bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cardiovascular and Sympathetic Neural Responses to Cognitive Tasks in Women with Posttraumatic Stress Disorder
Authors: Washio Takuro , Yoo Jeung‐Ki , Anderson Elizabeth H. , Takeda Ryosuke , Hissen Sarah L. , Nelson Michael D. , North Carol S. , Suris Alina , Fu Qi 
Published: May 2022

BackgroundPosttraumatic stress disorder (PTSD) is more prevalent in women than men and is associated with an increased risk for dementia. Indeed, we previously showed that cognitive function is impaired in women with PTSD, but the underlying mechanisms remain unknown. In patients with mild cognitive impairment, the cardiovascular response during cognitive tasks have been shown to be blunted. Thus, we hypothesized that cardiovascular and sympathetic neural responses to a cognitive task would be smaller in women with PTSD than healthy women.MethodsWe measured heart rate (HR), mean arterial pressure (MAP), cardiac output (CO, Modelflow), total peripheral resistance (TPR = MAP/CO), and muscle sympathetic nerve activity (MSNA, microneurography) in 16 women with PTSD (42 ± 11 [SD] yrs) and 9 age‐matched healthy women (controls; 41 ± 9 yrs) during 3 min of the Stroop Color and Word Test (SCWT) in the supine position.ResultsIn response to SCWT, HR, MAP, and CO increased (all P < 0.001) but TPR remained unchanged (P = 0.753) in both groups. Increases (Δ) in HR (6 ± 4 vs. 11 ± 6 bpm) and CO (0.6 ± 0.6 vs. 0.9 ± 0.4 L/min) during SCWT were smaller in PTSD than controls (both P < 0.05), while ΔMAP was similar between groups (P = 0.169). MSNA burst frequency and incidence were significantly higher in women with PTSD than controls at baseline and throughout SCWT (P = 0.003), but ΔMSNA during SCWT was similar between groups.ConclusionsCardiovascular, but not sympathetic neural responses to SCWT were blunted in women with PTSD. Our findings suggest that cognitive impairment in women with PTSD may be related to the insufficient cardiac response rather than sympathetic vasoconstriction during cognitive tasks.
Intestinal AMPK modulation of gut microbiota mediates cross‐talk with brown fat to control metabolism
Authors: Huang Wendong , Zhang Eryun , Jin Lihua , Wang Yangmeng , Fang Zhipeng , Al‐Abdullah Ismail , Shuck Sarah 
Published: May 2022

The energy‐dissipating capacity of brown adipose tissue through thermogenesis can be targeted to improve energy balance. Mammalian 5′‐AMP‐activated protein kinase (AMPK), a key nutrient sensor for maintaining cellular energy status, is a known therapeutic target for glucose control in Type II diabetes (T2D). Despite current understandings of its well‐established roles in regulating glucose metabolism in various tissues, the functions of AMPK in the intestine, an organ for nutrient processing, remain largely unexplored. In this study, we generated the intestinal AMPKα1 specific knock out mice (IKO) and observed that the AMPKα1 IKO mice displayed impaired thermogenesis function of brown adipose tissue both in chow diet and high fat diet condition. Moreover, HFD‐fed AMPKα1 IKO mice showed more severe impaired glucose tolerance and insulin resistance. Mechanistically, we revealed that intestinal AMPK can regulate the anti‐microbial peptides (AMPs) Reg3 and result in a shift in the gut microbiota composition, which leading to the elevation of the fermentation products methylglyoxal, and methylglyoxal can significantly suppress the UCP1 expression in the brown adipose tissue. While transplantation of the microbiota from AMPKα1 IKO mice to antibiotic‐induced microbiome depletion (AIMD) mice, the mice also showed impaired thermogenesis function of brown adipose tissue and elevated serum methylglyoxal level. In addition, we found that the metabolic effect and the AMP regulation of metformin is dependent on the intestinal AMPK.These results demonstrated that the intestinal nutrient sensor AMPKα1 can regulate the thermogenesis function of brown adipose tissue through modulating AMKP expression and reshaping the gut microbiome. These findings provide a new gut‐brown adipose tissue axis mechanism for activating energy expenditure and treating metabolic diseases.
Pressure Only Wave Separation Pulsatile Hemodynamics in Adolescents: Accuracy and Associations with Left Ventricular Mass Index
Authors: Armstrong Matthew K. , Chirinos Julio A. , Kapuku Gaston K. , Pierce Gary L. 
Published: May 2022

IntroductionEarly‐life exposure to cardiovascular disease (CVD) risk factors, such as high blood pressure (BP), is associated with cardiovascular target organ damage in later life. However, not all BP‐related risk is explained by higher systolic and diastolic BP alone. In adolescence, aortic wave separation (WS) pulsatile hemodynamic parameters are associated with adverse left ventricular (LV) structure but are limited by the requirement for measured aortic flow. Several methods for estimating aortic flow from pressure waveforms have emerged, but their accuracy and associations with LV structure have never been tested in adolescents. We hypothesized that pressure‐only estimated flow waveforms would: 1) accurately approximate measured flow hemodynamic WS parameters and 2) be similarly associated with LV mass as measured flow hemodynamics among healthy adolescents.Methods. BP waveforms were acquired via carotid tonometry in 58 adolescents (age 16±1.5 years, 59% females). Measured (aortic) flow and LV mass index (LVMI) were measured via 2D echocardiography. Three pressure‐only approximations of aortic flow waveforms were synthesized from analysis of the BP waveform, including triangular, excess, and individualized physiologic flow. A 4th aortic flow waveform (average flow) was approximated from the average of all 58 measured flow waveforms. Forward (Pf) and backward (Pb) pressure and reflection magnitude (Rm) were derived from WS analysis.Results. Compared to measured flow, individualized physiologic and average flow produced the best approximations of Pf (mean difference ± SD, ‐0.15±2.38 and 1.23±2.84 mmHg respectively), Pb (0.14±0.25 and 0.67±0.10 mmHg), and Rm (0.01±0.02 and ‐0.01±0.02 mmHg). Pf derived using all flow waveforms, measured, and estimated, was associated with LVMI (R >0.44, P <0.001 for all), and these associations yielded similar effect estimates in all instances (z‐score <1.1, P >0.28). All associations persisted after adjusting for age, systolic BP, heart rate, and aortic diameter (P <0.05 all).Conclusion. Of the estimated flow waveforms, individualized physiologic flow yielded the best approximation of WS hemodynamic parameters. It may provide important physiological and clinical insight related to cardiovascular target organ damage among adolescents.
Inhibition of Phosphoinositide 3‐kinase delta (PIK3CD) Suppresses Hepatocyte Proliferation by More than 50% in the Regenerating Liver after Partial Hepatectomy
Authors: Martucci Nicole J. , Stoops John W. , Bowen William C. , Mars Wendy M. , Michalopoulos George K. 
Published: May 2022

Background and ObjectiveThe extracellular matrix (ECM) is important for survival, differentiation, and normal functioning of cells within the liver; integrins are key signaling receptors in this process. Previous data from our lab has shown that with hepatocyte specific knockout of integrin linked kinase (hILK KO), there is hepatocyte proliferation, increased matrix deposition, and unorganized biliary cell/ductal proliferation; this led us to investigate the signaling pathways downstream of hILK KO that might be responsible for the observed phenotype. Through this, we uncovered a possible central role of Phosphoinositide 3‐kinase (PI3K) delta (PIK3CD), a protein thought to be immune specific and absent in hepatocytes. The objective of this study was to determine the role PIK3CD has in the liver. From literature searches and our initial data collection, our hypothesis was that the inhibition of PIK3CD would suppress hepatocyte proliferation.MethodsData array analyses were performed on livers from 7‐ and 14‐week old chronic hILK KO and WT mice. Partial Hepatectomies (PHx) were performed on C57BL/6J mice injected IP with vehicle control or the PIK3CD inhibitor, Cal‐101, at 10mg/kg, two days prior to PHx, and every day following until harvest. Days 0, 1, 2, 4 and 7 post‐surgery were examined through immunohistological and western blot analyses. RNA was generated and pooled (n=6) for each condition and timepoint and sent out for analyses. Additionally, in vitro cell culture was performed using primary hepatocytes isolated from hILK WT mice. Hepatocytes were seeded at 300K cells per well, with media changed every other day and treated with or without 5uM CAL‐101 over the course of 6 days. BrdU was added 2 hours prior to harvest of cells to assess proliferation.ResultsData array analyses on ILK KO and WT animals by IPA identified PIK3CD as common to several pathways in the ILK KO mice. WT mice that were treated with the PIK3CD inhibitor, Cal‐101, exhibited a significant decrease in hepatocyte proliferation on days 1, 2, 4, and 7 after PHx, compared to vehicle control, through quantification of nuclear Ki67 staining. By day 7, proliferation subsided in both the control and Cal‐101 mice and liver to body weight ratios were similar. Additionally, western blot analyses revealed differences in p‐AKT and p‐ERK on days 0,1, and 2 after PHx, as well as changes in p‐MET at days 0 and 1. In vitro culture data also supported a role for PIK3CD in hepatocyte proliferation as a significant decrease was observed in primary hepatocytes treated with Cal‐101 compared to control over a 6‐day culture period.ConclusionThis data shows a previously unknown essential role for PIK3CD in controlling hepatocyte proliferation in the regenerating liver.
Selective Transport in the Nuclear Pore Complex
Authors: Cowburn David 
Published: May 2022

Nuclear pore complexes (NPCs) mediate nucleocytoplasmic exchange controlling the flow of molecules into and out of the nucleus. The selective filter properties of NPCs enable translocation of specific molecules known as nuclear transport factors (NTRs) and their cargo. Central to this selectivity barrier is a group of largely intrinsically disordered nucleoporins (Nups) that contain multiple phenylalanine‐glycine repeats, termed FG Nups. The interactions between FG Nups and NTRs enable NTRs to translocate rapidly yet selectively through the NPC in what is referred to as the “transport paradox”. FG Nups in the NPC have a small folded anchor region tethering them to the NPC outer ring and otherwise are fully disordered, random coil polymers that remain predominantly disordered while engaged to NTRs. FG Nups interact with NTRs using mainly their FG motifs and minimally their intervening spacer residues. The overall enthalpy of the interaction increases as multivalency increases the frequency of individually weak FG‐NTR contacts. Tight binding is limited by an entropy penalty that disfavors simultaneous engagements of FG motifs. Small angle neutron scattering (SANS) shows that the entropy loss is partly due to the local rigidity of an FG motif in the interacting state(Fig 1). All‐atom molecular dynamics (MD) simulation indicates that spacers between the FG motifs behave as “entropic springs”, disfavoring any static binding of the FG repeats. The dynamics of FG Nups enables the FG motifs to slide along the hydrophobic patches of NTRs enabling FG motifs to be easily displaced by other competing FG motifs (Fig. 2). This explanation provides a simple hypothesis for the rapid exchange of FG motif contacts during transport, focusing on the entropic exclusion of non‐NTRs, and ‘solubilization’ of NTR complexes, in contrast to possible condensate formation which would provide a compartmentalization of components. These results reveal fundamental aspects of the functioning mechanisms underlying NPC transport at high structural resolution, something lacking in current models of nuclear transport.1. Sparks, S., et al., Analysis of Multivalent IDP Interactions: Stoichiometry, Affinity, and Local Concentration Effect Measurements. Methods Mol Biol, 2020. 2141: p. 463‐475.2. Sparks, S., et al., Deciphering the “Fuzzy” Interaction of FG Nucleoporins and Transport Factors Using Small‐Angle Neutron Scattering. Structure, 2018. 26(3): p. 477‐484 e4.3. Hayama, R., et al., Thermodynamic characterization of the multivalent interactions underlying rapid and selective translocation through the nuclear pore complex. J Biol Chem, 2018. 293(12): p. 4555‐4563.4. Hough, L.E., et al., The molecular mechanism of nuclear transport revealed by atomic‐scale measurements. Elife, 2015. 4.5. Raveh, B., et al., Slide‐and‐exchange mechanism for rapid and selective transport through the nuclear pore complex. Proc Natl Acad Sci U S A, 2016. 113(18): p. E2489‐97.
Intra and inter‐day reproducibility of the functional sympatholysis protocol during rhythmic handgrip exercise in healthy humans
Authors: Teixeira André L. , Garland Matthew , Lee Jordan B. , Nardone Massimo , Millar Philip J. 
Published: May 2022

IntroductionThe effects of increased sympathetic activity on vasoconstriction are blunted in active skeletal muscle during exercise. This mechanism, termed functional sympatholysis (FSY), plays a vital role in the maintenance of blood perfusion and oxygen delivery to meet the metabolic demands of active skeletal muscle. In humans, FSY can be determined experimentally by applying low‐levels of lower‐body negative pressure (LBNP) to unload the cardiopulmonary baroreceptors and induce a reflex sympathoexcitation at rest and simultaneously during rhythmic handgrip exercise. In young healthy individuals, LBNP causes a pronounced vasoconstrictor response at rest, but not during exercise in the working forearm. Although this paradigm has been used extensively to assess the FSY in humans, to date, no studies have examined the reproducibility of this protocol. Therefore, the aim of the present study is to assess the within‐visit and between‐visit reproducibility of the FSY protocol in healthy adults.MethodsTwenty‐three (12 females) young, healthy adults (26 ± 4 years; 73 ± 13 kg [mean ± SD]) participated in the study. Forearm blood flow (Doppler ultrasound) and beat‐to‐beat BP (finger photoplethysmography) were measured continuously at rest and during 6‐min of rhythmic handgrip exercise at 30% of maximum voluntary contraction. LBNP at ‐20 mmHg was applied for 2 min at rest and from the 3rd to the 5th min of handgrip. Participants performed two visits separated by ≥48h where two FSY bouts were completed. Forearm vascular conductance (FVC) was calculated as FBF/Mean blood pressure. The FSY index (FSYi) was calculated using the following formula: FSYi = (∆%handgrip ‐ ∆%rest)/100. Intraclass correlation coefficients (ICC; two‐way mixed effects, average measures, and absolute agreement) were used as a primary reproducibility measure (ICC values >0.75 are considered very good).ResultsAt rest, LBNP induced a decrease in forearm blood flow (Visit 1 trial 1: ∆‐43±16%; Visit 1 trial 2: ∆‐38±10%; Visit 2: ∆‐39±14%) while these responses were attenuated during LBNP+handgrip (Visit 1 trial 1: ∆‐7±7%; Visit 1 trial 2: ∆‐5±8%; Visit 2: ∆‐4±7%). Each of these responses was similar across the trials (all P≥0.17). The FSYi calculated based on the forearm blood flow responses demonstrated excellent intra (ICC=0.93 [95% CI: 0.82‐0.97]; P<0.001) and inter‐day (ICC=0.94 [95% CI: 0.85‐0.97]; P<0.001) reproducibility. Similarly, FVC responses demonstrated very good intra (ICC=0.81 [95% CI: 0.55‐0.92]; P<0.001) and inter‐day (ICC=0.86 [95% CI: 0.65‐0.95]; P<0.001) reproducibility.ConclusionThis is the first study to demonstrate that Doppler ultrasound‐derived assessments of FSY using LBNP and forearm handgrip exercise possess high intra‐ and inter‐day reproducibility in young, healthy adults.
Impact of Maternal Obesity on Resting Muscle Sympathetic Nerve Activity during Normotensive Pregnancy
Authors: Hissen Sarah L. , Takeda Ryosuke , Yoo Jeung‐Ki , Badrov Mark B. , Tomlinson Andrew , Khan Safia , Nelson David B. , Babb Tony G. , Fu Qi 
Published: May 2022

Maternal obesity increases the risk of adverse pregnancy outcomes. The mechanisms that contribute to this elevated risk are unclear but may be related to overactivation of the sympathetic nervous system. Indeed, sympathetic activation during pregnancy is now regarded as a normal adaptation to maintain homeostasis. However, sympathetic overactivation is associated with gestational hypertensive disorders. It is unknown whether the health related problems linked to maternal obesity (i.e., inflammation, insulin resistance, dyslipidemia) results in sympathetic overactivation during pregnancy. We hypothesized that maternal obesity would induce greater increases in resting muscle sympathetic nerve activity (MSNA) during pregnancy when compared with normal‐weight women.Blood pressure (BP), heart rate and MSNA (microneurography) were recorded during 5 min of supine rest in 14 normal‐weight (Age 30±1.6 [SE] yrs; BMI 22.1±0.6 kg/m2) and 14 obese (Age 28±0.8 yrs; BMI 33.9±1.0 kg/m2) women during early pregnancy (5‐12 weeks), late pregnancy (32 to 34 weeks) and 6‐10 weeks postpartum.Gestational weight gain from early to late pregnancy was not significantly different between groups (11.8±0.9 kg vs. 9.2±2.1 kg, P=0.23). Resting MSNA burst frequency was not different between normal‐weight and obese groups during early pregnancy (17±3 bursts/min vs. 22±4 bursts/min, P=0.35) or postpartum (10±2 bursts/min vs. 8±2 bursts/min P=0.74) but was significantly greater in the obese group during late pregnancy (23±4 bursts/min vs. 35±4 bursts/min, Figure A, P=0.031). There were no significant changes in resting MSNA from early to late pregnancy in the normal‐weight group (P=0.67) whereas the obese group had significant increases in MSNA from early to late pregnancy (P=0.002). These findings were also apparent when MSNA was characterized as burst incidence and total activity (Figure B and C). Although still within the normotensive range, women with obesity had greater levels of systolic BP when compared with normal‐weight women across all time points (Figure D, group main effect P=0.002). Diastolic BP was lower during pregnancy when compared with postpartum and this was similar between groups (Figure E, gestation main effect P<0.001). Heart rate was greater during early pregnancy when compared with postpartum and increased similarly in both groups during late pregnancy (Figure F, gestation main effect P<0.001).These findings suggest that maternal obesity is associated with greater increases in sympathetic activation even during normotensive pregnancy and may play a role in the increased risk of adverse maternal and fetal outcomes in women with obesity.
P‐cadherin regulates intestinal epithelial repair, but is dispensable for colitis associated colon cancer development
Authors: Naydenov Nayden G. , Lechuga Susana , Zalavadia Ajaykumar , Huang Emina , Ivanov Andrei I. 
Published: May 2022

Recurrent chronic mucosal inflammation, which is characteristics for inflammatory bowel diseases (IBD), triggers significant changes in the intestinal epithelial homeostasis. These changes include leakiness of the gut barrier, formation of mucosal wounds and, in most severe cases, oncogenic transformation of colonic epithelium resulting in colitis‐associated colon cancer (CAC). Altered structure and dynamics of epithelial junctions is a hallmark of intestinal inflammation, mediating epithelial barrier injury and repair. P‐cadherin (gene name: CDH3) is an important component of adherens junctions (AJ), which is poorly expressed in normal intestinal epithelium, but could be induced in inflamed and injured mucosa. The goal of this his study was to investigate the roles of P‐cadherin in regulating intestinal inflammation, mucosal repair and CAC.P‐cadherin expression was markedly induced in the colonic epithelium of human IBD patients and CAC tissues. Roles of P‐cadherin in intestinal inflammation and tumorigenesis in vivo were investigated using a mouse strain with total P‐cadherin knockout. Dextran sulfate sodium (DSS)‐induced colitis was utilized to study mucosal inflammation, whereas CAC was established using a classical azoxymetane (AOM)/DSS model. Severity of acute DSS colitis was not affected by P‐cadherin knockout, however, P‐cadherin null mice exhibited faster recovery after DSS withdrawal indicating accelerated repair of injured mucosa. No significant differences in the number and size of colonic tumors was observed in P‐cadherin null and control mice after AOM/DSS induced CAC. Consistently, CRISPR/Cas9‐mediated knockout of P‐cadherin in SK‐CO15 and HCA7 human colonic epithelial cell lines accelerated epithelial wound healing without affecting cell proliferation. The faster migration of P‐cadherin depleted cells was associated with diminished cell‐matrix adhesions and increased cell spreading. Loss of P‐cadherin resulted in activation of Src kinase and the pro‐migratory phenotype of P‐cadherin depleted cell was reversed by pharmacological inhibition of Src. Furthermore, accelerated epithelial wound healing caused by loss of P‐cadherin was prevented by Rac1 inhibition. Our findings highlight P‐cadherin as a negative regulator of intestinal epithelial would heling in vitro and mucosal repair in vivo. By contrast, this AJ protein appears to be dispensable for intestinal epithelial cell proliferation and CAC development.