bluuebunny/crossref_metadata_2025 huggingface dataset:
Feasible Actuator Range Modifier (FARM), a Tool Aiding the Solution of Unit Dispatch Problems for Advanced Energy Systems
Authors: Wang Haoyu , Ponciroli Roberto , Alfonsi Andrea , Talbot Paul W. , Elmer Thomas W. , Epiney Aaron S. , Vilim Richard B.
Published: June 2024

Integrated energy systems (IESs) seek to minimize power generating costs in future power grids through the coupling of different energy technologies. To accommodate fluctuations in load demand due to the penetration of renewable energy sources, flexible operation capabilities must be fully exploited, and even power plants that are traditionally considered as base-load units need to be operated according to unconventional paradigms. Thermomechanical loads induced by frequent power adjustments can accelerate the wear and tear. If a unit is flexibly operated without respecting limits on materials, the risk of failures of expensive components will eventually increase, nullifying the additional profits ensured by flexible operation. In addition to the bounds on power variations (explicit constraints),the solution of the unit dispatch problem needs to meet the limits on the variation of key process variables, including temperature, pressure and flow rate (implicit constraints).The FARM (Feasible Actuator Range Modifier) module was developed to enable existing optimization algorithms to identify solutions to the unit dispatch problem that are both economically favorable and technologically sustainable. Thanks to the iterative dispatcher–validator scheme, FARM permits addressing all the imposed constraints without excessively increasing the computational costs. In this work, the algorithms constituting the module are described, and the performance was assessed by solving the unit dispatch problem for an IES composed of three units, i.e., balance of plant, gas turbine, and high-temperature steam electrolysis. Finally, the FARM module provides dedicated tools for visualizing the response of the constrained variables of interest during operational transients and a tool aiding the operator at making decisions. These techniques might represent the first step towards the deployment of an ecological interface design (EID) for IES units.
Integrated Risk-Aware Smart Disassembly Planning for Scrap Electric Vehicle Batteries
Authors: Yang Shibo , Zhuo Xiaojun , Ning Wei , Xia Xing , Huang Yong
Published: June 2024

With the increase in the production of electric vehicles (EVs) globally, a significant volume of waste power battery modules (WPBM) will be generated accordingly, posing challenges for their disposal. An intelligent scrap power battery disassembly sequence planning method, integrated with operational risk perception, is proposed to automate the planning process. Taking into consideration the risk coefficients, energy consumption, and costs during disassembly, this method maximizes profits, minimizes energy usage, and ensures safety. Utilizing an extended part priority graph, an optimized model for integrated risk-aware disassembly sequence planning (IRA-DSP) is constructed. With the Guangqi Toyota LB7A-FX1 as a case study, and using real data from resource recovery enterprises, an improved MOPSO-GA algorithm is proposed to solve the model and generate disassembly plans. The results demonstrate the method’s ability to achieve unit-level disassembly of WPBM, avoid high-risk sequences, and optimize profit and energy consumption, exhibiting its practicality and feasibility.
Riemann–Hilbert Method Equipped with Mixed Spectrum for N-Soliton Solutions of New Three-Component Coupled Time-Varying Coefficient Complex mKdV Equations
Authors: Zhang Sheng , Wang Xianghui , Xu Bo
Published: June 2024

This article extends the celebrated Riemann–Hilbert (RH) method equipped with mixed spectrum to a new integrable system of three-component coupled time-varying coefficient complex mKdV equations (ccmKdVEs for short) generated by the mixed spectral equations (msEs). Firstly, the ccmKdVEs and the msEs for generating the ccmKdVEs are proposed. Then, based on the msEs, a solvable RH problem related to the ccmKdVEs is constructed. By using the constructed RH problem with mixed spectrum, scattering data for the recovery of potential formulae are further determined. In the case of reflectionless coefficients, explicit N-soliton solutions of the ccmKdVEs are ultimately obtained. Taking N equal to 1 and 2 as examples, this paper reveals that the spatiotemporal solution structures with time-varying nonlinear dynamic characteristics localized in the ccmKdVEs is attributed to the multiple selectivity of mixed spectrum and time-varying coefficients. In addition, to further highlight the application of our work in fractional calculus, by appropriately selecting these time-varying coefficients, the ccmKdVEs are transformed into a conformable time-fractional order system of three-component coupled complex mKdV equations. Based on the obtained one-soliton solutions, a set of initial values are assigned to the transformed fractional order system, and the N-th iteration formulae of approximate solutions for this fractional order system are derived through the variational iteration method (VIM).
Fractal Characterization of the Pore-Throat Structure in Tight Sandstone Based on Low-Temperature Nitrogen Gas Adsorption and High-Pressure Mercury Injection
Authors: He Taping , Zhou Yaoqi , Chen Zhaobing , Zhang Zhenwei , Xie Huanyu , Shang Yuehan , Cui Gaixia
Published: June 2024

The pore-throat structure is a critical factor in the study of unconventional oil and gas reservoirs, drawing particular attention from petroleum geologists, and it is of paramount significance to analyze to enhance oil and gas production. In tight sandstone, which serves as a significant hydrocarbon reservoir, the internal pore-throat structure plays a decisive role in the storage and migration of fluids such as water, gases, and hydrocarbons. This paper employs casting thin section (CTS), field emission scanning electron microscope (FE-SEM), high-pressure mercury injection (HPMI), and low-temperature nitrogen gas adsorption (LT−N2−GA) experimental tests to qualitatively and quantitatively analyze the characteristics of the pore-throat structure in tight sandstone. The results indicate that the pore types in tight sandstone include intergranular residual pores, dissolution pores, intercrystalline pores, and microfractures, while the throat types encompass sheet-shaped, curved-sheet-shaped, and tubular throats. Analysis of the physical and structural parameters from 13 HPMI and 5 LT−N2−GA samples reveals a bimodal distribution of pore-throat radii. The complexity of the pore-throat structure is identified as a primary controlling factor for reservoir permeability. The fractal dimension (D) exhibits an average value of 2.45, displaying a negative correlation with porosity (R2 = 0.22), permeability (R2 = 0.65), the pore-throat diameter (R2 = 0.58), and maximum mercury saturation (R2 = 0.86) and a positive correlation with threshold pressure (R2 = 0.56), median saturation pressure (R2 = 0.49), BET specific surface area (R2 = 0.51), and BJH total pore volume (R2 = 0.14). As D increases, reservoir pores tend to decrease in size, leading to reduced flow and deteriorated physical properties, indicative of a more complex pore-throat structure.
An Exploration of the Gastronomic Potential of the North American Pawpaw—A Case Study from the Pawpaw Cookoff at the Ohio Pawpaw Festival
Authors: Brannan Robert , Powell Ronald
Published: June 2024

The pawpaw (Asimina triloba) is a tropical-tasting fruit from a tree indigenous to North America’s temperate climates. Pawpaw has a sweet, sour, and often bitter taste, which is a combination of banana and mango flavor. Fresh fruits are rarely available for retail purchase other than at farm sales or farmers’ markets. Frozen pulp is commercially available but supply is often limited due to increased wholesale demand. The purpose of this paper is to analyze seven years of entries from the Pawpaw Cookoff at the Ohio Pawpaw Festival using case study methodology to provide a basis from which to track trends, make recommendations, and discuss gastronomic opportunities of the pawpaw. Analysis of the data indicates that pawpaw is a versatile fruit that has been incorporated into a wide variety of beverages, savories, sauces, condiments, sweets, and desserts. Pawpaw pairs well with both alcoholic and non-alcoholic beverages, especially certain ales, sour beers, innovative cocktails with rum, coffee and tea drinks, and smoothies. Pawpaw is easily incorporated directly into salsas, dips, salad dressings, and frozen desserts that do not require cooking. In cooked savory dishes, sauces, and condiments, pawpaw should be added at the end of preparation. Pawpaw can be used in a wide range of baked and fried sweets and desserts.
The Families of Non-LTR Transposable Elements within Neritimorpha and Other Gastropoda
Authors: Colgan Donald James
Published: June 2024

Repeated sequences, especially transposable elements (TEs), are known to be abundant in some members of the important invertebrate class Gastropoda. TEs that do not have long terminal repeated sequences (non-LTR TEs) are frequently the most abundant type but have not been well characterised in any gastropod. Despite this, sequences in draft gastropod genomes are often described as non-LTR TEs, but without identification to family type. This study was conducted to characterise non-LTR TEs in neritimorph snails, using genomic skimming surveys of three species and the recently published draft genome of Theodoxus fluviatilis. Multiple families of non-LTR TEs from the I, Jockey, L1, R2 and RTE superfamilies were found, although there were notably few representatives of the first of these, which is nevertheless abundant in other Gastropoda. Phylogenetic analyses of amino acid sequences of the reverse transcriptase domain from the elements ORF2 regions found considerable interspersion of representatives of the four neritimorph taxa within non-LTR families and sub-families. In contrast, phylogenetic analyses of sequences from the elements’ ORF1 region resolved the representatives from individual species as monophyletic. However, using either region, members of the two species of the Neritidae were closely related, suggesting their potential for investigation of phyletic evolution at the family level.
Genetic Analysis of the Plasmid-Based Temperature-Lethal Mutant pa1792|lpxH(Ts) in Pseudomonas aeruginosa
Authors: Zhang Haoyang , Yang Zhili , Liu Jianhua
Published: June 2024

Many enzymes in the Raetz pathway for lipid A biosynthesis in Escherichia coli are essential. A homologous protein Pa1792|LpxH in Pseudomonas aeruginosa is known to complement the loss of LpxH in E. coli. Genome-wide transposon-insertion sequencing analysis indicates that lpxH is essential in P. aeruginosa. However, genetic analysis of lpxH in P. aeruginosa has not been carried out, partly because the conditional alleles of essential genes are not readily constructed. In this study, we first constructed a plasmid-based temperature-sensitive mutant ΔlpxH/pTS-lpxH or lpxH(Ts) in P. aeruginosa PAO1. Spot-plating assay indicated that lpxH(Ts) was lethal at a restrictive temperature, confirming its essentiality for growth. Microscopic analysis revealed that lpxH(Ts) exhibited an oval-shaped morphology, suggesting that lpxH was required for rod-shape formation. SDS-PAGE and Western blotting analysis showed that lpxH(Ts) failed to synthesize lipid A, consistent with its function in lipid A biosynthesis. Strong expression of lpxH but not the non-homologous isoenzyme lpxI or lpxG impeded growth and caused cell lysis, implying that lpxH-specific cofactors were required for this toxic effect in P. aeruginosa. Together, our results demonstrate that lpxH is essential for lipid A biosynthesis, rod-shaped growth, and viability in P. aeruginosa. We propose that this plasmid-based conditional allele is a useful tool for the genetic study of essential genes in P. aeruginosa.
Disaggregation of Green Space Access, Walkability, and Behavioral Risk Factor Data for Precise Estimation of Local Population Characteristics
Authors: Guha Saurav , Alonzo Michael , Goovaerts Pierre , Brink LuAnn L. , Ray Meghana , Bear Todd , Pyne Saumyadipta
Published: June 2024

Background: Social and Environmental Determinants of Health (SEDH) provide us with a conceptual framework to gain insights into possible associations among different human behaviors and the corresponding health outcomes that take place often in and around complex built environments. Developing better built environments requires an understanding of those aspects of a community that are most likely to have a measurable impact on the target SEDH. Yet data on local characteristics at suitable spatial scales are often unavailable. We aim to address this issue by application of different data disaggregation methods. Methods: We applied different approaches to data disaggregation to obtain small area estimates of key behavioral risk factors, as well as geospatial measures of green space access and walkability for each zip code of Allegheny County in southwestern Pennsylvania. Results: Tables and maps of local characteristics revealed their overall spatial distribution along with disparities therein across the county. While the top ranked zip codes by behavioral estimates generally have higher than the county’s median individual income, this does not lead them to have higher than its median green space access or walkability. Conclusion: We demonstrated the utility of data disaggregation for addressing complex questions involving community-specific behavioral attributes and built environments with precision and rigor, which is especially useful for a diverse population. Thus, different types of data, when comparable at a common local scale, can provide key integrative insights for researchers and policymakers.
Extreme Biocatalysts: From Basic Research to Biotechnological Applications
Authors: Fusco Salvatore , Siebers Bettina
Published: June 2024

Biocatalysis, a cornerstone of modern biotechnology, is poised to revolutionize industrial processes across diverse sectors [...]
Integrated Multi-Omics Analysis to Reveal the Molecular Mechanisms of Inflorescence Elongation in Medicago sativa
Authors: Huang Xiuzheng , Liu Lei , Qiang Xiaojing , Meng Yuanfa , Li Zhiyong , Huang Fan
Published: June 2024

The morphological architecture of inflorescence influences seed production. The regulatory mechanisms underlying alfalfa (Medicago sativa) inflorescence elongation remain unclear. Therefore, in this study, we conducted a comparative analysis of the transcriptome, proteome, and metabolome of two extreme materials at three developmental stages to explore the mechanisms underlying inflorescence elongation in alfalfa. We observed the developmental processes of long and short inflorescences and found that the elongation capacity of alfalfa with long inflorescence was stronger than that of alfalfa with short inflorescences. Furthermore, integrative analysis of the transcriptome and proteome indicated that the phenylpropanoid biosynthesis pathway was closely correlated with the structural formation of the inflorescence. Additionally, we identified key genes and proteins associated with lignin biosynthesis based on the differential expressed genes and proteins (DEGs and DEPs) involved in phenylpropanoid biosynthesis. Moreover, targeted hormone metabolome analysis revealed that IAA, GA, and CK play an important role in the peduncle elongation of alfalfa inflorescences. Based on omics analysis, we detected key genes and proteins related to plant hormone biosynthesis and signal transduction. From the WGCNA and WPCNA results, we furthermore screened 28 candidate genes and six key proteins that were correlated with lignin biosynthesis, plant hormone biosynthesis, and signaling pathways. In addition, 19 crucial transcription factors were discovered using correlation analysis that might play a role in regulating candidate genes. This study provides insight into the molecular mechanism of inflorescence elongation in alfalfa and establishes a theoretical foundation for improving alfalfa seed production.
Emerging Roles of Exosomes in Stroke Therapy
Authors: Larson Anthony , Natera-Rodriguez Dilmareth E. , Crane Andrew , Larocca Dana , Low Walter C. , Grande Andrew W. , Lee Jieun
Published: June 2024

Stroke is the number one cause of morbidity in the United States and number two cause of death worldwide. There is a critical unmet medical need for more effective treatments of ischemic stroke, and this need is increasing with the shift in demographics to an older population. Recently, several studies have reported the therapeutic potential of stem cell-derived exosomes as new candidates for cell-free treatment in stoke. This review focuses on the use of stem cell-derived exosomes as a potential treatment tool for stroke patients. Therapy using exosomes can have a clear clinical advantage over stem cell transplantation in terms of safety, cost, and convenience, as well as reducing bench-to-bed latency due to fewer regulatory milestones. In this review article, we focus on (1) the therapeutic potential of exosomes in stroke treatment, (2) the optimization process of upstream and downstream production, and (3) preclinical application in a stroke animal model. Finally, we discuss the limitations and challenges faced by exosome therapy in future clinical applications.
JP4-039, a Mitochondria-Targeted Nitroxide, Mitigates the Effect of Apoptosis and Inflammatory Cell Migration in the Irradiated Mouse Retina
Authors: Adeghate Jennifer O. , Epperly Michael W. , Davoli Katherine Anne , Lathrop Kira L. , Wipf Peter , Hou Wen , Fisher Renee , Thermozier Stephanie , Huq M. Saiful , Sahel Jose-Alain , Greenberger Joel S. , Eller Andrew W.
Published: June 2024

We hypothesize that the injection of JP4-039, a mitochondria-targeted nitroxide, prior to irradiation of the mouse retina may decrease apoptosis and reduce neutrophil and macrophage migration into the retina. In our study, we aimed to examine the effects of JP4-039 in the mouse retina using fluorescent microscopy, a terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, and flow cytometry. Forty-five mice and one eye per mouse were used. In Group 1, fluorescent microscopy was used to determine retinal uptake of 10 µL (0.004 mg/µL) of intravitreally injected BODIPY-labeled JP4-039 at 0, 15, and 60 min after injection. In Group 2, the TUNEL assay was performed to investigate the rate of apoptosis after irradiation in addition to JP4-039 injection, compared to controls. In Group 3, flow cytometry was used to determine the extent of inflammatory cell migration into the retina after irradiation in addition to JP4-039 injection, compared to controls. Maximal retinal uptake of JP4-039 was 15 min after intravitreal injection (p < 0.0001). JP4-039-treated eyes had lower levels of retinal apoptosis (35.8 ± 2.5%) than irradiated controls (49.0 ± 2.7%; p = 0.0066) and demonstrated reduced migration of N1 cells (30.7 ± 11.7% vs. 77.7 ± 5.3% controls; p = 0.004) and M1 cells (76.6 ± 4.2 vs. 88.1 ± 3.7% controls, p = 0.04). Pretreatment with intravitreally injected JP4-039 reduced apoptosis and inflammatory cell migration in the irradiated mouse retina, marking the first confirmed effect of this molecule in retinal tissue. Further studies may allow for safety profiling and potential use for patients with radiation retinopathy.
The Versatility of Collagen in Pharmacology: Targeting Collagen, Targeting with Collagen
Authors: Revert-Ros Francisco , Ventura Ignacio , Prieto-Ruiz Jesús A. , Hernández-Andreu José Miguel , Revert Fernando
Published: June 2024

Collagen, a versatile family of proteins with 28 members and 44 genes, is pivotal in maintaining tissue integrity and function. It plays a crucial role in physiological processes like wound healing, hemostasis, and pathological conditions such as fibrosis and cancer. Collagen is a target in these processes. Direct methods for collagen modulation include enzymatic breakdown and molecular binding approaches. For instance, Clostridium histolyticum collagenase is effective in treating localized fibrosis. Polypeptides like collagen-binding domains offer promising avenues for tumor-specific immunotherapy and drug delivery. Indirect targeting of collagen involves regulating cellular processes essential for its synthesis and maturation, such as translation regulation and microRNA activity. Enzymes involved in collagen modification, such as prolyl-hydroxylases or lysyl-oxidases, are also indirect therapeutic targets. From another perspective, collagen is also a natural source of drugs. Enzymatic degradation of collagen generates bioactive fragments known as matrikines and matricryptins, which exhibit diverse pharmacological activities. Overall, collagen-derived peptides present significant therapeutic potential beyond tissue repair, offering various strategies for treating fibrosis, cancer, and genetic disorders. Continued research into specific collagen targeting and the application of collagen and its derivatives may lead to the development of novel treatments for a range of pathological conditions.
A-Syn(ful) MAM: A Fresh Perspective on a Converging Domain in Parkinson’s Disease
Authors: Barbuti Peter A.
Published: June 2024

Parkinson’s disease (PD) is a disease of an unknown origin. Despite that, decades of research have provided considerable evidence that alpha-synuclein (αSyn) is central to the pathogenesis of disease. Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are functional domains formed at contact sites between the ER and mitochondria, with a well-established function of MAMs being the control of lipid homeostasis within the cell. Additionally, there are numerous proteins localized or enriched at MAMs that have regulatory roles in several different molecular signaling pathways required for cellular homeostasis, such as autophagy and neuroinflammation. Alterations in several of these signaling pathways that are functionally associated with MAMs are found in PD. Taken together with studies that find αSyn localized at MAMs, this has implicated MAM (dys)function as a converging domain relevant to PD. This review will highlight the many functions of MAMs and provide an overview of the literature that finds αSyn, in addition to several other PD-related proteins, localized there. This review will also detail the direct interaction of αSyn and αSyn-interacting partners with specific MAM-resident proteins. In addition, recent studies exploring new methods to investigate MAMs will be discussed, along with some of the controversies regarding αSyn, including its several conformations and subcellular localizations. The goal of this review is to highlight and provide insight on a domain that is incompletely understood and, from a PD perspective, highlight those complex interactions that may hold the key to understanding the pathomechanisms underlying PD, which may lead to the targeted development of new therapeutic strategies.
Extracellular Vesicles as Next-Generation Diagnostics and Advanced Therapy Medicinal Products
Authors: Stawarska Agnieszka , Bamburowicz-Klimkowska Magdalena , Runden-Pran Elise , Dusinska Maria , Cimpan Mihaela Roxana , Rios-Mondragon Ivan , Grudzinski Ireneusz P.
Published: June 2024

Extracellular vesicles (EVs) hold great promise for clinical application as new diagnostic and therapeutic modalities. This paper describes major GMP-based upstream and downstream manufacturing processes for EV large-scale production, also focusing on post-processing technologies such as surface bioengineering and uploading studies to yield novel EV-based diagnostics and advanced therapy medicinal products. This paper also focuses on the quality, safety, and efficacy issues of the bioengineered EV drug candidates before first-in-human studies. Because clinical trials involving extracellular vesicles are on the global rise, this paper encompasses different clinical studies registered on clinical-trial register platforms, with varying levels of advancement, highlighting the growing interest in EV-related clinical programs. Navigating the regulatory affairs of EVs poses real challenges, and obtaining marketing authorization for EV-based medicines remains complex due to the lack of specific regulatory guidelines for such novel products. This paper discusses the state-of-the-art regulatory knowledge to date on EV-based diagnostics and medicinal products, highlighting further research and global regulatory needs for the safe and reliable implementation of bioengineered EVs as diagnostic and therapeutic tools in clinical settings. Post-marketing pharmacovigilance for EV-based medicinal products is also presented, mainly addressing such topics as risk assessment and risk management.
Primitive and Definitive Neural Precursor Cells Are Present in Human Cerebral Organoids
Authors: Islam Rehnuma , Noman Humna , Azimi Ashkan , Siu Ricky , Chinchalongporn Vorapin , Schuurmans Carol , Morshead Cindi M.
Published: June 2024

Activation of neural stem cells (NSCs) correlates with improved functional outcomes in mouse models of injury. In the murine brain, NSCs have been extensively characterized and comprise (1) primitive NSCs (pNSCs) and (2) definitive NSCs (dNSCs). pNSCs are the earliest cells in the NSC lineage giving rise to dNSCs in the embryonic and adult mouse brain. pNSCs are quiescent under baseline conditions and can be activated upon injury. Herein, we asked whether human pNSCs and dNSCs can be isolated during the maturation of human cerebral organoids (COs) and activated by drugs known to regulate mouse NSC behavior. We demonstrate that self-renewing, multipotent pNSC and dNSC populations are present in human COs and express genes previously characterized in mouse NSCs. The drug NWL283, an inhibitor of apoptosis, reduced cell death in COs but did not improve NSC survival. Metformin, a drug used to treat type II diabetes that is known to promote NSC activation in mice, was found to expand human NSC pools. Together, these findings are the first to identify and characterize human pNSCs, advancing our understanding of the human NSC lineage and highlighting drugs that enhance their activity.
Ion Channel and Transporter Involvement in Chemotherapy-Induced Peripheral Neurotoxicity
Authors: Pozzi Eleonora , Terribile Giulia , Cherchi Laura , Di Girolamo Sara , Sancini Giulio , Alberti Paola
Published: June 2024

The peripheral nervous system can encounter alterations due to exposure to some of the most commonly used anticancer drugs (platinum drugs, taxanes, vinca alkaloids, proteasome inhibitors, thalidomide), the so-called chemotherapy-induced peripheral neurotoxicity (CIPN). CIPN can be long-lasting or even permanent, and it is detrimental for the quality of life of cancer survivors, being associated with persistent disturbances such as sensory loss and neuropathic pain at limb extremities due to a mostly sensory axonal polyneuropathy/neuronopathy. In the state of the art, there is no efficacious preventive/curative treatment for this condition. Among the reasons for this unmet clinical and scientific need, there is an uncomplete knowledge of the pathogenetic mechanisms. Ion channels and transporters are pivotal elements in both the central and peripheral nervous system, and there is a growing body of literature suggesting that they might play a role in CIPN development. In this review, we first describe the biophysical properties of these targets and then report existing data for the involvement of ion channels and transporters in CIPN, thus paving the way for new approaches/druggable targets to cure and/or prevent CIPN.
Aquaporins: Gatekeepers of Fluid Dynamics in Traumatic Brain Injury
Authors: Czyżewski Wojciech , Litak Jakub , Sobstyl Jan , Mandat Tomasz , Torres Kamil , Staśkiewicz Grzegorz
Published: June 2024

Aquaporins (AQPs), particularly AQP4, play a crucial role in regulating fluid dynamics in the brain, impacting the development and resolution of edema following traumatic brain injury (TBI). This review examines the alterations in AQP expression and localization post-injury, exploring their effects on brain edema and overall injury outcomes. We discuss the underlying molecular mechanisms regulating AQP expression, highlighting potential therapeutic strategies to modulate AQP function. These insights provide a comprehensive understanding of AQPs in TBI and suggest novel approaches for improving clinical outcomes through targeted interventions.
Precision Medicine for Blood Glutamate Grabbing in Ischemic Stroke
Authors: Hervella Pablo , Sampedro-Viana Ana , Fernández-Rodicio Sabela , Rodríguez-Yáñez Manuel , López-Dequidt Iria , Pumar José M. , Mosqueira Antonio J. , Bazarra-Barreiros Marcos , Abengoza-Bello María Teresa , Ortega-Espina Sara , Ouro Alberto , Pérez-Mato María , Campos Francisco , Sobrino Tomás , Castillo José , Alonso-Alonso Maria Luz , Iglesias-Rey Ramón
Published: June 2024

Glutamate grabbers, such as glutamate oxaloacetate transaminase (GOT), have been proposed to prevent excitotoxicity secondary to high glutamate levels in stroke patients. However, the efficacy of blood glutamate grabbing by GOT could be dependent on the extent and severity of the disruption of the blood–brain barrier (BBB). Our purpose was to analyze the relationship between GOT and glutamate concentration with the patient’s functional status differentially according to BBB serum markers (soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) and leukoaraiosis based on neuroimaging). This retrospective observational study includes 906 ischemic stroke patients. We studied the presence of leukoaraiosis and the serum levels of glutamate, GOT, and sTWEAK in blood samples. Functional outcome was assessed using the modified Rankin Scale (mRS) at 3 months. A significant negative correlation between GOT and glutamate levels at admission was shown in those patients with sTWEAK levels > 2900 pg/mL (Pearson’s correlation coefficient: −0.249; p < 0.0001). This correlation was also observed in patients with and without leukoaraiosis (Pearson’s correlation coefficients: −0.299; p < 0.001 vs. −0.116; p = 0.024). The logistic regression model confirmed the association of higher levels of GOT with lower odds of poor outcome at 3 months when sTWEAK levels were >2900 pg/mL (OR: 0.41; CI 95%: 0.28–0.68; p < 0.0001) or with leukoaraiosis (OR: 0.75; CI 95%: 0.69–0.82; p < 0.0001). GOT levels are associated with glutamate levels and functional outcomes at 3 months, but only in those patients with leukoaraiosis and elevated sTWEAK levels. Consequently, therapies targeting glutamate grabbing might be more effective in patients with BBB dysfunction.
Amelioration of Fibrosis via S1P Inhibition Is Regulated by Inactivation of TGF-β and SPL Pathways in the Human Cornea
Authors: Nicholas Sarah E. , Basu Sandip K. , Mandal Nawajes , Karamichos Dimitrios
Published: June 2024

Human corneal fibrosis can lead to opacity and ultimately partial or complete vision loss. Currently, corneal transplantation is the only treatment for severe corneal fibrosis and comes with the risk of rejection and donor shortages. Sphingolipids (SPLs) are known to modulate fibrosis in various tissues and organs, including the cornea. We previously reported that SPLs are tightly related to both, transforming growth factor beta (TGF-β) signaling and corneal fibrogenesis. The aim of this study was to investigate the effects of sphingosine-1-phosphate (S1P) and S1P inhibition on specific TGF-β and SPL family members in corneal fibrosis. Healthy human corneal fibroblasts (HCFs) were isolated and cultured in EMEM + FBS + VitC (construct medium) on 3D transwells for 4 weeks. The following treatments were prepared in a construct medium: 0.1 ng/mL TGF-β1 (β1), 1 μM sphingosine-1-phosphate (S1P), and 5 μM Sphingosine kinase inhibitor 2 (I2). Five groups were tested: (1) control (no treatment); rescue groups; (2) β1/S1P; (3) β1/I2; prevention groups; (4) S1P/β1; and (5) I2/β1. Each treatment was administered for 2 weeks with one treatment and switched to another for 2 weeks. Using Western blot analysis, the 3D constructs were examined for the expression of fibrotic markers, SPL, and TGF-β signaling pathway members. Scratch assays from 2D cultures were also utilized to evaluate cell migration We observed reduced fibrotic expression and inactivation of latent TGF-β binding proteins (LTBPs), TGF-β receptors, Suppressor of Mothers Against Decapentaplegic homologs (SMADs), and SPL signaling following treatment with I2 prevention and rescue compared to S1P prevention and rescue, respectively. Furthermore, we observed increased cell migration following stimulation with I2 prevention and rescue groups, with decreased cell migration following stimulation with S1P prevention and rescue groups after 12 h and 18 h post-scratch. We have demonstrated that I2 treatment reduced fibrosis and modulated the inactivation of LTBPs, TGF-β receptors, SPLs, and the canonical downstream SMAD pathway. Further investigations are warranted in order to fully uncover the potential of utilizing SphK I2 as a novel therapy for corneal fibrosis.
The Importance of the FUT2 rs602662 Polymorphism in the Risk of Cardiovascular Complications in Patients after Kidney Transplantation
Authors: Kotowski Maciej Józef , Ostrowski Piotr , Sieńko Jerzy , Czerny Bogusław , Tejchman Karol , Machaliński Bogusław , Górska Aleksandra , Mrozikiewicz Aleksandra E. , Bogacz Anna
Published: June 2024

The FUT2 gene encodes an enzyme called α-1,2-fucosyltransferase, which is involved in the formation of blood group antigens AB0(H) and is also involved in the processes of vitamin B12 absorption and its transport between cells. FUT2 gene polymorphisms are associated with vitamin B12 levels in the body. Vitamin B12 deficiency associated with hyperhomocysteinemia is a major risk factor for cardiovascular diseases (CVDs), which are one of the main causes of death in patients after kidney transplantation. The aim of our study was to determine the impact of the rs602662 (G>A) polymorphism of the FUT2 gene on the functionality of transplanted kidneys and the risk of CVD in patients after kidney transplantation. The study included 402 patients treated with immunosuppression (183 patients taking cyclosporine (CsA) and 219 patients taking tacrolimus (TAC)). The analysis of the FUT2 rs602662 (G>A) polymorphism was performed using real-time PCR. Patients with CsA were more likely to be underweight (1.64% vs. 0.91%) and obese (27.87% vs. 15.98%), while those taking TAC were more likely to be of normal weight (39.27%) or overweight (43.84%). No statistically significant differences were observed comparing the mean blood pressure, both systolic and diastolic. The renal profile showed a higher median urea nitrogen concentration in patients with CsA (26.45 mg/dL (20.60–35.40) vs. 22.95 mg/dL (17.60–33.30), p = 0.004). The observed frequency of rs602662 alleles of the FUT2 gene was similar in the analyzed groups. The A allele was present in 43.7% of patients with CsA and 41.1% of those taking TAC (OR = 0.898; 95% CI: 0.678–1.189; p = 0.453). In the group with CsA, the GG genotype was present in 32.2% of patients, the GA in 48.1% and the AA in 19.7%. A similar distribution was obtained in the TAC group: GG—33.8%, GA—50.2%, and AA—16.0%. An association of genotypes containing the G allele with a higher incidence of hypertension was observed. The G allele was present in 65% of people with hypertension and in 56% of patients with normal blood pressure (p = 0.036). Moreover, the evaluation of the renal parameters showed no effect of the FUT2 polymorphism on the risk of organ rejection because the levels of creatinine, eGFR, potassium, and urea nitrogen were prognostic of successful transplantation. Our results suggest that the rs6022662 FUT2 polymorphism may influence the risk of cardiovascular diseases.
Molecular Interactions of Selective Agonists and Antagonists with the Retinoic Acid Receptor γ
Authors: Powała Katarzyna , Żołek Teresa , Brown Geoffrey , Kutner Andrzej
Published: June 2024

All-trans retinoic acid (ATRA), the major active metabolite of all-trans retinol (vitamin A), is a key hormonal signaling molecule. In the adult organism, ATRA has a widespread influence on processes that are crucial to the growth and differentiation of cells and, in turn, the acquisition of mature cell functions. Therefore, there is considerable potential in the use of retinoids to treat diseases. ATRA binds to the retinoic acid receptors (RAR) which, as activated by ATRA, selectively regulate gene expression. There are three main RAR isoforms, RARα, RARβ, and RARγ. They each have a distinct role, for example, RARα and RARγ regulate myeloid progenitor cell differentiation and hematopoietic stem cell maintenance, respectively. Hence, targeting an isoform is crucial to developing retinoid-based therapeutics. In principle, this is exemplified when ATRA is used to treat acute promyelocytic leukemia (PML) and target RARα within PML-RARα oncogenic fusion protein. ATRA with arsenic trioxide has provided a cure for the once highly fatal leukemia. Recent in vitro and in vivo studies of RARγ have revealed the potential use of agonists and antagonists to treat diseases as diverse as cancer, heterotopic ossification, psoriasis, and acne. During the final drug development there may be a need to design newer compounds with added modifications to improve solubility, pharmacokinetics, or potency. At the same time, it is important to retain isotype specificity and activity. Examination of the molecular interactions between RARγ agonists and the ligand binding domain of RARγ has revealed aspects to ligand binding that are crucial to RARγ selectivity and compound activity and key to designing newer compounds.
Predatory Odor Exposure as a Potential Paradigm for Studying Emotional Modulation of Memory Consolidation—The Role of the Noradrenergic Transmission in the Basolateral Amygdala
Authors: Peshev Bogomil , Ivanova Petya , Krushovlieva Desislava , Kortenska Lidia , Atanasova Dimitrinka , Rashev Pavel , Lazarov Nikolai , Tchekalarova Jana
Published: June 2024

The pivotal role of the basolateral amygdala (BLA) in the emotional modulation of hippocampal plasticity and memory consolidation is well-established. Specifically, multiple studies have demonstrated that the activation of the noradrenergic (NA) system within the BLA governs these modulatory effects. However, most current evidence has been obtained by direct infusion of synthetic NA or beta-adrenergic agonists. In the present study, we aimed to investigate the effect of endogenous NA release in the BLA, induced by a natural aversive stimulus (coyote urine), on memory consolidation for a low-arousing, hippocampal-dependent task. Our experiments combined a weak object location task (OLT) version with subsequent mild predator odor exposure (POE). To investigate the role of endogenous NA in the BLA in memory modulation, a subset of the animals (Wistar rats) was treated with the non-selective beta-blocker propranolol at the end of the behavioral procedures. Hippocampal tissue was collected 90 min after drug infusion or after the OLT test, which was performed 24 h later. We used the obtained samples to estimate the levels of phosphorylated CREB (pCREB) and activity-regulated cytoskeleton-associated protein (Arc)—two molecular markers of experience-dependent changes in neuronal activity. The result suggests that POE has the potential to become a valuable behavioral paradigm for studying the interaction between BLA and the hippocampus in memory prioritization and selectivity.
The Use of AI in Software Engineering: A Synthetic Knowledge Synthesis of the Recent Research Literature
Authors: Kokol Peter
Published: June 2024

Artificial intelligence (AI) has witnessed an exponential increase in use in various applications. Recently, the academic community started to research and inject new AI-based approaches to provide solutions to traditional software-engineering problems. However, a comprehensive and holistic understanding of the current status needs to be included. To close the above gap, synthetic knowledge synthesis was used to induce the research landscape of the contemporary research literature on the use of AI in software engineering. The synthesis resulted in 15 research categories and 5 themes—namely, natural language processing in software engineering, use of artificial intelligence in the management of the software development life cycle, use of machine learning in fault/defect prediction and effort estimation, employment of deep learning in intelligent software engineering and code management, and mining software repositories to improve software quality. The most productive country was China (n = 2042), followed by the United States (n = 1193), India (n = 934), Germany (n = 445), and Canada (n = 381). A high percentage (n = 47.4%) of papers were funded, showing the strong interest in this research topic. The convergence of AI and software engineering can significantly reduce the required resources, improve the quality, enhance the user experience, and improve the well-being of software developers.
Silver-Doped Titanium Oxide Layers for Improved Photocatalytic Activity and Antibacterial Properties of Titanium Implants
Authors: Ali Aya , Polepalli Likhitha , Chowdhury Sheetal , Carr Mary A. , Janorkar Amol V. , Marquart Mary E. , Griggs Jason A. , Bumgardner Joel D. , Roach Michael D.
Published: June 2024

Titanium has a long history of clinical use, but the naturally forming oxide is not ideal for bacterial resistance. Anodization processes can modify the crystallinity, surface topography, and surface chemistry of titanium oxides. Anatase, rutile, and mixed phase oxides are known to exhibit photocatalytic activity (PCA)-driven bacterial resistance under UVA irradiation. Silver additions are reported to enhance PCA and reduce bacterial attachment. This study investigated the effects of silver-doping additions to three established anodization processes. Silver doping showed no significant influence on oxide crystallinity, surface topography, or surface wettability. Oxides from a sulfuric acid anodization process exhibited significantly enhanced PCA after silver doping, but silver-doped oxides produced from phosphoric-acid-containing electrolytes did not. Staphylococcus aureus attachment was also assessed under dark and UVA-irradiated conditions on each oxide. Each oxide exhibited a photocatalytic antimicrobial effect as indicated by significantly decreased bacterial attachment under UVA irradiation compared to dark conditions. However, only the phosphorus-doped mixed anatase and rutile phase oxide exhibited an additional significant reduction in bacteria attachment under UVA irradiation as a result of silver doping. The antimicrobial success of this oxide was attributed to the combination of the mixed phase oxide and higher silver-doping uptake levels.
Surgical Management of Patients with Parotid Involvement from Non-Melanoma Skin Cancer of the Head and Neck
Authors: Carta Filippo , Corrias Simone , Tatti Melania , Marrosu Valeria , Bontempi Mauro , Mariani Cinzia , Gerosa Clara , Ferreli Caterina , Atzeni Matteo , Boriani Filippo , Figus Andrea , Puxeddu Roberto
Published: June 2024

We conducted a retrospective, longitudinal study on a single-center series of patients who underwent parotidectomy in the management of advanced head and neck non-melanoma skin cancer (hnNMSC). The aim of this study was to identify prognostic factors associated with worse outcomes. Forty-one men and nine women were included. The mean age at the time of surgery was 78.9 years. The 5-year overall survival, disease-specific survival, locoregional recurrence-free survival, and distant metastasis-free survival calculated with Kaplan–Meier curves were 39.9%, 56.3%, 58.6%, and 82.1%, respectively. A univariate analysis showed that the status of the margins, facial nerve direct involvement, lymph vascular invasion, and histological grading were associated with worse outcomes (p < 0.05). Positive margins were associated with worse disease-specific survival also in a multivariate analysis (p = 0.001, HR = 32.02, and CIs 4.338 to 351.3). Because the resection in free margins is the most important prognostic factor, early diagnosis or, in the case of advanced disease, extensive surgical resection with concomitant reconstruction is needed. Adjuvant therapy is indicated in selected cases.
Value-Based Health Care Implementation: The Case Study of mTBI Biomarkers
Authors: Zibetti Martina , Di Resta Chiara , Banfi Giuseppe , Tomaiuolo Rossella
Published: June 2024

Traumatic brain injury is a significant global health issue, affecting approximately 69 million people annually. Early diagnosis is crucial for effective management, and biomarkers provide a promising approach to identifying traumatic brain injury in various settings. This study investigates the perceived usefulness of biomarker testing in two distinct contexts: emergency departments and sports settings. Comprehensive interviews were conducted among healthcare professionals in emergency departments and sports-related medical staff. The interviews assessed their perceptions of the diagnostic accuracy, practicality, and overall value of traumatic brain injury biomarker testing. The findings indicate that the perceived usefulness of biomarker testing is high among professionals in both settings. However, significant differences emerged in the perceived barriers to implementation, with emergency department staff citing logistical issues and sports professionals expressing cost concerns. Addressing identified barriers could enhance the adoption and effectiveness of these tests, ultimately improving patient outcomes. Future research should focus on optimizing testing protocols and reducing implementation challenges. This study aims to evaluate the implementation of mild traumatic brain injury biomarkers within the framework of value-based health care, focusing on diagnostic accuracy and patient outcomes.