bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of sleep positional therapy on nocturnal gastroesophageal reflux measured by esophageal pH‐impedance monitoring
Authors: Schuitenmaker Jeroen M. , Kuipers Thijs , Schijven Marlies P. , Smout André J. P. M. , Fockens Paul , Bredenoord Albert J.
Published: May 2023

Background & Aims

The aim of the study was to evaluate the effect of an electronic positional therapy wearable device on nocturnal gastroesophageal reflux measured by pH‐impedance reflux monitoring.

Methods

We performed a single‐center, prospective, interventional study in 30 patients with nocturnal reflux symptoms and a nocturnal esophageal acid exposure time (AET) ≥1.5% measured off acid‐suppressive medication by ambulatory pH‐impedance reflux monitoring. Patients were treated with an electronic positional therapy wearable device for 2 weeks. The device vibrates in the right lateral decubitus position so it conditions patients to avoid that sleep position. After 2 weeks treatment, the pH‐impedance study was repeated. Primary outcome was the change in nocturnal AET. Secondary outcomes include change in number of reflux episodes and reflux symptoms.

Results

Complete data were available for 27 patients (13 females, mean age 49.8 years). The median nocturnal AET decreased from 6.0% (IQR, 2.3–15.3) to 3.1% (0.1–10.8) after 2 weeks of treatment (p = 0.079). The number of reflux episodes was significantly reduced after 2 weeks of treatment (baseline: 8.0 (3.0–12.3) vs. end: 3.0 (1.0–8.0); p = 0.041). Treatment led to a statistically significant decrease in time spent in right lateral decubitus position (baseline: mean 36.9% ± 15.2% vs. end: 2.7% ± 8.2%; p = <0.001) and an increase in the left lateral decubitus position (baseline 29.2% ± 14.8% vs. end: 63.3% ± 21.9%; p = <0.001). Symptom improvement was reported by 70.4% of the patients.

Conclusions

Sleep positional therapy using an electronic wearable device promotes sleeping in the left lateral decubitus position and improves reflux parameters measured by pH‐impedance reflux monitoring.
SlMYB99‐mediated auxin and abscisic acid antagonistically regulate ascorbic acids biosynthesis in tomato
Authors: Xu Xin , Huang Baowen , Fang Xu , Zhang Qiongdan , Qi Tiancheng , Gong Min , Zheng Xianzhe , Wu Mengbo , Jian Yongfei , Deng Jie , Cheng Yulin , Li Zhengguo , Deng Wei
Published: May 2023

Ascorbic acid (AsA) is a water‐soluble antioxidant that plays important roles in plant development and human health. Understanding the regulatory mechanism underlying AsA biosynthesis is imperative to the development of high AsA plants.

In this study, we reveal that the auxin response factor SlARF4 transcriptionally inhibits SlMYB99, which subsequently modulates AsA accumulation via transcriptional activation of AsA biosynthesis genes GPP, GLDH, and DHAR. The auxin‐dependent transcriptional cascade of SlARF4‐SlMYB99‐GPP/GLDH/DHAR modulates AsA synthesis, while mitogen‐activated protein kinase SlMAPK8 not only phosphorylates SlMYB99, but also activates its transcriptional activity. Both SlMYB99 and SlMYB11 proteins physically interact with each other, thereby synergistically regulating AsA biosynthesis by upregulating the expression of GPP, GLDH, and DHAR genes.

Collectively, these results demonstrate that auxin and abscisic acid antagonistically regulate AsA biosynthesis during development and drought tolerance in tomato via the SlMAPK8‐SlARF4‐SlMYB99/11 module.

These findings provide new insights into the mechanism underlying phytohormone regulation of AsA biosynthesis and provide a theoretical basis for the future development of high AsA plants via molecular breeding.
The specific value of upgrading to left bundle branch area pacing in patients with pacing‐induced cardiomyopathy or non‐pacing‐induced cardiomyopathy related upgrade status: A retrospective study
Authors: Shan Yu , Lin Maoning , Sun Yaxun , Zhang Jiefang , Jiang Hangpan , Fu Guosheng , Zhang Wenbin , Wang Min
Published: May 2023

Aims

Left bundle branch area pacing (LBBaP) upgrade can improve cardiac function and clinical outcomes in patients with pacing‐induced cardiomyopathy (PICM), but the specific value of LBBaP upgrade, especially compared with the cardiac function level before right ventricular pacing (RVP) in patients with PICM and non‐pacing‐induced cardiomyopathy‐related upgrade status (Non‐PICMUS) is still unknown.

Methods

This study retrospectively enrolled 70 patients with LBBaP upgrade (38 patients with PICM and 32 patients with Non‐PICMUS). All upgrade patients experienced three stages: before RVP (Pre‐RVP), before LBBaP upgrade (Pre‐LBBaP), and after LBBaP upgrade (Post‐LBBaP). QRS duration (QRSd), lead parameters, echocardiographic indicators, and clinical outcomes evaluation were recorded at multiple time points.

Results

At the follow‐up of 12 months, for PICM patients, left ventricular ejection fraction (LVEF) significantly increased from 36.6% ± 7.2% to 51.3% ± 8.7% Post‐LBBaP (p < .001), and left ventricular end‐diastolic diameter (LVEDD) significantly decreased from 61.5 ± 6.4 mm to 55.2 ± 6.5 mm Post‐LBBaP (p < .001), but they both failed to restore the level Pre‐RVP (both p < .001). For PICM patients, New York Heart Association (NYHA) classification, the number of moderate‐to‐severe heart failure (NYHA III–IV), and diuretics using rate after the LBBaP upgrade also could not restore to the level Pre‐RVP (all p < .001). At the follow‐up of 12 months, Non‐PICMUS patients after the LBBaP upgrade had no significant improvement in LVEF, LVEDD, and NYHA classification (all p > .05).

Conclusion

LBBaP upgrade effectively improved the cardiac function and clinical outcomes in PICM patients, but its effectiveness seemed to be limited as the deteriorated cardiac function cannot be completely reversed. For Non‐PICMUS patients, the cardiac function and clinical outcomes Post‐LBBaP had no significant improvement.
Border Disputes: Recent Debates along the Perception–Cognition Border
Authors: Clarke Sam , Beck Jacob
Published: May 2023

The distinction between perception and cognition frames countless debates in philosophy and cognitive science. But what, if anything, does this distinction actually amount to? In this introductory article, we summarize recent work on this question. We first briefly consider the possibility that a perception‐cognition border should beeliminatedfrom our scientific ontology, and then introduce and critically examine five positive approaches to marking a perception–cognition border, framed in terms ofphenomenology, revisability, modularity, format,andstimulus‐dependence.
Creativity in policy capacity: Organizational and individual determinants
Authors: Fleischer Julia , Wanckel Camilla
Published: May 2023

Creativity is a crucial part of policy capacity in governments. Existing studies on creative behavior in the public sector assess employees' openness to new ideas and creative solutions, and they confirm the relevance of organizational and individual determinants for pro‐creativity attitudes. Yet we lack systemic evidence on the explicit level of work‐related creativity among policy officials in government organizations. At the same time, novel technologies and particularly social networking services change the working environment of policy officials radically, alter organizational features, and may also yield crucial individual effects. Our study analyses “policy creativity” of policy officials in three European governments. We demonstrate the importance of organizational and individual features, including the stress triggered by using social networking services. Our study captures officials' creativity explicitly and adds to debates on creativity and innovation in the public sector as well as the micro‐level foundations of the digital transformation in the public sector.
Antecubital perforating vein stent‐grafting for radiocephalic arteriovenous fistula recovery: A case report
Authors: Mendes Daniel , Almeida Paulo , Pinelo Andreia , Castro João , Norton‐de‐Matos António
Published: May 2023

Stent‐grafts have been increasingly used in hemodialysis arteriovenous accesses, particularly in recurrent stenosis or in cases of vein rupture after percutaneous transluminal angioplasty (PTA). Although they limit neointimal hyperplasia, stenosis development at stent edges remains a concern. Despite their advantages, they are seldom used on the forearm veins due to fracture risk associated with elbow motion and the potential to limit cannulation sites. This report presents a novel application of stent‐grafts in salvaging a radio‐cephalic arteriovenous fistula in an 84‐year‐old male to treat a single outflow path at the elbow through a stenosed antecubital perforating vein, after failed PTA. The vascular access remained patent 18 months after the procedure, with no need for additional treatments at this target lesion, even though a PTA was required for juxta‐anastomotic stenosis. This report highlights a possible further use of covered stents in arteriovenous vascular accesses.
The role of liquidity in monetary policy transmission: Evidence from Indian banks1
Authors: Ansari Md Gyasuddin , Sensarma Rudra
Published: May 2023

The role of bank liquidity in monetary policy transmission has received insufficient attention in the literature. Faced with monetary tightening, banks with more liquidity can sell off securities and protect their loan portfolios. We test this proposition using panel data for Indian banks during 2005–2020. Employing dynamic threshold panel regressions with liquid assets as the threshold variable, we show that bank lending declines with monetary policy tightening in low liquidity regimes, but not in high liquidity regimes. We also find evidence for different portfolio reallocation behaviour by banks in high versus low liquidity regimes in response to monetary policy changes.
The effect of late‐onset CMV infection on the outcome of renal allograft considering initial graft function
Authors: Shahmirzadi Mohammadreza R. , Gunaratnam Lakshman , Jevnikar Anthony M. , Luke Patrick , House Andrew A. , Silverman Michael S. , Hosseini‐Moghaddam Seyed M.
Published: May 2023

Background

Delayed graft function (DGF) increases the renal allograft failure risk. Late‐onset Cytomegalovirus (CMV) infection's effect on the association between DGF and allograft failure has not been determined.

Methods

In this retrospective cohort, we included all renal allograft recipients at London Health Sciences Centre from January 1, 2014 to December 30, 2017, and continued clinical follow‐up until February 28, 2020. We determined whether late‐onset CMV infection affects the association between DGF and allograft failure in stratified and Cox proportional hazard analyses.

Results

Of 384 patients (median age [interquartile range]: 55 [43.3–63]; 38.7% female), 57 recipients (14.8%) were diagnosed with DGF. Patients with DGF were at a greater risk of CMV infection than patients without DGF (22.8% vs. 11.3%, p = .017). Late‐onset CMV infection (odds ratio [OR]: 4.7, 95% CI: 2.07–10.68) and rejection (OR: 9.59, 95% CI: 4.15–22.16) significantly increased the risk of allograft failure in recipients with DGF. Patients with DGF had a significantly greater risk of graft failure than those without DGF (17.5% vs. 6.1%, p = .007). In the adjusted Cox hazard model, CMV infection significantly increased the risk of allograft failure (aHR: 3.19, 95% CI: 1.49–6.84).

Conclusion

Late‐onset CMV infection considerably increased the risk of graft failure in patients with DGF. A hybrid preventive model including prophylaxis followed by CMV‐specific cell‐mediated immunity monitoring may decrease the risk of allograft failure in recipients with DGF.

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Effect of vincristine on intraocular pressure and tear fluid oxidative stress biomarkers in canine transmissible venereal tumor
Authors: Keyvanfard Ghazal , Cheraghi Hadi , Aryaei Tabar Hamid
Published: May 2023

Background

The ocular side effects of cancer chemotherapeutic drugs are relatively uncommon. Nonetheless, the ocular system has a potentially high sensitivity to toxic substances. This study proposed a framework to assess the effect of vincristine chemotherapy on intraocular pressure, tear protein, and oxidative stress in canines with transmissible venereal tumor (TVT).

Methods

The study group comprised 10 dogs with TVT, whose diagnosis was based on cytology, and all dogs were treated with vincristine for 4 weeks. Each animal was given a complete ophthalmic examination, followed by a standard Schirmer tear test. Before and 20 min after administering vincristine, intraocular pressure (IOP) was measured in the eyes with a noncontact tonometer. At any of the times mentioned, tear samples were collected using the Schirmer test procedure and were subjected to protein analysis—oxidative stress index (OSI), total antioxidant capacity (TAC), total oxidant status (TOS), nitric oxide (NO), and malondialdehyde (MDA) were determined, and standard statistical analysis was applied.

Results

No significant differences were found in protein in tears, but mean Pre and Postinjection IOP revealed a significant decrease in the eyes each week. Also, results indicated significant differences in oxidative stress markers: increased OSI, NO, and MDA, and reduced TAC.

Conclusion

The importance of an increase in oxidative stress levels in the tears of vincristine‐treated patients should be taken seriously, as it appears to play a role in the pathogenesis of eye disease. Therefore, during the treatment weeks prior to prescribing vincristine, eye diseases should be evaluated and considered.
Migration of di(2‐ethylhexyl) phthalate, diisononylcyclohexane‐1,2‐dicarboxylate and di(2‐ethylhexyl) terephthalate from transfusion medical devices in labile blood products: A comparative study
Authors: Thelliez Aurélie , Sumian Chryslain , Chazard Emmanuel , Reichenberg Stefan , Lecoeur Marie , Decaudin Bertrand
Published: May 2023

Background and Objectives

Polyvinyl chloride (PVC) plasticized with di(2‐ethylhexyl) phthalate (DEHP) is a widely used material for medical transfusion devices. Not covalently bound to PVC, DEHP can migrate into blood products during storage. Recognized as an endocrine disruptor and raising concerns about its potential carcinogenicity and reprotoxicity, DEHP is gradually being withdrawn from the medical device market. Therefore, the use of alternative plasticizers, such as diisononylcyclohexane‐1,2‐dicarboxylate (DINCH) and di(2‐ethylhexyl) terephthalate (DEHT), as potential candidates for the replacement of DEHP in medical transfusion devices has been investigated. The purpose of this study was to evaluate the quantity of PVC‐plasticizers in the blood components according to their preparation, storage conditions and in function of the plasticizer.

Materials and Methods

Whole blood was collected, and labile blood products (LBPs) were prepared by the buffy‐coat method with a PVC blood bag plasticized either with DEHP, DINCH or DEHT. DINCH and DEHT equivalent concentrations were quantified in LBPs by liquid chromatography–tandem mass spectrometry or coupled with UV and compared to DEHP equivalent concentrations.

Results

The plasticizer equivalent concentration to which a patient is exposed during a transfusion depends on the preparation of LBPs as well as their storage conditions, that is, temperature and storage time. At day 1, for all LBPs, the migration of DEHP is 5.0 and 8.5 times greater than DINCH and DEHT, respectively. At the end of the 49 days storage period, the DEHP equivalent concentration in red blood cells concentrate is statistically higher when compared to DINCH and DEHT, with maximal values of 1.85, 1.13 and 0.86 μg/dm2/mL, respectively.

Conclusion

In addition to lower toxicity, transfused patients using PVC‐DEHT or PVC‐DINCH blood bags are less exposed to plasticizers than using PVC‐DEHP bags with a ranging exposure reduction from 38.9% to 87.3%, due to lower leachability into blood components.
Structure of breeding calls in three closely related bird species (Calidris Merrem, 1804; Scolopacidae)
Authors: Miller Edward H. , Tomkovich Pavel S. , Arkhipov Vladimir Yu. , Handel Colleen M.
Published: May 2023

We studied calls of three sandpiper species to document species’ similarities and differences. We hypothesized that functionally different calls would differ in degree of divergence. We studied two nuptial calls (complex “Song” and rhythmically repeated aerial call, RRC) of males, and a general-purpose call (“alarm” trill, AT) given by parents of both sexes in the presence of humans and other potential predators, in great knot, Calidris tenuirostris (Horsfeld, 1821); surfbird, Calidris virgata (Gmelin, 1789); and red knot, Calidris canutus (Linnaeus, 1758). Calls diverged unevenly across species—RRCs and Song diverged the most and ATs the least. Vocalizations of great knot and surfbird were most similar to one another, in agreement with a recently proposed phylogeny. Despite species differences in single acoustic traits, calls were evolutionarily conservative at higher structural levels, such as rhythmic temporal delivery of RRCs and harmonic structure (e.g., the fundamental frequency was suppressed in some call types). Some acoustic qualities that differed across species were similar across call types within species (e.g., tonality in red knot calls). Trait similarity across different calls suggests that a species’ calls cannot evolve independently of one another: common mechanisms of vocal production across different calls may impede differentiation within a species’ repertoire.
Online Schedule Randomization to Mitigate Timing Attacks in 5G Periodic URLLC Communications
Authors: Samaddar Ankita , Easwaran Arvind
Published: May 2023

Ultra-reliable low-latency communication (URLLC) in 5G networks is designed to support time-critical applications such as industrial control systems (ICSs), where user equipment (UEs) communicate with a base station (BS) with very high reliability and low latency. Most of these communications in ICSs are periodic and associated with hard deadlines. To provide a reliable service while satisfying the hard deadlines, the BS usually reserves slots and frequencies and precomputes the schedule for such UEs. The same schedule repeats over time, which makes the slots and frequencies predictable. However, an attacker can exploit this aspect and launch timing attacks disrupting specific communication, thereby, undermining the safety of the system. To mitigate such attacks, we present an online strategy that randomizes the scheduled slots and frequencies over time without violating the flow deadlines. We use Kullback-Leibler divergence to measure the randomness in the schedules generated by our strategy with reference to a hypothetical truly random strategy. We perform security analysis of our proposed strategy using Prediction Probability to measure the predictability in the slots of the generated schedules. We evaluate the performance of our strategy against a state-of-the-art baseline, and show that our strategy performs better than the baseline across all parameter settings.
Review—Photoluminescence Characterization of Halide Perovskite Materials and Solar Cells
Authors: Handa Taketo , Yamada Takumi , Kanemitsu Yoshihiko
Published: May 2023

Photoluminescence spectroscopy is a powerful technique for investigating carrier dynamics in semiconductor materials and photovoltaic devices. In this short review, we present our recent luminescence spectroscopic studies on halide perovskites, including thin films and solar cell devices, and discuss their photocarrier dynamics with relevance to photovoltaic performance.
MiR-128 and MiR-195 Modulate Ligand-Dependent Downregulation of Guanylyl Cyclase/Atrial Natriuretic Peptide Receptor-A
Authors: Ramasamy Chandramohan , Khurana Madan , Mani Indra , Kumar Prerna , Pandey Kailash
Published: May 2023

Purpose of Study Atrial and brain natriuretic peptides (ANP, BNP) are circulating hormones of cardiac origin that play an important role in regulating blood pressure (BP) and cardiovascular homeostasis. The aim of this study was to investigate the role of natriuretic peptides (NPs) and microRNAs (miRs) in the ANP-dependent downregulation of NPRA, guanylyl cyclase (GC) activity, and cGMP accumulation, utilizing recombinant and/or native endogenous receptors. Methods Human embryonic kidney-293 (HEK-293) cells expressing recombinant receptor and MA-10 cells harboring native endogenous NPRA were cultured and pretreated with 100 nM ANP and BNP to determine 125I-ANP binding to NPRA. Cells were pretreated with 1 μM A71915 (GC inhibitor) to determine the effect on GC activity and with KT-5823 (PKG inhibitor) to examine the involvement of PKG in the regulation of NPRA. To confirm the role of miR-128 and miR-195 in NPRA regulation, the recombinant HEK-293 cells were transfected with the corresponding miRNA precursor sequences cloned into pCMV-MIR-GFP vector and treated with ANP for varying time periods. To estimate the visual production of cGMP, we performed immunofluorescence of cGMP. Results Treatment with ANP (100 nM) for 12 h led to an 80% decrease in 125I-ANP binding of NPRA, and BNP decreased it by 62%. Neither 100 nM c-ANF (truncated ANP) nor C-type natriuretic peptide (CNP) had any effect. ANP (100 nM) treatment also decreased GC activity by 68% and intracellular accumulation cGMP by 45%, while the NPRA antagonist A719151 (1 μM) almost completely blocked ANP-dependent downregulation of NPRA. Treatment with the protein kinase G (PKG) stimulator 8-(4-chlorophenylthio)-cGMP (CPT-cGMP) (1 μM) caused a significant increase in 125I-ANP binding, whereas the PKG inhibitor KT 5823 (1 μM) potentiated the effect of ANP on the downregulation of NPRA. The transfection of miR-128 significantly reduced NPRA protein levels by three-fold compared to control cells. Conclusions The present findings suggest that ligand-dependent mechanisms involving miRs could play an important role in the regulation of GC-coupled receptor, NPRA, which may have important implications in the cardiovascular health and disease.

This research work was supported by the National Institutes of Health grants (HL062147 and DK133833).

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Regulation of human sodium-dependent vitamin C transporter-2 function in neuronal cells by ubiquitin E3 ligase Nedd4-1
Authors: Subramanian Veedamali , Teafatiller Trevor , Kitazawa Masashi , Agrawal Anshu
Published: May 2023

The ubiquitin pathway regulates the functional expression of several transporters in many cellular systems. However, currently, nothing is known about the role of ubiquitination E3 ligase, neural precursor cell expressed developmentally down-regulated gene 4 (Nedd4-1) in regulating human vitamin C transporter-2 (hSVCT2, the product of the SLC23A2 gene) in neuronal cells. Nedd4-1 has been identified as a putative interactor with hSVCT2 and in the brain, hSVCT2 is predominantly expressed and mediates the cellular uptake of ascorbic acid (AA). Our aim in this investigation was to address this issue using in vitro (SH-SY5Y and HEK-293 cells), and in vivo (mouse) models, together with an array of physiological, cellular and molecular biological approaches. The results showed that the expression of Nedd4-1 in neuronal samples (human and mouse hippocampi and SH-SY5Y cells) is markedly higher than that of Nedd4-2. Interestingly, Nedd4-1 expression was shown to be significantly higher in the hippocampi of patients with Alzheimer’s disease (AD) and a J20 mouse model of AD. In addition, Nedd4-1-GFP and hSVCT2-DsRed co-localized in intracellular vesicles and at the cell membrane in HEK-293 cells. Further, the co-expression of Nedd4-1 with hSVCT2 showed a marked decrease in AA uptake. In contrast, Nedd4-1 siRNA knockdown significantly increased the AA uptake. Further, we have mutated a classical Nedd4 protein interacting motif (‘PPXY’) within the hSVCT2 polypeptide and observed significantly reduced AA uptake due to the intracellular retention of the hSVCT2 mutant compared to hSVCT2 wild-type. Collectively, our data demonstrate that Nedd4-1 dependent ubiquitination regulates hSVCT2 functional expression in neuronal cells.

Supported by NIH grant DK 107474

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Co-activation of diaphragm and bicep in response to trans-spinal magnetic stimulation in healthy males
Authors: Ren Ming-Yue , Lee Kun-Ze
Published: May 2023

Magnetic stimulation is a non-invasive approach to activate the neural tissue and induce the motor evoked potential. Diaphragm and bicep are innervating by motoneurons located within the mid-cervical spine cord; thus, the present study was designed to evaluate whether trans-spinal magnetic stimulation can co-activate the diaphragm and bicep in healthy male subjects (n=12) (KMUHIRB-F(I)-20210039). The two wings of the figure-of-eight magnetic coil (MCF-B65, inner diameter: 35 mm; out diameter: 75 mm) were placed on the dorsal vertebrae from the fifth cervical to the second thoracic vertebral column and its handle was vertical to the spine. The surface electromyogram of the bilateral diaphragm and bicep was recorded in response to trans-spinal magnetic stimulation with 20-100% maximum output of the stimulatory device. The results showed that trans-spinal magnetic stimulation can co-activate both muscles when the stimulatory intensity reached 60%. Notably, the intensity-response curve of motor evoked potential was significantly different between diaphragm and bicep. Specifically, the normalized response curve of the bicep was generally greater than that of the diaphragm, suggesting the excitability and responsiveness of bicep were greater than that of the diaphragm during trans-spinal magnetic stimulation. In addition, the motor evoked potential of the right diaphragm and bicep was greater than the left side during low stimulatory intensity, indicating there are anatomical and/or physiological differences between left and right muscles. In conclusion, trans-spinal magnetic stimulation with two coil wings along the vertebrae can co-activate the diaphragm and bicep. This trans-spinal magnetic stimulatory configuration can be considered as a feasible and efficient neuro-rehabilitative strategy to activate muscles innervating by the cervical spinal cord in subjects with impaired respiratory and forelimb motor function.

The Ministry of Science and Technology (MOST 110-2636-B-110-001 & 111-2636-B-110-001).

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Applying patient personalized organoid model system to understand complex GI manifestations in cystic fibrosis disease
Authors: Arora Kavisha , Sundaram Nambirajan , Ramananda Yashaswini , Helmrath Michael , Naren Anjaparavanda P
Published: May 2023

Background: Stem cell-derived organotypic culture has become a revolutionary tool in transforming care for patients with multiple GI-disorders. Cystic fibrosis is a deadly genetic disorder with multiple GI complications, such as Distal intestinal obstruction syndrome (DIOS), chronic constipation, Gastroesophageal reflux disease (GERD), and in some cases pancreatitis, caused by loss of function mutations in the gene that encodes for the cystic fibrosis transmembrane conductance regulator (CFTR) chloride/bicarbonate ion channel. Due to genetic and environmental influences, CF patients exhibit large phenotypic variation. These factors make clinical trials difficult and largely impractical due to limited and heterogenous patient pools, and additionally, the benefit of approved small-molecule CF therapy in a large number of rare mutation patients is not known. Moreover, critical questions of whether CFTR contributes to the development of intestine and how it contributes to GI-related issues remain unanswered. Results: In this study, we performed a comprehensive bench-side study using in vitro patient enteroids and in vivo mice implanted Human Intestinal Organoids (HIOs) to test highly effective CFTR modulators -Ivacaftor response for a rare CF mutation patient. Based on the positive Ivacaftor response in the enteroids, the patient was enrolled in N=1 clinical trial and showed improved GI outcomes upon Ivacaftor treatment. HIO implantation model allowed in vivo modulator dosing and provided an elegant human organ-based demonstration of bench-to-bedside testing of modulator effects. Additionally, using the CF HIO model the role of CFTR function in the maturation of human intestine was reported for the first time. In HIOs derived from a stop mutation CF patient and CFTR-corrected HIOs as control, we performed single cell RNAseq analysis to generate a molecular map of GI-cell type specific transcriptomic alterations and identify key targetable pathways relevant to stop mutations in CFTR for which currently there is no small molecule therapy. Conclusion: In all, we demonstrate that these models effectively serve to translate data from the lab to the clinic and back so that patient specific therapies could be validated, or new therapies be devised. Additionally, single-cell RNA sequencing in patient HIOs will provide useful insights into cell population specific and transcriptomic level alterations that are associated with abnormalities in GI function in CF.

Nothing to disclose

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Distinct roles of kindlin-3 and talin-1 in neutrophil beta2 integrin clustering
Authors: Wu Yuanyuan , Wen Lai , Ley Klaus , Fan Zhichao
Published: May 2023

Neutrophils are the most abundant leukocytes in human blood. Neutrophil malfunction may cause various immunological diseases. Beta2 integrins are critical for neutrophil recruitment. Kindlin-3 and talin-1 are important regulators for beta2 integrin activation. We have confirmed this using conformation-specific antibodies KIM127 and mAb24 that recognize activation epitopes in beta2 integrin. Besides activation, clustering is also critical for beta2 integrin avidity and adhesion of neutrophils. Whether kindlin-3 and talin-1 are involved in beta2 integrin clustering remains unclear. Here we used super-resolution stochastic optical reconstruction microscopy (STORM) to study their roles in beta2 integrin clustering on human neutrophil-like HL60 cells. We find that lymphocyte function-associated antigen 1 (LFA-1) and macrophage-1 antigen (Mac-1) are significantly clustered in wild-type cells after IL-8 or fMLP stimulation. Using CRISPR-Cas9-mediated kindlin-3 and talin-1 knockout HL60 cells, we found that kindlin-3 but not talin-1 are responsible for beta2 integrin clustering. Our study provides new insights into the regulation of beta2 integrin clustering and leukocyte recruitment.

Supported by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute, USA (R01HL145454), and a startup fund from UConn Health.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Comparing psychological and physiological factors involved in perceived threats in behaviorally inhibited individuals
Authors: Wiseman Connor , Ehlert Luke , Apostoli Giana , Wolf Olivia , Harshberger Mary , Miller Justin , Martino Paul , Miller Daniel , Terrill Sarah , Allen Michael
Published: May 2023

Behavioral inhibition (BI) is a temperament characteristic which is associated with increased vulnerability to stress compared to non-behaviorally inhibited (NBI) counterparts. The physiologic and psychologic substrate which underlies the difference between BI and NBI individuals is unknown. Our previously published study demonstrated that BI individuals have decreased heart rate variability (HRV) relative to NBI individuals suggesting that BI individuals have less parasympathetic nervous system (PNS) output; however, it is unknown how BI affects perceived stress. Our current study tested the hypothesis that BI individuals would have higher perceived stress and physiologic stress during transdermal electrical stimulation (TES). Participants were administered TES beginning at 5mV and increased by 5mV increments until 100mV was reached. We used the Adult Measure of Behavioral Inhibition (AMBI) and the Perceived Stress Scale (PSS) to measure perceived stress, State-Trait Anxiety Inventory (STAI) scores to measure current stress, and a series of self-reported questionnaires to measure BI. Additionally, we used a BIOPAC data acquisition system to measure heart rate (HR), HRV, and blood pressure (BP) to measure physiological stress. Our pilot data suggests there was a non-significant trend of higher perceived stress after TES in BI individuals; however, there was a significant relationship between perceived stress and STAI scores. There was no significant difference in HR, HRV and BP between BI and NBI individuals. In conclusion, our pilot data suggests that a person’s BI or NBI status affects their perceived stress after a stressor is induced. BI individuals will have higher perceived stress after a stressor is presented as opposed to NBI individuals. We will conduct further studies using TES to further study this finding. Identification of these physiological factors could provide an additional mechanism for identifying individuals who are at a higher risk for developing stress and anxiety disorders.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Effect of behavioral inhibition on avoidance behavior during transdermal electrical stimulation
Authors: Apostoli Giana , Ehlert Luke , Wiseman Connor , Wolf Olivia , Harshberger Mary , Martino Paul , Miller Daniel , Miller Justin , Terrill Sarah , Allen Michael
Published: May 2023

Behavioral inhibition (BI) is a temperament characteristic that is associated with increased vulnerability to stress compared to their non-behaviorally inhibited (NBI) counterparts. Our previous study demonstrated that BI individuals have lower heart rate variability (HRV) than NBI individuals. This suggests that BI individuals have significantly less parasympathetic nervous system (PNS) output at rest. However, it is unknown how BI affects avoidance acquisition using a mildly stressful stimulus. Previous studies have shown that there are differences in the behavior found in Wistar-Kyoto rats, which exhibit BI behavior, compared to Sprague-Dawley control rats. Our current study will test the hypothesis that BI individuals learn to make escape and avoidance responses using subdermal ulnar nerve transdermal electrical stimulation (TES) more rapidly than NBI individuals, and also experience a greater increase in heart rate (HR) and blood pressure (BP). BI individuals were identified through a series of self-reported questionnaires. Three levels (30 mV, 50 mV, and 70 mV) of subdermal ulnar nerve TES were delivered to participants while receiving warning signals that predict the delivery of the TES. Participants had access to a button that when pressed during the light the warning signal prevented the delivery of the TES. This was scored as an avoidance response. If the button was pressed during the TES, it terminated the stimulation and was scored as an escape. HR and BP were also measured during TES using a BIOPAC data acquisition system. Our preliminary results do not suggest a difference between BI and NBI individual differences in HR or BP during TES (n=13); however, our future studies will investigate the differences in HRV and the acquisition of avoidance behavior during TES.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Glucagon-like peptide-1 receptor agonists and cardiometabolic risk factors in Polycystic Ovary Syndrome: role of race/ethnicity
Authors: Pruett Jacob , Romero Damian , Yanes Cardozo Licy
Published: May 2023

Background: Polycystic Ovary Syndrome (PCOS), the most common endocrine disorder in reproductive-age women, is characterized by androgen excess, polycystic appearance of the ovaries, and ovulatory dysfunction. PCOS women have an increased prevalence of cardiovascular risk factors, such as increased blood pressure, insulin resistance (IR), and obesity. We have previously demonstrated that glucagon-like peptide-1 receptor agonists (GLP1RA) improve IR and obesity in a rat model of PCOS. Recent evidence suggests that Black Women (BW) with PCOS have an increased incidence of cardiometabolic risk factors compared to their White Women (WW) counterparts. We tested the hypothesis that GLP1RA has a differential effect on cardiometabolic risk factors in BW with PCOS versus WW with PCOS. Methods: The University of Mississippi Medical Center de-identified patient data from January 2013 – September 2022 were obtained from electronic medical records (EMR) using UMMC's Research Data Warehouse. Patients with 1) PCOS, 2) type 2 diabetes mellitus (T2DM), 3) documented hemoglobin A1c (HbA1c), and 4) GLP1RA prescription were identified. Cardiometabolic risk factors such as HbA1c, body mass index (BMI), and systolic and diastolic blood pressure (SBP and DBP respectively) were analyzed and compared between BW and WW with PCOS/T2DM. ICD-10 code of PCOS and T2DM: E28.2 and E11.9 respectively. Data are presented as mean ± standard deviation. Results: EMRs of 3756 PCOS patients were obtained. 13.8% of PCOS patients also had a diagnosis of T2DM with documented HbA1c, and 10.4% of them (54 patients) were on a GLP1RA. Of the 54 patients, 35 were BW. In our cohort, BW with PCOS/T2DM had a similar age (38 ± 12 vs 34 ± 11 years of age, p=NS), perimenopausal status, and smoking status as WW with PCOS/T2DM. Compared to WW with PCOS/T2DM on GLP1RA, BW women with PCOS/T2DM had significantly higher HbA1c (8.0 ± 1.0 vs 7.0 ± 0.7 %, p<0.05). There was no difference in BMI, SBP, or DBP between groups. Furthermore, on GLP1RA, there was no difference in the magnitude of change of HbA1c, BMI, SBP, or DBP in BW compared in WW on GLP1RA. Conclusions: BW with PCOS/T2DM had higher HbA1c on GLP1RA compared to WW counterparts. However, there was similar BMI, SBP, and DBP between the two groups. Furthermore, there was no difference in the magnitude of change in cardiometabolic parameters on GLP1RA between the two groups. Race/ethnicity may significantly effect HbA1c, but it does not appear to affect the efficaciousness of GLP1RA on the cardiometabolic profile in women with PCOS.

NIGMS P20GM121334 and P20GM104357, NIDDK R21DK11350 and F30DK127527, NHLBI P01HL51971

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Neuro-glial underpinning mechanisms in myelin plasticity for memory enhancement
Authors: Wahid Reham , Hassan Nancy , Samy Walaa , Talaat Aliaa , Elsayed Heba
Published: May 2023

Background and aim: Learning continually shapes our neuronal circuits to form new memories. Neural plasticity was considered as the principal mechanism for learning many decades ago. Although myelin was considered for a long time as static inert insulator, recent studies showed that myelination is dynamically changed to enhance neuronal activity under neural plasticity umbrella in terms of myelin plasticity, so our study aims to figure out the underlying mechanisms of myelin plasticity associated with learning and memory. Hypothesis: We hypothesized that many mechanisms promote memory consolidation by enhancing myelination and that glial cells have a crucial role in this myelin plasticity effect. Methods: The study was conducted on 24 rats, divided into 3 groups, with 8 rats in each; Group I (control); rats remained in their home cage, Group II (control untrained); rats were allowed to move and explore the maze for equal time but there was no active platform location learning, and Group III (trained); rats were trained using Barnez maze behavior test including three days of acquisition trials (AT), followed by two probe trials (PT). The gene expression analysis for SOX10, MYRF, NRG, EDGF, SERPINE2 and MBP was evaluated by qRT-PCR in hippocampus tissues, in addition, histopathological assessment was done with immunohistochemistry for Myelin Basic Protein (MBP), Glial Fibrillary Acidic Protein (GFAP), and Gallyas-Braak Silver staining. Furthermore, Pearson correlation was done comparing all genes with MBP expression. Results and data: The present study showed improved spatial memory with increased myelination in the trained group compared to all other groups (P<0.001), in addition to increase of SOX10, and MYRF expression in the trained group indicating more OPC differentiation into mature oligodendrocytes (P<0.001). NRG and EDGF were highly expressed in the trained group compared to other groups, in addition to the marked increase of number of the neuronal cells with more dendrites formation. SERPINE 2 and GFAP as markers of astrocytes showed high expression in the trained group in comparison with other groups (P<0.001) with strong positive correlation between SEPRINE 2 and MBP (r= 0.76, P=0.02). Conclusion: Myelin plasticity as one of the crucial learning mechanisms, was influenced by different neural and environmental signals. Although role of glial cells was almost apparent in oligodendrocytes differentiation and proliferation, there was a significant role of astrocytes in promoting such myelination effect.

There were no external funding sources for this study, it is self-funding

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Surfactant dysfunction due to e-cigarette aerosol exposure with and without additional insults
Authors: Graham Emma , McCaig Lynda , Tejura Akash , Shui-Kei Lau Gloria , Cao Anne , Veldhuizen Ruud
Published: May 2023

Introduction: The use of e-cigarettes (ECs) remains a popular habit for young populations, in part due to the variety of appealing flavours available. However, EC use has been associated with acute lung injury via unknown mechanisms. During a deep inhalation, one of the first compounds the EC aerosol comes into contact within the lungs is pulmonary surfactant. This complex mixture of lipids and surfactant associated proteins lines the alveolar surface and reduces surface tension to near zero values upon exhalation. Surfactant dysfunction, associated with serum protein leak and oxidative stress, contributes to lung injury. We hypothesized that exposure to EC aerosol impairs pulmonary surfactant function, and thereby increases its susceptibility to protein inhibition or oxidative stress. Methods: Bovine lipid extract surfactant (BLES) was used as a model exogenous surfactant. 2ml of BLES (2mg/ml) was placed in a syringe (30ml) attached to an EC, drawing in and expelling the aerosol 30 times. Vehicle e-liquid (VG:PG 50:50) as well as e-liquid containing flavouring additives and nicotine were utilized. Two models of injury were used, the first being addition of serum containing plasma proteins and the second oxidization by hypochlorous acid following aerosol exposure. Surface tension reduction of all samples after exposure was performed using a constrained drop surfactometer (CDS), where samples underwent 20 dynamic compression and expansion cycles. Results: Minimum surfaces tensions were significantly higher after exposure to EC aerosol across 20 compression/expansion cycles. Menthol and red wedding flavoured aerosol exposure resulted in significantly increased minimum surface tensions compared to unflavoured vehicle e-liquid, although nicotine had no additional effects beyond that of the vehicle e-liquid. The addition of plasma containing serum proteins significantly increased minimum surface tensions in aerosol exposed samples compared to those unexposed to serum and air controls. Oxidized surfactant had higher minimum surface tensions compared to control, however EC aerosol exposure had no additional effect on the inhibition of the surfactant’s function. Conclusion: EC aerosols alter surfactant function through increases in minimum surface tension. Variability in the severity of inhibition exists between flavouring additives, however the base common across all e-liquids is able to effectively inhibit surfactant. This inhibition is amplified in the presence of serum proteins. From these results we conclude that vaping impairs the pulmonary surfactant system and increases susceptibility to damage by secondary insults.

Lawson Health Research Institute, NSERC

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
Diet-Induced weight loss improves vascular insulin sensitivity in patients with type 2 diabetes
Authors: Smith James , Soares Rogerio , Burr Katherine , Ramirez-Perez Francisco , Martinez-Lemus Luis , Padilla Jaume , Manrique-Acevedo Camila
Published: May 2023

Background: Insulin-stimulated blood flow plays a key role in glucose and insulin delivery to target tissues, such as skeletal muscle. With the development of obesity and type 2 diabetes (T2D), there are impairments in vascular insulin signaling and, consequently, blunting of insulin-induced vasodilation. However, it remains unknown if diet-induced weight loss attenuates vascular insulin resistance in both men and women with T2D. Methods: Nine women (aged 61.9±2.8 yrs; BMI 36.1±1.8) and seven men (aged 54.9±6.0 yrs; BMI 37.6±2.6) with T2D were recruited to undergo a six-month diet to induce weight loss by reducing sugar intake to <5% of energy and total daily energy intake by 500 kilocalories. Anthropometrics, superficial femoral artery blood flow and skeletal muscle perfusion responses to systemic insulin infusion, brachial artery flow-mediated dilation (FMD), carotid-to-femoral pulse wave velocity (PWV), and biochemical parameters were assessed at baseline and at the end of the six-month dietary intervention. Dietary records were analyzed using Nutrition Data System for Research software. Results: The low-energy diet was effective at reducing body weight, as well as other metabolic outcomes including markers of liver function and inflammation. These improvements were accompanied with an increase in FMD, but not a reduction in PWV. Lastly, leg blood flow and skeletal muscle perfusion responses to insulin infusion were enhanced following the dietary intervention, an effect primarily driven by women. Conclusions: Our results indicate that diet-induced weight loss enhances vascular insulin sensitivity in patients with T2D and that these effects are primarily observed in women.

This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.