bluuebunny/crossref_metadata_2025 huggingface dataset:
Intrathecal baclofen pump in pregnancy: case report, literature review, and management considerations
Authors: Yang Kevin , Mistry Porus D , Richeimer Steven H
Published: May 2024

Background

Baclofen, a gamma-aminobutyric acid receptor type B agonist in the central nervous system, is the first-line medication among central nervous system modulating agents for the treatment of neurogenic muscle spasticity. While baclofen is most often administered enterally, patients with severe spasticity may be candidates for baclofen delivered by intrathecal pump. Currently, there are only nine studies reporting on the use of intrathecal baclofen (ITB) during pregnancy and childbirth.

Case presentation

We described a female patient with a history of childhood idiopathic spasticity of the bilateral lower extremities that was controlled by ITB pump who became pregnant in her late third decade of life and delivered a healthy infant. The patient required multiple increases of her baclofen course over the course of her pregnancy.

Discussion

Our case, alongside the existing literature on ITB during pregnancy, suggests that ITB therapy in pregnancy poses a low risk of teratogenicity and infant withdrawal seizures; however, larger, controlled studies are necessary to make those conclusions with confidence. Healthcare providers caring for pregnant ITB patients should be cognizant of the potential for such patients to require increased doses of ITB during pregnancy to achieve adequate symptom control.
Urinary methotrexate dosage in rheumatoid arthritis, in patients treated for at least 6 months: a potential marker of adherence
Authors: Théate Noémie , Geoffroy Marion , Kanagaratnam Lukshe , Gozalo Claire , Charlot Isabelle , Bolko Lois , Hittinger-Roux Ambre , Djerada Zoubir , Salmon Jean-Hugues
Published: May 2024

Objectives

Non-adherence to rheumatoid arthritis (RA) treatments must be identified. A methotrexate (MTX) urinary dosage (METU) was recently developed. The aim of our study was to assess adherence to MTX in RA using METU in real-life conditions and to compare it with indirect adherence measurement technics.

Methods

We performed a cross-sectional study at Reims University Hospital. We included over 18-year-old patients with RA treated by MTX for more than 6 months. Patients were invited to complete demographic, clinical and psychological questionnaires and adherence measurement technics (Compliance Questionnaire of Rheumatology (CQR) and Medication Possession Ratio (MPR)). A urinary sample was collected to measure MTX and information about tolerance was evaluated through Methotrexate Intolerance Severity Score.

Results

84 patients were included, 26 using oral MTX, 58 subcutaneous (SC) MTX. Among them, 73% were female, mean age was 61.5 years, MTX mean dose was 15 mg/week and 61.9% were treated by biological DMARDs (Disease Modifying Antirheumatic Drugs). 77 patients (91.7%) were adherent to treatment according to METU, whereas MPR and CQR reported less adherence (69.5% and 61.9%, respectively). MPR and METU were not significantly different in SC MTX users (p=0.059). Non-adherent patients had a higher number of tender joints and C reactive protein value (p<0.05).

Conclusion

This is the first largest study evaluating MTX adherence in patients with RA using a urinary dosage. We identified that indirect adherence measurements did not reflect real-life adherence. It would be appreciable to realise METU, in a new study, in patients with RA with unexplained response to treatment, to consider it before escalating therapeutic strategy.
Intentionally self-injured patients have lower mortality when treated at trauma centers versus non-trauma centers in South Korea
Authors: Woo Jin , Choi Han Zo , Kang Jongkyeong
Published: May 2024

Objective

This study investigated the characteristics and survival rates of patients with intentional severe trauma (self-harm or suicide) who were transported to either a regional trauma center (TC) or a non-TC facility.

Methods

This retrospective, national, population-based, observational, case-control study included patients who sustained intentional severe trauma and had an abnormal Revised Trauma Score at the injury site between January 2018 and December 2019. The data were a community-based severe trauma survey based on data collected from severe injury and multiple casualty patients transported by 119 emergency medical services (EMS), distributed by the Korea Disease Control and Prevention Agency. The treatment hospitals were divided into two types, TC and non-TCs, and several variables, including in-hospital mortality, were compared. Propensity score matching (PSM) was used to mitigate the influence of confounding variables on the survival outcomes.

Results

Among the 3864 patients, 872 and 2992 visited TC and non-TC facilities, respectively. The injury severity did not differ significantly between patients treated at TCs and non-TCs (TC, 9; non-TC, 9; p=0.104). However, compared with those treated at non-TCs, patients treated at TCs had a higher rate of surgery or transcatheter arterial embolization (14.2% vs 38.4%; p<0.001) and a higher admission rate to the emergency department (34.4% vs 60.6%; p<0.001). After PSM, 872 patients from both groups were analyzed. Patients treated at TCs exhibited a higher overall survival rate than those treated at non-TCs (76.1% vs 66.9%; p<0.001), and multiple variable logistic regression analysis demonstrated that the causes of injury and transport to the TC were significantly associated.

Conclusion

Using Korean EMS data, the results of this study revealed that initial transport to TCs was associated with reduced mortality rates. However, considering the limitations of using data from only 2 years and the retrospective design, further research is warranted.

Study type

Retrospective national, population-based observational case-control study.

Level of evidence

Level III
Determination of the theory uncertainties from missing higher orders on NNLO parton distributions with percent accuracy
Authors:   NNPDF Collaboration, Ball Richard D. , Barontini Andrea , Candido Alessandro , Carrazza Stefano , Cruz-Martinez Juan , Del Debbio Luigi , Forte Stefano , Giani Tommaso , Hekhorn Felix , Kassabov Zahari , Laurenti Niccolò , Magni Giacomo , Nocera Emanuele R. , Rabemananjara Tanjona R. , Rojo Juan , Schwan Christopher , Stegeman Roy , Ubiali Maria
Published: May 2024

We include uncertainties due to missing higher order corrections to QCD computations (MHOU) used in the determination of parton distributions (PDFs) in the recent NNPDF4.0 set of PDFs. We use our previously published methodology, based on the treatment of MHOUs and their full correlations through a theory covariance matrix determined by scale variation, now fully incorporated in the new NNPDF theory pipeline. We assess the impact of the inclusion of MHOUs on the NNPDF4.0 central values and uncertainties, and specifically show that they lead to improved consistency of the PDF determination. PDF uncertainties on physical predictions in the data region are consequently either unchanged or moderately reduced by the inclusion of MHOUs.
Fast X-ray ptychography: towards nanoscale imaging of large volume of brain
Authors: Cipiccia Silvia , Fratini Michela , Erin Ecem , Palombo Marco , Vogel Silvia , Burian Max , Zhou Fenglei , Parker Geoff J. M. , Batey Darren J.
Published: May 2024

X-ray ptychography, a scanning coherent diffraction imaging technique, is one of the most used techniques at synchrotron facilities for high resolution imaging, with applications spanning from life science to nano-electronics. In the recent years there has been a great effort to make the technique faster to enable high throughput nanoscale imaging. Here we apply a fast ptychography scanning method to image in 3D $$10^6\upmu \mathrm{{m}}^3$$

10
6

μ

m

3

of brain-like phantom at 3 kHz, in a 7 h acquisition with a resolution of 270 nm. We then present the latest advances in fast ptychography by showing 2D images acquired at 110 kHz by combining the fast-acquisition scheme with a high-acquisition rate prototype detector from DECTRIS Ltd. We finally review the experimental outcome and discuss the prospective use of fast ptychography schemes for the investigation of mm$$^{3}$$

3

size samples of brain-like phantom, by extrapolating the current results to the high coherent flux scenario of diffraction limited storage rings.
Simulation of the Stark/Zeeman-hyperfine-rotational spectra of 79BrF molecule within its vibronic ground state
Authors: Ouyang Qi , Chen Run , Shao Xu-Ping , Huang Yun-Xia , Yang Xiao-Hua
Published: May 2024

Transition dipole moments of Stark/Zeeman-hyperfine-rotational spectra of [Formula: see text] within the vibronic ground state of BrF molecule are deduced, and thus, the transition selection rules are summarized. Unlike the nearly equal linewidth in the other spectral region, the hyperfine-rotational spectral linewidth strongly depends on its transition probability due to the only natural broadening acts. Thereafter, the Stark/Zeeman-hyperfine-rotational spectra are simulated, which could help to assign the experimental spectra. In addition, the quadratic dependence of the Stark spectral shift on the applied electric field is fitted with the fitting correlation of 0.9999, which may be applied in the mapping of a complex electrostatic field. Our results are helpful for the investigations of the field-controlled cold molecular collision, the cold molecular manipulation, the cold molecular further cooling, and other related aspects as well.
Synthesis and luminescence study of the rare earth ion (Nd3+) doped Sr3Bi(PO4)3 phosphor
Authors: Kshetrapal Supriya , Ugemuge N. S. , Nafdey Renuka , Moharil S. V.
Published: May 2024

Results of a first investigations on luminescence in Nd[Formula: see text] doped Sr3Bi(PO4)3 are presented. Typical emission is in near infrared (NIR) region consisting of lines attributable to f–f transitions. The excitation also comes from f–f transitions involving higher energy levels, spanning a broad spectral range starting from near ultraviolet (nUV) running through NIR. As much as 5[Formula: see text]mol.% of Nd[Formula: see text] could be doped before concentration quenching of luminescence set in. The quenching was attributed to energy transfer between Nd[Formula: see text] ions taking place through a multipolar mechanism; the critical distance being 21.64[Formula: see text]Å. An easy synthesis method involving low-cost chemicals and favorable luminescence properties makes this phosphor a potential candidate for NIR applications.
Numerical investigation and thermal transport features of magnetic hybrid nanoparticles flow over a poignant tiny needle subject to Joule heating and slip boundary conditions
Authors: Iqbal Zahoor , Priya S. , Abdul Hakeem A. K. , Selmi Ridha , Alsawi Abdulrahman , Nour Manasik M. , Hajjej Fahima , Ameer Ahammad N. , Ahmed Alyami Maryam , Yousef El Sayed
Published: May 2024

The primary purpose of this study is to provide more information on the stable and incompressible stream of a hybrid nanofluid over a poignant tiny needle in two dimensions under slip boundary conditions. In the hybrid nanofluid flow, Al2O3and Fe3O4are nanoparticles, water and ethylene glycol (50:50) are considered as the base fluids. Furthermore, the impacts of Joule heating and inclined magnetic fields are considered. The PDE’s governing equations are converted into ODEs by using similarity transformations and solved by a numerical technique based on Runge–Kutta fourth-order method. The results illustrate that the crucial parameters such as the magnetic parameter, Eckert number, nanoparticles of solid volume fractions, inclined angle parameter, and Prandtl numbers significantly affect the momentum and thermal profiles. The heat transfer rate and skin friction factors are used to calculate the numerical values of various parameters, which are displayed in a table. These analyses manifest that raising the magnetic parameter results in a decrease in the hybrid nanofluid velocity under slip and no-slip circumstances. The Nusselt number has also grown as a result of the volumetric fractions of nanoparticles and the intensification of the angle parameter. This analysis might include areas such as microfluidics, biomedical devices, heat exchangers, and other engineering applications where precise control over fluid behavior and temperature distribution is important.
Comparison study between as-synthesized ZnO and ZnO derived from ZiF-8 metalorganic framework in removing methylene blue
Authors: Aboraia Abdelaziz M. , Almohammedi Abdullah , Alraddadi Shoroog , Taha Safeya A. , Saad Mohamed , Sharaf I. , Ismail Yasser A. M.
Published: May 2024

The nanoporous materials derived from the ZiF-8 metalorganic framework are highly interesting because of their features like good thermal stability, catalytic performance, and electric conductivity. Therefore, ZiF-derived metal oxide was utilized in several applications, for instance, energy storage and environmental remediations. Herin, we compare the as-prepared ZnO, ZiF-8, and ZnO derived from ZiF-8 in terms of structural, thermal, and morphological properties. Thus, the photocatalytic performance of all compositions. The preparation process is an effective parameter in the morphology of the sample surface. The as-synthesized ZnO had nanoparticle morphology with a size of 50–80[Formula: see text]nm. However, the ZiF-8 has cubic morphology with a long rod. The decomposition of ZiF-8 converted the sample to ZnO coated by carbon, indicating a high surface and fit morphology for photocatalysis. These results mean that ZnO derivative from ZiF-8 nanoparticles has the best efficiency for water desalination with 95%. ZnO drives from ZiF-8 demonstrated the smallest charge transfer resistance compared to that of as-prepared ZnO, and ZIF-8, coinciding with the conclusion of the EIS results. The transient photoresponses and electrochemical impedance spectra of the compounds were used further to explore the separation efficiency of the photogenerated charge carriers.
Impacts of activation energy and electroosmosis on peristaltic motion of micropolar Newtonian nanofluid inside a microchannel
Authors: Eldabe N. T. , Abouzeid M. Y. , Abdelmoneim M. M. , Ouaf M. E.
Published: May 2024

This study investigates the impact of electroosmosis on the peristaltic flow of unsteady micropolar nanofluid with heat transfer. The findings could enhance the design of peristaltic pumps, potentially improving drug delivery systems, simulations of blood flow in medical devices, and cancer treatments. The fluid under investigation adheres to a micropolar model and flows through a microchannel that exhibits peristalsis along its walls. Moreover, the system is subjected to various external effects, including a uniform magnetic field, the electroosmotic phenomenon, heat absorption, and a chemical reaction with activation energy. Consequently, the problem is mathematically modulated by a system of nonlinear partial differential equations governing the velocity, temperature, and nanoparticle concentration. By employing wave transformation, these governing equations are reduced to ordinary differential equations (ODEs). The reduced equations were solved both analytically, using the homotopy perturbation method, and numerically, using the Runge–Kutta–Merson method. A comparison was made between the solutions, which were found to be closely aligned. Furthermore, a series of figures were employed to provide visual representation and discussion of the implications of the physical properties. The calculations reveal that the electroosmotic flow (EOF) enhances the axial flow of the micropolar fluid along the direction of the applied electric field. It is also observed that the increase in the activation energy (which indicates a low reaction rate) increases the concentration profile whereas the increase in the reaction rate parameter reduces the concentration profile. Additionally, the spin velocity of the particles is diminished by either an increase in the magnetic parameter or the coupling parameter.
Unveiling and Modelling the Impact of Learning Organisations on Information Technology Employees’ Career Advancement and Retention
Authors: Chidambaram Vijayabanu , Aravamudhan Rajagopalan
Published: May 2024

Learning organisations facilitate the acquisition of new knowledge and skills for both organisations and their members, enabling the application of the latest insights in a dynamic environment. This study addresses a research gap by constructing a model identifying the factors influencing learning organisations and their subsequent impact. The research delves into uncovering the catalysts behind learning organisations concerning the career advancement of information technology (IT) employees and their intent to remain in their roles. The study, conducted in a developing country, India, employs an explanatory research design to explore the interrelationship between learning organisations, career progression and employee retention. Primary and secondary data have been used for this study. The primary data has been collected from 389 IT sector employees at various employment positions in Chennai through a structured and standard questionnaire based on the Dimensions of Learning Organizations Questionnaire (DLOQ) by Watkins, KE and Marsick, VJ (2023) [Rethinking workplace learning and development catalyzed by complexity. Human Resource Development Review, 22(3), 333-344. doi:10.1177/15344843231186629], demonstrating a high reliability at 96.4%.
MANAGERS’ PURSUIT OF AMBIDEXTERITY IN THE CONTEXT OF ARTIFICIAL INTELLIGENCE IMPLEMENTATIONS: INSIGHTS INTO SITUATIONALLY INDUCED REGULATORY FOCUS
Authors: LEE KYOOTAI , WOO HAN-GYUN , PARK TAEYOUNG , JONG SIMON DE
Published: May 2024

This study identifies a key cognitive mechanism through which information encountered by managers influences their pursuit of ambidexterity when implementing artificial intelligence (AI) in organisations. Additionally, it investigates the roles of managers’ understanding of technological environments and risk-taking strategies of their organisations in this relationship. We conducted three studies with managers at the above-middle level. The results indicate that managers with situationally induced promotion focus tend to have greater opportunity appraisal (Studies 1, 2, and 3) and pursuit of ambidexterity (Studies 2 and 3) compared to those with situationally induced prevention focus. Opportunity appraisal mediates the relationship between situationally induced regulatory focus and ambidexterity pursuit (Studies 2 and 3). Further, organisational risk-taking strategy moderates the links from situationally induced regulatory focus to opportunity appraisal to ambidexterity (Study 3). This study contributes to the theoretical understanding of the cognitive processes underlying managers’ pursuit of ambidexterity when facing technological uncertainty.
Graphuzz: Data-driven Seed Scheduling for Coverage-guided Greybox Fuzzing
Authors: Xu Hang , Chen Liheng , Gan Shuitao , Zhang Chao , Li Zheming , Ji Jiangan , Chen Baojian , Hu Fan
Published: May 2024

Seed scheduling is a critical step of greybox fuzzing, which assigns different weights to seed test cases during seed selection, and significantly impacts the efficiency of fuzzing. Existing seed scheduling strategies rely on manually designed models to estimate the
potentials
of seeds and determine their weights, which fails to capture the rich information of a seed and its execution and thus the estimation of seeds’ potentials is not optimal. In this article, we introduce a new seed scheduling solution, Graphuzz, for coverage-guided greybox fuzzing, which utilizes deep learning models to estimate the potentials of seeds and works in a data-driven way. Specifically, we propose an extended control flow graph called e-CFG to represent the control-flow and data-flow features of a seed's execution, which is suitable for graph neural networks (GNN) to process and estimate seeds’ potential. We evaluate each seed's code coverage increment and use it as the label to train the GNN model. Further, we propose a self-attention mechanism to enhance the GNN model so that it can capture overlooked features. We have implemented a prototype of Graphuzz based on the baseline fuzzer AFLplusplus. The evaluation results show that our model can estimate the potential of seeds and has the robust capability to generalize to different targets. Furthermore, the evaluation using 12 benchmarks from FuzzBench shows that Graphuzz outperforms AFLplusplus and the state-of-the-art seed scheduling solution K-Scheduler and other coverage-guided fuzzers in terms of code coverage, and the evaluation using 8 benchmarks from Magma shows that Graphuzz outperforms the baseline fuzzer AFLplusplus and SOTA solutions in terms of bug detection.
A Survey on Malware Detection with Graph Representation Learning
Authors: Bilot Tristan , El Madhoun Nour , Al Agha Khaldoun , Zouaoui Anis
Published: May 2024

Malware detection has become a major concern due to the increasing number and complexity of malware. Traditional detection methods based on signatures and heuristics are used for malware detection, but unfortunately, they suffer from poor generalization to unknown attacks and can be easily circumvented using obfuscation techniques. In recent years, Machine Learning (ML) and notably Deep Learning (DL) achieved impressive results in malware detection by learning useful representations from data and have become a solution preferred over traditional methods. Recently, the application of Graph Representation Learning (GRL) techniques on graph-structured data has demonstrated impressive capabilities in malware detection. This success benefits notably from the robust structure of graphs, which are challenging for attackers to alter, and their intrinsic explainability capabilities. In this survey, we provide an in-depth literature review to summarize and unify existing works under the common approaches and architectures. We notably demonstrate that Graph Neural Networks (GNNs) reach competitive results in learning robust embeddings from malware represented as expressive graph structures such as Function Call Graphs (FCGs) and Control Flow Graphs (CFGs). This study also discusses the robustness of GRL-based methods to adversarial attacks, contrasts their effectiveness with other ML/DL approaches, and outlines future research for practical deployment.
Self-Supervised Bot Play for Transcript-Free Conversational Critiquing with Rationales
Authors: Li Shuyang , Prasad Majumder Bodhisattwa , McAuley Julian
Published: May 2024

Conversational critiquing in recommender systems offers a way for users to engage in multi-turn conversations to find items they enjoy. For users to trust an agent and give effective feedback, the recommender system must be able to
explain
its suggestions and rationales. We develop a two-part framework for training multi-turn conversational critiquing in recommender systems that provide recommendation rationales that users can effectively interact with to receive better recommendations. First, we train a recommender system to jointly suggest items and explain its reasoning via subjective rationales. We then fine-tune this model to incorporate iterative user feedback via self-supervised bot-play. Experiments on three real-world datasets demonstrate that our system can be applied to different recommendation models across diverse domains to achieve state-of-the-art performance in multi-turn recommendation. Human studies show that systems trained with our framework provide more useful, helpful, and knowledgeable suggestions in warm- and cold-start settings. Our framework allows us to use only product reviews during training, avoiding the need for expensive dialog transcript datasets that limit the applicability of previous conversational recommender agents.
Na3Zr2Si2PO12 Solid Electrolyte Separator for Aqueous Sodium-Ion Batteries: Synthesis via the One-Step Sintering of Glass-Ceramics
Authors: Ogasa Kazuhito , Mitsunori Kitta
Published: May 2024

A dense Na₃Zr₂Si₂PO₁₂ (NZSP) solid electrolyte suitable for aqueous sodium-ion secondary batteries was synthesized using a glass-ceramic composite. The sintering process at temperatures ranging from 1050 to 1150 °C achieved a higher density at lower temperatures than sintering NZSP alone. This temperature range also allowed for greater density consistency. The ionic conductivity of the solid electrolyte was measured to be in the order of 1 mS/cm. Upon testing for water leakage, the electrolyte demonstrated sufficient density. Moreover, batteries employing this solid electrolyte achieved a stable voltage of 2 V and exhibited robust cycle performance, enduring over 100 cycles with good stability.
Communication — The Impact of Co-solvent Selection for Dimethyl-2,5-dioxahexane carboxylate in Sodium Ion Batteries
Authors: Jayakumar Rishivandhiga , Shipitsyn Vadim , Chak Chanmonirath (Michael) , Zuo Wenhua , Sun Bing , Lu Xiaochuan , Ma Lin
Published: May 2024

Traditional linear carbonates including dimethyl carbonate (DMC), diethyl carbonate (DEC), and ethyl methyl carbonate (EMC) were investigated as co-solvents for the dimethyl-2,5-dioxahexane carboxylate (DMOHC)-based electrolyte in Na0.97Ca0.03[Mn0.39Fe0.31Ni0.22Zn0.08]O2 (NCMFNZO)/hard carbon (HC) pouch cells. The EMC-containing cell displays excellent electrochemical performance, exhibiting only a 1.6 mAh irreversible capacity loss during 500 h of storage at 4 V and 40 °C, and maintaining over 80% capacity retention after 200 cycles up to 4 V at 40 °C. Severe gas evolution and Na plating issues are present in all the tested systems.
Infertility in POMC-deficient mice
Authors: Geddes Andrew , Thompson Zoe
Published: May 2024

The pro-opiomelanocortin (POMC) gene is expressed in the hypothalamus and pituitary and its product is cleaved into several peptides including the melanocyte stimulating hormones (α, β, or γ-MSH), adrenocorticotropic hormone (ACTH), and beta-endorphin. Alpha-MSH is involved in regulating appetite, sexual behavior, and melanin, while ACTH regulates secretion of glucocorticoids from the adrenal cortex. Humans who have a POMC mutation either produce an abnormally short version of POMC or are missing the protein completely and therefore lack these hormones. This has biological consequences including red hair and fair skin, early-onset obesity (due to severe hyperphagia), and potentially hypothyroidism, hypogonadism, and infertility. Many of these same effects are seen with mice containing this deficiency. We are interested in studying infertility through a mouse model of hypothalamic-specific POMC-deficiency. These mice also experience early-onset obesity and infertility. Estradiol is a key reproductive hormone that is essential for fertility. POMC deficiency may lead to hypogonadism, which can cause low levels of estrogen so we hypothesize that POMC-deficient mice have reduced estrogen levels, which may contribute to their infertility. To test this hypothesis, we will measure estrogen levels in POMC-deficient mice at different stages of the estrus cycle using an estradiol ELISA kit. We expect the POMC-deficient mice to have lower estrogen levels than control mice. We also plan to use liquid chromatography mass spectrometry (LC-MS) to measure estrogen levels. Before collecting the blood samples, vaginal cell samples are obtained and viewed under a microscope to analyze the ratio of cells and determine which stage the females were in—proestrus, estrus, metestrus, or diestrus. Blood samples are then collected into 1.5 mL microcentrifuge tubes with 10 microliters of 0.5 M EDTA to prevent blood clotting. After blood is collected, it is centrifuged at 2,000 g for 20 minutes at 4 degrees Celsius. The plasma is then stored at -80 degrees Celsius until analysis. Based on preliminary results we expect the POMC deficient mice to have reduced estrogen and/or altered levels throughout the cycle. So far, our results have indicated that POMC-deficient female mice have abnormal estrus cycles and also reduced uterine weights. The conclusions from this study will help us understand more about the causes of infertility in POMC-deficient mice, which may also lead to greater understanding on how to treat humans with infertility due to a POMC mutation.

Support for this research was provided by IRACDA grant NIHK12GM111725 to Z.T. and UVU Scholarly Activities Grant to A.G.

This is the full abstract presented at the American Physiology Summit 2024 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.
Physical and functional interaction between NHE3 and SGLT2 in the renal proximal tubule of male and female rats
Authors: Polidoro Juliano , Osorio Nadia , Girardi Adriana
Published: May 2024

Sodium-glucose cotransporter type 2 (SGLT2) and sodium/hydrogen exchanger-3 (NHE3) serve as the primary renal proximal tubule transporters responsible for the apical uptake of filtered glucose and NaHCO3/NaCl, respectively. Our previous studies demonstrated that chronic treatment with the selective SGLT2 inhibitor empagliflozin reduces NHE3 activity in the proximal tubule. Furthermore, we observed that the non-specific SGLT1/SGLT2 inhibitor, phlorizin, acutely inhibits NHE3 in the absence of luminal glucose, suggesting that the impact of SGLT inhibition on NHE3 may not be attributed to high tubular glucose concentrations. Additionally, our investigations revealed that SGLT2, but not SGLT1, colocalizes with NHE3 in the renal proximal tubule. This study aimed to gain insights into the functional and physical association of NHE3 and SGLT2 in the renal proximal tubule. In vivo microperfusion was conducted in male and female Wistar rats using glucose-free perfusates containing vehicle or empagliflozin (1 μM). Empagliflozin treatment significantly decreased the flow rate of bicarbonate reabsorption (JHCO3−) in both male (2.109±0.091 vs. 1.119±0.096 nmol/cm2∙s) and female rats (1.750±0.037 vs. 1.128±0.062 nmol/cm2∙s), indicating that SGLT2 inhibitors inhibit NHE3 activity through glucose-independent mechanisms. By employing nondenaturant detergents, we utilized blue native polyacrylamide gel electrophoresis (BN-PAGE) to preserve native protein-protein interactions. Double staining with antibodies against specific partner candidates revealed that bands attributed to NHE3, MAP17, PDZK1, and SGLT2 migrate similarly at ~480 kDa in samples from rat renal cortex, as supported by independent experiments. Rigorous controls were implemented to address concerns related to autofluorescence, antibody cross-reactivity, and signal specificity, confirming the validity of our results. Furthermore, complexes involving SGLT2 and NHE3 at an apparent ~480 kDa molecular weight were observed in male and female rats. Unlike SGLT2, SGLT1 bands in BN-PAGE did not overlap with the NHE3 signal, which is consistent with our earlier immunofluorescence experiments. Collectively, our data suggest that NHE3 and SGLT2 are functionally and physically associated with the renal proximal tubule. Future experiments will be undertaken to further characterize the physical association between NHE3 and SGLT2 and to determine whether the inhibition of NHE3 by SGLT2 inhibitors is mediated through the disruption of the NHE3-PDZK1-MAP17-SGLT2 multiprotein complex.

Funding: São Paulo Research Foundation (FAPESP).

This is the full abstract presented at the American Physiology Summit 2024 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.
A Sexually Dimorphic Hepatic Cycle of Very Low Density Lipoprotein Uptake and Assembly
Authors: Martini Tomaz , Gobet Cedric , Salati Andrea , Blanc Jerome , Mookhoek Aart , Knott Graham , Sordet-Dessimoz Jessica
Published: May 2024

The liver shows striking sexual dimorphism, which is reflected in differences between women and men in pathologies inherently associated with hepatic function. Recent single-cell transcriptomes revealed spatiotemporal programmes of liver function on the sublobular scale. However, how sexual dimorphism affects this space-time logic remains poorly understood. To address this, we performed single-cell RNA-seq in the mouse liver, which allowed us to model how lobular position, circadian time and sex shape the transcriptome. We found that sex, space and time markedly influence xenobiotic detoxification and lipid processing, including lipoprotein metabolism. Crucially, the very low density lipoprotein receptor (VLDLR) is restricted to the pericentral zone, with significantly higher mRNA and protein levels in female mice. Using human samples, we were able to recapitulate both VLDLR's pericentral expression as well as higher mRNA and protein levels in premenopausal women compared to similarly aged men. In humans, we found that VLDLR expression depends not just on age but also body mass index. Conversely, several genes involved in VLDL assembly are periportally biased, and we corroborated periportal VLDL generation with electron microscopy, optimized for detecting low density lipid particles. Together, this suggests a hepatic cycle of periportal formation and pericentral uptake of VLDL. Crucially, these processes provide a new window into the sexual dimorphism characterizing differences in VLDL kinetics and atherosclerotic cardiovascular disease.

The work was supported by a Swiss National Science Foundation grant. The authors declare no conflicting interests.

This is the full abstract presented at the American Physiology Summit 2024 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.
OMICmAge: An integrative multi-omics approach to quantify biological age with electronic medical records
Authors: Dwaraka Varun , Chen Qingwen , Carreras-Gallo Natalia , Mendez Kevin , Chen Yulu , Begum Sofina , Kachroo Priyadarshini
Published: May 2024

Biological aging is a multifactorial process involving complex interactions of cellular and biochemical processes that is reflected in omic profiles. Using common clinical laboratory measures in ~30,000 individuals from the MGB-Biobank with balanced sex representation, we developed a robust, predictive biological aging phenotype, EMRAge, that balances clinical biomarkers with overall mortality risk and can be broadly recapitulated across EMRs. We then applied elastic-net regression to model EMRAge with DNA-methylation (DNAm) and multiple omics, generating DNAmEMRAge and OMICmAge, respectively. Both biomarkers demonstrated strong associations with chronic diseases and mortality that outperform current biomarkers across our discovery (MGB-ABC, n=3,451) and validation (TruDiagnostic, n=12,666) cohorts. Furthermore, both DNAmEMRAge and OMICmAge exhibit greater accuracy (average ROC = 0.88) in predicting 5-year and 10-year mortality than current biological age predictors. Through the use of epigenetic biomarker proxies, OMICmAge has the unique advantage of expanding the predictive search space to include epigenomic, proteomic, metabolomic, and clinical data while distilling this in a measure with DNAm alone, providing opportunities to identify clinically-relevant interconnections central to the aging process.

This work was funded in part by TruDiagnostic for data generation and manuscript writing. Efforts for RK, KM, YC, SB, and JALS are supported by R01HL123915 from the NIH/NHLBI; PK is supported by K99HL159234 from the NIH/NHLBI; RSK is supported by K01HL146980 from the NIH/NHLBI; SHC is supported by K01HL153941 from the NIH/NHLBI; YC and JAILS are supported by R01HL141826 from the NIH/NHLBI; AD is supported by K01HL130629 from the NIH/NHLBI; AD and JALS are supported by 1R01HL152244 from the NIH/NHLBI; MM and JALS are supported by R01HL155742 from the NIH/NHLBI; MM is supported by R01HL139634 from the NIH/NHLBI; JALS, STW, EWK are supported by the NIH U01HG008685; VNG is supported by NIH AG065403 and AG064223; CEW is supported by the JSPS KAKENHI Grant (JP19K21239), the Japanese Environment Research and Technology Development Fund (No. 5- 1752), JPJ SBP-1201854), HLF 20180290, HLF 20200693), and the Swedish Research Council (2016-02798); NJWR is supported by MR/Y010736/1 and IF\R1\231034; EM is supported by the NIH (ZICTR000410-03).

This is the full abstract presented at the American Physiology Summit 2024 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.
Loss of Acid Ceramidase in Myeloid Cells Impairs MHC II Expression on Dendritic Cells and Macrophages to Alleviate Chronic Colitis in IL10−/− Mice
Authors: Espinoza Keila , Marron Marilyn , Snider Justin , Snider Ashley
Published: May 2024

Inflammatory bowel disease (IBD) is characterized by chronic inflammation in the colon and drastically increases the risk in the development of colorectal cancer (CRC). Over expression of acid ceramidase (AC) resulting in accumulation of sphingosine-1-phosphate (S1P), which amplify inflammatory pathways, has been implicated in patients with IBD and CRC. The conditional loss of AC in myeloid cells (ACMYE) has demonstrated promise as a therapeutic target in an acute colitis model. We sought to expand the investigation of AC loss in a physiologically relevant model of IBD using IL-10 deficient mice. IL10−/− mice were crossed with AC conditional knockout mice where AC is deleted in myeloid cells to generate ACMYE/IL10−/−, with ACfl/fl/IL10−/− mice used as control. Male and female animals were collected at 8, 12, and 24 weeks of age and assessed for intestinal inflammation. Upon examination of basic parameters of colitis, ACMYE mice exhibited reduced body weight and enlarged spleens at 12 weeks of age. Histologic assessment revealed no difference between genotypes in colitis severity at 8 or 12 weeks of age. Flow cytometry analysis was utilized to define the role of AC in immune cell recruitment. ACMYE mice exhibit reduced MHC II surface expression on antigen presenting cells (APCs) as well as reductions in neutrophil activation markers in peripheral tissues and the colon at 8 weeks of age. Interestingly, at 12 weeks of age ACfl/fl mice demonstrate significant immunosuppression across various cell types in the colon compared to ACMYE mice, whose colonic immune cells demonstrate little change over time. Furthermore, CD8+ cytotoxic T cell populations were significantly elevated in peripheral tissues despite continued reductions of MHC II surface expression on APCs in ACMYE mice at 12 weeks of age. These data indicate that loss of AC may provide protection in early age while resulting in altered inflammation in later age; however, loss of AC may also disrupt MHC II expression as seen consistently in APCs, and may indicate interference with cell-to-cell cross talk. Realtime qPCR revealed that ACMYE mice exhibited significant ablation in the expression of several pro-inflammatory cytokines at 24 weeks of age. Together these data implicate AC as a potential therapeutic target in reducing inflammation in chronic IBD.

This work is supported by the National Institute of Diabetes and Digestive and Kidney Diseases R01 DK132079 (AJS).

This is the full abstract presented at the American Physiology Summit 2024 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.
Selective Timing of Maternal Immune Activation Alters Developmental Milestones, Behavior, and Blood-Brain Barrier Integrity
Authors: Sheng Julietta A. , Tobet Stuart A.
Published: May 2024

Background and Hypothesis: Maternal immune activation (MIA) has been associated with increased risk for neuropsychiatric disease. Fetal exposure to maternal infection activates different toll-like receptors (TLRs) to initiate innate inflammatory responses in mother and fetus. The goal of the current study is to determine sex-dependent aspects of MIA during mid-gestation on neurodevelopment. Methods: Timed-pregnant female mice were administered RQ (TLR7 agonist) or vehicle saline on embryonic day (E) 12.5. Maternal and fetal cytokines were measured to ensure infection of pregnant dam (E15). Offspring were assessed postnatally for developmental milestones and behavior. Adult offspring were perfused with fluorescein isothiocyanate (FITC; 100mg/mL) to visualize blood vessel integrity (FITC leakage; Frahm & Tobet, 2015). To determine neural molecular mechanisms for behavioral changes, sections through the paraventricular nucleus of the hypothalamus (PVN) of offspring were immunolabeled for Glial Fibrillary Acidic Protein (GFAP; astrocytic end feet), Desmin (pericytes) and IBA-1 (microglia). Results: Maternal cytokines IL-6 (p<0.05) and IL-10 (p<0.01) were higher while TNFα (p<0.01) and IL-17 were lower 3 days after RQ-exposure. In fetuses (E15), IL-6 (p<0.05) and IL-17 (p<0.0001) were greater, while IL-10 was higher only in males (p<0.001) exposed to maternal infection. RQ-exposed males also had reduced TNFα (p<0.05). Additionally, RQ-exposed offspring had lower body weights at birth and delayed eye openings. Females exposed to maternal RQ exhibited slower onset of puberty with delayed vaginal openings. On the behavioral side, juvenile and adult offspring of RQ injected moms exhibited less social-like behavior (p<0.001 for all groups) with lower hedonic-like behavior selectively in females (p<0.001). RQ-offspring further showed greater leakage in the PVN indicated by more FITC in the extravascular space (males p<0.001, females p<0.01). GFAP + (astrocytic end feet) coverage of FITC-labeled vessels was higher in the PVN selectively in RQ males (p<0.001). Desmin+ (pericyte) coverage was greater in the PVN of RQ males (p<0.01) and females (p<0.001). Finally, there was greater number of IBA-1+ cells in the adult offspring PVN of both sexes (p<0.01) after maternal injection of RQ. Conclusions: This study provides support for sex-dependent influences of fetal antecedents for altered brain development and behavioral outputs that could be indicative of increased susceptibility for adult disorders through immune mechanisms. Future studies will examine how timing of infection during gestation (mid vs. late) changes neurodevelopmental outputs in offspring.

Supported by ORWH-NIMH U54 SCORE-MH118919.

This is the full abstract presented at the American Physiology Summit 2024 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.
Optogenetic stimulation of Phox2b-expressing neurons in the respiratory parafacial region rescue fentanyl-induced respiratory depression
Authors: Burgraff Nicholas , Moreira Thiago , Takakura Ana , Ramirez Jan Marino
Published: May 2024

The primary cause of death from opioid overdose is opioid-induced respiratory depression (OIRD), which results in substantial suppression of respiratory rate, destabilization of breathing patterns, severe hypercapnia, and a heightened risk for life-threatening apnea. A crucial chemosensitive brainstem region, located in the rostral ventrolateral medullary reticular formation, contains a bilateral cluster of approximately 800 non-opioid receptor-expressing glutamatergic, non-catecholaminergic, Phox2b+ propriobulbar neurons. These neurons are stimulated by CO2 and acidification and play a vital role in regulating breathing to prevent respiratory acidosis. Under normal circumstances, opioid induced hypercapnia should stimulate these cells to restore ventilation and prevent disturbances in arterial blood gases. However, during OIRD, it remains unclear whether these neurons can effectively rescue breathing in the response to opioid induced hypercapnia. The present study aims to address this question by investigating whether the ability of these neurons to stimulate breathing is significantly altered during opioid-induced respiratory depression. Using optogenetic stimulation, we stimulated these Phox2b+ cells before and after fentanyl to test for whether their ability to stimulate ventilation is reduced during OIRD. As expected, fentanyl (500 μg/kg, ip) resulted in respiratory rate suppression and destabilization of breathing pattern. Before fentanyl administration optogenetic stimulation of Phox2b+ cells increased breathing activity in a pulse stimulation frequency dependent (5-20Hz) manner. Unexpectedly, following fentanyl administration, similar optogenetic stimulation of Phox2b+ cells resulted in a significantly greater frequency dependent (5-20Hz) increase in breathing activity compared to pre-fentanyl levels. Additionally, both hypercapnia (FiCO2 = 0.1) or hypoxia (FiO2 = = 0.1) produced an increase breathing activity in a similar manner in pre- and post-fentanyl conditions. The results suggest that fentanyl paradoxically increases the ability of Phox2b+ cells to stimulate breathing but shifts the steady-state relationship between ventilation and arterial blood gases, such that resting ventilation is reduced.

FAPESP, NIH.

This is the full abstract presented at the American Physiology Summit 2024 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.