bluuebunny/crossref_metadata_2025 huggingface dataset:
Lipid Profile of Larix cajanderi Mayr in Adaptation to Natural Conditions in the Cryolithozone
Authors: Nokhsorov Vasiliy V. , Tatarinova Tatiana D. , Dudareva Lyubov V. , Semenova Natalia V. , Maximov Trofim C.
Published: December 2024

The prevalence of coniferous trees in the forest landscapes of northeastern Siberia is conditioned by their high frost resistance. The Kajander larch (Larix cajanderi Mayr), which can survive under natural conditions (down to −60 °C) in the cryolithozone of Yakutia, is the dominant forest-forming species. We hypothesise that our study using HPTLC–UV/Vis/FLD, TLC–GC/FID, and GC–MS methods of seasonal features of the lipid profile of Kajander larch tissues will bring us closer to understanding the mechanisms of participation of lipid components in the adaptation of this valuable tree species to the cold climate of the cryolithozone. Rare delta5-unsaturated polymethylene-interrupted fatty acids (∆5-UPIFA) were identified in the fatty acids (FAs) of L. cajanderi shoots, including 18:2(Δ5.9) (taxoleic), 18:3(Δ5.9.12) (pinolenic), and 18:4(Δ5.9.12.15) (coniferonic). It was found that the content of ∆5-UPIFA in L. cajanderi shoots markedly increased (1.5-fold, representing up to 23.9% of sum FAs) during the autumnal transition of trees to dormancy. It was observed that the ranges of low temperatures experienced during the prolonged winter period primarily determined the structural diversity of membrane lipids and their constituent FAs during the cold adaptation of L. cajanderi. The results obtained can be used for the selection of molecular markers of cold tolerance in woody plants, including fruit trees.
A Cytosolic Phosphoglucose Isomerase, OsPGI1c, Enhances Plant Growth and Herbivore Resistance in Rice
Authors: Chen Lin , Kuai Peng , Lu Jing , Li Leilei , Lou Yonggen
Published: December 2024

Glucose-6-phosphate isomerase (PGI), a key enzyme that catalyzes the reversible conversion of glucose-6-phosphate and fructose-6-phosphate, plays an important role in plant growth, development, and responses to abiotic stresses and pathogen infections. However, whether and how PGI modulates herbivore-induced plant defenses remain largely unknown. The Brown planthopper (BPH, Nilaparvata lugens) is a devastating insect pest of rice, causing significant damage to rice plants through feeding, oviposition, and disease transmission, resulting in great yield losses. Here, we isolated a rice cytosolic PGI gene, OsPGI1c, which is ubiquitously expressed in rice plants; the highest transcript levels are found in leaves, outer leaf sheaths, and seeds. The expression of OsPGI1c was induced by infestation by gravid females of the BPH, mechanical wounding, and treatment with jasmonic acid (JA). Overexpressing OsPGI1c in rice (oePGI) enhanced both the masses of plant shoots and roots and basal levels of trehalose; however, when infested by gravid BPH females for 2 days, trehalose levels were significantly lower in oePGI plants than in wild-type (WT) plants. Additionally, the overexpression of OsPGI1c increased the BPH-induced levels of JA, jasmonoyl-L-isoleucine, and abscisic acid, but decreased the levels of ethylene and H2O2. Bioassays revealed that gravid BPH females preferred WT plants over oePGI plants for laying eggs; moreover, BPH eggs exhibited lower hatching rates and required longer developmental durations on oePGI plants than WT plants. These results indicate that OsPGI1c positively modulates both rice growth and BPH resistance.
Combination of sST2/LVMI Ratio and Modified MELD Scores Predicts Mortality in End-Stage Heart Failure
Authors: Szczurek-Wasilewicz Wioletta , Jurkiewicz Michał , Skrzypek Michał , Romuk Ewa , Jóźwiak Jacek , Gąsior Mariusz , Szyguła-Jurkiewicz Bożena
Published: December 2024

Biomarkers are critical for heart failure (HF) management by facilitating risk stratification, therapeutic decision-making, and monitoring treatment response. This prospective, single-center study aimed to assess predictors of death during one-year follow-up in patients with end-stage HF, with particular emphasis on the soluble suppression of tumorigenicity 2/left ventricular mass index (sST2/LVMI) ratio, modified Model for End-stage Liver Disease (modMELD), and Model for End-stage Liver Disease excluding INR (MELD-XI). This study comprised 429 consecutive patients with end-stage HF hospitalized between 2018 and 2023. The median age was 56.0 (50.0–60.0) years; and 89.2% were male. During the follow-up, 134 (31.2%) patients died. The area under the receiver operating characteristics (ROC) curves showed good predictive powers of sST2/LVMI-MELDXI (AUC: 0.90 [CI: 0.87–0.93]; specificity 85% and sensitivity 80%) and sST2/LVMI-modMELD (AUC: 0.92 [95% CI: 0.90–0.95]; specificity 92%, sensitivity 81%) for assessment of one-year mortality. In conclusion: the sST2/LVMI-modMELD and sST2/LVMI-MELD-XI ratios are independently related to one-year mortality in the analyzed group of patients. The prognostic power of these new models is significantly better than their individual components. This single-center study comprised a relatively small group of patients, so the prognostic value of these new models cannot be generalized to the entire HF population. Considering the limitations of this analysis, further randomized trials with a large cohort are necessary to confirm the utility of the new prognostic models in HF patients.
Dead or Alive: Exploratory Analysis of Selected Apoptosis- and Autophagy-Related Proteins in Human Endometrial Stromal Cells of Fertile Females and Their Potential Role During Embryo Implantation
Authors: Scheliga Iwona , Baston-Buest Dunja M. , Haramustek Djamila , Knebel Alexandra , Kruessel Jan-Steffen , Bielfeld Alexandra P.
Published: December 2024

To date, very little is known about how apoptosis and autophagy affect human endometrial stromal cells (ESCs), particularly how these processes might determine the depth of implantation in humans. Before investigating how apoptosis and autophagy might modulate the implantation process in an infertile population, it is necessary to clarify how these processes are regulated in healthy individuals. This study examined the protein expression related to apoptosis and autophagy in primary ESCs from fertile women, particularly in the context of decidualization and embryo contact, using Western blot analysis. This study evaluated the protein expression of apoptosis receptors and autophagy markers during the window of implantation. Previous research has shown that a syndecan 1 (Sdc1) knockdown (kd) in endometrial stromal cell lines increased the sensitivity to apoptosis induced by embryonic stimuli. We aimed to determine if this effect is also present in primary cells and if Sdc1 regulates autophagy. The expression of autophagy- and apoptosis-associated proteins in primary ESCs from fertile individuals was investigated in this preliminary study, along with their impact on the process of human embryo implantation. During decidualization and exposure to embryo contact, we observed an upregulation of apoptosis- and autophagy-related proteins in ESCs. Decidualized ESCs exhibited higher levels of apoptosis receptors, indicating increased sensitivity to embryo-induced apoptosis. Additionally, the increase in basal autophagy proteins suggests a significant role in the implantation process. Sdc1 is potentially involved in regulating apoptosis and autophagy, demonstrating its possible role in modulating implantation-related cell activities. These findings suggest a complex interplay between apoptosis and autophagy in regulating human embryo implantation. The changes in the expression of apoptotic and autophagic proteins in ESCs after decidualization and upon contact with the embryo provide new insights into the cellular mechanisms that underlie successful implantation. These results have potential implications for understanding the pathophysiology of implantation disorders and improving assisted reproductive technologies. The first results of this pilot study need to be verified with a larger sample size in the future.
S6K2 in Focus: Signaling Pathways, Post-Translational Modifications, and Computational Analysis
Authors: Khalil Mahmoud I. , Helal Mohamed , El-Sayed Ahmed F. , El Hajj Rana , Holail Jasmine , Houssein Marwa , Waraky Ahmed , Pardo Olivier E.
Published: December 2024

S6 Kinase 2 (S6K2) is a key regulator of cellular signaling and is crucial for cell growth, proliferation, and survival. This review is divided into two parts: the first focuses on the complex network of upstream effectors, downstream modulators, and post-translational modifications (PTMs) that regulate S6K2 activity. We emphasize the dynamic nature of S6K2 regulation, highlighting its critical role in cellular homeostasis and its potential as a therapeutic target in diseases like cancer. The second part utilizes in silico analyses, employing computational tools to model S6K2’s three-dimensional structure and predict its interaction networks. Molecular dynamics simulations and docking studies reveal potential binding sites and interactions with novel known inhibitors. We also examine the effects of environmental contaminants that potentially disrupt S6K2 function and provide insights into the role of external factors that could impact its regulatory mechanisms. These computational findings provide a deeper understanding of the conformational dynamics of S6K2 and its interactions with its inhibitors. Together, this integrated biochemical and computational approach enhances our understanding of S6K2 regulation and identifies potential new therapeutic strategies targeting S6K2 in the oncology setting.
TH301 Emerges as a Novel Anti-Oncogenic Agent for Human Pancreatic Cancer Cells: The Dispensable Roles of p53, CRY2 and BMAL1 in TH301-Induced CDKN1A/p21CIP1/WAF1 Upregulation
Authors: Farmakis Danae , Stravopodis Dimitrios J. , Prombona Anastasia
Published: December 2024

Background: Pancreatic Ductal Adeno-Carcinoma (PDAC) is a highly aggressive cancer, with limited treatment options. Disruption of the circadian clock, which regulates key cellular processes, has been implicated in PDAC initiation and progression. Hence, targeting circadian clock components may offer new therapeutic opportunities for the disease. This study investigates the cytopathic effects of TH301, a novel CRY2 stabilizer, on PDAC cells, aiming to evaluate its potential as a novel therapeutic agent. Methods: PDAC cell lines (AsPC-1, BxPC-3 and PANC-1) were treated with TH301, and cell viability, cell cycle progression, apoptosis, autophagy, circadian gene, and protein expression profiles were analyzed, using MTT assay, flow cytometry, Western blotting, and RT-qPCR technologies. Results: TH301 proved to significantly decrease cell viability and to induce cell cycle arrest at the G1-phase across all PDAC cell lines herein examined, especially the AsPC-1 and BxPC-3 ones. It caused dose-dependent apoptosis and autophagy, and it synergized with Chloroquine and Oxaliplatin to enhance anti-oncogenicity. The remarkable induction of p21 by TH301 was shown to follow clock- and p53-independent patterns, thereby indicating the critical engagement of alternative mechanisms. Conclusions: TH301 demonstrates significant anti-cancer activities in PDAC cells, thus serving as a promising new therapeutic agent, which can also synergize with approved treatment schemes by targeting pathways beyond circadian clock regulation. Altogether, TH301 likely opens new therapeutic windows for the successful management of pancreatic cancer in clinical practice.
Skin Disorders and Osteoporosis: Unraveling the Interplay Between Vitamin D, Microbiota, and Epigenetics Within the Skin–Bone Axis
Authors: Papa Vincenzo , Li Pomi Federica , Minciullo Paola Lucia , Borgia Francesco , Gangemi Sebastiano
Published: December 2024

Growing scientific evidence suggests a strong interconnection between inflammatory skin diseases and osteoporosis (OP), a systemic condition characterized by decreased bone density and structural fragility. These conditions seem to share common pathophysiological mechanisms, including immune dysregulation, chronic inflammation, and vitamin D deficiency, which play a crucial role in both skin and bone health. Additionally, the roles of gut microbiota (GM) and epigenetic regulation via microRNAs (miRNAs) emerge as key elements influencing the progression of both conditions. This review aims to examine the skin–bone axis, exploring how factors such as vitamin D, GM, and miRNAs interact in a subtle pathophysiological interplay driving skin inflammation and immune-metabolic bone alterations. Recent research suggests that combined therapeutic approaches—including vitamin D supplementation, targeted microbiota interventions, and miRNA-based therapies—could be promising strategies for managing comorbid inflammatory skin diseases and OP. This perspective highlights the need for multidisciplinary approaches in the clinical management of conditions related to the skin-bone axis.
Amphetamine Injection into the Nucleus Accumbens and Electrical Stimulation of the Ventral Tegmental Area in Rats After Novelty Test—Behavioral and Neurochemical Correlates
Authors: Jerzemowska Grażyna , Podlacha Magdalena , Orzeł-Gryglewska Jolanta
Published: December 2024

Amphetamine abuse is a global health epidemic that is difficult to treat due to individual differences in response to environmental factors, including stress reactivity and anxiety levels, as well as individual neuronal differences, which may result in increased/decreased vulnerability to addiction. In the present study, we investigated whether the Wistar rats behavioral traits of high (HR) and low (LR) locomotor activity to novelty influence motivational behavior (induced feeding model; iFR by electrical stimulation of the ventral tegmental area; Es-VTA) supported by amphetamine injection into the nucleus accumbens shell (AcbSh) (HRAmph, n = 5; LRAmph, n = 5). A correlation was found between the novelty test’s locomotor activity score and the frequency threshold percentage change (p < 0.001, Rs = −0.867). In HRAmph, there was a shortening (−24.16%), while in LRAmph, there was a lengthening (+51.84%) of iFR latency. Immunofluorescence studies showed differential neuronal density (activity of tyrosine hydroxylase, choline acetyltransferase, and cFos protein) in the selected brain structures in HRAmph and LRAmph animals as well as in comparison to a control group (HRACSF, n = 5; LRACSF, n = 5). These results contribute to expanding the state of knowledge of the behavioral and neuronal propensity to take drug abuse.
Enhanced Dissipation of Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) in Soil by the Bioaugmentation with Newly Isolated Strain Acinetobacter johnsonii MC5
Authors: Cycoń Mariusz , Żmijowska Agnieszka , Klim Magdalena
Published: December 2024

The presented study investigated the possibility of using the Acinetobacter johnsonii MC5 strain, isolated from raw sewage by the enrichment culture method, in the bioremediation of soil contaminated with selected NSAIDs, i.e., ibuprofen (IBF), diclofenac (DCF), and naproxen (NPX), using the bioaugmentation technique. The degradation potential of A. johnsonii MC5 was first evaluated using a mineral salt medium containing drugs as the only sources of carbon and energy. The results show that the strain MC5 was capable of utilizing the tested compounds in medium, indicating that the drugs might be metabolically degraded. IBF and NPX were degraded with a similar rate and DT50 values were determined to be approximately 5 days, while the degradation process for DCF was slower, and the DT50 value was about 5 times higher (22.7 days) compared to those calculated for IBF and NPX. Bioaugmentation of non-sterile soil with A. johnsonii MC5 increased the rate of disappearance of the tested drugs, and DT50 values decreased 5.4-, 3.6-, or 6.5-fold for IBF, DCF, or NPX, respectively, in comparison with the values obtained for the soil with indigenous microorganisms only. The obtained results suggest that A. johnsonii MC5 may have potential for use in bioremediation of NSAID-contaminated soils; however, detailed studies are needed before using this strain in such process on a larger scale.
Comparison of Three Chimeric Zika Vaccine Prototypes Developed on the Genetic Background of the Clinically Proven Live-Attenuated Japanese Encephalitis Vaccine SA14-14-2
Authors: Song Byung-Hak , Frank Jordan C. , Yun Sang-Im , Julander Justin G. , Mason Jeffrey B. , Polejaeva Irina A. , Davies Christopher J. , White Kenneth L. , Dai Xin , Lee Young-Min
Published: December 2024

Zika virus (ZIKV) is a medically important mosquito-borne orthoflavivirus, but no vaccines are currently available to prevent ZIKV-associated disease. In this study, we compared three recombinant chimeric viruses developed as candidate vaccine prototypes (rJEV/ZIKVMR-766, rJEV/ZIKVP6-740, and rJEV/ZIKVPRVABC-59), in which the two neutralizing antibody-inducing prM and E genes from each of three genetically distinct ZIKV strains were used to replace the corresponding genes of the clinically proven live-attenuated Japanese encephalitis virus vaccine SA14-14-2 (rJEV). In WHO-certified Vero cells (a cell line suitable for vaccine production), rJEV/ZIKVP6-740 exhibited the slowest viral growth, formed the smallest plaques, and displayed a unique protein expression profile with the highest ratio of prM to cleaved M when compared to the other two chimeric viruses, rJEV/ZIKVMR-766 and rJEV/ZIKVPRVABC-59, as well as their vector, rJEV. In IFNAR−/− mice, an animal model of ZIKV infection, subcutaneous inoculation of rJEV/ZIKVP6-740 caused a low-level localized infection limited to the spleen, with no clinical signs of infection, weight loss, or mortality; in contrast, the other two chimeric viruses and their vector caused high-level systemic infections involving multiple organs, consistently leading to clear clinical signs of infection, rapid weight loss, and 100% mortality. Subsequently, subcutaneous immunization with rJEV/ZIKVP6-740 proved highly effective, offering complete protection against a lethal intramuscular ZIKV challenge 28 days after a single-dose immunization. This protection was specific to ZIKV prM/E and likely mediated by neutralizing antibodies targeting ZIKV prM/E. Therefore, our data indicate that the chimeric virus rJEV/ZIKVP6-740 is a highly promising vaccine prototype for developing a safe and effective vaccine for inducing neutralizing antibody-mediated protective immunity against ZIKV.
Unraveling the microRNAs Involved in Fasciolosis: Master Regulators of the Host–Parasite Crosstalk
Authors: Barrero-Torres Diana María , Herrera-Torres Guillem , Pérez José , Martínez-Moreno Álvaro , Martínez-Moreno Francisco Javier , Flores-Velázquez Luis Miguel , Buffoni Leandro , Rufino-Moya Pablo José , Ruiz-Campillo María Teresa , Molina-Hernández Verónica
Published: December 2024

Fasciolosis is a neglected tropical disease caused by helminth parasites of the genus Fasciola spp., including Fasciola hepatica (F. hepatica) and Fasciola gigantica (F. gigantica), being a major zoonotic problem of human and animal health. Its control with antihelminthics is becoming ineffective due to the increase in parasite resistance. Developing new therapeutic protocols is crucial to a deeper knowledge of the molecular bases in the host–parasite interactions. The high-throughput omics technologies have dramatically provided unprecedented insights into the complexity of the molecular host–parasite crosstalk. MicroRNAs (miRNAs) are key players as critical regulators in numerous biological processes, modifying the gene expression of cells by degradation of messenger RNA (mRNA), regulating transcription and translation functions, protein positioning, cell cycle integrity, differentiation and apoptosis. The large-scale exploration of miRNAs, including the miRNome, has offered great scientific knowledge of steps in fasciolosis, further scrutinizing the pathogenesis, the growth and development of their strains and their interaction with the host for the survival of the different parasite stages. This review compiles the updated knowledge related to miRNAs involved in fasciolosis and the generated miRNome, highlighting the importance of these key molecules in the host–parasite interactions and the pathogenesis of Fasciola spp. directing towards the development of new biotherapeutic protocols for the control of fasciolosis.
A Brief History of Ferritin, an Ancient and Versatile Protein
Authors: Arosio Paolo , Cairo Gaetano , Bou-Abdallah Fadi
Published: December 2024

Ferritin, a highly conserved iron storage protein, is among the earliest proteins that have been purified, named, and characterized due to its unique properties that continue to captivate researchers. Ferritin is composed of 24 subunits that form an almost spherical shell delimiting a cavity where thousands of iron atoms can be stored in a nontoxic ferric form, thereby preventing cytosolic iron from catalyzing oxidative stress. Mitochondrial and extracellular ferritin have also been described and characterized, with the latter being associated with several signaling functions. In addition, serum ferritin serves as a reliable indicator of both iron stores and inflammatory conditions. First identified and purified through crystallization in 1937, ferritin has since drawn significant attention for its critical role in iron metabolism and regulation. Its unique structural features have recently been exploited for many diverse biological and technological applications. To date, more than 40,000 publications have explored this remarkable protein. Here, we present a historical overview, tracing its journey from discovery to current applications and highlighting the evolution of biochemical techniques developed for its structure–function characterization over the past eight decades.
Using the Radial Distribution Function to Analyze Atomic Force Microscopy Images of Colloidal Systems
Authors: Kraevsky Sergey V. , Valueva Anastasia A. , Ershova Maria O. , Shumov Ivan D. , Ivanova Irina A. , Kanashenko Sergey L. , Ryazantsev Ilya A. , Ivanov Yuri D. , Pleshakova Tatyana O.
Published: December 2024

Biomacromolecules generally exist and function in aqueous media. Is it possible to estimate the state and properties of molecules in an initial three-dimensional colloidal solution based on the structure properties of biomolecules adsorbed on the two-dimensional surface? Using atomic force microscopy to study nanosized objects requires their immobilization on a surface. Particles undergoing Brownian motion in a solution significantly reduce their velocity near the surface and become completely immobilized upon drying. Using radial distribution function (RDF) methods, it is possible to obtain information about the presence of short-range or long-range order in the arrangement of immobilized colloidal particles. In this work, RDF is applied to immobilized gold nanoparticles (AuNPs) and horseradish peroxidase molecules on mica. It is shown that AuNPs maintain mobility on the mica surface when water is present. Upon immobilization, AuNPs organize into an amorphous structure exhibiting short-range order. Protein molecules are immobilized randomly, and their surface density is well described by the Poisson distribution.
Isolation of a Novel Low-Temperature-Active and Organic-Solvent-Stable Mannanase from the Intestinal Metagenome of Hermetia illucens
Authors: Kim Dong-Gwan , Lee Chang-Muk , Lee Young-Seok , Yoon Sang-Hong , Kim Su-Yeon
Published: December 2024

The black soldier fly, Hermetia illucens, is a voracious scavenger of various organic materials; therefore, it could be exploited as a biological system for processing daily food waste. In order to survey novel hydrolytic enzymes, we constructed a fosmid metagenome library using unculturable intestinal microorganisms from H. illucens. Through functional screening of the library on carboxymethyl cellulose plates, we identified a fosmid clone, the product of which displayed hydrolytic activity. Sequence analysis of the fosmid revealed a novel mannan-degrading gene, ManEM6, composed of 1185 base pairs encoding 394 amino acids, with a deduced 20-amino-acid N-terminal signal peptide sequence. The conceptual translation of ManEM6 exhibited the highest identity (78%) to endo-1,4-β-mannosidase from Dysgonomonas mossii. Phylogenetic and domain analyses indicated that ManEM6 encodes a novel mannanase with a glycoside hydrolase family 26 domain. The recombinant protein rManEM6 showed its highest activity at 40 °C and pH 7.0, and it remained stable in the range of pH 5–10.0. rManEM6 hydrolyzed substrates with β-1,4-glycosidic mannoses, showing maximum enzymatic activity toward locust bean gum galactomannan, while it did not hydrolyze p-nitrophenyl-β-pyranosides, demonstrating endo-form mannosidase activity. rManEM6 was highly stable under stringent conditions, including those of polar organic solvents, as well as reducing and denaturing reagents. Therefore, ManEM6 may be an attractive candidate for the degradation of mannan under high-organic-solvent and protein-denaturing processes in the food and feed industries.
Comparative Transcriptomics Reveal Differential Expression of Coding and Non-Coding RNAs in Clinical Strains of Mycobacterium tuberculosis
Authors: Mvubu Nontobeko Eunice , Govender Divenita , Pillay Manormoney
Published: December 2024

Coding and non-coding RNAs (ncRNAs) are potential novel markers that can be exploited for TB diagnostics in the fight against Mycobacterium tuberculosis. The current study investigated the mechanisms of transcript regulation and ncRNA signatures through Total RNA Seq and small (smRNA) RNA Seq followed by Bioinformatics analysis in Beijing and F15/LAM4/KZN (KZN) clinical strains compared to the laboratory strain. Total RNA Seq revealed differential regulation of RNA transcripts in Beijing (n = 1095) and KZN (n = 856) strains compared to the laboratory H37Rv strain. The KZN vs. H37Rv coding transcripts uniquely enriched fatty acids, steroid degradation, fructose, and mannose metabolism as well as a bacterial secretion system. In contrast, Tuberculosis and biosynthesis of siderophores KEGG pathways were enriched by the Beijing vs. H37Rv-specific transcripts. Novel sense and antisense ncRNAs, as well as the expression of these transcripts, were observed, and these targeted RNA transcripts are involved in cell wall synthesis and bacterial metabolism in a strain-specific manner. RNA transcripts identified in the current study offer insights into gene regulation of transcripts involved in the growth and metabolism of the clinically relevant KZN and Beijing strains compared to the laboratory H37Rv strain and thus can be exploited in the fight against Tuberculosis.
Antibody–Drug Conjugates in Non-Small Cell Lung Cancer: State of the Art and Future Perspectives
Authors: Zanchetta Carol , De Marchi Lorenzo , Macerelli Marianna , Pelizzari Giacomo , Costa Jacopo , Aprile Giuseppe , Cortiula Francesco
Published: December 2024

Antibody–drug conjugates (ADCs) represent one of the most promising and rapidly emerging anti-cancer therapies because they combine the cytotoxic effect of the conjugate payload and the high selectivity of the monoclonal antibody, which binds a specific membrane antigen expressed by the tumor cells. In non-small cell lung cancer (NSCLC), ADCs are being investigated targeting human epidermal growth factor receptor 2 (HER2), human epidermal growth factor receptor 3 (HER3), trophoblast cell surface antigen 2 (TROP2), Mesenchymal–epithelial transition factor (c-MET), and carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5). To date, Trastuzumab deruxtecan is the only ADC that has been approved by the FDA for the treatment of patients with NSCLC, but several ongoing studies, both using ADCs as monotherapy and combined with other therapies, are investigating the efficacy of new ADCs. In this review, we describe the structures and mechanism of action of different ADCs; we present the evidence derived from the main clinical trials investigating ADCs’ efficacy, focusing also on related toxicity; and, finally, we discuss future perspectives in terms of toxicity management, possible biomarkers, and the identification of resistance mechanisms.
Identification and Characterization of Key Genes for Nitrogen Utilization from Saccharum spontaneum Sub-Genome in Modern Sugarcane Cultivar
Authors: Hui Qianlong , Song Ting , Yang Dantong , Wu Qibin , Guo Jinlong , Que Youxiong , Xu Liping
Published: December 2024

Sugarcane (Saccharum spp.) is globally considered an important crop for sugar and biofuel production. During sugarcane production, the heavy reliance on chemical nitrogen fertilizer has resulted in low nitrogen use efficiency (NUE) and high loss. Up until now, there has been extensive research on the transcriptomic dynamics during sugarcane response to low nitrogen (LN) stress. However, the specific contribution of S. spontaneum to the NUE of modern sugarcane remains unclear. In the present study, the comparative transcriptome analysis of two contrasting sugarcane cultivars in response to nitrogen deficiency was performed via the combination of genomes of S. spontaneum and S. officinarum. Sub-genome analysis indicated that S. spontaneum supports the high NUE of modern sugarcane by providing genes related to nitrogen and carbohydrate metabolism, photosynthesis, and amino acid metabolism. Additionally, the key genes involved in nitrogen metabolism from the S. spontaneum were successfully identified through weighted gene co-expression network analyses (WGCNA), and a high-affinity nitrate transporter named ScNRT2.3 was subsequently cloned. Heterogeneous expression of the ScNRT2.3, a cell membrane-localized protein, could enhance the growth of Arabidopsis under low nitrate conditions. Furthermore, a conserved protein module known as NAR2.1/NRT2.3 was shown to regulate the response to LN stress in sugarcane roots through molecular interaction. This work helps to clarify the contribution of S. spontaneum to the NUE in modern sugarcane, and the function of the ScNRT2.3 in sugarcane.
Improving Ni2+ Tolerance of Arabidopsis by Overexpressing Bacterial rcnA Gene Encoding a Membrane-Bound Exporter of Ni2+
Authors: Wang Xuxu , Qiu Gengcheng , Yang Jiading
Published: December 2024

The prerequisite for breeding a plant to be used in phytoremediation is its high tolerance to grow normally in soil contaminated by certain heavy metals. As mechanisms of plant uptake and transport of nickel (Ni) are not fully understood, it is of significance to utilize exogenous genes for improving plant Ni tolerance. In this study, rcnA from Escherichia coli encoding an exporter of Ni and cobalt was overexpressed constitutively in Arabidopsis thaliana, and the performance of transgenic plants was assayed under Ni stress. The subcellular localization of rcnA in plant cells was found to be the plasma membrane. Constitutive overexpression of rcnA in Arabidopsis rendered better growth of either seedlings on agar medium containing 85, 100, and 120 μM NiCl2 or adult plants in a nutrient solution with 5 mM NiCl2 added. Compared to the wildtype, rcnA-OE transgenic plants under Ni stress accumulated lower levels of reactive oxygen species (i.e., superoxide and hydrogen peroxide) in leaves and exhibited less oxidative damage in shoots, as demonstrated by less electrolyte leakage and the lower malondialdehyde content. Notably, rcnA-OE transgenic plants retained a higher content of Ni in roots and had a lower content of Ni in shoots. Therefore, our findings indicated that the bacterial rcnA gene may be utilized to improve plant Ni tolerance through genetic transformation.
Systematic Evaluation of Extracellular Coating Matrix on the Differentiation of Human-Induced Pluripotent Stem Cells to Cortical Neurons
Authors: Li Siyao , Liu Yan , Luo Xianyang , Hong Wei
Published: December 2024

Induced pluripotent stem cell (iPSC)-derived neurons (iNs) have been widely used as models of neurodevelopment and neurodegenerative diseases. Coating cell culture vessels with extracellular matrixes (ECMs) gives structural support and facilitates cell communication and differentiation, ultimately enhances neuronal functions. However, the relevance of different ECMs to the natural environment and their impact on neuronal differentiation have not been fully characterized. In this study, we report the use of four commonly used extracellular matrixes, poly-D-lysine (PDL), poly-L-ornithine (PLO), Laminin and Matrigel, which we applied to compare the single-coating and double-coating conditions on iNs differentiation and maturation. Using the IncuCyte live-cell imaging system, we found that iNs cultured on single Matrigel- and Laminin-coated vessels have significantly higher density of neurite outgrowth and branch points than PLO or PDL but produce abnormal highly straight neurite outgrowth and larger cell body clumps. All the four double-coating conditions significantly reduced the clumping of neurons, in which the combination of PDL+Matrigel also enhanced neuronal purity. Double coating with PDL+Matrigel also tended to improve dendritic and axonal development and the distribution of pre and postsynaptic markers. These results demonstrate that the extracellular matrix contributes to the differentiation of cultured neurons and that double coating with PDL+Matrigel gives the best outcomes. Our study indicates that neuronal differentiation and maturation can be manipulated, to a certain extent, by adjusting the ECM recipe, and provides important technical guidance for the use of the ECM in neurological studies.
Surface Molecular Markers for the Isolation of Viable Fibroblast Subpopulations in the Female Reproductive Tract: A Comprehensive Review
Authors: Łuszczyński Krzysztof , Komorowski Michał , Soszyńska Marta , Lewandowska Paulina , Zdanowski Robert , Szafarowska Monika , Kamiński Paweł , Niemcewicz Marcin , Malejczyk Jacek , Lutyńska Anna , Ścieżyńska Aneta
Published: December 2024

Advancements in single-cell analyzis technologies, particularly single-cell RNA sequencing (scRNA-seq) and Fluorescence-Activated Cell Sorting (FACS), have enabled the analyzis of cellular diversity by providing resolutions that were not available previously. These methods enable the simultaneous analyzis of thousands of individual transcriptomes, facilitating the classification of cells into distinct subpopulations, based on transcriptomic differences, adding a new level of complexity to biomolecular and medical research. Fibroblasts, despite being one of the most abundant cell types in the human body and forming the structural backbone of tissues and organs, remained poorly characterized for a long time. This is largely due to the high morphological similarity between different types of fibroblasts and the lack of specific markers to identify distinct subpopulations. Once thought to be cells responsible solely for the synthesis of extracellular matrix (ECM) components, fibroblasts are now recognized as active participants in diverse physiological processes, including inflammation and antimicrobial responses. However, defining the molecular profile of fibroblast subpopulations remains a significant challenge. In this comprehensive review, which is based on over two thousand research articles, we focus on the identification and characterization of fibroblast subpopulations and their specific surface markers, with an emphasis on their potential as molecular targets for selective cell isolation. By analyzing surface markers, alongside intra- and extracellular protein profiles, we identified multiple fibroblast subtypes within the female reproductive system. These subtypes exhibit distinct molecular signatures and functional attributes, shaped by their anatomical localization and the surrounding physiological or pathological conditions. Our findings underscore the heterogeneity of fibroblasts and their diverse roles in various biological contexts. This improved understanding of fibroblast subpopulations paves the way for innovative diagnostic and therapeutic strategies, offering the potential for precision targeting of specific fibroblast subsets in clinical applications.
Dynamic Changes in Circulating Tumor DNA During Immunotherapy for Head and Neck Cancer: SHIZUKU-HN Study
Authors: Noji Rika , Tohyama Kohki , Nakamura Shin , Naito Takahiro , Oikawa Yu , Kuroshima Takeshi , Tomioka Hirofumi , Michi Yasuyuki , Ikeda Sadakatsu , Asakage Takahiro , Miura Masahiko , Hamamoto Yasuo , Harada Hiroyuki , Kano Yoshihito
Published: December 2024

Immune checkpoint inhibitors (ICIs) are effective in treating recurrent/metastatic head and neck squamous cell carcinoma (HNSCC), but only 20% of patients achieve durable responses. This study evaluated circulating tumor DNA (ctDNA) as a real-time biomarker for monitoring treatment response in HNSCC. The SHIZUKU-HN study prospectively collected and analyzed serial plasma samples (n = 27) from HNSCC patients undergoing ICIs, using Guardant360 to assess ctDNA variant allele frequency (VAF) and genetic mutations. Tumor volumes were quantified using 3D reconstruction of CT scans, and data from Japan’s C-CAT database (n = 2255) provided insights into ctDNA testing in HNSCC. C-CAT data showed that ctDNA testing was underutilized, performed in only 7% of head and neck cancer cases. In SHIZUKU-HN, mean VAF significantly correlated with tumor volume (Spearman’s ρ = 0.70, p = 0.001), often preceding radiographic progression. BRAF and APC mutations disappeared in partial responders, while GNAS mutations varied. EGFR and PIK3CA amplifications, detectable via ctDNA but missed in tissue biopsies, indicated emerging resistance mechanisms. The SHIZUKU-HN study demonstrates the potential of ctDNA as a dynamic biomarker in HNSCC, offering early insights into treatment efficacy and informing personalized ICI therapy.
Long-Term 5-HT1A Receptor Agonist NLX-112 Treatment Improves Functional Recovery After Spinal Cord Injury
Authors: Lin Ching-Yi , Li Kevin , Gitchell Thomas , Lee Yu-Shang
Published: December 2024

Spinal cord injury (SCI) results in functional deficits below the injured spinal level. The descending serotonergic system in the spinal cord is critically involved in the control of motor and autonomic functions. Specifically, SCI damages the projections of serotonergic fibers, which leads to reduced serotonin inputs and increased amounts of spinal serotonergic receptors. Our previous pharmacological study demonstrated that brief administration of a highly selective 5-HT1A receptor agonist, NLX-112, improves lower urinary tract (LUT) function at the termination stage of thoracic 8 (T8) contusive SCI in rats. However, whether chronic activation of serotonin 5-HT1A receptors by NLX-112 after SCI is beneficial remains an unanswered question. Here, we evaluated the efficacy of long-term NLX-112 intervention starting from two weeks post-T8 contusive SCI for an additional six weeks. We evaluated locomotion, LUT function, bladder morphology, and the number of spinal 5-HT1A receptors in both L4 and L6/S1 spinal cord segments. Our results indicate that NLX-112 treatment significantly improves locomotion in a dose-dependent fashion, improves LUT function, reduces bladder weight and bladder wall thickness, and reduces the SCI-upregulated spinal 5-HT1A receptors compared to vehicle-treated SCI animals. These data suggest promising therapeutic potential for long-term NLX-112 activation of 5-HT1A receptors to treat SCI.
Advancing Alzheimer’s Disease Modelling by Developing a Refined Biomimetic Brain Microenvironment for Facilitating High-Throughput Screening of Pharmacological Treatment Strategies
Authors: Mohd Murshid Nuraqila , Mohd Sahardi Nur Fatin Nabilah , Makpol Suzana
Published: December 2024

Alzheimer’s disease (AD) poses a significant worldwide health challenge, requiring novel approaches for improved models and treatment development. This comprehensive review emphasises the systematic development and improvement of a biomimetic brain environment to address the shortcomings of existing AD models and enhance the efficiency of screening potential drug treatments. We identify drawbacks in traditional models and emphasise the necessity for more physiologically accurate systems through an in-depth analysis of current literature. This review aims to study the development of an advanced AD model that accurately replicates key AD pathophysiological aspects using cutting-edge biomaterials and microenvironment design. Incorporating biomolecular elements like Tau proteins and beta-amyloid (Aβ) plaques improve the accuracy of illustrating disease mechanisms. The expected results involve creating a solid foundation for high-throughput screening with enhanced scalability, translational significance, and the possibility of speeding up drug discovery. Thus, this review fills the gaps in AD modelling and shows potential for creating precise and efficient drug treatments for AD.
Almond Grafting for Plum Pox Virus Resistance Triggers Significant Transcriptomic and Epigenetic Shifts in Peaches
Authors: Corell-Sierra Julia , Corrêa Régis L. , Gómez Gustavo G. , Elena Santiago F. , Oliveros Juan C. , Rodamilans Bernardo , Martínez-García Pedro J. , Martínez-Gómez Pedro , Rubio Manuel
Published: December 2024

Sharka disease, caused by the plum pox virus (PPV), negatively impacts stone fruit production, resulting in economic losses. It has been demonstrated that grafting the almond (Prunus dulcis (Miller) D.A. Webb) variety ‘Garrigues’ into susceptible peach (Prunus persica (L.) Batsch) rootstocks can result in PPV resistance. The molecular circuits related to grafting in Prunus species, however, have not been fully investigated. In this study, susceptible peach rootstocks ‘GF305’ were either heterografted with ‘Garrigues’ almond or homografted with the same cultivar. Peach samples were collected at two stages of scion development, with ungrafted plants utilized as controls. Profiles of transcripts, small RNAs (sRNAs), and DNA methylation were obtained and analyzed on a genome-wide scale. Homografting and heterografting significantly altered the transcriptome and methylome of peach rootstocks, with these modifications being more pronounced during the early stages of scion development. The profiles of sRNAs were significantly more impacted when almonds were used as a scion as opposed to peaches, likely due to the transmission of PPV-unrelated viral sequences. Gene expression differences resulting from DNA methylation alterations are more thoroughly documented at the promoter sequences of genes than within their bodies. This study suggests that the ‘Garrigues’ almond variety triggers a complex defense response in the peach rootstock, potentially involving the interplay of epigenetic modifications and small RNA-mediated priming of antiviral defenses, which ultimately may contribute to PPV resistance.
Engineered Phage Enables Efficient Control of Gene Expression upon Infection of the Host Cell
Authors: Wei Ting , Lai Wangsheng , Chen Qian , Sun Chenjian
Published: December 2024

Recently, we developed a spatial phage-assisted continuous evolution (SPACE) system. This system utilizes chemotaxis coupled with the growth of motile bacteria during their spatial range expansion in soft agar to provide fresh host cells for iterative phage infection and selection pressure for preserving evolved genes of interest carried by phage mutants. Controllable mutagenesis activated only in a subpopulation of the migrating cells is essential in this system to efficiently generate mutated progeny phages from which desired individuals are selected during the directed evolution process. But, the widely adopted small molecule-dependent inducible system could hardly fulfill this purpose because it always affects all cells homogeneously. In this study, we developed a phage infection-induced gene expression system using modified Escherichia coli (E. coli) phage shock protein operon or sigma factors from Bacillus subtilis. Results showed that this system enabled efficient control of gene expression upon phage infection with dynamic output ranges from small to large using combinations of different engineered phages and corresponding promoters. This system was incorporated into SPACE to function as a phage infection-induced mutagenesis module and successfully facilitated the evolution of T7 RNA polymerase, which generated diverse mutants with altered promoter recognition specificity. We expect that phage infection-induced gene expression system could be further extended to more applications involving partial induction in a portion of a population and targeted induction in specific strains among a mixed bacterial community, which provides an important complement to small molecule-dependent inducible systems.
The Significance of Aldehyde Dehydrogenase 1 in Cancers
Authors: Nguyen Anh L. , Facey Caroline O. B. , Boman Bruce M.
Published: December 2024

The goal of this paper is to discuss the role of ALDH isozymes in different cancers, review advances in ALDH1-targeting cancer therapies, and explore a mechanism that explains how ALDH expression becomes elevated during cancer development. ALDH is often overexpressed in cancer, and each isoform has a unique expression pattern and a distinct role in different cancers. The abnormal expression of ALDHs in different cancer types (breast, colorectal, lung, gastric, cervical, melanoma, prostate, and renal) is presented and correlated with patient prognosis. ALDH plays a significant role in various cellular functions, such as metabolism, oxidative stress response, detoxification, and cellular differentiation. Among the ALDH families, ALDH1 has gained considerable attention as a cancer stem cell (CSC) marker due to its significant role in the maintenance of stemness and the differentiation of stem cells (SCs), along with its involvement in tumorigenesis. A description of the cellular mechanisms and physiology of ALDH1 that underlies cancer development is provided. Moreover, current advances in ALDH1-targeting cancer therapies are discussed.
The Role and Mechanisms of the Hypocretin System in Zebrafish (Danio rerio)
Authors: Dyachuk Vyacheslav
Published: December 2024

Sleep is the most important physiological function of all animals studied to date. Sleep disorders include narcolepsy, which is characterized by excessive daytime sleepiness, disruption of night sleep, and muscle weakness—cataplexy. Narcolepsy is known to be caused by the degeneration of orexin-synthesizing neurons (hypocretin (HCRT) neurons or orexin neurons) in the hypothalamus. In mammals, HCRT neurons primarily regulate the sleep/wake cycle, nutrition, reward seeking, and addiction development. The hypocretin system of the brain is involved in a number of neurological disorders. The distinctive pathologies associated with the disruption of HCRT neurons are narcolepsy and cataplexy, which are caused by the loss of hypocretin neurons that produce HCRT. In Danio, the hypocretin system is also involved in the regulation of sleep and wakefulness. It is represented by a single hcrt gene that encodes the peptides HCRT1 and HCRT2, as well as one HCRT receptor (HCRTR), which is structurally closest to the mammalian HCRTR2. The overexpression of the hcrt gene in Danio rerio larvae causes wakefulness, whereas the physical destruction of HCRT cells or a pharmacological blockade of the type 2 hypocretin receptor leads to fragmentation of sleep in fish larvae, which is also observed in patients with narcolepsy. These data confirm the evolutionary conservatism of the hypocretin system. Thus, Danio rerio is an ideal model for studying the functions of HCRT neural networks and their functions.