical fitness was evaluated by spiroergometry (maximum graded exercise test) and senior fitness tests. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp. Samples of subcutaneous AT were used to analyze mRNA gene expression, cytokine secretion, and immune cell populations.

Results

Trained women had lower mRNA levels of inflammation and oxidative stress markers, lower relative content of CD36+ macrophages, and higher relative content of γδT-cells in AT when compared with untrained women. Similar effects were recapitulated in response to a 4-month ET intervention. Content of CD36+ cells, γδT-cells, and mRNA expression of several inflammatory and oxidative stress markers correlated to insulin sensitivity and cardiorespiratory fitness.

Conclusions

In older women, physical fitness is associated with less inflammation in AT. This may contribute to beneficial metabolic outcomes achieved by ET. When combined with ET, omega-3 supplementation had no additional beneficial effects on AT inflammatory characteristics.
ARMC5 Alterations in Patients With Sporadic Neuroendocrine Tumors and Multiple Endocrine Neoplasia Type 1 (MEN1)
Authors: Damjanovic Svetozar S , Antic Jadranka A , Elezovic-Kovacevic Valentina I , Dundjerovic Dusko M , Milicevic Ivana T , Beleslin-Cokic Bojana B , Ilic Bojana B , Rodic Gordana S , Berthon Annabel , Maria Andrea Gutierrez , Faucz Fabio R , Stratakis Constantine A
Published: September 2020

Context

Adrenal lesions are frequent among patients with sporadic neuroendocrine tumors (spNETs) or multiple endocrine neoplasia type 1 (MEN1). Armadillo repeat-containing 5 (ARMC5)-inactivating variants cause adrenal tumors and possibly other neoplasms.

Objective

The objective of this work is to investigate a large cohort spNETs or MEN1 patients for changes in the ARMC5 gene.

Patients and Methods

A total of 111 patients, 94 with spNET and 17 with MEN1, were screened for ARMC5 germline alterations. Thirty-six tumors (18 spNETs and 18 MEN1 related) were collected from 20 patients. Blood and tumor DNA samples were genotyped using Sanger sequencing and microsatellite markers for chromosomes. ARMC5 and MEN1 expression were assessed by immunohistochemistry.

Results

In 76 of 111 (68.4%) patients, we identified 16 different ARMC5 germline variants, 2 predicted as damaging. There were no differences in the prevalence of ARMC5 variants depending on the presence of MEN1-related adrenal lesions. Loss of heterozygosity (LOH) at chromosome 16p and ARMC5 germline variants were present together in 23 or 34 (67.6%) tumors; in 7 of 23 (30.4%) their presence led to biallelic inactivation of the ARMC5 gene. The latter was more prevalent in MEN1-related tumors than in spNETs (88.9% vs 38.9%; P = .005). LOH at the chromosome 16p (ARMC5) and 11q (MEN1) loci coexisted in 16/18 MEN1-related tumors, which also expressed lower ARMC5 (P = .02) and MEN1 (P = .01) proteins compared to peritumorous tissues.

Conclusion

Germline ARMC5 variants are common among spNET and MEN1 patients. ARMC5 haploinsufficiency or biallelic inactivation in spNETs and MEN1-related tumors suggests that ARMC5 may have a role in modifying the phenotype of patients with spNETs and/or MEN1 beyond its known role in macronodular adrenocortical hyperplasia.
Loss of CREBRF Reduces Anxiety-like Behaviors and Circulating Glucocorticoids in Male and Female Mice
Authors: Frahm Krystle A , Williams Akeem A , Wood Ashlee N , Ewing Michael C , Mattila Polly E , Chuan Byron W , Guo Lanping , Shah Faraaz A , O’Donnell Christopher P , Lu Ray , DeFranco Donald B
Published: September 2020

Glucocorticoid signaling controls many key biological functions ranging from stress responses to affective states. The putative transcriptional coregulator CREB3 regulatory factor (CREBRF) reduces glucocorticoid receptor levels in vitro, suggesting that CREBRF may impact behavioral and physiological outputs. In the present study, we examined adult male and female mice with global loss of CREBRF (CrebrfKO) for anxiety-like behaviors and circulating glucocorticoids in response to various acute stress conditions. Results demonstrate that both male and female CrebrfKO mice have preserved locomotor activity but reduced anxiety-like behaviors during the light–dark box and elevated plus maze. These behavioral phenotypes were associated with lower plasma corticosterone after restraint stress. Further studies using unhandled female mice also demonstrated a loss of the diurnal circulating corticosterone rhythm in CrebrfKO mice. These results suggest that CREBRF impacts anxiety-like behavior and circulating glucocorticoids in response to acute stressors and serves as a basis for future mechanistic studies to define the impact of CREBRF in glucocorticoid-associated behavioral and physiological responses.