bluuebunny/crossref_metadata_2025 huggingface dataset:
Establishment and Application of Mismatch Amplification Mutation Assay-PCR for Rapid Detection and Differentiation of Duck Hepatitis A Virus-1 Attenuated Vaccine and Wild Strains
Authors: Yu Cheng-Dong , Choi Yu-Ri , Park Jong-Yeol , Kim Sang-Won , Cha Se-Yeoun , Jang Hyung-Kwan , Kang Min , Wei Bai
Published: September 2024

Duck hepatitis A virus type 1 (DHAV-1) is the main pathogen causing viral hepatitis in ducks, marked by high contagion and acute mortality. Live attenuated DHAV-1 vaccines are widely used to control the disease. This study aims to develop a mismatch amplification mutation assay (MAMA)-PCR for the rapid detection and differentiation of Korean DHAV-1 wild-type strains from vaccine strains. A MAMA primer was designed to target a single nucleotide polymorphism (SNPs) at position 2276 within the VP1 gene, allowing differentiation in a single PCR reaction. The MAMA-PCR accurately identified both strains, with detection limits of 100.5 ELD50/mL and 102.3 ELD50/mL, respectively. The MAMA-PCR demonstrated specificity, showing no cross-reactivity with 12 other viral and bacterial pathogens. The MAMA-PCR was applied to 89 farms, yielding results consistent with nested-PCR and sequence determination, identifying four positive farms for DHAV-1 vaccine strains. In conclusion, this study is the first to employ the MAMA-PCR method to distinguish between DHAV-1 wild-type and vaccine strains. The developed method is rapid, simple, specific, and sensitive, thereby serving as an effective tool for clinical diagnostics in identifying and differentiating between Korean DHAV-1 wild-type and vaccine strains.
Influence of Starvation on Biochemical, Physiological, Morphological, and Transcriptional Responses Associated with Glucose and Lipid Metabolism in the Liver of Javelin Goby (Synechogobius hasta)
Authors: Cui Xiangyu , Huang Xiaoyang , Chen Xiangning , Li Honghui , Wu Yanru , Yang Zikui , Liu Zhiyu , Feng Rui , Xu Jianhe , Wei Chaoqing , Ding Zhujin , Cheng Hanliang
Published: September 2024

In this study, the influence of fasting on hepatic glucose and lipid metabolism was explored by examining biochemical, antioxidative, and morphological indicators and transcriptional expression in the liver of javelin goby (Synechogobius hasta) after 0, 3, 7, or 14 days of starvation. Marked reductions in hepatic glycogen and triglycerides occurred from the seventh day of starvation until the end of the trial (p < 0.05). However, no alterations in hepatic cholesterol or protein were detected throughout the entire experiment (p > 0.05). During fasting, the activities of pyruvate kinase, lactate dehydrogenase, and glycogen phosphorylase a all rose firstly and then fell (p < 0.05). The activities of hepatic fatty acid synthase and acetyl-CoA carboxylase were minimized to their lowest levels at the end of food deprivation (p < 0.05), while lipase was elevated after 7–14 days of fasting (p < 0.05). Catalase, glutathione, and the total antioxidative capacity were increased and maintained their higher values in the later stage of fasting (p < 0.05), whereas malondialdehyde was not significantly changed (p > 0.05). Hepatic vein congestion, remarkable cytoplasmic vacuoles, and irregular cell shape were present in S. hasta which endured 3–7 days of fasting and were less pronounced when food shortage was prolonged. In terms of genes associated with glucose and lipid metabolism, the hepatic phosphofructokinase gene was constantly up-regulated during fasting (p < 0.05). However, the mRNA levels of glycogen synthase and glucose-6-phosphatase were obviously lower when the food scarcity extended to 7 days or more (p < 0.05). Fatty acid synthase, stearoyl-CoA desaturase 1, and peroxisome proliferator-activated receptor γ were substantially down-regulated in S. hasta livers after 7–14 days of food deprivation (p < 0.05). However, genes involved in lipolysis and fatty acid transport were transcriptionally enhanced to varying extents and peaked at the end of fasting (p < 0.05). Overall, starvation lasting 7 days or more could concurrently mobilize hepatic carbohydrates and fat as energy resources and diminished their hepatic accumulation by suppressing biosynthesis and enhancing catabolism and transport, ultimately metabolically and structurally perturbing the liver in S. hasta. This work presents preliminary data on the dynamic characteristics of hepatic glucose and lipid metabolism in S. hasta in response to starvation, which may shed light on the sophisticated mechanisms of energetic homeostasis in fish facing nutrient unavailability and may benefit the utilization/conservation of S. hasta.
Characterizing Marine Medaka (Oryzias melastigma) Haploid Embryonic Stem Cells: A Valuable Tool for Marine Fish Genetic Research
Authors: Zhang Wanwan , Chen Huiquan , Liu Wei , Jia Kuntong , Yi Meisheng
Published: September 2024

Haploid embryonic stem cells (ESCs), which combine the properties of haploidy and pluripotency, hold significant potential for advancing developmental biology and reproductive technology. However, while previous research has largely focused on haploid ESCs in freshwater species like Japanese medaka (Oryzias latipes), little is known about their counterparts in marine species. This study hypothesizes that haploid ESCs from marine fish could offer unique insights and tools for genetic and virological research. To address this, we successfully established and characterized a novel haploid ESC line, hMMES1, derived from marine medaka (Oryzias melastigma). The hMMES1 cells contain 24 chromosomes, exhibit core stem cell characteristics, and express key pluripotency markers. In vitro, hMMES1 cells form embryonic bodies (EBs) capable of differentiating into the three germ layers. In vivo, hMMES1 cells were successfully transplanted into marine medaka and zebrafish, resulting in the generation of interspecies and interordinal chimeras. Additionally, hMMES1 cells demonstrate high efficiency in transfection and transduction, and show susceptibility to major aquaculture viruses, nodavirus (NNV) and iridovirus (SGIV). These findings suggest that hMMES1 cells represent a valuable model for genetic manipulation and virological studies in marine fish species.
Pedigree-Based Description of Danubia Alba Rabbit Breed Lines
Authors: Posta János , Demeter Csongor , Német Zoltán , Sándor Máté , Gerencsér Zsolt , Matics Zsolt
Published: September 2024

The diversity of livestock animal breeds is an integral part of global biodiversity and requires careful management for sustainability and future availability. Avoiding inbreeding is a crucial aspect of mating of breeding animals. Our aims were to describe the quality of the pedigree, generation interval, gene origin, inbreeding, and effective population size of Danubia Alba rabbit lines. Line “D” is the maternal, whereas lines “C” and “X” are used as the paternal lines. The pedigree information was followed back from the actual breeding rabbits up to the founder animals. The rabbits having offspring in 2023 were chosen as reference populations for each line. The complete generation equivalent (GenCom) was 17.68 for line “C”, 18.32 for line “D”, and 17.49 for line “X”, respectively. The maximum number of generations (GenMax) was above 30 for each line. The estimated bottleneck effect is mostly the result of selection and not a real genetic loss. The Wright inbreeding coefficient (F_Wright) was the highest for the “X” line rabbits, whereas it was the lowest for the line “D”. Kalinowski’s decomposition of inbreeding showed that it originated mostly from the past; the current fixation of alleles was quite similar for the line “C” and “D”. Based on the predicted effective population sizes, it seems that there is no problem in maintaining of Danubia Alba lines.
Bovine Coronavirus Prevalence and Risk Factors in Calves on Dairy Farms in Europe
Authors: Berge Anna Catharina , Vertenten Geert
Published: September 2024

This study evaluated prevalence and risk factors in health, management, and biosecurity of bovine coronavirus (BCoV) in neonatal and weaned dairy calves on 125 dairy farms in Europe. Nasal and fecal swabs from neonatal calves, weaned calves, and fresh cows were analyzed for BCoV using RT-PCR, and blood and bulk milk samples were collected for BCoV antibody levels using ELISA. Multiple logistic regression models with random effects of herds were used to evaluate the herd health status, husbandry, management, and biosecurity associated with BCoV shedding (nasal and/or fecal PCR positive samples) in neonatal and weaned calves. BCoV was detected in 80% of herds and in 24% of neonatal calves, 23% of weaned calves, and 5% of fresh cows. The biosecurity scored on 109 dairies with Biocheck.Ugent was, on average, 60% (external score 71%, internal score 47%), and there was no clear association between various biosecurity measures on BCoV shedding in calves. Dry cow vaccination against BCoV reduced shedding in neonatal calves, whereas it was linked to increased shedding in weaned calves in these farms. Several husbandry factors, including nutrition (transition milk feeding and milk feeding levels) and management (group housing and weaning age), were associated with BCoV shedding in calves.
Effects of Different Photoperiods on the Transcriptome of the Ovary and Small White Follicles in Zhedong White Geese
Authors: Huang Tao , Fei Meina , Zhou Xiaolong , He Ke , Yang Songbai , Zhao Ayong
Published: September 2024

Photoperiod can regulate the broodiness of geese and thus increase their egg-laying rate. The laying performance of geese is mainly determined by ovary and follicle development. To understand the effect of photoperiod on the ovary and small white follicles, sixteen 220-day-old healthy female Zhedong white geese were randomly divided into two groups for long photoperiods (15L:9D) and short photoperiods (9L:15D). The geese were euthanized after two months of feeding, and their ovaries and follicles were collected for transcriptome sequencing. RNA-seq analysis identified 187 and 448 differentially expressed genes in ovaries and small white follicles of different photoperiod groups, respectively. A long photoperiod promotes high expression of SPP1, C6, MZB1, GP1BA, and FCGBP genes in the ovaries, and increases the expression of SPP1, ANGPTL5, ALPL, ZP1, and CHRNA4 genes in small white follicles. Functional enrichment analysis showed that photoperiod could affect respiratory system development, smooth muscle cell proliferation in ovaries, and extracellular matrix-related function in small white follicles. WGCNA revealed 31 gene modules, of which 2 were significantly associated with ovarian weight and 17 with the number of small white follicles. Our results provide a better understanding of the molecular regulation in the photoperiod affecting goose reproduction.
Exogenous Ergothioneine and Glutathione Limit Postharvest Senescence of Arugula
Authors: Sivakumar Dhanya , Bozzo Gale
Published: September 2024

Arugula is susceptible to postharvest deterioration. We tested the impact of exogenous antioxidant (i.e., ergothioneine and glutathione) dip solutions on arugula quality during storage at 4 °C or 10 °C for up to 17 days relative to a non-antioxidant treatment. Leaves from each dip treatment and storage temperature were assessed for visual quality and endogenous antioxidant metabolite profiles. Overall, leaf discolouration, wilting, and decay were more rapid at 10 °C than at 4 °C. Both antioxidant treatments limited leaf discolouration at 4 °C. Exogenous ergothioneine reduced wilting at 4 °C, whereas exogenous glutathione limited the incidence of leaf decay. At 10 °C, glutathione reduced the incidence of discolouration and decay, whereas both antioxidant dip treatments limited the decline in leaf yellowing. Ergothioneine was solely detected in ergothioneine-treated leaves; a decrease occurred within the first two days of storage but was unchanged thereafter. Although both antioxidant treatments did not affect endogenous glutathione concentrations at either storage temperature, glutathione disulfide was stable within the glutathione-treated leaves, whereas it increased in the other treatments. Ascorbate degradation was delayed in ergothioneine-treated leaves at 4 °C relative to all other treatments, whereas both antioxidant treatments little affected ascorbate metabolism in leaves stored at 10 °C.
Synthesis, Characterization and Assessment of Antioxidant and Melanogenic Inhibitory Properties of Edaravone Derivatives
Authors: Divya Mohan R. , Anaswara S. A. , Kulkarni Naveen V. , Bojilov Dimitar G. , Manolov Stanimir P. , Ivanov Iliyan I. , Al-Otaibi Jamelah S. , Sheena Mary Y.
Published: September 2024

A series of edaravone derivatives and the corresponding Cu(II) complexes were synthesized and characterized using spectroscopic and analytical techniques such as IR, UV, NMR and elemental analysis. Antioxidant activities of all compounds were examined using free radical scavenging methods such as hydrogen peroxide scavenging activity (HPSA), 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2-2′-azino-bis-(3-ethylbenzothiazoline-6-sulfonate) (ABTS) assays. All of the tested compounds exhibited good antioxidant activity. Further, the frontier orbital energy levels, as well as various chemical properties, were determined using the density functional theory (DFT) calculations. The MEP maps of all of the derivatives were plotted to identify the nucleophilic and electrophilic reactive sites. Further, binding energies of all of the organic compounds with the protein tyrosinase was investigated to determine their potential anti-melanogenic applications. The selected ligand, L6 was subjected to molecular dynamics simulation analysis to determine the stability of the ligand–protein complex. The MD simulation was performed (150 ns) to estimate the stability of the tyrosinase–L6 complex. Other key parameters, such as, RMSD, RMSF, Rg, hydrogen bonds, SASA and MMPBSA were also analyzed to understand the interaction of L6 with the tyrosinase protein.
Lactobacillus delbrueckii subsp. bulgaricus 1.0207 Exopolysaccharides Attenuate Hydrogen Peroxide-Induced Oxidative Stress Damage in IPEC-J2 Cells through the Keap1/Nrf2 Pathway
Authors: Liu Deyu , Yue Yingxue , Ping Lijun , Sun Cuicui , Zheng Tingting , Cheng Yang , Huo Guicheng , Li Bailiang
Published: September 2024

Lactobacillus delbrueckii subsp. bulgaricus (L. bulgaricus) is one of the most commonly employed Lactobacillus in the food industry. Exopolysaccharides (EPS) of Lactobacillus, which are known to exhibit probiotic properties, are secondary metabolites produced during the growth of Lactobacillus. This study identified the structure of the EPS produced by L. bulgaricus 1.0207 and investigated the mitigation of L. bulgaricus 1.0207 EPS on H2O2-induced oxidative stress in IPEC-J2 cells. L. bulgaricus 1.0207 EPS consisted of glucose and galactose and possessed a molecular weight of 4.06 × 104 Da. L. bulgaricus 1.0207 EPS exhibited notable scavenging capacity against DPPH, hydroxyl radicals, superoxide anions, and ABTS radicals. Additionally, L. bulgaricus 1.0207 EPS enhanced cell proliferation, reduced intracellular reactive oxygen species (ROS) accumulation, increased activity of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and total antioxidant capacity (T-AOC) elevated the relative expression of CAT, SOD, HO-1, NQO1, ZO-1, and Occludin genes. Moreover, L. bulgaricus 1.0207 EPS improved the expression of Nrf2, pNrf2, pNrf2/Nrf2, and Bcl-2 proteins, while decreasing the expression of Keap1, Caspase3, and Bax proteins, with the best effect at a concentration of 100 μg/mL. L. bulgaricus 1.0207 EPS mitigated H2O2-induced oxidative stress injury in IPEC-J2 cells by activating the Keap1/Nrf2 pathway. Meanwhile, L. bulgaricus 1.0207 EPS exhibited the potential to decrease apoptosis and restore the integrity of the gut barrier. The findings establish a theoretical foundation for the development and application of L.bulgaricus 1.0207 and its EPS.
The Fold as a Design Strategy: Analogy between Architecture and Issey Miyake’s Work
Authors: Muñoz Marta , Cordero Ángel
Published: September 2024

There is a notable similarity between the objectives of Architecture and Fashion Design. Both disciplines aim to protect and establish a sense of identity for their users. Similarly, analogous design strategies may be employed. One such strategy is the fold. The act of folding a surface results in the formation of a three-dimensional volume. The intrinsic two-dimensionality of the surface gives rise to the formation of space, which is characterised by three dimensions. The air that is trapped by the envelope provides the necessary space for the users. In the context of clothing, the enclosed space is relatively limited and personal. In contrast, in the field of Architecture, the space is of a larger scale and serves a collective purpose, accommodating a variety of activities. Consequently, the processes of designing a building or a piece of clothing are analogous, differing only in terms of scale, time, and materials. The employment of the fold as a point of departure for architectural and Fashion Design projects entails a comparable design process in which concepts such as continuity, superposition, and faceting are associated with this folded mechanism. Consequently, the resulting outcomes, particularly those pertaining to mass and aesthetic perception, exhibit notable similarities.
Effects of Surface Layer Physics Schemes on the Simulated Intensity and Structure of Typhoon Rai (2021)
Authors: Hoang Thi-Huyen , Huang Ching-Yuang , Nguyen Thi-Chinh
Published: September 2024

The influences of surface layer (SL) physics schemes on the simulated intensity and structure of Typhoon Rai (2021) are investigated using the WRF model. Numerical experiments using different SL physics schemes—revised MM5 scheme (MM5), Eta similarity scheme (CTL), and Mellor–Yamada–Nakanishi–Niino scheme (MYNN)—are conducted. The results show that the intensity forecast of Typhoon Rai is largely influenced by SL physics schemes, while its track forecast is not significantly affected. All three experiments can successfully capture the movement of Rai, while CTL provides better intensity simulation compared to the other two experiments. The higher ratio of enthalpy exchange coefficient to drag coefficient (CK/CD) in CTL than MM5 and MYNN leads to significantly increased surface enthalpy fluxes, which are crucial for the typhoon intensification of the former. To explore the influence of SL physics on the structural evolution of the typhoon, the azimuthal-mean angular momentum (AM) budget is utilized. The results indicate that asymmetric eddy terms may also largely contribute to the AM tendencies, which are relatively more comparable in the weaker TC for MM5, compared to the stronger TC with the dominant symmetric mean terms for CTL. Furthermore, the extended Sawyer–Eliassen (SE) equation is solved to quantify the transverse circulations of the typhoon induced by different forcing sources for CTL and MM5. The SE solution indicates that the transverse circulation above and within the boundary layer is predominantly induced by diabatic heating and turbulent friction, respectively, for both CTL and MM5, while all other physical forcing terms are relatively insignificant for the induced transverse circulation for CTL, except for the large contribution from the eddy forcing in the upper-tropospheric outflow for MM5. With the stronger connective heating in the eyewall and boundary-layer radial inflow, the linear SE analysis agrees much better with the nonlinear simulation for CTL than MM5.
Improving Circulation Half-Life of Therapeutic Candidate N-TIMP2 by Unfolded Peptide Extension
Authors: Shirian Jason , Hockla Alexandra , Gleba Justyna J. , Coban Matt , Rotenberg Naama , Strik Laura M. , Alasonyalilar Demirer Aylin , Pawlush Matt L. , Copland John A. , Radisky Evette S. , Shifman Julia M.
Published: September 2024

Matrix metalloproteinases (MMPs) are significant drivers of many diseases, including cancer, and are established targets for drug development. Tissue inhibitors of metalloproteinases (TIMPs) are endogenous MMP inhibitors and are being pursued for the development of anti-MMP therapeutics. TIMPs possess many attractive properties for drug candidates, such as complete MMP inhibition, low toxicity, low immunogenicity, and high tissue permeability. However, a major challenge with TIMPs is their rapid clearance from the bloodstream due to their small size. This study explores a method for extending the plasma half-life of the N-terminal domain of TIMP2 (N-TIMP2) by appending it with a long, intrinsically unfolded tail containing Pro, Ala, and Thr (PATylation). We designed and produced two PATylated N-TIMP2 constructs with tail lengths of 100 and 200 amino acids (N-TIMP2-PAT100 and N-TIMP2-PAT200). Both constructs demonstrated higher apparent molecular weights and retained high inhibitory activity against MMP-9. N-TIMP2-PAT200 significantly increased plasma half-life in mice compared to the non-PATylated variant, enhancing its therapeutic potential. PATylation offers distinct advantages for half-life extension, such as fully genetic encoding, monodispersion, and biodegradability. It can be easily applied to N-TIMP2 variants engineered for high affinity and selectivity toward individual MMPs, creating promising candidates for drug development against MMP-related diseases.
Identification of Exhaled Metabolites Correlated with Respiratory Function and Clinical Features in Adult Patients with Cystic Fibrosis by Real-Time Proton Mass Spectrometry
Authors: Mustafina Malika , Silantyev Artemiy , Krasovskiy Stanislav , Chernyak Alexander , Naumenko Zhanna , Suvorov Aleksandr , Gognieva Daria , Abdullaev Magomed , Suvorova Olga , Schmidt Anna , Gadzhiakhmedova Aida , Bykova Aleksandra , Avdeev Sergey , Betelin Vladimir , Syrkin Abram , Kopylov Philipp
Published: September 2024

Cystic fibrosis (CF) is a hereditary disease characterized by the progression of respiratory disorders, especially in adult patients. The purpose of the study was to identify volatile organic compounds (VOCs) as predictors of respiratory dysfunction, chronic respiratory infections of Staphylococcus aureus, Pseudomonas aeruginosa, Burkholderia cepacia, and VOCs associated with severe genotype and highly effective modulator treatment (HEMT). Exhaled breath samples from 102 adults with CF were analyzed using PTR-TOF-MS, obtained during a forced expiratory maneuver and normal quiet breathing. Using cross-validation and building gradient boosting classifiers (XGBoost), the importance of VOCs for functional and clinical outcomes was determined. The presence of the previously identified VOCs indole, phenol, and dimethyl sulfide were metabolic outcomes associated with impaired respiratory function. New VOCs associated with respiratory disorders were methyl acetate, carbamic acid, 1,3-Pentadiene, and 2,3-dimethyl-2-butene; VOCs associated with the above mentioned respiratory pathogens were non-differentiable nitrogen-containing organic compounds m/z = 47.041 (CH5NO)+ and m/z = 44.044 (C2H5NH+), hydrocarbons (cyclopropane, propene) and methanethiol; and VOCs associated with severe CFTR genotype were non-differentiable VOC m/z = 281.053. No significant features associated with the use of HEMT were identified. Early non-invasive determination of VOCs as biomarkers of the severity of CF and specific pathogenic respiratory flora could make it possible to prescribe adequate therapy and assess the prognosis of the disease. However, further larger standardized studies are needed for clinical use.
Single-Atom Ce-N-C Nanozyme Ameliorates Type 2 Diabetes Mellitus by Improving Glucose Metabolism Disorders and Reducing Oxidative Stress
Authors: Lin Yitong , Wang Yanan , Zhang Qi , Gao Ruxin , Chang Fei , Li Boran , Huang Kunlun , Cheng Nan , He Xiaoyun
Published: September 2024

Type 2 diabetes mellitus (T2DM) as a chronic metabolic disease has become a global public health problem. Insulin resistance (IR) is the main pathogenesis of T2DM. Oxidative stress refers to an imbalance between free radical production and the antioxidant system, causing insulin resistance and contributing to the development of T2DM via several molecular mechanisms. Besides, the reduction in hepatic glycogen synthesis also leads to a decrease in peripheral insulin sensitivity. Thus, reducing oxidative stress and promoting glycogen synthesis are both targets for improving insulin resistance and treating T2DM. The current study aims to investigate the pharmacological effects of single-atom Ce-N-C nanozyme (SACe-N-C) on the improvement of insulin resistance and to elucidate its underlying mechanisms using HFD/STZ-induced C57BL/6J mice and insulin-resistant HepG2 cells. The results indicate that SACe-N-C significantly improves hepatic glycogen synthesis and reduces oxidative stress, as well as pancreatic and liver injury. Specifically, compared to the T2DM model group, fasting blood glucose decreased by 29%, hepatic glycogen synthesis increased by 17.13%, and insulin secretion increased by 18.87%. The sod and GPx in the liver increased by 17.80% and 25.28%, respectively. In terms of mechanism, SACe-N-C modulated glycogen synthesis through the PI3K/AKT/GSK3β signaling pathway and activated the Keap1/Nrf2 pathway to alleviate oxidative stress. Collectively, this study suggests that SACe-N-C has the potential to treat T2DM.
SEPT9_i1 and Septin Dynamics in Oncogenesis and Cancer Treatment
Authors: Jędrzejczak Piotr , Saramowicz Kamil , Kuś Justyna , Barczuk Julia , Rozpędek-Kamińska Wioletta , Siwecka Natalia , Galita Grzegorz , Wiese Wojciech , Majsterek Ireneusz
Published: September 2024

Despite significant advancements in the field of oncology, cancers still pose one of the greatest challenges of modern healthcare. Given the cytoskeleton’s pivotal role in regulating mechanisms critical to cancer development, further studies of the cytoskeletal elements could yield new practical applications. Septins represent a group of relatively well-conserved GTP-binding proteins that constitute the fourth component of the cytoskeleton. Septin 9 (SEPT9) has been linked to a diverse spectrum of malignancies and appears to be the most notable septin member in that category. SEPT9 constitutes a biomarker of colorectal cancer (CRC) and has been positively correlated with a high clinical stage in breast cancer, cervical cancer, and head and neck squamous cell carcinoma. SEPT9_i1 represents the most extensively studied isoform of SEPT9, which substantially contributes to carcinogenesis, metastasis, and treatment resistance. Nevertheless, the mechanistic basis of SEPT9_i1 oncogenicity remains to be fully elucidated. In this review, we highlight SEPT9’s and SEPT9_i1’s structures and interactions with Hypoxia Inducible Factor α (HIF-1 α) and C-Jun N-Terminal Kinase (JNK), as well as discuss SEPT9_i1’s contribution to aneuploidy, cell invasiveness, and taxane resistance—key phenomena in the progression of malignancies. Finally, we emphasize forchlorfenuron and other septin inhibitors as potential chemotherapeutics and migrastatics.
Engineering a Bifunctional Fusion Purine/Pyrimidine Nucleoside Phosphorylase for the Production of Nucleoside Analogs
Authors: Hormigo Daniel , Del Arco Jon , Acosta Javier , Fürst Maximilian J. L. J. , Fernández-Lucas Jesús
Published: September 2024

Nucleoside phosphorylases (NPs) are pivotal enzymes in the salvage pathway, catalyzing the reversible phosphorolysis of nucleosides to produce nucleobases and α-D-ribose 1-phosphate. Due to their efficiency in catalyzing nucleoside synthesis from purine or pyrimidine bases, these enzymes hold significant industrial importance in the production of nucleoside-based drugs. Given that the thermodynamic equilibrium for purine NPs (PNPs) is favorable for nucleoside synthesis—unlike pyrimidine NPs (PyNPs, UP, and TP)—multi-enzymatic systems combining PNPs with PyNPs, UPs, or TPs are commonly employed in the synthesis of nucleoside analogs. In this study, we report the first development of two engineered bifunctional fusion enzymes, created through the genetic fusion of purine nucleoside phosphorylase I (PNP I) and thymidine phosphorylase (TP) from Thermus thermophilus. These fusion constructs, PNP I/TP-His and TP/PNP I-His, provide an innovative one-pot, single-step alternative to traditional multi-enzymatic synthesis approaches. Interestingly, both fusion enzymes retain phosphorolytic activity for both purine and pyrimidine nucleosides, demonstrating significant activity at elevated temperatures (60–90 °C) and within a pH range of 6–8. Additionally, both enzymes exhibit high thermal stability, maintaining approximately 80–100% of their activity when incubated at 60–80 °C over extended periods. Furthermore, the transglycosylation capabilities of the fusion enzymes were explored, demonstrating successful catalysis between purine (2′-deoxy)ribonucleosides and pyrimidine bases, and vice versa. To optimize reaction conditions, the effects of pH and temperature on transglycosylation activity were systematically examined. Finally, as a proof of concept, these fusion enzymes were successfully employed in the synthesis of various purine and pyrimidine ribonucleoside and 2′-deoxyribonucleoside analogs, underscoring their potential as versatile biocatalysts in nucleoside-based drug synthesis.
Reinforcement Learning: A Paradigm Shift in Personalized Blood Glucose Management for Diabetes
Authors: Dénes-Fazakas Lehel , Szilágyi László , Kovács Levente , De Gaetano Andrea , Eigner György
Published: September 2024

Background/Objectives: Managing blood glucose levels effectively remains a significant challenge for individuals with diabetes. Traditional methods often lack the flexibility needed for personalized care. This study explores the potential of reinforcement learning-based approaches, which mimic human learning and adapt strategies through ongoing interactions, in creating dynamic and personalized blood glucose management plans. Methods: We developed a mathematical model specifically for patients with type IVP diabetes, validated with data from 10 patients and 17 key parameters. The model includes continuous glucose monitoring (CGM) noise and random carbohydrate intake to simulate real-life conditions. A closed-loop system was designed to enable the application of reinforcement learning algorithms. Results: By implementing a Policy Optimization (PPO) branch, we achieved an average Time in Range (TIR) metric of 73%, indicating improved blood glucose control. Conclusions: This study presents a personalized insulin therapy solution using reinforcement learning. Our closed-loop model offers a promising approach for improving blood glucose regulation, with potential applications in personalized diabetes management.
Unraveling the Impact of COVID-19 on Rheumatoid Arthritis: Insights from Two Romanian Hospitals—Preliminary Results
Authors: Vlădulescu-Trandafir Andreea-Iulia , Onose Gelu , Munteanu Constantin , Iancu Ioana , Bălănescu Andra-Rodica , Opriș-Belinski Daniela , Berghea Florian , Prefac Cristiana , Grădinaru Elena , Aurelian Sorina , Ciobanu Vlad , Bojincă Violeta-Claudia
Published: September 2024

Background: Rheumatoid arthritis (RA) patients are at heightened risk of Coronavirus Disease—19 (COVID-19) complications due to immune dysregulation, chronic inflammation, and treatment with immunosuppressive therapies. This study aims to characterize the clinical and laboratory parameters of RA patients diagnosed with COVID-19, identify predictive risk factors for severe forms of this infection for RA patients, and determine if any RA immunosuppressive therapy is associated with worse COVID-19 outcomes. Methods: A retrospective observational case-control study included 86 cases (43 diagnosed with RA and 43 cases without any inflammatory or autoimmune disease) that suffered from SARS-CoV-2 in two Romanian hospitals between March 2020 and February 2024. Data on demographics, RA disease characteristics, COVID-19 severity, treatment regimens, and outcomes were analyzed. Results: RA patients exhibited a distinct symptom profile compared to non-RA controls, with higher incidences of neurological, musculoskeletal, and gastrointestinal symptoms, while the control group showed more respiratory and systemic manifestations. Severe COVID-19 is correlated with age and laboratory markers like erythrocyte sedimentation rate (ESR), leucocytes, neutrophils, neutrophil-to-lymphocyte ratio (NLR), aspartate aminotransferase (AST), serum creatinine, and urea. Additionally, RA treatments, particularly rituximab (RTX), were associated with more severe COVID-19 outcomes (but with no statistical significance), potentially due to the advanced disease stage and comorbidities in these patients. Post-infection, a significant number of RA patients experienced disease flares, necessitating adjustments in their treatment regimens. Conclusions: This study underscores the complex interplay between RA and COVID-19, highlighting significant clinical heterogeneity and the need for tailored management strategies. Limitations include sample size constraints, possible selection, and information bias, as well as the lack of adjustments for potential confounding variables that hinder the ability to formulate definitive conclusions. Future research plans to expand the research group size and further elucidate these relationships.
The Importance of Predictive Biomarkers and Their Correlation with the Response to Immunotherapy in Solid Tumors—Impact on Clinical Practice
Authors: Mihaila Raluca Ioana , Gheorghe Adelina Silvana , Zob Daniela Luminita , Stanculeanu Dana Lucia
Published: September 2024

Background/Objectives: Immunotherapy has changed the therapeutic approach for various solid tumors, especially lung tumors, malignant melanoma, renal and urogenital carcinomas, demonstrating significant antitumor activity, with tolerable safety profiles and durable responses. However, not all patients benefit from immunotherapy, underscoring the need for predictive biomarkers that can identify those most likely to respond to treatment. Methods: The integration of predictive biomarkers into clinical practice for immune checkpoint inhibitors (ICI) holds great promise for personalized cancer treatment. Programmed death ligand 1 (PD-L1) expression, tumor mutational burden (TMB), microsatellite instability (MSI), gene expression profiles and circulating tumor DNA (ctDNA) have shown potential in predicting ICI responses across various cancers. Results: Challenges such as standardization, validation, regulatory approval, and cost-effectiveness must be addressed to realize their full potential. Predictive biomarkers are crucial for optimizing the clinical use of ICIs in cancer therapy. Conclusions: While significant progress has been made, further research and collaboration among clinicians, researchers, and regulatory institutes are essential to overcome the challenges of clinical implementation. However, little is known about the relationship between local and systemic immune responses and the correlation with response to oncological therapies and patient survival.
The Proteasome-Family-Members-Based Prognostic Model Improves the Risk Classification for Adult Acute Myeloid Leukemia
Authors: Sheng Guangying , Tao Jingfen , Jin Peng , Li Yilu , Jin Wen , Wang Kankan
Published: September 2024

Background: The accumulation of diverse molecular and cytogenetic variations contributes to the heterogeneity of acute myeloid leukemia (AML), a cluster of hematologic malignancies that necessitates enhanced risk evaluation for prognostic prediction and therapeutic guidance. The ubiquitin–proteasome system plays a crucial role in AML; however, the specific contributions of 49 core proteasome family members (PSMs) in this context remain largely unexplored. Methods: The expression and survival significance of 49 PSMs in AML were evaluated using the data from BeatAML2.0, TCGA, and the GEO database, mainly through the K-M plots, differential genes enrichment analysis, and candidate compounds screening via R language and statistical software. Results: we employed LASSO and Cox regression analyses and developed a model comprising three PSMs (PSMB8, PSMG1, and PSMG4) aimed at predicting OS in adult AML patients, utilizing expression profiles from the BeatAML2.0 training datasets. Patients with higher risk scores were predominantly found in the AML–M2 subtype, exhibited poorer ELN stratification, showed no complete remission following induction therapies, and had a higher mortality status. Consistently, significantly worse OS was observed in high-risk patients across both the training and three validation datasets, underscoring the robust predictive capability of the three-PSMs model for AML outcomes. This model elucidated the distinct genetic abnormalities landscape between high- and low-risk groups and enhanced the ELN risk stratification system. Ultimately, the three-PSMs risk score captured AML-specific gene expression signatures, providing a molecular basis for selecting potential therapeutic agents. Conclusions: In summary, these findings manifested the significant potential of the PSM model for predicting AML survival and informed treatment strategies.
Retinal Imaging-Based Oculomics: Artificial Intelligence as a Tool in the Diagnosis of Cardiovascular and Metabolic Diseases
Authors: Ghenciu Laura Andreea , Dima Mirabela , Stoicescu Emil Robert , Iacob Roxana , Boru Casiana , Hațegan Ovidiu Alin
Published: September 2024

Cardiovascular diseases (CVDs) are a major cause of mortality globally, emphasizing the need for early detection and effective risk assessment to improve patient outcomes. Advances in oculomics, which utilize the relationship between retinal microvascular changes and systemic vascular health, offer a promising non-invasive approach to assessing CVD risk. Retinal fundus imaging and optical coherence tomography/angiography (OCT/OCTA) provides critical information for early diagnosis, with retinal vascular parameters such as vessel caliber, tortuosity, and branching patterns identified as key biomarkers. Given the large volume of data generated during routine eye exams, there is a growing need for automated tools to aid in diagnosis and risk prediction. The study demonstrates that AI-driven analysis of retinal images can accurately predict cardiovascular risk factors, cardiovascular events, and metabolic diseases, surpassing traditional diagnostic methods in some cases. These models achieved area under the curve (AUC) values ranging from 0.71 to 0.87, sensitivity between 71% and 89%, and specificity between 40% and 70%, surpassing traditional diagnostic methods in some cases. This approach highlights the potential of retinal imaging as a key component in personalized medicine, enabling more precise risk assessment and earlier intervention. It not only aids in detecting vascular abnormalities that may precede cardiovascular events but also offers a scalable, non-invasive, and cost-effective solution for widespread screening. However, the article also emphasizes the need for further research to standardize imaging protocols and validate the clinical utility of these biomarkers across different populations. By integrating oculomics into routine clinical practice, healthcare providers could significantly enhance early detection and management of systemic diseases, ultimately improving patient outcomes. Fundus image analysis thus represents a valuable tool in the future of precision medicine and cardiovascular health management.
Role of Circulating Biomarkers in Diabetic Cardiomyopathy
Authors: Ianoș Raluca Diana , Cozma Angela , Lucaciu Roxana Liana , Hangan Adriana Corina , Negrean Vasile , Mercea Delia Corina , Ciulei George , Pop Călin , Procopciuc Lucia Maria
Published: September 2024

Type 2 diabetes mellitus (T2DM) is a metabolic disorder that has alarmingly increased in incidence in recent decades. One of the most serious complications of T2DM is diabetic cardiomyopathy (DCM), an often underrecognized yet severe condition that is a leading cause of mortality among diabetic patients. In the early stages of DCM, patients typically show no symptoms and maintain normal systolic and diastolic left ventricle function, making early detection challenging. Currently available clinical markers are often not specific enough to detect the early stage of DCM. Conventional biomarkers of cardiac mechanical stress and injury, such as natriuretic peptides (NPs) and cardiac troponin I (cTnI), have shown limited predictive value for patients with T2DM. NPs have proven efficacy in detecting diastolic dysfunction in diabetic patients when used alongside 2D echocardiography, but their utility as biomarkers is limited to symptomatic individuals. While cTnI is a reliable indicator of general cardiac damage, it is not specific to cardiac injury caused by high glucose levels or T2DM. This underscores the need for research into biomarkers that can enable early diagnosis and management of DCM to reduce mortality rates. Promising novel biomarkers that showed good performance in detecting diastolic dysfunction or heart failure in diabetic patients include galectin-3, ST2, FGF-21, IGFBP-7, GDF-15, and TGF-β. This review summarizes the current understanding of DCM biomarkers, aiming to generate new ideas for the early recognition and treatment of DCM by exploring related pathophysiological mechanisms.
Biomarker Profiling of Upper Tract Urothelial Carcinoma Only and with Synchronous or Metachronous Bladder Cancer
Authors: Meireles Sara , Dias Carolina , Martins Diana , Marques Ana , Dias Nuno , Pacheco-Figueiredo Luís , Silva João , Silva Carlos Martins , Barbosa Miguel , Costa Luís , Lopes José Manuel , Soares Paula
Published: September 2024

Background: Molecular profiling in upper tract urothelial carcinoma (UTUC) with synchronous or metachronous urothelial bladder cancer (UBC) is scarce. We intended to assess immunohistochemical (IHC) and genetic differences between UTUC-only and UTUC with synchronous or metachronous UBC (UTUC + UBC) and evaluate the effect of subsequent UBC on the outcome of UTUC patients stratified by luminal-basal subtypes. Methods: A retrospective cohort of UTUC was divided into UTUC-only (n = 71) and UTUC + UBC (n = 43). IHC expression of cytokeratin 5/6 (CK5/6), CK20, GATA3, and p53 was evaluated to assess relevant subtypes. Genetic characterization comprised TERTp, FGFR3, RAS, and TP53 status. Kaplan–Meier and Cox regression analyses estimated the effect of clinicopathological variables and molecular profiles on progression-free survival (PFS) and overall survival (OS) of UTUC patients. Results: No meaningful differences were detected among both subgroups according to luminal-basal stratification and genetic analysis. UTUC + UBC was independently associated with a worse PFS when stratified by luminal-basal phenotype (HR 3.570, CI 95% 1.508–8.453, p = 0.004) but with no impact in OS (HR 1.279, CI 95% 0.513–3.190, p = 0.597). Conclusions: This study reveals that both subgroups exhibited equivalent genomic features and luminal-basal subtypes. The involvement of the bladder relates to shorter PFS but does not seem to influence the survival outcome of UTUC, independently of the IHC phenotype.
In Vitro Models of Cardiovascular Calcification
Authors: Tóth Andrea , Balogh Enikő , Jeney Viktória
Published: September 2024

Cardiovascular calcification, characterized by hydroxyapatite deposition in the arterial wall and heart valves, is associated with high cardiovascular morbidity and mortality. Cardiovascular calcification is a hallmark of aging but is frequently seen in association with chronic diseases, such as chronic kidney disease (CKD), diabetes, dyslipidemia, and hypertension in the younger population as well. Currently, there is no therapeutic approach to prevent or cure cardiovascular calcification. The pathophysiology of cardiovascular calcification is highly complex and involves osteogenic differentiation of various cell types of the cardiovascular system, such as vascular smooth muscle cells and valve interstitial cells. In vitro cellular and ex vivo tissue culture models are simple and useful tools in cardiovascular calcification research. These models contributed largely to the discoveries of the numerous calcification inducers, inhibitors, and molecular mechanisms. In this review, we provide an overview of the in vitro cell culture and the ex vivo tissue culture models applied in the research of cardiovascular calcification.
From Voxel to Gene: A Scoping Review on MRI Radiogenomics’ Artificial Intelligence Predictions in Adult Gliomas and Glioblastomas—The Promise of Virtual Biopsy?
Authors: Le Guillou Horn Xavier Maximin , Lecellier François , Giraud Clement , Naudin Mathieu , Fayolle Pierre , Thomarat Céline , Fernandez-Maloigne Christine , Guillevin Rémy
Published: September 2024

Background: Gliomas, including the most severe form known as glioblastomas, are primary brain tumors arising from glial cells, with significant impact on adults, particularly men aged 45 to 70. Recent advancements in the WHO (World Health Organization) classification now correlate genetic markers with glioma phenotypes, enhancing diagnostic precision and therapeutic strategies. Aims and Methods: This scoping review aims to evaluate the current state of deep learning (DL) applications in the genetic characterization of adult gliomas, addressing the potential of these technologies for a reliable virtual biopsy. Results: We reviewed 17 studies, analyzing the evolution of DL algorithms from fully convolutional networks to more advanced architectures (ResNet and DenseNet). The methods involved various validation techniques, including k-fold cross-validation and external dataset validation. Conclusions: Our findings highlight significant variability in reported performance, largely due to small, homogeneous datasets and inconsistent validation methods. Despite promising results, particularly in predicting individual genetic traits, the lack of robust external validation limits the generalizability of these models. Future efforts should focus on developing larger, more diverse datasets and integrating multidisciplinary collaboration to enhance model reliability. This review underscores the potential of DL in advancing glioma characterization, paving the way for more precise, non-invasive diagnostic tools. The development of a robust algorithm capable of predicting the somatic genetics of gliomas or glioblastomas could accelerate the diagnostic process and inform therapeutic decisions more quickly, while maintaining the same level of accuracy as the traditional diagnostic pathway, which involves invasive tumor biopsies.