bluuebunny/crossref_metadata_2025 huggingface dataset:
Capacity Demand Analysis of Rural Biogas Power Generation System with Independent Operation Considering Source-Load Uncertainty
Authors: Zhou Miao , Liu Jun , Tang Aihong , You Xinyu
Published: April 2024

With the greatly increased penetration rate of wind power, photovoltaic, and other new energy sources in the power system, the proportion of controllable units gradually decreased, resulting in increased system uncertainty. The biogas power generation system can effectively alleviate the pressure caused by source-load uncertainty in such high-permeability systems of new energy sources such as wind power and photovoltaic. Hence, from the perspective of the power system, this paper introduces a capacity demand analysis method for a rural biogas power generation system capable of independent operation amidst source-load uncertainty. To enhance the depiction of pure load demand uncertainty, a scene set generation method is proposed, leveraging quantile regression analysis and Gaussian mixture model clustering. Each scene’s data and probability of occurrence elucidate the uncertainty of pure load demand. An integrated optimal operation model for new energy and biogas-generating units, free from energy storage capacity constraints, is established based on the generated scenario set. Addressing considerations such as biogas utilization rate and system operation cost, a biogas storage correction model, utilizing the gas storage deviation degree index and the cost growth rate index, is developed to determine biogas demand and capacity. The example results demonstrate the significant reduction in gas storage construction costs and charging and discharging imbalances achieved by the proposed model while ensuring systemic operational cost effectiveness.
Congestion Control Mechanism Based on Backpressure Feedback in Data Center Networks
Authors: Li Wei , Ren Mengzhen , Liu Yazhi , Li Chenyu , Qian Hui , Zhang Zhenyou
Published: April 2024

In order to solve the congestion problem caused by the dramatic growth of traffic in data centers, many end-to-end congestion controls have been proposed to respond to congestion in one round-trip time (RTT). In this paper, we propose a new congestion control mechanism based on backpressure feedback (BFCC), which is designed with the primary goal of switch-to-switch congestion control to resolve congestion in a one-hop RTT. This approach utilizes a programmable data plane to continuously monitor network congestion in real time and identify real-congested flows. In addition, it employs targeted flow control through backpressure feedback. We validate the feasibility of this mechanism on BMV2, a programmable virtual switch based on programming protocol-independent packet processors (P4). Simulation results demonstrate that BFCC greatly enhances flow completion times (FCTs) compared to other end-to-end congestion control mechanisms. It achieves 1.2–2× faster average completion times than other mechanisms.
Advances in Hydrogel-Based Drug Delivery Systems
Authors: Liu Boya , Chen Kuo
Published: April 2024

Hydrogels, with their distinctive three-dimensional networks of hydrophilic polymers, drive innovations across various biomedical applications. The ability of hydrogels to absorb and retain significant volumes of water, coupled with their structural integrity and responsiveness to environmental stimuli, renders them ideal for drug delivery, tissue engineering, and wound healing. This review delves into the classification of hydrogels based on cross-linking methods, providing insights into their synthesis, properties, and applications. We further discuss the recent advancements in hydrogel-based drug delivery systems, including oral, injectable, topical, and ocular approaches, highlighting their significance in enhancing therapeutic outcomes. Additionally, we address the challenges faced in the clinical translation of hydrogels and propose future directions for leveraging their potential in personalized medicine and regenerative healthcare solutions.
Stereochemical Behavior of Pyrrolo-Pyrazole Peptidomimetics Promoting Phase-Selective Supramolecular Organogels
Authors: Chiesa Enrica , Anastasi Francesco , Clerici Francesca , Lumina Edoardo Mario , Genta Ida , Pellegrino Sara , Gelmi Maria Luisa
Published: April 2024

Supramolecular gels were developed by taking advantage of an assembly of small dipeptides containing pyrrolo-pyrazole scaffolds. The dipeptides were prepared through a robust and ecofriendly synthetic approach from the commercially available starting materials of diazoalkanes and maleimides. By playing with the functionalization of the scaffold, the choice of the natural amino acid, and the stereochemistry, we were able to obtain phase-selective gels. In particular, one peptidomimetic showed gelation ability and thermoreversibility in aromatic solvents at very low concentrations. Rheology tests showed a typical viscoelastic solid profile, indicating the formation of strong gels that were stable under high mechanical deformation. NMR studies were performed, allowing us to determine the conformational and stereochemical features at the base of the supramolecular interactions.
Hydrophobic Silk Fibroin–Agarose Composite Aerogel Fibers with Elasticity for Thermal Insulation Applications
Authors: Du Yuxiang , Jiang Pengjie , Yang Xin , Fu Rui , Liu Lipeng , Miao Changqing , Wang Yaxiong , Sai Huazheng
Published: April 2024

Aerogel fibers, characterized by their ultra-low density and ultra-low thermal conductivity, are an ideal candidate for personal thermal management as they hold the potential to effectively reduce the energy consumption of room heating and significantly contribute to energy conservation. However, most aerogel fibers have weak mechanical properties or require complex manufacturing processes. In this study, simple continuous silk fibroin–agarose composite aerogel fibers (SCAFs) were prepared by mixing agarose with silk fibroin through wet spinning and rapid gelation, followed by solvent replacement and supercritical carbon dioxide treatment. Among them, the rapid gelation of the SCAFs was achieved using agarose physical methods with heat-reversible gel properties, simplifying the preparation process. Hydrophobic silk fibroin–agarose composite aerogel fibers (HSCAFs) were prepared using a simple chemical vapor deposition (CVD) method. After CVD, the HSCAFs’ gel skeletons were uniformly coated with a silica layer containing methyl groups, endowing them with outstanding radial elasticity. Moreover, the HSCAFs exhibited low density (≤0.153 g/cm3), a large specific surface area (≥254.0 m2/g), high porosity (91.1–94.7%), and excellent hydrophobicity (a water contact angle of 136.8°). More importantly, they showed excellent thermal insulation performance in low-temperature (−60 °C) or high-temperature (140 °C) environments. The designed HSCAFs may provide a new approach for the preparation of high-performance aerogel fibers for personal thermal management.
The Nepalese Diaspora and Adaptation in the United States
Authors: Thapa-Oli Soni , Yang Philip Q.
Published: April 2024

The Nepalese in the United States of America (USA) are an emerging diasporic community. In spite of the phenomenal growth of the Nepalese diaspora in the USA in the last more than two decades, little is known about this new diasporic community, especially regarding how the Nepalese adapt to American life. This study documents the rapid growth in Nepalese immigration to the USA in the twenty-first century, based on data from the U.S. Department of Homeland Security. Using the data from an online survey, it analyzes the experiences of the Nepalese in cultural adaptation, structural adaptation, marital adaptation, identificational adaptation, and receptional adaptation. The results show that although the Nepalese have become partly assimilated to American culture, they still to a large extent retain their ethnic culture, ethnic association, ethnic identity, and ethnic marital partners, and they have had mixed experiences of prejudice and discrimination. The findings have significant scholarly and practical implications.
Determinants of mer Promoter Activity from Pseudomonas aeruginosa
Authors: Hu Qingyuan , Wang Jue , Liu Chunhong , Feng Yu , Chen Hao
Published: April 2024

Since the MerR family is known for its special regulatory mechanism, we aimed to explore which factors determine the expression activity of the mer promoter. The Tn501/Tn21 mer promoter contains an abnormally long spacer (19 bp) between the −35 and −10 elements, which is essential for the unique DNA distortion mechanism. To further understand the role of base sequences in the mer promoter spacer, this study systematically engineered a series of mutant derivatives and used luminescent and fluorescent reporter genes to investigate the expression activity of these derivatives. The results reveal that the expression activity of the mer promoter is synergistically modulated by the spacer length (17 bp is optimal) and the region upstream of −10 (especially −13G). The spacing is regulated by MerR transcription factors through symmetrical sequences, and −13G presumably functions through interaction with the RNA polymerase sigma-70 subunit.
Association of Gene Polymorphisms with Normal Tension Glaucoma: A Systematic Review and Meta-Analysis
Authors: Pan Lijie , Wu Jian , Wang Ningli
Published: April 2024

Background: Normal tension glaucoma (NTG) is becoming a more and more serious problem, especially in Asia. But the pathological mechanisms are still not illustrated clearly. We carried out this research to uncover the gene polymorphisms with NTG. Methods: We searched in Web of Science, Embase, Pubmed and Cochrane databases for qualified case-control studies investigating the association between single nucleotide polymorphisms (SNPs) and NTG risk. Odds ratios (ORs) and 95% confidence intervals (CIs) for each SNP were estimated by fixed- or random-effect models. Sensitivity analysis was also performed to strengthen the reliability of the results. Results: Fifty-six studies involving 33 candidate SNPs in 14 genetic loci were verified to be eligible for our meta-analysis. Significant associations were found between 16 SNPs (rs166850 of OPA1; rs10451941 of OPA1; rs735860 of ELOVL5; rs678350 of HK2; c.603T>A/Met98Lys of OPTN; c.412G>A/Thr34Thr of OPTN; rs10759930 of TLR4; rs1927914 of TLR4; rs1927911 of TLR4; c.*70C>G of EDNRA; rs1042522/-Arg72Pro of P53; rs10483727 of SIX1-SIX6; rs33912345 of SIX1-SIX6; rs2033008 of NCK2; rs3213787 of SRBD1 and c.231G>A of EDNRA) with increased or decreased risk of NTG. Conclusions: In this study, we confirmed 16 genetic polymorphisms in 10 genes (OPA1, ELOVL5, HK2, OPTN, TLR4, EDNRA, P53, NCK2, SRBD1 and SIX1-SIX6) were associated with NTG.
Identification of Key Genes and Imbalanced SNAREs Assembly in the Comorbidity of Polycystic Ovary Syndrome and Depression
Authors: Cao Yi , Wang Weijing , Song Xuxia , Wen Qian , Xie Jing , Zhang Dongfeng
Published: April 2024

Background: Women with polycystic ovary syndrome (PCOS) have increased odds of concurrent depression, indicating that the relationship between PCOS and depression is more likely to be comorbid. However, the underlying mechanism remains unclear. Here, we aimed to use bioinformatic analysis to screen for the genetic elements shared between PCOS and depression. Methods: Differentially expressed genes (DEGs) were screened out through GEO2R using the PCOS and depression datasets in NCBI. Protein–protein interaction (PPI) network analysis and enrichment analysis were performed to identify the potential hub genes. After verification using other PCOS and depression datasets, the associations between key gene polymorphism and comorbidity were further studied using data from the UK biobank (UKB) database. Results: In this study, three key genes, namely, SNAP23, VTI1A, and PRKAR1A, and their related SNARE interactions in the vesicular transport pathway were identified in the comorbidity of PCOS and depression. The rs112568544 at SNAP23, rs11077579 and rs4458066 at PRKAR1A, and rs10885349 at VTI1A might be the genetic basis of this comorbidity. Conclusions: Our study suggests that the SNAP23, PRKAR1A, and VTI1A genes can directly or indirectly participate in the imbalanced assembly of SNAREs in the pathogenesis of the comorbidity of PCOS and depression. These findings may provide new strategies in diagnosis and therapy for this comorbidity.
Use of and Beliefs toward Novel Tobacco and Nicotine Products among Portuguese University Students: A Pandemic Survey
Authors: Vaz Marina , Cascais Pedro , Lourenço Olga
Published: April 2024

Over the last decade, novel tobacco and nicotine product experimentation and use have dramatically increased among the youth, even in countries with strong tobacco control and anti-smoking social norms. We performed an online questionnaire-based cross-sectional study in March-June 2021, targeting students from the University of Beira Interior, Portugal. The aim was to assess the experimentation and use of tobacco and nicotine products and students’ beliefs towards these products. Of the 452 participants, 67.0% were female; the mean age was 21.9 ± 3 years. Most students (60.4%) reported experimenting with tobacco/nicotine products; 31.2% were current users; polyconsumption was common. Of the current users, all used cigarettes, 41.1% used heated tobacco, 20.6% e-cigarettes, and 14.9% used water pipes. Our multivariate analysis showed that being male, being in the third year of study, and cohabiting or socializing with smokers were strongly associated with tobacco/nicotine use. While most students agree that heated tobacco and e-cigarettes are addictive, that they are not less harmful than cigarettes, and that second-hand exposure may cause health problems, few tobacco/nicotine users are ready to quit, and few students support a smoke-free university campus. These findings indicate high experimentation and the regular dual use of novel tobacco and nicotine products and suggest a pro-smoking social norm among university students.
No Women’s Land: Australian Women Veterans’ Experiences of the Culture of Military Service and Transition
Authors: Lawn Sharon , Waddell Elaine , Roberts Louise , Rioseco Pilar , Beks Tiffany , Sharp Tiffany , McNeill Liz , Everitt David , Bowes Lee , Mordaunt Dylan , Tarrant Amanda , Van Hooff Miranda , Lane Jonathan , Wadham Ben
Published: April 2024

Women’s experiences of military service and transition occur within a highly dominant masculinized culture. The vast majority of research on military veterans reflects men’s experiences and needs. Women veterans’ experiences, and therefore their transition support needs, are largely invisible. This study sought to understand the role and impact of gender in the context of the dominant masculinized culture on women veterans’ experiences of military service and transition to civilian life. In-depth qualitative interviews with 22 Australian women veterans elicited four themes: (1) Fitting in a managing identity with the military; (2) Gender-based challenges in conforming to a masculinized culture—proving worthiness, assimilation, and survival strategies within that culture; (3) Women are valued less than men—consequences for women veterans, including misogyny, sexual harassment and assault, and system failures to recognize women’s specific health needs and role as mothers; and (4) Separation and transition: being invisible as a woman veteran in the civilian world. Gendered military experiences can have long-term negative impacts on women veterans’ mental and physical health, relationships, and identity due to a pervasive masculinized culture in which they remain largely invisible. This can create significant gender-based barriers to services and support for women veterans during their service, and it can also impede their transition support needs.
Attitudes to Short-Term Staffing and Workforce Priorities of Community Users of Remote Aboriginal Community-Controlled Health Services: A Qualitative Study
Authors: Liddle Zania , Fitts Michelle S. , Bourke Lisa , Murakami-Gold Lorna , Campbell Narelle , Russell Deborah J. , Mathew Supriya , Bonson Jason , Mulholland Edward , Humphreys John S. , Zhao Yuejen , Boffa John , Ramjan Mark , Tangey Annie , Schultz Rosalie , Wakerman John
Published: April 2024

In recent years, there has been an increasing trend of short-term staffing in remote health services, including Aboriginal Community-Controlled Health Services (ACCHSs). This paper explores the perceptions of clinic users’ experiences at their local clinic and how short-term staffing impacts the quality of service, acceptability, cultural safety, and continuity of care in ACCHSs in remote communities. Using purposeful and convenience sampling, community users (aged 18+) of the eleven partnering ACCHSs were invited to provide feedback about their experiences through an interview or focus group. Between February 2020 and October 2021, 331 participants from the Northern Territory and Western Australia were recruited to participate in the study. Audio recordings were transcribed verbatim, and written notes and transcriptions were analysed deductively. Overall, community users felt that their ACCHS provided comprehensive healthcare that was responsive to their health needs and was delivered by well-trained staff. In general, community users expressed concern over the high turnover of staff. Recognising the challenges of attracting and retaining staff in remote Australia, community users were accepting of rotation and job-sharing arrangements, whereby staff return periodically to the same community, as this facilitated trusting relationships. Increased support for local employment pathways, the use of interpreters to enhance communication with healthcare services, and services for men delivered by men were priorities for clinic users.
Multi-Criteria Framework for Routing on Access Land: A Case Study on Dartmoor National Park
Authors: Sprent Rafael Felipe , Haworth James , Cavazzi Stefano , Ilyankou Ilya
Published: April 2024

Creating routes across open areas is challenging due to the absence of a defined routing network and the complexity of the environment, in which multiple criteria may affect route choice. In the context of urban environments, research has found Visibility and Spider-Grid subgraphs to be effective approaches that generate realistic routes. However, the case studies presented typically focus on plazas or parks with defined entry and exit points; little work has been carried out to date on creating routes across open areas in rural settings, which are complex environments with varying terrain and obstacles and undefined entry or exit points. To address this gap, this study proposes a method for routing across open areas based on a Spider-Grid subgraph using queen contiguity. The method leverages a Weighted Sum–Dijkstra’s algorithm to allow multiple criteria such as surface condition, total time, and gradient to be considered when creating routes. The method is tested on the problem of routing across two areas of Dartmoor National Park, United Kingdom. The generated routes are compared with benchmark algorithms and real paths created by users of the Ordnance Survey’s Maps App. The generated routes are found to be more realistic than those of the benchmark methods and closer to the real paths. Furthermore, the routes are able to bypass hazards and obstacles while still providing realistic and flexible routes to the user.
Zinc Ionophore Pyrithione Mimics CD28 Costimulatory Signal in CD3 Activated T Cells
Authors: Jakobs Jana , Rink Lothar
Published: April 2024

Zinc is an essential trace element that plays a crucial role in T cell immunity. During T cell activation, zinc is not only structurally important, but zinc signals can also act as a second messenger. This research investigates zinc signals in T cell activation and their function in T helper cell 1 differentiation. For this purpose, peripheral blood mononuclear cells were activated via the T cell receptor-CD3 complex, and via CD28 as a costimulatory signal. Fast and long-term changes in intracellular zinc and calcium were monitored by flow cytometry. Further, interferon (IFN)-γ was analyzed to investigate the differentiation into T helper 1 cells. We show that fast zinc fluxes are induced via CD3. Also, the intracellular zinc concentration dramatically increases 72 h after anti-CD3 and anti-CD28 stimulation, which goes along with the high release of IFN-γ. Interestingly, we found that zinc signals can function as a costimulatory signal for T helper cell 1 differentiation when T cells are activated only via CD3. These results demonstrate the importance of zinc signaling alongside calcium signaling in T cell differentiation.
Low-Level Expression of p-S6 Is Associated with Nodal Metastasis in Patients with Head and Neck Cutaneous Squamous Cell Carcinoma
Authors: Gómez-de Castro Celia , Santos-Juanes Raquel , Nuñez-Gómez Borja , Fernández-Vega Iván , Vivanco Blanca , Fernández-Velasco Adela , Reyes-García Sebastián , Carrero-Martín Jimena , García-Pedrero Juana M. , Rodrigo Juan P. , González-Vela María del Carmen , Santos-Juanes Jorge , Galache Cristina
Published: April 2024

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer. The incidence of metastasis for cSCC is estimated to be around 1.2–5%. Ribosomal protein S6 (p-S6) and the p21 protein (p21) are two proteins that play central roles in other cancers. These proteins may be equally important in cSCC, and together, these could constitute a good candidate for metastasis risk assessment of these patients. We investigate the relationship of p-S6 and p21 expression with the impact on the prognosis of head and neck cSCC (cSCCHN). p-S6 and p21 expression was analyzed by immunohistochemistry on paraffin-embedded tissue samples from 116 patients with cSCCHN and associations sought with clinical characteristics. Kaplan–Meier estimators and Cox proportional hazard regression models were also used. The expression of p-S6 was significantly inversely associated with tumor thickness, tumor size, desmoplastic growth, pathological stage, perineural invasion and tumor buds. p21 expression was significantly inversely correlated with >6 mm tumor thickness, desmoplastic growth, and perineural invasion. p-S6-negative expression significantly predicted an increased risk of nodal metastasis (HR = 2.63, 95% CI 1.51–4.54; p < 0.001). p21 expression was not found to be a significant risk factor for nodal metastasis. These findings demonstrate that p-S6-negative expression is an independent predictor of nodal metastasis. The immunohistochemical expression of p-S6 might aid in better risk stratification and management of patients with cSCCHN.
Endometriosis-Associated Ovarian Cancer: From Molecular Pathologies to Clinical Relevance
Authors: Steinbuch Sophie Charlotte , Lüß Anne-Marie , Eltrop Stephanie , Götte Martin , Kiesel Ludwig
Published: April 2024

Endometriosis is a chronic condition affecting reproductive-aged women, characterized by the growth of ectopic endometrial tissue. Despite being benign, endometriosis is associated with an increased risk of certain cancers, including endometriosis-associated ovarian cancer (EAOC). Ovarian cancer is rare, but more common in women with endometriosis, particularly endometrioid and clear-cell carcinomas. Factors such as hormonal imbalance, reproductive history, environmental exposures, and genetic predisposition contribute to the malignant transformation of endometriosis. Thus, understanding potential risk factors causing malignancy is crucial. Over the past few decades, various genetic mutations, microRNAs, as well as tumor microenvironmental factors have been identified, impacting pathways like PI3K/AKT/mTOR, DNA repair mechanisms, oxidative stress, and inflammation. Thus, this review aims to summarize molecular studies involved in EAOC pathogenesis as potential therapeutic targets. However, further research is needed to better understand the molecular and environmental factors driving EAOC development, to target the susceptibility of endometriotic lesions to malignant progression, and to identify effective therapeutic strategies.
Targeting Molecular Mechanisms of Obesity- and Type 2 Diabetes Mellitus-Induced Skeletal Muscle Atrophy with Nerve Growth Factor
Authors: Jun Lauren , Ding Xiao-Wen , Robinson Megan , Jafari Hassan , Knight Emily , Geetha Thangiah , Greene Michael W. , Babu Jeganathan Ramesh
Published: April 2024

Skeletal muscle plays a critical role in metabolic diseases, such as obesity and type 2 diabetes mellitus (T2DM). Muscle atrophy, characterized by a decrease in muscle mass and function, occurs due to an imbalance between the rates of muscle protein synthesis and degradation. This study aimed to investigate the molecular mechanisms that lead to muscle atrophy in obese and T2DM mouse models. Additionally, the effect of nerve growth factor (NGF) on the protein synthesis and degradation pathways was examined. Male mice were divided into three groups: a control group that was fed a standard chow diet, and two experimental groups that were fed a Western diet. After 8 weeks, the diabetic group was injected with streptozotocin to induce T2DM. Each group was then further divided into NGF-treated or non-treated control group. In the gastrocnemius muscles of the Western diet group, increased expressions of myostatin, autophagy markers, and ubiquitin ligases were observed. Skeletal muscle tissue morphology indicated signs of muscle atrophy in both obese and diabetic mice. The NGF-treated group showed a prominent decrease in the protein levels of myostatin and autophagy markers. Furthermore, the NGF-treated group showed an increased Cyclin D1 level. Western diet-induced obesity and T2DM may be linked to muscle atrophy through upregulation of myostatin and subsequent increase in the ubiquitin and autophagy systems. Moreover, NGF treatment may improve muscle protein synthesis and cell cycling.
MyoD Over-Expression Rescues GST-bFGF Repressed Myogenesis
Authors: Fan Shu-Hsin , Li Ning , Huang Kai-Fan , Chang Yun-Ting , Wu Chuan-Che , Chen Shen-Liang
Published: April 2024

During embryogenesis, basic fibroblast growth factor (bFGF) is released from neural tube and myotome to promote myogenic fate in the somite, and is routinely used for the culture of adult skeletal muscle (SKM) stem cells (MuSC, called satellite cells). However, the mechanism employed by bFGF to promote SKM lineage and MuSC proliferation has not been analyzed in detail. Furthermore, the question of if the post-translational modification (PTM) of bFGF is important to its stemness-promoting effect has not been answered. In this study, GST-bFGF was expressed and purified from E.coli, which lacks the PTM system in eukaryotes. We found that both GST-bFGF and commercially available bFGF activated the Akt–Erk pathway and had strong cell proliferation effect on C2C12 myoblasts and MuSC. GST-bFGF reversibly compromised the myogenesis of C2C12 myoblasts and MuSC, and it increased the expression of Myf5, Pax3/7, and Cyclin D1 but strongly repressed that of MyoD, suggesting the maintenance of myogenic stemness amid repressed MyoD expression. The proliferation effect of GST-bFGF was conserved in C2C12 over-expressed with MyoD (C2C12-tTA-MyoD), implying its independence of the down-regulation of MyoD. In addition, the repressive effect of GST-bFGF on myogenic differentiation was almost totally rescued by the over-expression of MyoD. Together, these evidences suggest that (1) GST-bFGF and bFGF have similar effects on myogenic cell proliferation and differentiation, and (2) GST-bFGF can promote MuSC stemness and proliferation by differentially regulating MRFs and Pax3/7, (3) MyoD repression by GST-bFGF is reversible and independent of the proliferation effect, and (4) GST-bFGF can be a good substitute for bFGF in sustaining MuSC stemness and proliferation.
Loose Coupling between the Voltage Sensor and the Activation Gate in Mammalian HCN Channels Suggests a Gating Mechanism
Authors: Wu Xiaoan , Cunningham Kevin P. , Bruening-Wright Andrew , Pandey Shilpi , Larsson H. Peter
Published: April 2024

Voltage-gated potassium (Kv) channels and hyperpolarization-activated cyclic nucleotide-gated (HCN) channels share similar structures but have opposite gating polarity. Kv channels have a strong coupling (>109) between the voltage sensor (S4) and the activation gate: when S4s are activated, the gate is open to >80% but, when S4s are deactivated, the gate is open <10−9 of the time. Using noise analysis, we show that the coupling between S4 and the gate is <200 in HCN channels. In addition, using voltage clamp fluorometry, locking the gate open in a Kv channel drastically altered the energetics of S4 movement. In contrast, locking the gate open or decreasing the coupling between S4 and the gate in HCN channels had only minor effects on the energetics of S4 movement, consistent with a weak coupling between S4 and the gate. We propose that this loose coupling is a prerequisite for the reversed voltage gating in HCN channels.
Effect of Low-Level Tragus Stimulation on Cardiac Metabolism in Heart Failure with Preserved Ejection Fraction: A Transcriptomics-Based Analysis
Authors: Chakraborty Praloy , Niewiadomska Monika , Farhat Kassem , Morris Lynsie , Whyte Seabrook , Humphries Kenneth M. , Stavrakis Stavros
Published: April 2024

Abnormal cardiac metabolism precedes and contributes to structural changes in heart failure. Low-level tragus stimulation (LLTS) can attenuate structural remodeling in heart failure with preserved ejection fraction (HFpEF). The role of LLTS on cardiac metabolism is not known. Dahl salt-sensitive rats of 7 weeks of age were randomized into three groups: low salt (0.3% NaCl) diet (control group; n = 6), high salt diet (8% NaCl) with either LLTS (active group; n = 8), or sham stimulation (sham group; n = 5). Both active and sham groups received the high salt diet for 10 weeks with active LLTS or sham stimulation (20 Hz, 2 mA, 0.2 ms) for 30 min daily for the last 4 weeks. At the endpoint, left ventricular tissue was used for RNA sequencing and transcriptomic analysis. The Ingenuity Pathway Analysis tool (IPA) was used to identify canonical metabolic pathways and upstream regulators. Principal component analysis demonstrated overlapping expression of important metabolic genes between the LLTS, and control groups compared to the sham group. Canonical metabolic pathway analysis showed downregulation of the oxidative phosphorylation (Z-score: −4.707, control vs. sham) in HFpEF and LLTS improved the oxidative phosphorylation (Z-score = −2.309, active vs. sham). HFpEF was associated with the abnormalities of metabolic upstream regulators, including PPARGC1α, insulin receptor signaling, PPARα, PPARδ, PPARGC1β, the fatty acid transporter SLC27A2, and lysine-specific demethylase 5A (KDM5A). LLTS attenuated abnormal insulin receptor and KDM5A signaling. HFpEF is associated with abnormal cardiac metabolism. LLTS, by modulating the functioning of crucial upstream regulators, improves cardiac metabolism and mitochondrial oxidative phosphorylation.
The Induction of Combined Hyperthermal Ablation Effect of Irreversible Electroporation with Polydopamine Nanoparticle-Coated Electrodes
Authors: Jeon Sung-Min , Davaa Enkhzaya , Jenjob Ratchapol , Pechyen Chiravoot , Natphopsuk Sitakan , Jeong Seok , Yoo Hye Jin , Yang Su-Geun
Published: April 2024

Irreversible electroporation (IRE) is a prominent non-thermal ablation method widely employed in clinical settings for the focal ablation therapy of solid tumors. Utilizing high-voltage, short-duration electric pulses, IRE induces perforation defects in the cell membrane, leading to apoptotic cell death. Despite the promise of irreversible electroporation (IRE) in clinical applications, it faces challenges concerning the coverage of target tissues for ablation, particularly when compared to other thermal ablation therapies such as radiofrequency ablation, microwave ablation, and cryoablation. This study aims to investigate the induced hyperthermal effect of IRE by applying a polydopamine nanoparticle (Dopa NP) coating on the electrode. We hypothesize that the induced hyperthermal effect enhances the therapeutic efficacy of IRE for cancer ablation. First, we observed the hyperthermal effect of IRE using Dopa NP-coated electrodes in hydrogel phantom models and then moved to in vivo models. In particular, in in vivo animal studies, the IRE treatment of rabbit hepatic lobes with Dopa NP-coated electrodes exhibited a two-fold higher increase in temperature (ΔT) compared to non-coated electrodes. Through a comprehensive analysis, we found that IRE treatment with Dopa NP-coated electrodes displayed the typical histological signatures of hyperthermal ablation, including the disruption of the hepatic cord and lobular structure, as well as the infiltration of erythrocytes. These findings unequivocally highlight the combined efficacy of IRE with Dopa NPs for electroporation and the hyperthermal ablation of target cancer tissues.
Evaluation of Ouabain’s Tissue Distribution in C57/Black Mice Following Intraperitoneal Injection, Using Chromatography and Mass Spectrometry
Authors: Abaimov Denis A. , Kazanskaya Rogneda B. , Ageldinov Ruslan A. , Nesterov Maxim S. , Timoshina Yulia A. , Platova Angelina I. , Aristova Irina J. , Vinogradskaia Irina S. , Fedorova Tatiana N. , Volnova Anna B. , Gainetdinov Raul R. , Lopachev Alexander V.
Published: April 2024

Cardiotonic steroids (CTSs), such as digoxin, are used for heart failure treatment. However, digoxin permeates the brain–blood barrier (BBB), affecting central nervous system (CNS) functions. Finding a CTS that does not pass through the BBB would increase CTSs’ applicability in the clinic and decrease the risk of side effects on the CNS. This study aimed to investigate the tissue distribution of the CTS ouabain following intraperitoneal injection and whether ouabain passes through the BBB. After intraperitoneal injection (1.25 mg/kg), ouabain concentrations were measured at 5 min, 15 min, 30 min, 1 h, 3 h, 6 h, and 24 h using HPLC–MS in brain, heart, liver, and kidney tissues and blood plasma in C57/black mice. Ouabain was undetectable in the brain tissue. Plasma: Cmax = 882.88 ± 21.82 ng/g; Tmax = 0.08 ± 0.01 h; T1/2 = 0.15 ± 0.02 h; MRT = 0.26 ± 0.01. Cardiac tissue: Cmax = 145.24 ± 44.03 ng/g (undetectable at 60 min); Tmax = 0.08 ± 0.02 h; T1/2 = 0.23 ± 0.09 h; MRT = 0.38 ± 0.14 h. Kidney tissue: Cmax = 1072.3 ± 260.8 ng/g; Tmax = 0.35 ± 0.19 h; T1/2 = 1.32 ± 0.76 h; MRT = 1.41 ± 0.71 h. Liver tissue: Cmax = 2558.0 ± 382.4 ng/g; Tmax = 0.35 ± 0.13 h; T1/2 = 1.24 ± 0.7 h; MRT = 0.98 ± 0.33 h. Unlike digoxin, ouabain does not cross the BBB and is eliminated quicker from all the analyzed tissues, giving it a potential advantage over digoxin in systemic administration. However, the inability of ouabain to pass though the BBB necessitates intracerebral administration when used to investigate its effects on the CNS.
Renal Endothelial Single-Cell Transcriptomics Reveals Spatiotemporal Regulation and Divergent Roles of Differential Gene Transcription and Alternative Splicing in Murine Diabetic Nephropathy
Authors: Zhou Alex-Xianghua , Jeansson Marie , He Liqun , Wigge Leif , Tonelius Pernilla , Tati Ramesh , Cederblad Linda , Muhl Lars , Uhrbom Martin , Liu Jianping , Björnson Granqvist Anna , Lerman Lilach O. , Betsholtz Christer , Hansen Pernille B. L.
Published: April 2024

Endothelial cell (EC) injury is a crucial contributor to the progression of diabetic kidney disease (DKD), but the specific EC populations and mechanisms involved remain elusive. Kidney ECs (n = 5464) were collected at three timepoints from diabetic BTBRob/ob mice and non-diabetic littermates. Their heterogeneity, transcriptional changes, and alternative splicing during DKD progression were mapped using SmartSeq2 single-cell RNA sequencing (scRNAseq) and elucidated through pathway, network, and gene ontology enrichment analyses. We identified 13 distinct transcriptional EC phenotypes corresponding to different kidney vessel subtypes, confirmed through in situ hybridization and immunofluorescence. EC subtypes along nephrons displayed extensive zonation related to their functions. Differential gene expression analyses in peritubular and glomerular ECs in DKD underlined the regulation of DKD-relevant pathways including EIF2 signaling, oxidative phosphorylation, and IGF1 signaling. Importantly, this revealed the differential alteration of these pathways between the two EC subtypes and changes during disease progression. Furthermore, glomerular and peritubular ECs also displayed aberrant and dynamic alterations in alternative splicing (AS), which is strongly associated with DNA repair. Strikingly, genes displaying differential transcription or alternative splicing participate in divergent biological processes. Our study reveals the spatiotemporal regulation of gene transcription and AS linked to DKD progression, providing insight into pathomechanisms and clues to novel therapeutic targets for DKD treatment.
The Effect of Diesel Exhaust Particles on Adipose Tissue Mitochondrial Function and Inflammatory Status
Authors: Warren Cali E. , Campbell Kennedy M. , Kirkham Madison N. , Saito Erin R. , Remund Nicole P. , Cayabyab Kevin B. , Kim Iris J. , Heimuli Micah S. , Reynolds Paul R. , Arroyo Juan A. , Bikman Benjamin T.
Published: April 2024

Air pollution poses a significant global health risk, with fine particulate matter (PM2.5) such as diesel exhaust particles (DEPs) being of particular concern due to their potential to drive systemic toxicities through bloodstream infiltration. The association between PM2.5 exposure and an increased prevalence of metabolic disorders, including obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM), is evident against a backdrop of rising global obesity and poor metabolic health. This paper examines the role of adipose tissue in mediating the effects of PM2.5 on metabolic health. Adipose tissue, beyond its energy storage function, is responsive to inhaled noxious stimuli, thus disrupting metabolic homeostasis and responding to particulate exposure with pro-inflammatory cytokine release, contributing to systemic inflammation. The purpose of this study was to characterize the metabolic response of adipose tissue in mice exposed to either DEPs or room air (RA), exploring both the adipokine profile and mitochondrial bioenergetics. In addition to a slight change in fat mass and a robust shift in adipocyte hypertrophy in the DEP-exposed animals, we found significant changes in adipose mitochondrial bioenergetics. Furthermore, the DEP-exposed animals had a significantly higher expression of adipose inflammatory markers compared with the adipose from RA-exposed mice. Despite the nearly exclusive focus on dietary factors in an effort to better understand metabolic health, these results highlight the novel role of environmental factors that may contribute to the growing global burden of poor metabolic health.
Stereoselective Synthesis and Catalytical Application of Perillaldehyde-Based 3-Amino-1,2-diol Regioisomers
Authors: Háznagy Márton Benedek , Csámpai Antal , Ugrai Imre , Molnár Barnabás , Haukka Matti , Szakonyi Zsolt
Published: April 2024

A library of regioisomeric monoterpene-based aminodiols was synthesised and applied as chiral catalysts in the addition of diethylzinc to benzaldehyde. The synthesis of the first type of aminodiols was achieved starting from (−)-8,9-dihydroperillaldehyde via reductive amination, followed by Boc protection and dihydroxylation with the OsO4/NMO system. Separation of formed stereoisomers resulted in a library of aminodiol diastereoisomers. The library of regioisomeric analogues was obtained starting from (−)-8,9-dihydroperillic alcohol, which was transformed into a mixture of allylic trichloroacetamides via Overman rearrangement. Changing the protecting group to a Boc function, the protected enamines were subjected to dihydroxylation with the OsO4/NMO system, leading to a 71:16:13 mixture of diastereoisomers, which were separated, affording the three isomers in isolated form. The obtained primary aminodiols were transformed into secondary derivatives. The regioselectivity of the ring closure of the N-benzyl-substituted aminodiols with formaldehyde was also investigated, resulting in 1,3-oxazines in an exclusive manner. To explain the stability difference between diastereoisomeric 1,3-oxazines, a series of comparative theoretical modelling studies was carried out. The obtained potential catalysts were applied in the reaction of aromatic aldehydes and diethylzinc with moderate to good enantioselectivities (up to 94% ee), whereas the opposite chiral selectivity was observed between secondary aminodiols and their ring-closed 1,3-oxazine analogues.
Modeling PAH Mixture Interactions in a Human In Vitro Organotypic Respiratory Model
Authors: Colvin Victoria C. , Bramer Lisa M. , Rivera Brianna N. , Pennington Jamie M. , Waters Katrina M. , Tilton Susan C.
Published: April 2024

One of the most significant challenges in human health risk assessment is to evaluate hazards from exposure to environmental chemical mixtures. Polycyclic aromatic hydrocarbons (PAHs) are a class of ubiquitous contaminants typically found as mixtures in gaseous and particulate phases in ambient air pollution associated with petrochemicals from Superfund sites and the burning of fossil fuels. However, little is understood about how PAHs in mixtures contribute to toxicity in lung cells. To investigate mixture interactions and component additivity from environmentally relevant PAHs, two synthetic mixtures were created from PAHs identified in passive air samplers at a legacy creosote site impacted by wildfires. The primary human bronchial epithelial cells differentiated at the air–liquid interface were treated with PAH mixtures at environmentally relevant proportions and evaluated for the differential expression of transcriptional biomarkers related to xenobiotic metabolism, oxidative stress response, barrier integrity, and DNA damage response. Component additivity was evaluated across all endpoints using two independent action (IA) models with and without the scaling of components by toxic equivalence factors. Both IA models exhibited trends that were unlike the observed mixture response and generally underestimated the toxicity across dose suggesting the potential for non-additive interactions of components. Overall, this study provides an example of the usefulness of mixture toxicity assessment with the currently available methods while demonstrating the need for more complex yet interpretable mixture response evaluation methods for environmental samples.
Transport Properties in Multicomponent Systems Containing Cyclodextrins and Nickel Ions
Authors: Fangaia Sónia I. G. , Silva Daniela S. A. , Messias Ana , Nicolau Pedro M. G. , Valente Artur J. M. , Rodrigo M. Melia , Ribeiro Ana C. F.
Published: April 2024

In this work, we propose a comprehensive experimental study of the diffusion of nickel ions in combination with different cyclodextrins as carrier molecules for enhanced solubility and facilitated transport. For this, ternary mutual diffusion coefficients measured by Taylor dispersion method are reported for aqueous solutions containing nickel salts and different cyclodextrins (that is, α-CD, β-CD, and γ-CD) at 298.15 K. A combination of Taylor dispersion and other methods, such as UV-vis spectroscopy, will be used to obtain complementary information on these systems. The determination of the physicochemical properties of these salts with CDs in aqueous solution provides information that allows us to understand solute–solvent interactions, and gives a significant contribution to understanding the mechanisms underlying diffusional transport in aqueous solutions, and, consequently, to mitigating the potential toxicity associated with these metal ions. For example, using mutual diffusion data, it is possible to estimate the number of moles of each ion transported per mole of the cyclodextrin driven by its own concentration gradient.
The Characterization of G-Quadruplexes in Tobacco Genome and Their Function under Abiotic Stress
Authors: Song Kangkang , Li Bin , Li Haozhen , Zhang Rui , Zhang Xiaohua , Luan Ruiwei , Liu Ying , Yang Long
Published: April 2024

Tobacco is an ideal model plant in scientific research. G-quadruplex is a guanine-rich DNA structure, which regulates transcription and translation. In this study, the prevalence and potential function of G-quadruplexes in tobacco were systematically analyzed. In tobacco genomes, there were 2,924,271,002 G-quadruplexes in the nuclear genome, 430,597 in the mitochondrial genome, and 155,943 in the chloroplast genome. The density of the G-quadruplex in the organelle genome was higher than that in the nuclear genome. G-quadruplexes were abundant in the transcription regulatory region of the genome, and a difference in G-quadruplex density in two DNA strands was also observed. The promoter of 60.4% genes contained at least one G-quadruplex. Compared with up-regulated differentially expressed genes (DEGs), the G-quadruplex density in down-regulated DEGs was generally higher under drought stress and salt stress. The G-quadruplex formed by simple sequence repeat (SSR) and its flanking sequence in the promoter region of the NtBBX (Nitab4.5_0002943g0010) gene might enhance the drought tolerance of tobacco. This study lays a solid foundation for further research on G-quadruplex function in tobacco and other plants.
Gelatine Blends Modified with Polysaccharides: A Potential Alternative to Non-Degradable Plastics
Authors: Dzeikala Oleksandra , Prochon Miroslawa , Sedzikowska Natalia
Published: April 2024

Non-degradable plastics of petrochemical origin are a contemporary problem of society. Due to the large amount of plastic waste, there are problems with their disposal or storage, where the most common types of plastic waste are disposable tableware, bags, packaging, bottles, and containers, and not all of them can be recycled. Due to growing ecological awareness, interest in the topics of biodegradable materials suitable for disposable items has begun to reduce the consumption of non-degradable plastics. An example of such materials are biodegradable biopolymers and their derivatives, which can be used to create the so-called bioplastics and biopolymer blends. In this article, gelatine blends modified with polysaccharides (e.g., agarose or carrageenan) were created and tested in order to obtain a stable biopolymer coating. Various techniques were used to characterize the resulting bioplastics, including Fourier-transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA)/differential scanning calorimetry (DSC), contact angle measurements, and surface energy characterization. The influence of thermal and microbiological degradation on the properties of the blends was also investigated. From the analysis, it can be observed that the addition of agarose increased the hardness of the mixture by 27% compared to the control sample without the addition of polysaccharides. In addition, there was an increase in the surface energy (24%), softening point (15%), and glass transition temperature (14%) compared to the control sample. The addition of starch to the gelatine matrix increased the softening point by 15% and the glass transition temperature by 6%. After aging, both compounds showed an increase in hardness of 26% and a decrease in tensile strength of 60%. This offers an opportunity as application materials in the form of biopolymer coatings, dietary supplements, skin care products, short-term and single-contact decorative elements, food, medical, floriculture, and decorative industries.