bluuebunny/crossref_metadata_2025 huggingface dataset:
Research on the Impact of Economic Policy Uncertainty and Investor Sentiment on the Growth Enterprise Market Return in China—An Empirical Study Based on TVP-SV-VAR Model
Authors: Gui Junxiao , Naktnasukanjn Nathee , Yu Xi , Ramasamy Siva Shankar
Published: October 2024

This study employs the economic policy uncertainty index to gauge the level of economic policy uncertainty in China. Utilizing textual data from the growth enterprise market internet community, we construct the growth enterprise market investor sentiment index by applying the deep learning ERNIE (Enhanced Representation through Knowledge Integration) model, thereby capturing investors’ sentiment within the growth enterprise market. The dynamic interplay between economic policy uncertainty, investor sentiment, and returns of the growth enterprise market is scrutinized via the TVP-SV-VAR (time-varying parameter stochastic volatility vector auto-regression) model, and the asymmetric response of different industries’ stock returns within the growth enterprise market to economic policy uncertainty and investor sentiment shock. The findings of this research are that economic policy uncertainty exerts a negative influence on both investor sentiment and returns of the growth enterprise market. While it may trigger a temporary decline in stock prices, the empirical evidence suggests that the impact is of short duration. The influence of investor sentiment on the growth enterprise market returns is characterized by a reversal effect, suggesting that improved sentiment may initially boost stock prices but could lead to a subsequent decline over the long term. The relationship between economic policy uncertainty, investor sentiment, and returns of the growth enterprise market is time-variant, with heightened sensitivity observed during bull markets. Lastly, the effects of economic policy uncertainty and investor sentiment on the returns of different industries within the growth enterprise market are found to be asymmetric. These conclusions contribute to the existing body of literature on the Chinese capital market, offering a deeper understanding of the complex dynamics and the factors influencing market behavior.
Mitochondrial Dysfunction in Parkinson’s Disease: A Contribution to Cognitive Impairment?
Authors: Scorziello Antonella , Sirabella Rossana , Sisalli Maria Josè , Tufano Michele , Giaccio Lucia , D’Apolito Elena , Castellano Lorenzo , Annunziato Lucio
Published: October 2024

Among the non-motor symptoms associated with Parkinson’s disease (PD), cognitive impairment is one of the most common and disabling. It can occur either early or late during the disease, and it is heterogeneous in terms of its clinical manifestations, such as Subjective Cognitive Dysfunction (SCD), Mild Cognitive Impairment (MCI), and Parkinson’s Disease Dementia (PDD). The aim of the present review is to delve deeper into the molecular mechanisms underlying cognitive decline in PD. This is extremely important to delineate the guidelines for the differential diagnosis and prognosis of the dysfunction, to identify the molecular and neuronal mechanisms involved, and to plan therapeutic strategies that can halt cognitive impairment progression. Specifically, the present review will discuss the pathogenetic mechanisms involved in the progression of cognitive impairment in PD, with attention to mitochondria and their contribution to synaptic dysfunction and neuronal deterioration in the brain regions responsible for non-motor manifestations of the disease.
Regulation of HTT mRNA Biogenesis: The Norm and Pathology
Authors: Zubkova Alexandra E. , Yudkin Dmitry V.
Published: October 2024

Huntington’s disease (HD) is a neurodegenerative disorder caused by the expansion of the CAG repeat in exon 1 of the HTT gene, leading to the formation of a toxic variant of the huntingtin protein. It is a rare but severe hereditary disease for which no effective treatment method has been found yet. The primary therapeutic targets include the mutant protein and the mutant mRNA of HTT. Current clinical trial approaches in gene therapy involve the application of splice modulation, siRNA, or antisense oligonucleotides for RNA-targeted knockdown of HTT. However, these approaches do not take into account the diversity of HTT transcript isoforms in the normal conditions and in HD. In this review, we discuss the features of transcriptional regulation and processing that lead to the formation of various HTT mRNA variants, each of which may uniquely contribute to the progression of the disease. Furthermore, understanding the role of known transcription factors of HTT in pathology may aid in the development of potentially new therapeutic tools based on endogenous regulators.
Synthesis and Structure of Novel Hybrid Compounds Containing Phthalazin-1(2H)-imine and 4,5-Dihydro-1H-imidazole Cores and Their Sulfonyl Derivatives with Potential Biological Activities
Authors: Balewski Łukasz , Gdaniec Maria , Hering Anna , Furman Christophe , Ghinet Alina , Kokoszka Jakub , Ordyszewska Anna , Kornicka Anita
Published: October 2024

A novel hybrid compound—2-(4,5-dihydro-1H-imidazol-2-yl)phthalazin-1(2H)-imine (5) was synthesized and converted into di-substituted sulfonamide derivatives 6a–o and phthalazine ring opening products—hydrazonomethylbenzonitriles 7a–m. The newly prepared compounds were characterized using elemental analyses, IR and NMR spectroscopy, as well as mass spectrometry. Single crystal X-ray diffraction data were collected for the representative compounds 5, 6c, 6e, 7g, and 7k. The antiproliferative activity of compound 5, sulfonyl derivatives 6a–o and benzonitriles 7a–m was evaluated on approximately sixty cell lines within nine tumor-type subpanels, including leukemia, lung, colon, CNS, melanoma, ovarian, renal, prostate, and breast. None of the tested compounds showed any activity against the cancer cell lines used. The antioxidant properties of all compounds were assessed using the DPPH, ABTS, and FRAP radical scavenging methods, as well as the β-carotene bleaching test. Antiradical tests revealed that among the investigated compounds, a moderate ABTS antiradical effect was observed for sulfonamide 6j (IC50 = 52.77 µg/mL). Benzonitrile 7i bearing two chlorine atoms on a phenyl ring system showed activity in a β-carotene bleaching test (IC50 = 86.21 µg/mL). Finally, the interaction AGE/RAGE in the presence of the selected phthalazinimines 6a, 6b, 6g, 6m, and hydrazonomethylbenzonitriles 7a, 7c–g, and 7i–k was determined by ELISA assay. A moderate inhibitory potency toward RAGE was found for hydrazonomethylbenzonitriles—7d with an electron-donating methoxy group (R = 3-CH3O-C6H4) and 7f, 7k with an electron-withdrawing substituent (7f, R = 2-Cl-C6H4; 7k, R = 4-NO2-C6H4).
Comparative Metabolome and Transcriptome Analysis Reveals the Possible Roles of Rice Phospholipase A Genes in the Accumulation of Oil in Grains
Authors: Cao Huasheng , Gong Rong , Xiong Liang , Wang Fujun , Gu Haiyong , Li Shuguang , He Gao , Liang Shihu , Luo Wenyong , Qiu Xianjin
Published: October 2024

The phospholipase A (PLA) gene family plays a crucial role in the regulation of plant growth, development and stress response. Although PLA genes have been identified in various plant species, their specific functions and characteristics in oil quality formation of rice grains (Oryza sativa L.) have not been studied yet. Here, we identified and characterized 35 rice PLA genes, which were divided into three subgroups based on gene structures and phylogenetic relationships. These genes are distributed unevenly across 11 rice chromosomes. The promoter sequence of rice PLAs contain multiple plant hormones and stress-related elements. Gene expression analyses in various tissues and under stress conditions indicated that PLAs may be involved in rice growth, development and stress response. In addition, metabolomics, transcriptomics and qRT-PCR analyses between two rice varieties Guang8B (G8B, high oil content) and YueFengB (YFB, low oil content) revealed that the different expressional levels of rice PLA genes were closely related to the differences in the oil content between ‘G8B’ and ‘YFB’ grains. The findings of this study provide potential novel insights into the molecular information of the phospholipase A gene family in rice, and underscore the potential functions of PLA genes in rice oil content accumulation, providing valuable resources for future genetic improvement and breeding strategies.
Dairy: Friend or Foe? Bovine Milk-Derived Extracellular Vesicles and Autoimmune Diseases
Authors: Ou Hairui , Csuth Tamas Imre , Czompoly Tamas , Kvell Krisztian
Published: October 2024

Due to the availability, scalability, and low immunogenicity, bovine milk-derived extracellular vesicles (MEVs) are increasingly considered to be a promising carrier of nanomedicines for future therapy. However, considering that extracellular vesicles (EVs) are of biological origin, different sources of EVs, including the host origin and the specific cells that produce the EVs, may have different effects on the structure and function of EVs. Additionally, MEVs play an important role in immune regulation, due to their evolutionary conserved cargo, such as cytokines and miRNAs. Their potential effects on different organs, as well as their accumulation in the human body, should not be overlooked. In this review, we have summarized current impacts and research progress brought about by utilizing MEVs as nano-drug carriers. Nevertheless, we also aim to explore the possible connections between the molecules involved in cellular immunity, cytokines and miRNAs of MEVs produced under different health conditions, and autoimmune diseases.
Amelanotic Melanoma—Biochemical and Molecular Induction Pathways
Authors: Misiąg Piotr , Molik Klaudia , Kisielewska Monika , Typek Paulina , Skowron Izabela , Karwowska Anna , Kuźnicki Jacek , Wojno Aleksandra , Ekiert Marcin , Choromańska Anna
Published: October 2024

Amelanotic melanoma (AM) is a subtype of hypomelanotic or completely amelanotic melanoma. AM is a rare subtype of melanoma that exhibits a higher recurrence rate and aggressiveness as well as worse surveillance than typical melanoma. AM shows a dysregulation of melanin production, cell cycle control, and apoptosis pathways. Knowing these pathways has an application in medicine due to targeted therapies based on the inhibiting elements of the abovementioned pathways. Therefore, we summarized and discussed AM biochemical and molecular induction pathways and personalized medicine approaches, clinical management, and future directions due to the fact that AM is relatively rare. AM is commonly misdiagnosed. Hence, the role of biomarkers is becoming significant. Nonetheless, there is a shortage of biomarkers specific to AM. BRAF, NRAS, and c-KIT genes are the main targets of therapy. However, the role of BRAF and KIT in AM varied among studies. BRAF inhibitors combined with MAK inhibitors demonstrate better results. Immune checkpoint inhibitors targeting CTLA-4 combined with a programmed death receptor 1 (PD-1) show better outcomes than separately. Fecal microbiota transplantation may overcome resistance to immune checkpoint therapy of AM. Immune-modulatory vaccines against indoleamine 2,3-dioxygenase (IDO) and PD ligand (PD-L1) combined with nivolumab may be efficient in melanoma treatment.
Effects of Target of Rapamycin and Phosphatidylinositol 3-Kinase Inhibitors and Other Autophagy-Related Supplements on Life Span in y w Male Drosophila melanogaster
Authors: Bearden Aaron A. , Stewart Emily M. , Casher Candace C. , Shaddix Meredith A. , Nobles Amber C. , Mockett Robin J.
Published: October 2024

Various dietary supplements have been shown to extend the life span of Drosophila melanogaster, including several that promote autophagy, such as rapamycin and spermidine. The goal of the study presented here was to test numerous additional potential anti-aging supplements, primarily inhibitors of the target of rapamycin (TOR) and/or phosphatidylinositol 3-kinase (PI3K). Using a single, comparatively long-lived y w test strain, screening was performed in male flies supplemented either throughout adulthood or, in a few cases, beginning in middle or late adult life, with concentrations spanning 4–6 orders of magnitude in most cases. Supplementation with PP242 and deferiprone, an iron chelator, beginning in late adult life had no positive effect on life span. Lifelong supplementation with Ku-0063794, LY294002, PX-866-17OH, Torin2 and WYE-28 had no effect at any dose. Rapamycin, spermidine and wortmannin all had significant life-shortening effects at the highest doses tested. AZD8055, PI-103 hydrochloride and WYE-132 yielded slight beneficial effects at 1–2 doses, but only 100 nM AZD8055 was confirmed to have a minor (1.3%) effect in a replicate experiment, which was encompassed by other control groups within the same study. These compounds had no effect on fly fecundity (egg laying) or fertility (development of progeny to adulthood), but equivalent high doses of rapamycin abolished fertility. The solvent DMSO had no significant effect on life span at the concentrations used to solubilize most compounds in the fly medium, but it drastically curtailed both survival and fertility at higher concentrations. 2-Hydroxypropyl-β-cyclodextrin also failed to extend the life span when provided throughout adulthood or beginning in mid-adult life. Collectively, the results suggest that inhibition of the TOR/PI3K pathway and autophagy through dietary intervention is not a straightforward anti-aging strategy in Drosophila and that further extension of life is difficult in comparatively long-lived flies.
Treatment of Oroantral Communication and Fistulas with the Use of Blood-Derived Platelet-Rich Preparations Rich in Growth Factors: A Systematic Review
Authors: Adamska Paulina , Kaczoruk-Wieremczuk Magdalena , Pylińska-Dąbrowska Dorota , Stasiak Marcin , Bartmański Michał , Zedler Adam , Studniarek Michał
Published: October 2024

The formation of an oroantral communication (OAC) or fistula (OAF) is a rare complication resulting from the presence of processes in the lateral parts of the maxilla or for iatrogenic reasons. The most common causes of OAC or OAF are tooth extraction with periapical lesions. The aims of this systematic review were to assess the use of platelet-derived preparations rich in growth factors in the treatment of OAC or OAF, to determine the success of treating the communication or fistula, as well as impact on postoperative complications and the course of healing. The study was performed following PRISMA guidelines (PROSPERO: CRD42024570758). The inclusion criteria were as follows: at least ten patients, the presence of oroantral communication or oroantral fistula, treatment with platelet-derived preparations rich in growth factors, and information regarding the response to treatment. In order to find relevant studies, international databases, including PubMed, Google Scholar, Web of Science Core Collection, MDPI, Wiley, and Cochrane Library were searched. The last search was performed on 31 August 2024. Seven articles were included in the systematic review. In total, platelet-derived preparations rich in growth factors were used in 164 patients. Only studies in which OAC was treated and with platelet-rich fibrin (PRF) met the inclusion criteria. Only PRF was used as the sole treatment method in three studies. When OAC is greater than 5 mm, platelet-derived preparations rich in growth factors should be considered adjuncts to treatment, not the sole treatment method. The success rate of OAC treatment was 90–100%. The use of blood products to close OAC may be an effective therapeutic alternative. Proper patient qualification and the use of an appropriate protocol are crucial. There is a need for future well-designed case-control or cohort studies as well as randomized controlled trials to provide the required level of evidence.
Fundamental and Practical Perspectives in Regenerative Medicine
Authors: Makarevich Pavel I. , Tkachuk Vsevolod A.
Published: October 2024

As regenerative medicine continues to advance as a growing field in modern biology and the healthcare industry, it attracts enormous interest from the general public and scientists [...]
Assessing Mild Traumatic Brain Injury-Associated Blood–Brain Barrier (BBB) Damage and Restoration Using Late-Phase Perfusion Analysis by 3D ASL MRI: Implications for Predicting Progressive Brain Injury in a Focused Review
Authors: Joseph Charles R.
Published: October 2024

Mild traumatic brain injury (mTBI) is a common occurrence around the world, associated with a variety of blunt force and torsion injuries affecting all age groups. Most never reach medical attention, and the identification of acute injury and later clearance to return to usual activities is relegated to clinical evaluation—particularly in sports injuries. Advanced structural imaging is rarely performed due to the usual absence of associated acute anatomic/hemorrhagic changes. This review targets physiologic imaging techniques available to identify subtle blood–brain barrier dysfunction and white matter tract shear injury and their association with chronic traumatic encephalopathy. These techniques provide needed objective measures to assure recovery from injury in those patients with persistent cognitive/emotional symptoms and in the face of repetitive mTBI.
ALKBH5 Protects Against Hepatic Ischemia–Reperfusion Injury by Regulating YTHDF1-Mediated YAP Expression
Authors: Wang Pixiao , Xiang Mei , Zhu Ling , Zhang Rixin , Zheng Xiaolin , Zheng Zhi , Li Kai
Published: October 2024

Ischemia/reperfusion (I/R) injury with severe cell death is a major complication involved in liver transplantation and resection. The identification of key regulators improving hepatocyte activity may provide potential strategies to clinically resolve I/R-induced injury. N6-methyladenosine (m6A) RNA modification is essential for tissue homeostasis and pathogenesis. However, the potential involvement of m6A in the regulation of hepatocyte activity and liver injury has not been fully explored. In the present study, we found that hepatocyte AlkB homolog H5 (ALKBH5) levels were decreased both in vivo and in vitro I/R models. Hepatocyte-specific ALKBH5 overexpression effectively attenuated I/R-induced liver necrosis and improved cell proliferation in mice. Mechanistically, ALKBH5-mediated m6A demethylation improved the mRNA stability of YTH N6-methyladenosine RNA-binding protein 1 (YTHDF1), thereby increasing its expression, which consequently promoted the translation of Yes-associated protein (YAP). In conclusion, ALKBH5 is a regulator of hepatic I/R injury that improves hepatocyte repair and proliferation by maintaining YTHDF1 stability and YAP content. The ALKBH5–m6A–YTHDF1–YAP axis represents promising therapeutic targets for hepatic I/R injury to improve the prognosis of liver surgery.
Cartilage Laser Engraving for Fast-Track Tissue Engineering of Auricular Grafts
Authors: Kisel Anastas A. , Stepanov Vladimir A. , Isaeva Elena V. , Demyashkin Grigory A. , Isaev Evgeny I. , Smirnova Ekaterina I. , Yatsenko Elena M. , Afonin Grigoriy V. , Ivanov Sergey A. , Atiakshin Dmitrii A. , Shegay Petr V. , Kaprin Andrey D. , Klabukov Ilya D. , Baranovskii Denis S.
Published: October 2024

In this study, the optimal engraving parameters were determined through the analysis of scanning electron microscopy (SEM) data, as follows: a laser power density of 5.5 × 105 W/cm2, an irradiation rate of 0.1 mm/s, a well radius of 60 μm, a distance between well centers of 200 μm, and a number of passes for each well of 20. After 1 week of in vitro cultivation, chondrocytes were located on the surface of the scaffolds, in the sockets and lacunae of decellularized cartilage. When implanted into animals, both cellular and acellular scaffolds were able to support cartilage in-growth and complete regeneration of the defect without clear boundaries with normal tissue. Nevertheless, the scaffolds populated with cells exhibited superior biocompatibility and were not subject to rejection, in contrast to cell-free constructs.
Research on the Molecular Mechanisms and Key Gene Discovery in Quercus variabilis Root Pruning Based on Transcriptomics and Hormone Profiling
Authors: Dou Hao , Sun Jiajia , Feng Xi , Lyu Huyang , Qin Zhen , Ni Ruoyi , Wang Yilin , Sun Huijuan , Zhou Xin , Tang Wu , Quan Jin’e , Yang Xitian
Published: October 2024

Quercus variabilis (Q. variabilis), a significant broadleaf species used in afforestation across high, sandy, and mountainous regions, presents unique challenges for transplantation. This species is characterized by its slow above-ground growth and rapid taproot development, which suppresses the proliferation of lateral and fibrous roots, negatively impacting post-transplant survival. Research indicates that targeted root pruning—specifically, the removal of one-third of the roots—promotes the development of lateral roots in these seedlings. This study involved pruning the root systems of Q. variabilis and assessing the subsequent root development in comparison to an unpruned control group. Our analysis, which included transcriptome sequencing and plant hormone metabolism assays conducted at 2, 12, and 25 days post-pruning, yielded 126.02 Gb of clean data and identified 7662 differentially expressed genes (DEGs). These genes were primarily enriched in the plant hormone signal transduction pathway. Further investigation of this pathway, along with hormone content measurements, elucidated the mechanisms that contribute to enhanced root growth following pruning. Additionally, through a weighted correlation network analysis (WGCNA), we identified 20 key genes that are instrumental in promoting root development in Q. variabilis saplings. This research advances the theoretical framework for forestry seedling production and afforestation, laying the groundwork for scientifically informed vegetation restoration techniques.
The Impact of Pentraxin 3 on Crohn’s Disease Phenotype
Authors: Kofla-Dlubacz Anna , Pawlik-Sobecka Lilla , Pytrus Tomasz , Borys-Iwanicka Agnieszka , Gorka-Dynysiewicz Joanna
Published: October 2024

Pentraxin 3 [PTX3] is an acute-phase protein playing an important role in the regulation of the humoral arm of immune response. As one of the molecules from the conservative family of pentraxins, PTX3 is a soluble mediator involved in the transduction of pro-inflammatory signals between immunocompetent cells. Additionally, recognizing damage-associated molecular patterns (DAMPs) during tissue injury mediates wound healing; therefore, its concentration potentially correlates with the severity of fibrosis. The aim of our study was to evaluate the value of the PTX3 measurement as a phenotypic marker of the stenotic form of Crohn’s disease. The research covered 63 patients, 35 with the narrowing type (B2) and 28 with the inflammatory type (B2) of CD. The mean concentrations of PTX3 in the study were as follows: 3.06 ng/mL (95% CI: 1.27–6.99) for the B1 phenotype, 4.89 ng/mL (95% CI: 2.98–13.65) for the B2 phenotype, and 3.04 ng/mL (95% CI: 1.01–4.97) for the control group. PTX3 concentrations reached the highest values in the B2 group and the lowest in the control group. The differences between the B1 and B2 groups were statistically significant at p < 0.001. The presented studies indicate the potential role of PTX3 in the monitoring of tissue remodeling and the development of fibrosis in CD.
Platelet Glycoprotein Ibα Cytoplasmic Tail Exacerbates Thrombosis During Bacterial Sepsis
Authors: Xia Yue , Sun Chenglin , Zhou Kangxi , Shen Jie , Li Jiaojiao , Huang Qiuxia , Du Jiahao , Zhang Sai , Sun Kang , Hu Renping , Yan Rong , Dai Kesheng
Published: October 2024

Septic patients, coupling severe disseminated intravascular coagulation (DIC) and thrombocytopenia, have poor prognoses and higher mortality. The platelet glycoprotein Ibα (GPIbα) is involved in thrombosis, hemostasis, and inflammation response. However, it remains unclear whether the GPIbα cytoplasmic tail regulates sepsis-mediated platelet activation and inflammation, especially in Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli) infections. Using a mouse model of S. aureus-induced bacteremia, we found that both 10 amino acids of GPIbα C-terminal sequence deficiency and pharmacologic inhibition of protein kinase C (PKC) alleviated pathogenesis by diminishing platelet activation and aggregate formation. Furthermore, the GPIbα cytoplasmic tail promoted the phagocytosis of platelets by Kupffer cells in vivo. The genetically deficient GPIbα cytoplasmic tail also downregulated inflammatory cytokines and reduced liver damage, ultimately improving the survival rate of the septic mice. Our results illustrate that the platelet GPIbα cytoplasmic domain exacerbates excessive platelet activation and inflammation associated with sepsis through a PKC-dependent pathway. Thus, our findings provide insights for the development of effective therapeutic strategies using PKC inhibitor treatment against bacterial infection.
Pan-Genome-Wide Investigation and Co-Expression Network Analysis of HSP20 Gene Family in Maize
Authors: Yan Hengyu , Du Mingzhe , Ding Jieyao , Song Di , Ma Weiwei , Li Yubin
Published: October 2024

Heat shock protein 20 (HSP20) is a diverse and functionally important protein family that plays a crucial role in plants’ tolerance to various abiotic stresses. In this study, we systematically analyzed the structural and functional characteristics of the HSP20 gene family within the Zea pan-genome. By identifying 56 HSP20 pan-genes, we revealed the variation in the number of these genes across different maize inbreds or relatives. Among those 56 genes, only 31 are present in more than 52 inbreds or relatives. Further phylogenetic analysis classified these genes into four major groups (Class A, B, C, D) and explored their diversity in subcellular localization, physicochemical properties, and the terminal structures of those HSP20s. Through collinearity analysis and Ka/Ks ratio calculations, we found that most HSP20 genes underwent purifying selection during maize domestication, although a few genes showed signs of positive selection pressure. Additionally, expression analysis showed that several HSP20 genes were significantly upregulated under high temperatures, particularly in tassels and leaves. Co-expression network analysis revealed that HSP20 genes were significantly enriched in GO terms related to environmental stress responses, suggesting that HSP20 genes not only play key roles in heat stress but may also be involved in regulating various other biological processes, such as secondary metabolism and developmental processes. These findings expand our understanding of the functions of the maize HSP20 family and provide new insights for further research into maize’s response mechanisms to environmental stresses.
Genome Sequencing Identifies 13 Novel Candidate Risk Genes for Autism Spectrum Disorder in a Qatari Cohort
Authors: Ben-Mahmoud Afif , Gupta Vijay , Abdelaleem Alice , Thompson Richard , Aden Abdi , Mbarek Hamdi , Saad Chadi , Tolefat Mohamed , Alshaban Fouad , Stanton Lawrence W. , Kim Hyung-Goo
Published: October 2024

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social communication, restricted interests, and repetitive behaviors. Despite considerable research efforts, the genetic complexity of ASD remains poorly understood, complicating diagnosis and treatment, especially in the Arab population, with its genetic diversity linked to migration, tribal structures, and high consanguinity. To address the scarcity of ASD genetic data in the Middle East, we conducted genome sequencing (GS) on 50 ASD subjects and their unaffected parents. Our analysis revealed 37 single-nucleotide variants from 36 candidate genes and over 200 CGG repeats in the FMR1 gene in one subject. The identified variants were classified as uncertain, likely pathogenic, or pathogenic based on in-silico algorithms and ACMG criteria. Notably, 52% of the identified variants were homozygous, indicating a recessive genetic architecture to ASD in this population. This finding underscores the significant impact of high consanguinity within the Qatari population, which could be utilized in genetic counseling/screening program in Qatar. We also discovered single nucleotide variants in 13 novel genes not previously associated with ASD: ARSF, BAHD1, CHST7, CUL2, FRMPD3, KCNC4, LFNG, RGS4, RNF133, SCRN2, SLC12A8, USP24, and ZNF746. Our investigation categorized the candidate genes into seven groups, highlighting their roles in cognitive development, including the ubiquitin pathway, transcription factors, solute carriers, kinases, glutamate receptors, chromatin remodelers, and ion channels.
Adipose-Derived Stromal Cells and Cancer-Associated Fibroblasts: Interactions and Implications in Tumor Progression
Authors: El Alaa Rasha S. Abo , Al-Mannai Wafaa , Darwish Nour , Al-Mansoori Layla
Published: October 2024

Adipose-derived stromal cells (ASCs) and cancer-associated fibroblasts (CAFs) play pivotal roles in the tumor microenvironment (TME), significantly influencing cancer progression and metastasis. This review explores the plasticity of ASCs, which can transdifferentiate into CAFs under the influence of tumor-derived signals, thus enhancing their secretion of extracellular matrix components and pro-inflammatory cytokines that promote tumorigenesis. We discuss the critical process of the epithelial-to-mesenchymal transition (EMT) facilitated by ASCs and CAFs, highlighting its implications for increased invasiveness and therapeutic resistance in cancer cells. Key signaling pathways, including the transforming growth factor-β (TGF-β), Wnt/β-catenin, and Notch, are examined for their roles in regulating EMT and CAF activation. Furthermore, we address the impact of epigenetic modifications on ASC and CAF functionality, emphasizing recent advances in targeting these modifications to inhibit their pro-tumorigenic effects. This review also considers the metabolic reprogramming of ASCs and CAFs, which supports their tumor-promoting activities through enhanced glycolytic activity and lactate production. Finally, we outline potential therapeutic strategies aimed at disrupting the interactions between ASCs, CAFs, and tumor cells, including targeted inhibitors of key signaling pathways and innovative immunotherapy approaches. By understanding the complex roles of ASCs and CAFs within the TME, this review aims to identify new therapeutic opportunities that could improve patient outcomes in cancer treatment.
Prenatal Opioid and Alcohol Exposures: Association with Altered Placental Serotonin Transporter Structure and/or Expression
Authors: Darbinian Nune , Merabova Nana , Tatevosian Gabriel , Adele Sandra , Darbinyan Armine , Morrison Mary F. , DeVane C. Lindsay , Ramamoorthy Sammanda , Goetzl Laura , Selzer Michael E.
Published: October 2024

Fetal exposures to many drugs of abuse, e.g., opioids and alcohol (EtOH), are associated with adverse neurodevelopmental problems in early childhood, including abnormalities in activity of the serotonin (5HT) transporter (SERT), which transports 5HT across the placenta. Little is known about the effects of these drugs on SERT expression. Pregnant women who used EtOH or opioids were compared to gestational age-matched controls using a structured questionnaire to determine prenatal substance exposure. Following elective pregnancy termination, placental membranous vesicles and exosomes were prepared from first and second trimester human placentas. Changes in EtOH- or opioid-exposed placental SERT expression and modifications were assessed by quantitative western blot. Novel SERT isoforms were sequenced and analyzed. Opioid-exposed but not EtOH-exposed maternal placentas showed SERT cleavage and formation of new SERT fragments (isoforms). Alcohol-exposed cases showed reduced SERT levels. Antibodies to the N-terminal SERT region did not recognize either of the two cleavage products, while antibodies to the central and C-terminal regions recognized both bands. The secondary band seen in the opioid group may represent a hypophosphorylated SERT fragment. These changes in SERT modifications and expression may result in altered fetal brain serotonergic neurotransmission, which could have neurodevelopmental implications.
High-Level Production of a Recombinant Protein in Nicotiana benthamiana Leaves Through Transient Expression Using a Double Terminator
Authors: Lee Jihyea , Lee Kyeong-Ryeol , Kim Nan-Sun , Lee Juho , Lee Seon-Kyeong , Lee Sichul
Published: October 2024

Various bio-based recombinant proteins have been produced for industrial, medical, and research purposes. Plants are potential platforms for recombinant protein production because of several advantages. Therefore, establishing a system with high target gene expression to compensate for the low protein yield of plant systems is crucial. In particular, selecting and combining strong terminators is essential because the expression of target genes can be substantially enhanced. Here, we aimed to quantify the enhancement in the fluorescence intensity of the turbo green fluorescence protein (tGFP) caused by the best double-terminator combinations compared to that of the control vector using agroinfiltration in Nicotiana benthamiana leaves. tGFP fluorescence increased by 4.1-fold in leaf samples infiltrated with a vector containing a double terminator and markedly increased by a maximum of 23.7-fold when co-infiltrated with the geminiviral vector and P19 compared to that in constructs containing an octopine synthase terminator. Polyadenylation site analysis in leaf tissues expressing single or dual terminators showed that the first terminator influenced the polyadenylation site determination of the second terminator, resulting in different polyadenylation sites compared with when the terminator is located first. The combination of the high-expression terminators and geminiviral vectors can increase the production of target proteins.
Selenopolysaccharide Isolated from Lentinula edodes Mycelium Affects Human T-Cell Function
Authors: Kaleta Beata , Zielniok Katarzyna , Roszczyk Aleksander , Turło Jadwiga , Zagożdżon Radosław
Published: October 2024

Lentinula edodes polysaccharides are natural immunomodulators. SeLe30, analyzed in this study, is a new mixture of selenium-enriched linear 1,4-α-glucans and 1,3-β- and 1,6-β-glucans isolated from L. edodes mycelium. In the present study, we evaluated its immunomodulatory properties in human T cells. Peripheral blood mononuclear cells (PBMCs) and T cells were isolated from healthy donors’ buffy coats. The effects of SeLe30 on CD25, CD366, and CD279 expression, the subsets of CD8+ T cells, and IFN-γ, IL-6, and TNF-α production were analyzed. SeLe30 downregulated CD25, CD279, and CD366 expression on T cells stimulated by the anti-CD3 antibody (Ab) and upregulated in unstimulated and anti-CD3/CD28-Abs-stimulated T cells. It increased the percentage of central memory CD8+ T cells in unstimulated PBMCs and naïve and central memory T cells in anti-CD3-Ab-stimulated PBMCs. SeLe30 decreased the number of central memory and naïve CD8+ T cells in anti-CD3/CD28-stimulated T cells, whereas, in PBMCs, it reduced the percentage of effector memory CD8+ T cells. Moreover, SeLe30 upregulated cytokine production. SeLe30 exhibits context-dependent effects on T cells. It acts on unstimulated T cells, affecting their activation while increasing the expression of immune checkpoints, which sensitizes them to inhibitory signals that can silence this activation. In the case of a lack of costimulation, SeLe30 exhibits an inhibitory effect, reducing T-cell activation. In cells stimulated by dual signals, its effect is further enhanced, again increasing the “safety brake” of CD366 and CD279. However, the final SeLe30 effect is mediated by its indirect impacts by altering interactions with other immune cells.
An Update on Molecular Mechanisms of Scarring—A Narrative Review
Authors: Kohlhauser Michael , Mayrhofer Marcel , Kamolz Lars-Peter , Smolle Christian
Published: October 2024

Fibroblasts, the principal cellular mediators of connective tissue remodeling, play a crucial role in the formation of physiological and pathological scars. Understanding the intricate interplay between fibroblasts and other cellular and molecular components is essential for elucidating the underlying mechanisms driving scar formation. Hypertrophic scars, keloids and atrophic scars arise from dysregulated wound healing processes characterized by persistent inflammation, aberrant collagen deposition, and impaired extracellular matrix remodeling. Fibroblasts play a central role in the pathogenesis of such pathological scars, driving aberrant extracellular matrix remodeling, subsequently contributing to the formation of raised or depressed fibrotic lesions. The investigation of complex interactions between fibroblasts and the microenvironment is crucial for developing targeted therapeutic interventions aimed at modulating fibroblast activity and improving clinical outcomes in patients with pathological scars. Further research into the molecular pathways governing fibroblast behavior and their heterogeneity holds promise for advancing scar management strategies. This narrative review was performed to shed light on the mechanisms behind scar formation, with a special focus on the role of fibroblasts in the formation of different types of scars, providing insights into the pathophysiology of these conditions. Through the analysis of current knowledge, this review seeks to identify the key cellular and molecular mechanisms involved in fibroblast activation, collagen synthesis, and extracellular matrix remodeling in hypertrophic scar, keloid, or atrophic scar formation.
The Key Role of 3D TEE in Assessing the Morphology of Degenerative Mitral Valve Regurgitation
Authors: Faletra Francesco Fulvio , La Franca Eluisa , Leo Laura Anna , Sade Leyla Elif , Katz William , Musumeci Francesco , Gandolfo Caterina , Pilato Michele , Cipriani Manlio
Published: October 2024

Two-dimensional transthoracic echocardiography (2D TTE) and two-dimensional transesophageal echocardiography (2D TEE) are regarded as the main imaging techniques for the assessment of degenerative mitral valve regurgitation (DMVR). However, describing the complex morphology of DMVR with 2D TTE and 2D TEE remains at the very least challenging. Three-dimensional (3D) TEE is an ideal technique for illustrating the extremely variable morphology of DMVR, providing images of unparalleled quality in terms of anatomical detail. In this review, we describe the key role of 3D TEE in various morphological scenarios that reflect everyday experiences in an echocardiographic laboratory. We also discuss the growing role of 3D TEE in mitral valve (MV) transcatheter edge-to-edge repair (TEER) and new modalities such as photorealistic and transparent displays, surface rendering parametric color maps, new algorithms for MVR quantification, and the potential role of new mini-TEE probes in adult patients with DMVR.
Updates in Immunotherapy for Pancreatic Cancer
Authors: Chick Robert Connor , Pawlik Timothy M.
Published: October 2024

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited effective therapeutic options. Due to a variety of cancer cell-intrinsic factors, including KRAS mutations, chemokine production, and other mechanisms that elicit a dysregulated host immune response, PDAC is often characterized by poor immune infiltration and an immune-privileged fibrotic stroma. As understanding of the tumor microenvironment (TME) evolves, novel therapies are being developed to target immunosuppressive mechanisms. Immune checkpoint inhibitors have limited efficacy when used alone or with radiation. Combinations of immune therapies, along with chemotherapy or chemoradiation, have demonstrated promise in preclinical and early clinical trials. Despite dismal response rates for immunotherapy for metastatic PDAC, response rates with neoadjuvant immunotherapy are somewhat encouraging, suggesting that incorporation of immunotherapy in the treatment of PDAC should be earlier in the disease course. Precision therapy for PDAC may be informed by advances in transcriptomic sequencing that can identify immunophenotypes, allowing for more appropriate treatment selection for each individual patient. Personalized and antigen-specific therapies are an increasing topic of interest, including adjuvant immunotherapy using personalized mRNA vaccines to prevent recurrence. Further development of personalized immune therapies will need to balance precision with generalizability and cost.
The Association of Myocardial Infarction History and Geriatric Syndromes in the Elderly: Data from the Cross-Sectional Study EVKALIPT
Authors: Zakiev Vadim , Vorobyeva Natalya , Malaya Irina , Kotovskaya Yulia , Tkacheva Olga
Published: October 2024

Background/Objectives: In recent decades, the number of patients with chronic cardiovascular diseases (CVDs) has increased, and CVD survivors are more likely to be old and frail and to have multiple comorbidities. A better understanding of geriatric conditions and their prevalence would help improve the management of older patients with CVDs. The main objective of this study is to estimate the association of myocardial infarction (MI) history with geriatric syndromes (GSs) in people 65 years of age and older. Methods: The cross-sectional study EVKALIPT included patients who were 65 years of age and older. All patients underwent a comprehensive geriatric assessment. The presence of MI history was assessed by medical records. Results: A total of 4295 participants were included. The prevalence of MI history was 12.6%. According to univariate regression analysis, MI history was associated with an increase in the odds of 12 GSs by 1.3–2.4 times. Multivariate regression analysis showed that male sex and four GSs (impairment in basic and instrumental activities of daily living, depression, falls) were independently associated with a history of MI, with the odds ratio ranging from 1.28 to 1.86. Conclusions: This study showed the association between MI history and GSs.
The Interaction Effect of Age, Initial Rhythm, and Location on Outcomes After Out-of-Hospital Cardiac Arrest: A Retrospective Cohort Study
Authors: Lewandowski Łukasz , Mickiewicz Aleksander , Kędzierski Kamil , Wróblewski Paweł , Koral Mariusz , Kubielas Grzegorz , Smereka Jacek , Czapla Michał
Published: October 2024

Background: Out-of-hospital cardiac arrest (OHCA) is a critical global health challenge and a leading cause of mortality. This study investigates the combined effect of initial cardiac arrest rhythm, patient age, and location on the return of spontaneous circulation (ROSC) in OHCA patients. Methods: This retrospective study analyzed medical records from the National Emergency Medical Service (EMS) in Poland between January 2021 and June 2022. Data from 33,636 patients with OHCA who received cardiopulmonary resuscitation (CPR) at the scene were included. Results: Public incidents were associated with higher ROSC rates (54.10% vs. 31.53%, p < 0.001). Initial shockable rhythms (VF/pVT) significantly increased the odds of ROSC (OR = 3.74, 95% CI 3.39–4.13, p < 0.001). Obesity decreased the odds of ROSC in at-home cases (OR = 0.85, 95% CI 0.73–0.99, p = 0.036) but had no significant effect in public cases. The effect of age on ROSC outcomes varied significantly depending on the location. In patients younger than 60 years, better ROSC outcomes were observed in at-home cases, while for those older than 60 years, the odds of ROSC were higher in public locations. Each additional year of age decreased the odds of ROSC by 1.62% in at-home incidents (p < 0.001) and by 0.40% in public incidents (p = 0.009). Sex differences were significant in public locations, with women having higher odds of ROSC compared to men (OR = 0.57, 95% CI 0.37–0.87, p = 0.009 for VF/pVT). Conclusions: The interaction between the location of OHCA, initial cardiac rhythm, and patient age significantly impacts ROSC outcomes. Public locations show higher ROSC rates, especially in cases with shockable rhythms (VF/pVT). Age modifies ROSC outcomes, with younger patients benefiting more at home, and older patients showing better outcomes in public places.
Biomimetic Curcumin-Loaded Liposomes for the Treatment of Dry Eyes and Meibomian Gland Dysfunction: An In Vivo Study
Authors: Baranauskas Vytautas , Jaruseviciene Ruta , Grigalavicius Mantas , Galgauskas Saulius , Karabanovas Vitalijus , Steponkiene Simona
Published: October 2024

Background/Objectives: Meibomian gland dysfunction (MGD) and dry eye syndrome (DES) are common eye diseases characterized by altered tear film stability and inflammation of the ocular surface, causing significant discomfort and possible visual impairment. This study aimed to investigate the efficacy of curcumin-loaded liposomes (Lipo@Cur) compared to cyclosporine A-loaded liposomes (Lipo@CycA) in experimental rabbit models of MGD and DES, with a focus on their ability to improve tear film stability and reduce ocular surface inflammation. Methods: MGD and DES were induced using complete Freund’s adjuvant (CFA) and treated to evaluate the effect of liposomal formulations on tear break-up time (TBUT), clinical signs of inflammation (telangiectasia, conjunctival hyperemia, meibomian foramen occlusion), and corneal as well as conjunctival histological cells. Results: Lipo@Cur increased TBUT and reduced the signs of ocular surface inflammation, potentially approaching the effectiveness of clinically approved cyclosporine A encapsulated in liposomes (Lipo@CycA). Histological analysis suggested improvements in corneal epithelial thickness and goblet cell density in the treated groups, which may indicate a reversal of DES-induced damage to the ocular surface. Conclusions: Plant-originated curcumin encapsulated in liposomes offers a promising therapeutic strategy for the management of MGD and DES that may improve patient outcomes by addressing the underlying inflammatory mechanisms of these conditions.
A New Objective Diagnostic Tool for Attention-Deficit Hyper-Activity Disorder (ADHD): Development of the Distractor-Embedded Auditory Continuous Performance Test
Authors: Özaslan Ahmet , Sevri Mehmet , İşeri Elvan , Karacan Barış , Cengiz Mehmet , Karacan Hacer , Sarıpınar Esin Gökçe , Dikmen Asiye Uğraş , Güney Esra
Published: October 2024

Background/Objectives: Attention-Deficit Hyperactivity Disorder (ADHD) is a prevalent neurodevelopmental disorder characterized by inattention, hyperactivity, and impulsivity. Traditional diagnostic methods, which depend on subjective assessments, often lack precision. This study evaluates the validity and reliability of a newly developed diagnostic tool, the Distractor-Embedded Auditory Continuous Performance Test (da-CPT), which integrates auditory stimuli with distractors to enhance the clinical utility of ADHD diagnosis. Methods: The study included 160 children aged 6–12 years, comprising 80 with a confirmed ADHD diagnosis and 80 controls. All participants completed the da-CPT, a web-based tool designed to assess inattention, hyperactivity, impulsivity, and timing via an auditory-based task. To validate the da-CPT, participants also completed the Conners’ Parent Rating Scale—Revised Short Form (CPRS-R) and either the MOXO or IVA-2 tests. Data were analyzed using ROC curves and statistical correlations to assess sensitivity, specificity, and overall diagnostic accuracy. Results: The da-CPT demonstrated high diagnostic accuracy, with a sensitivity of 91.25% and specificity of 83.75%. ROC analysis indicated that the inattention index had the highest discriminatory power (AUC = 0.881), followed by timing, impulsivity, and hyperactivity (all p < 0.01). Furthermore, the da-CPT scores were strongly correlated with ADHD severity (p < 0.01). Conclusions: This study confirms that the da-CPT is a valid and reliable tool for diagnosing ADHD in children aged 6–12. By incorporating auditory stimuli and distractors, the tool offers a more ecologically valid assessment of ADHD symptoms in clinical settings, improving diagnostic precision and utility.