bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Ying And Yang Of Antibiotic Discovery And Resistance
Authors: Wright Gerry 
Published: November 2023

Resistance to antibiotics is ancient and pervasive in the microbial world. The presence of resistance elements in the genomes of virtually all bacteria and their ability to circulate across genera presents a daunting challenge to the drug discovery sector. The tension between antibiotic discovery and resistance must be managed in order to maintain an ability to produce new drugs and antimicrobial regimens needed by medicine. By harnessing our understanding of the natural history of antibiotic biosynthesis and resistance we can direct efforts to identify candidates for new drugs. One such approach is through applying resistance as a filter to identify microbes that produce known classes of antibiotics. Another is to target resistance itself to find potential co‐drugs that can be used in combination with antibiotics. We have develop a cell‐based platform that can be applied in both strategies. Using this approach, we have identified new inhibitors of resistance and producers of new and rare antibiotics.Support or Funding InformationThis work is supported by the Canadian Institutes of Health Research and the Natural Sciences and Engineering Research Council of Canada.
Greater β‐Adrenergic Receptor Mediated Vasodilation in Women Using Oral Contraceptives
Authors: Peltonen Garrett L , Limberg Jacqueline K , Johansson Rebecca E , Harrell John W , Kellawan J. Mikhail , Crain Meghan K , Eldridge Marlowe W , Sebranek Joshua J , Walker Benjamin J , Schrage William G 
Published: November 2023

Premenopausal women exhibit greater peripheral β‐adrenergic receptor (β‐AR) mediated vasodilation when compared to postmenopausal women, suggesting changes in female sex hormones may alter neurovascular control. Oral contraceptive use modulates cyclic hormonal profiles and therefore may influence β‐AR mediated vasodilation. We hypothesized β‐AR mediated vasodilation is greater in young (24±1 yrs), healthy women using oral contraceptives (OC+, n=13) compared to those not using oral contraceptives (OC−, n=12). Forearm blood flow (FBF) was measured by Doppler ultrasound during graded brachial artery infusion of the β‐AR agonist, isoproterenol (ISO: 1, 3, 6, and 12 ng/100g lean tissue/min). Forearm vascular conductance was calculated (FVC = FBF/MAP, ml/min/100mmHg), and the rise in FVC during ISO infusion (DFVC; FVCinfusion − FVCbaseline) was used to quantify β‐AR mediated vasodilation. Women were studied during the early follicular phase of the menstrual cycle (days 1–5) or low hormone phase of oral contraceptive use. ISO increased FVC in both groups (p<0.001). In support of our hypothesis, ISO mediated ΔFVC was greater in OC+ compared to OC− (main effect of group, p=0.020). Expressing data as FVC, FBF, and ΔFBF resulted in similar conclusions. These data are the first to demonstrate greater β‐AR mediated vasodilation in OC+ compared to OC−, and suggest altered hormonal profiles associated with oral contraceptive use may influence neurovascular control.Support or Funding InformationNIH R01 HL105820
Renal Afferent Neurons are altered by Lipopolysaccharides (LPS)
Authors: Rodionova Kristina , Ditting Tilmann , Loosen Sonja , Ziemer Martin , Linz Peter , Ott Christian , Schmieder Roland E , Amann Kerstin , Veelken Roland 
Published: November 2023

Sympathetic renal nerve activity (RSNA) is dramatically increased in lipopolycaccharide (LPS)‐incduced SIRS. This might be due to altered properties of renal afferent nerves (RANs), which exert complex neurogenic sympatho‐modulatory and paracrine effects. Hence, we wanted to test the hypotheses that LPS alters the TRPV1 receptor induced CGRP release from RANs in kidney tissue slices and/or the firing patterns and acid induced inward currents in cultured neurons. 1.) Anethetized male Sprague‐Dawley rats were treated with (E.coli O127/B8,20mg/kg IV) while blood pressure (BP), heart rate (HR), RSNA was measured. 2.)Dorsal root ganglion neurons (Th11‐L2) of rats were incubated with LPS (E.coli O127/B8,20mg/l) 12h before patch clamp recordings. Inward currents were assessed during stimulation of TRPV1 and ASICs with protons (pH6,9 and 5,0). Current clamp mode was performed at physiological conditions and after 12h of LPS‐incubation. Neurons were characterized as tonic, i.e. sustained AP firing or phasic, i.e.<5 APs in response to current injections. In an organ bath of kidney slices – incubated with or without LPS ‐ we stimulated TRPV1 receptors with Capsaicin and subsequently measured CGRP content in the organ bath supernatant (ELISA).1.) In vivo measurements showed a strong increase of RSNA (+250%, p<0.05) and HR (+25%, p<0.05) while BP did not change significantly. 2.) Firing patterns and currents induced by acidic superfusion were studied in 246 neurons. Renal neurons (RNs) exhibited in 59% tonic firing pattern under control conditions. The number of neurons with tonic response was significantly reduced by exposure to LPS (59% vs.42%, p<0,05). Under control conditions 70,8% of RNs exhibited both sustained and transient inward currents, whereas 29,2% showed sustained current only. LPS exposure significantly increased sustained, i.e. TRPV1 induced current (−793,18+/−66pA vs.−1224+/−200pA,p<0,05) and transient, i.e. ASICs induced inward current even under subthreshold proton stimulation (pH6,9) which could not be enhanced further by pH5,0. 3. Neurogenic CGRP release from kidney due to TRPV1 stimulation was also significantly increased after LPS incubation (LPS: 58□20 pg/ml, control: 14□2, *p<0.05).LPS altered the properties of neurons with renal axons in a complex way: while the ease of AP production was significantly decreased, the responsiveness to acidic milieu was increased. The TRPV1 induced CGRP release (likely from renal afferent nerves) was also increased.In how far these findings subserve neurogenic alterations in the kidney due to increased sympathetic drive and neural peptide release during experimental sepsis needs further research.
Functional changes of rostral ventrolateral medulla by nitric oxide from iNOS in conscious obese rats
Authors: Martins‐Pinge Marli Cardoso , Lopes Fernanda Novi Cortegoso , Zanluqui Nagela Ghabdan , Pinge‐Filho Phileno 
Published: November 2023

The literature shows that obese animals present changes in the production of nitric oxide (NO). NO plays an important role in cardiovascular function, and the production via the inducible NO‐synthase (iNOS) is linked to inflammatory processes. In the rostral ventrolateral medulla (RVLM), glutamate is an important neurotransmitter and is modulated by NO. We aimed to evaluate the effects of L‐glutamate microinjection in RVLM on mean arterial pressure (MAP) and heart rate (HR) before and after microinjection of iNOS inhibitors and to asses NO (nitrite) in punchs of RVLM. The protocols were approved by our institutional ethic committee (process number: 33645/2010‐29). Neonatal Wistar rats received subcutaneous administration of 4 mg/g body weight of monosodium glutamate (MSG) or saline in the first 5 days of life. At 90 days were implanted cannulas guide to RVLM and after after 5 days, we performed catheterization of the femoral artery. After 24 hours the MAP and HR were recorded. The cardiovascular effects of glutamate (5nmol/100 ml) were evaluated before and after microinjection of aminoguanidine (AG) (250pmol/100NL) or S‐methylisothiourea (SMT) (250 pmol/100 ml) or physiological saline (100 ml) at RVLM. The increased MAP by L‐glutamate was higher in the obese group after AG (before: 40 mmHg ± 8; after: 61 ± 4 mmHg, n = 5) and SMT (before: 45± 8 mmHg; after: 65 ± 2 mmHg, n = 5). NO contend in the RVLM, showed a trend of MSG group is increased compared to the CTR (CTR 1.24 ± 0.33 uM/mg, n = 6; MSG 2.7 ± 1 uM/mg, n = 5). The data suggest that NO, probable derived from iNOS seems to be increased in RVLM of obese rats, and may have a role in the RVLM‐mediated cardiovascular responses.Support or Funding InformationCAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior)
Renal Denervation in male rats attenuates changes in cardiac sympathetic innervation in post‐infarction heart failure
Authors: Pinkham Maximilian I , Loftus Michael , Amirapu Satya , Barrett Carolyn J 
Published: November 2023

Following myocardial infarction (MI) a decrease in the expression of sympathetic nerves in the myocardium remote from the infarct has been observed. Reduced sympathetic innervation of the cardiac ventricles is implicated in attenuated contractility and arrhythmia development, contributing to the development and progression of heart failure. Renal denervation is currently being investigated both clinically and experimentally as a treatment for heart failure, yet the precise mechanisms by which renal denervation may be beneficial are not completely understood. In the current study we set out to determine the effects of renal denervation on the expression of sympathetic nerves in the cardiac ventricles of rats with post‐infarction heart failure. MI or sham MI was performed in male Wistar rats and 4 weeks later renal denervation or sham surgery was performed. 7 weeks post‐MI, left ventricle function was assessed and then the hearts were removed and post‐fixed overnight in paraformaldehyde (4%). The hearts were then embedded in paraffin wax and stored until processing. Tyrosine‐hydroxylase (TH) immunoreactivity (IR) was used to visualize the sympathetic nerves and PGP 9.5 IR was used to visualize total nerves. The area density of the target nerves was quantitatively assessed using threshold discrimination. In sham MI animals, renal denervation did not alter the density or distribution of sympathetic and total nerves in the left and right ventricles. In the MI groups, the myocardium directly adjacent to the infarct border zone (peri‐infarct) displayed significantly reduced nerve density, almost complete denervation, when compared to areas remote from the infarct and this effect was unaltered by renal denervation. In both MI groups, particular areas within the infarct were observed to have a high density of sympathetic innervation. In animals with intact renal nerves, post‐infarction heart failure resulted in reduced expression of sympathetic and total nerves in the left and right ventricles, remote from the infarct. Renal denervation in animals with post‐infarction heart failure increased the sympathetic and total nerve density in the left and right ventricles remote from the infarct thereby abolishing the statistically significant difference in nerve density when compared to sham MI group. The current findings suggest that renal denervation may be beneficial in heart failure via attenuating adverse changes in cardiac innervation. In particular, renal denervation resulted in the conservation of sympathetic nerves in the ventricles consistent with improved contractility and reduced arrythmogenisis.Support or Funding InformationThis research was supported by a grant from The National Heart Foundation of New Zealand
High fat diet induced hypertension and impaired glucose tolerance in the Obesity‐Prone Sprague Dawley rat: Effect of increased salt intake and renal denervation
Authors: Han Ruijun , Banek Christopher T , Asirvatham‐Jeyaraj Ninitha , Wang Xinying , Osborn John 
Published: November 2023

Cardiovascular disease, including hypertension (HTN), remains a leading cause of morbidity and mortality worldwide. Indeed, high fat (HFD) and high salt (HSD) diets are closely linked to HTN development, but the mechanisms remain undefined. Moreover, HTN in these models is widely attributed to an increase in sympathetic nerve activity, particularly to the kidney, which is attenuated renal denervation (RDNX). This study was designed to elucidate the combined effects HFD and HSD in the development of HTN. Further, we hypothesized that HTN and impaired glucose tolerance commonly induced by a HFD would be exacerbated by increased salt intake. In addition, we predicted these effects would be attenuated or reversed by RDNX. To test this hypothesis, obesity prone Sprague Dawley male rats were fed with either a low fat diet (LFD; 10 KCal% fat, n=12) or a high fat diet (HFD; 45 KCal% fat, n=12) for 8 weeks, then switched to either a low (0.26% sodium chloride, LSD, n=5) or high sodium (4% sodium chloride, HSD, n=7) diet for an additional 6 weeks. Mean arterial pressure (MAP) was measured by radiotelemetry, and bodyweight and glucose clearance were also measured. At study termination, tissues and plasma were collected for further analysis. HFD rats exhibited increased body weight, and impaired glucose tolerance compared to LFD rats. Addition of HSD feeding had no additional effect on bodyweight or glucose tolerance. MAP in HFD rats was higher (123±2 mmHg) compared to LFD rats (114±2mmHg). HSD had no further hypertensive effect in HFD‐treated animals. RDNX normalized MAP in HFD fed rats and HFD+HSD fed rats, but had no effect on the bodyweight or glucose tolerance. Assessment of renal and peripheral inflammation is currently underway. Together, these findings indicate that addition of a HSD to obese hypertensive rats does not exacerbate HTN and or impaired glucose tolerance. Further study of these intriguing effects in experimental and clinical models is necessary to accurately assess the dietary contribution to cardiovascular and metabolic disease.Support or Funding InformationSupported by RO1HL116476
The Role of G Protein‐Coupled Estrogen Receptor (GPER) in the PVN of Renovascular Hypertensive Rats
Authors: Maruyama Nadia Oliveira , Estrela Heder Frank , Lucas Thais F. , Porto Catarina Segreti , Bergamaschi Cassia Toledo , de Campos Ruy Ribeiro 
Published: November 2023

It is well stablished that 17β‐estradiol acting on classic estrogen receptors is a cardiovascular protector in part via reduction of sympathetic vasomotor activity. However, there is no information regarding the G protein‐coupled estrogen receptor (GPER) actions in the paraventricular nucleus of hypothalamus (PVN) in the 2kidney‐1clip (2K‐1C) Goldblatt hypertension model. Thus, we investigated the role of GPER within the PVN on sympathetic vasomotor activity in 2K‐1C male Wistar rats. Protein expression of GPER within the PVN was evaluated by Western blot assay. Bilateral microinjection of G1 (GPER agonist) into the PVN was performed in control (C) and 2K‐1C rats, six weeks after renal clipping. Renal sympathetic nerve activity (rSNA) and mean arterial blood pressure (MAP) were recorded in urethane anesthetized rats (1,4 g/Kg, IV). A significant increase in GPER (563 ± 71% n=6) expression was found in 2K‐1C rats. G1 into the PVN induced significantly larger increase in rSNA in 2K‐1C rats (C,Δ 15.60 ± 4.885 n=5 and 2K1C,Δ 40.17 ± 4.199 n=6). However, there was no significant effect on MAP in both groups. Chronic 2K‐1C Losartan‐treated rats (30 mg/Kg/day for 7 consecutive days) significantly reduced GPER expression in the PVN (70%, n=4). The increase in GPER activity seems to contribute for the renal sympathoexcitation in renovascular hypertension. Apparently, Angiotensin II AT1 receptor is important for the PVN GPER upregulation in Goldblatt rats.Support or Funding InformationSuported by: FAPESP, CAPES and CNPq
Roles Of Central α2 And AT1 Signal Transduction Via Gαi2 Proteins In Blood Pressure Regulation In Response To An Acute Sodium Challenge
Authors: Shim Joon W , Wainford Richard David , Carmichael Casey Yumi 
Published: November 2023

AimWe have previously reported that central Gαi2 proteins are required to suppress sympathetic outflow and restore blood pressure to baseline levels following an acute 3M NaCl challenge in conscious rats. The objective of this study was to establish the roles of central α2 Adrenergic and Angiotensin II type I (AT1) receptors in the activation of brain Gαi2 pathways in response to an acute sodium challenge to restore normotension.MethodsMale Sprague Dawley rats pre‐treated (24‐h) with an intracerebroventricular injection of a targeted Gαi2 oligodeoxynucleotide (ODN) (25 μg/5 μL) to downregulate brain Gαi2 protein expression or a scrambled (SCR) control ODN and were challenged with an acute sodium load (HS: intravenous bolus 3 M NaCl; 0.14 mL/100 g). In additional groups rats were pretreated 10‐min prior to an acute 3M bolus NaCl challenge with either yohimbine (α2 adrenergic receptor antagonist, 5.9 μg in 5 μl), or losartan (AT1 antagonist, 7.5 μg in 2 μl). In all treatment groups cardiovascular parameters (HR, MAP) were monitored for 120‐minutes (N=4–6 group).ResultsIn response to an acute sodium load no difference was observed in peak change in mean arterial pressure (MAP) between Gαi2 and SCR ODN treated groups (peak ΔMAP [mmHg] SCR +17 ± 4 vs. Gαi2 +13 ± 3). However, MAP remained elevated 120‐min post sodium challenge in Gαi2 but not control SCR ODN treated rats (ΔMAP 100‐min post HS [mmHg] SCR +2 ± 3 vs. Gαi2 ODN: +13 ± 1, P<0.05). Central AT1 antagonism attenuated the peak pressor response to acute sodium challenge (peak ΔMAP [mmHg] SCR +17 ± 4 vs. losartan +11 ± 2, P<0.05) and decreased the time required to restore MAP to baseline from 100‐min to 50‐min (P<0.05). Central α2 adrenoceptor antagonism exacerbated the peak pressor response to acute sodium challenge (peak ΔMAP [mmHg] SCR +17 ± 4, Gαi2 +13 ± 3 vs. yohimbine +24 ± 3, P<0.05) and the magnitude of sodium evoked‐hypertension over the first 60‐min post sodium challenge.ConclusionThese data highlight differential roles of central α2 and AT1 receptors in blood pressure regulation in response to an acute sodium challenge. The sympathoexcitatory pressor response to IV bolus sodium is mediated, in part, via central AT1 receptor activated Gai2‐independent signal transduction pathways. In contrast both α2 adrenoceptors contribute to the sympathoinhibitory hypotensive response to restore normotension following an acute sodium challenge, in part, via Gai2 signal transduction pathways. These data, and our prior studies, suggest that in response to acute challenges to sodium homeostasis α2 adrenoceptor activation evokes sympathoinhibition and hypotension via down stream pathways that involve Gai2 protein‐gated signal transduction.Support or Funding InformationNHLBI R01HL107330, K02HL1127182
PETCO2 In Women at Sea‐Level and Upon Acute Exposure to Normobaric Hypoxic Environments Simulating 3,500 m
Authors: Kambis Ken , Yasukawa Michio , Moran Thomas , Pleasant Austen , Hafner Gabriella , Barbour Veronique , Duckworth Courtney , Muza Stephen , Looft‐Wilson Robin 
Published: November 2023

A prior study in men (Reeves, J. Appl. Physiol. 75: 1993) demonstrated that the ventilatory response to high altitude is highly variable among sea level residents, but the sea level end‐tidal PCO2 (PETCO2, a measurement of effective alveolar ventilation) is highly predictive of subsequent ventilation at high altitude. While prior work suggests that women and men have similar ventilatory responses to high altitude (Muza, J. Appl. Physiol. 91: 2001), no studies have determined if women's sea level PETCO2 is predictive of subsequent ventilation at high altitude. As part of a larger study examining individual variability upon acute exposure to normobaric hypoxia, PETCO2 was measured while subjects rested for >30 minutes at sea level (SL) and, no sooner than two days later, for >30 minutes in a normobaric hypoxia chamber at 13.55% FiO2 approximating oxygen partial pressures equivalent to those found at 3,500 m, or at a FiO2 of 20.93% in the case of control subjects.METHODSInformed volunteer female subjects participated in this IRB approved study. 47 (20.6±1.5 yr.; 165.6±6.9 cm; 62.9±10.4 kg; 22.9±3.4 kg/m2; VO2peak 42.6±7.4 ml/kg−1/min−1) subjects were assigned to the treatment group who were tested at SL then entered the normobaric chamber where the FiO2=13.55% (HYPO) and 9 subjects (21.8±4.3 yr.; 166.5±6.1 cm; 57.9 ±7.0 kg; 20.9 ±2.1 kg/m2; VO2peak 40.9 ±6.5 ml/kg−1/min−1) acted as controls (SHAM) who were in the normobaric chamber at a FiO2 = 20.93%. At both SL and chamber conditions, subjects rested for >30 minutes. PETCO2 was measured during the final 14 minutes of each rest period as was percent hemoglobin O2 saturation (SpO2), respiratory rate (RR), and heart rate (HR).RESULTSTwo‐way RM ANOVA revealed that there was no difference (P>0.5) in PETCO2 between the HYPO vs SHAM groups at SL (37.9±2.7 vs 36.0±2.9) but, as expected, there was a difference (P<0.001) between the SL and chamber conditions (PETCO2 = 37.9±2.7 vs 36.0±2.2) in the HYPO group. A significant (P < 0.001) Pearson correlation (r = 0.759) was also observed between SL PETCO2 and HYPO PETCO2 while no difference was observed between the SHAM conditions. A multiple regression model [Y = 79.617 – 0.452 X1 – 0.207 X2 – 0.016 X3 (Where Y= PETCO2_HYPO, X1 = SpO2_HYPO, X2 = RR_HYPO, X3 = HR_HYPO; R2 = 0.500, F = 19.15, P < 0.001)] was used to plot the actual and predictive values for PETCO2 at 3,500 m (Fig. 1).CONCLUSIONSWomen's SL PETCO2 is predictive of their ventilatory response to acute normobaric hypoxia and may be useful in predicting an individual's ventilation during travel to moderately high altitudes.Support or Funding InformationThe Doug Morton/Marilyn Brown Endowment for Biomedical Research, The Foundation for Aging Studies and Exercise Science Research, and The Borgenicht Program
Handgrip Training with Chronic Concomitant Exposure to Moderate Altitude Improves Blood Pressure Responses and Delays the Onset of Fatigue
Authors: Jarvis Sara Sun 
Published: November 2023

Exposure to moderate altitude (~2500 m) elicits a sympathoexcitatory response. There may also be long term changes such as a reduction in muscular strength and a quicker onset of muscular fatigue. The purpose of this study was to determine whether a training program with concomitant hypoxic exposure could blunt cardiovascular and neural responses, as well as delay the onset of fatigue. Twelve healthy males had heart rate (HR) and blood pressure (systolic, SBP; diastolic, DBP) measured during baseline (BL), static handgrip to fatigue, and post‐exercise circulatory arrest (PECA). A subset of subjects (n=5) had measurements of muscle sympathetic nerve activity (MSNA). Assessments were done before (PRE) and after (POST) a 6‐week rhythmic handgrip training program (5 days/week, 30% of maximal voluntary contraction, 2 sets of 30 repetitions/min until fatigue). HR was higher at fatigue compared to BL (PRE BL: 65±8 vs 96±20 beats/min, p<0.01) but was not different PRE vs POST (POST BL: 61±7 beats/min). SBP was higher at fatigue and during PECA than during BL (PRE BL: 126±11 vs 168±13 vs 154±12 mmHg, both p<0.01) and was lower POST (main effect, p<0.05). DBP was also higher at fatigue and during PECA (PRE BL: 64±5 vs 90±17 vs 78±8 mmHg, both p<0.05) and tended to be lower POST (main effect, p=0.075). Indices of MSNA were higher during fatigue compared to BL (burst frequency, PRE BL: 11±9 vs 42±29 bursts/min, p<0.01; burst incidence, PRE BL: 17±13 vs 45±23 bursts/100 heart beats, p<0.05) but were no different from PRE to POST (burst frequency, POST BL: 12±10 bursts/min; burst incidence, POST BL: 18±15 bursts/100 heart beats). Maximal voluntary contraction was unchanged after training (52±6 vs 50±5 kg, p=NS); however, time to fatigue was delayed POST training (141.4±32.6 vs 176.4±42.3 sec, p<0.05). After 6 weeks of rhythmic handgrip training we found improvements in cardiovascular parameters and a delay in the onset of fatigue but no change in MSNA indices or strength.Support or Funding InformationSupported by the Faculty Grant Program at Northern Arizona University