bluuebunny/crossref_metadata_2025 huggingface dataset:
An Overview of the Epigenetic Modifications in the Brain under Normal and Pathological Conditions
Authors: Lossi Laura , Castagna Claudia , Merighi Adalberto
Published: March 2024

Epigenetic changes are changes in gene expression that do not involve alterations to the DNA sequence. These changes lead to establishing a so-called epigenetic code that dictates which and when genes are activated, thus orchestrating gene regulation and playing a central role in development, health, and disease. The brain, being mostly formed by cells that do not undergo a renewal process throughout life, is highly prone to the risk of alterations leading to neuronal death and neurodegenerative disorders, mainly at a late age. Here, we review the main epigenetic modifications that have been described in the brain, with particular attention on those related to the onset of developmental anomalies or neurodegenerative conditions and/or occurring in old age. DNA methylation and several types of histone modifications (acetylation, methylation, phosphorylation, ubiquitination, sumoylation, lactylation, and crotonylation) are major players in these processes. They are directly or indirectly involved in the onset of neurodegeneration in Alzheimer’s or Parkinson’s disease. Therefore, this review briefly describes the roles of these epigenetic changes in the mechanisms of brain development, maturation, and aging and some of the most important factors dynamically regulating or contributing to these changes, such as oxidative stress, inflammation, and mitochondrial dysfunction.
Chemokine Fractalkine and Non-Obstructive Coronary Artery Disease—Is There a Link?
Authors: Stangret Aleksandra , Sadowski Karol Artur , Jabłoński Konrad , Kochman Janusz , Opolski Grzegorz , Grabowski Marcin , Tomaniak Mariusz
Published: March 2024

Non-obstructive coronary artery disease (NO-CAD) constitutes a heterogeneous group of conditions collectively characterized by less than 50% narrowing in at least one major coronary artery with a fractional flow reserve (FFR) of ≤0.80 observed in coronary angiography. The pathogenesis and progression of NO-CAD are still not fully understood, however, inflammatory processes, particularly atherosclerosis and microvascular dysfunction are known to play a major role in it. Chemokine fractalkine (FKN/CX3CL1) is inherently linked to these processes. FKN/CX3CL1 functions predominantly as a chemoattractant for immune cells, facilitating their transmigration through the vessel wall and inhibiting their apoptosis. Its concentrations correlate positively with major cardiovascular risk factors. Moreover, promising preliminary results have shown that FKN/CX3CL1 receptor inhibitor (KAND567) administered in the population of patients with ST-elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI), inhibits the adverse reaction of the immune system that causes hyperinflammation. Whereas the link between FKN/CX3CL1 and NO-CAD appears evident, further studies are necessary to unveil this complex relationship. In this review, we critically overview the current data on FKN/CX3CL1 in the context of NO-CAD and present the novel clinical implications of the unique structure and function of FKN/CX3CL1 as a compound which distinctively contributes to the pathomechanism of this condition.
Machine Learning-Based Characterization and Identification of Tertiary Lymphoid Structures Using Spatial Transcriptomics Data
Authors: Li Songyun , Wang Zhuo , Huang Hsien-Da , Lee Tzong-Yi
Published: March 2024

Tertiary lymphoid structures (TLSs) are organized aggregates of immune cells in non-lymphoid tissues and are associated with a favorable prognosis in tumors. However, TLS markers remain inconsistent, and the utilization of machine learning techniques for this purpose is limited. To tackle this challenge, we began by identifying TLS markers through bioinformatics analysis and machine learning techniques. Subsequently, we leveraged spatial transcriptomic data from Gene Expression Omnibus (GEO) and built two support vector classifier models for TLS prediction: one without feature selection and the other using the marker genes. The comparable performances of these two models confirm the efficacy of the selected markers. The majority of the markers are immunoglobulin genes, demonstrating their importance in the identification of TLSs. Our research has identified the markers of TLSs using machine learning methods and constructed a model to predict TLS location, contributing to the detection of TLS and holding the promising potential to impact cancer treatment strategies.
Specific IgE and Basophil Activation Test by Microarray: A Promising Tool for Diagnosis of Platinum Compound Hypersensitivity Reactions
Authors: Fernández-Lozano Carlos , Rita Claudia Geraldine , Barra-Castro Alicia , de la Hoz Caballer Belén , Roldán Ernesto , Pueyo López Cristina , Martinez-Botas Javier , Berges-Gimeno María Pilar
Published: March 2024

Drug hypersensitivity reactions (DHRs) to platinum-based compounds (PCs) are on the rise, and their personalized and safe management is essential to enable first-line treatment for these cancer patients. This study aimed to evaluate the usefulness of the basophil activation test by flow cytometry (BAT-FC) and the newly developed sIgE-microarray and BAT-microarray in diagnosing IgE-mediated hypersensitivity reactions to PCs. A total of 24 patients with DHRs to PCs (20 oxaliplatin and four carboplatin) were evaluated: thirteen patients were diagnosed as allergic with positive skin tests (STs) or drug provocation tests (DPTs), six patients were diagnosed as non-allergic with negative STs and DPTs, and five patients were classified as suspected allergic because DPTs could not be performed. In addition, four carboplatin-tolerant patients were included as controls. The BAT-FC was positive in 2 of 13 allergic patients, with a sensitivity of 15.4% and specificity of 100%. However, the sIgE- and BAT-microarray were positive in 11 of 13 DHR patients, giving a sensitivity of over 84.6% and a specificity of 90%. Except for one patient, all samples from the non-allergic and control groups were negative for sIgE- and BAT-microarray. Our experience indicated that the sIgE- and BAT-microarray could be helpful in the endophenotyping of IgE-mediated hypersensitivity reactions to PCs and may provide an advance in decision making for drug provocation testing.
Alzheimer’s Amyloid Hypothesis and Antibody Therapy: Melting Glaciers?
Authors: Høilund-Carlsen Poul F. , Alavi Abass , Castellani Rudolph J. , Neve Rachael L. , Perry George , Revheim Mona-Elisabeth , Barrio Jorge R.
Published: March 2024

The amyloid cascade hypothesis for Alzheimer’s disease is still alive, although heavily challenged. Effective anti-amyloid immunotherapy would confirm the hypothesis’ claim that the protein amyloid-beta is the cause of the disease. Two antibodies, aducanumab and lecanemab, have been approved by the U.S. Food and Drug Administration, while a third, donanemab, is under review. The main argument for the FDA approvals is a presumed therapy-induced removal of cerebral amyloid deposits. Lecanemab and donanemab are also thought to cause some statistical delay in the determination of cognitive decline. However, clinical efficacy that is less than with conventional treatment, selection of amyloid-positive trial patients with non-specific amyloid-PET imaging, and uncertain therapy-induced removal of cerebral amyloids in clinical trials cast doubt on this anti-Alzheimer’s antibody therapy and hence on the amyloid hypothesis, calling for a more thorough investigation of the negative impact of this type of therapy on the brain.
Stress-Induced Changes in Nucleocytoplasmic Localization of Crucial Factors in Gene Expression Regulation
Authors: Khamit Ali , Chakraborty Payal , Zahorán Szabolcs , Villányi Zoltán , Orvos Hajnalka , Hermesz Edit
Published: March 2024

This study investigates the toxic effect of harmful materials, unfiltered by the placenta, on neonatal umbilical cord (UC) vessels, focusing on stress-induced adaptations in transcriptional and translational processes. It aims to analyze changes in pathways related to mRNA condensate formation, transcriptional regulation, and DNA damage response under maternal smoking-induced stress. UC vessels from neonates born to smoking (Sm) and nonsmoking mothers (Ctr) were examined. Immunofluorescence staining and confocal microscopy assessed the localization of key markers, including Transcription Complex Subunit 1 (CNOT1) and the largest subunit of RNA polymerase II enzyme (RPB1). Additionally, markers of DNA damage response, such as Poly(ADP-ribose) polymerase-1, were evaluated. In Sm samples, dissolution of CNOT1 granules in UC vessels was observed, potentially aiding stalled translation and enhancing transcription via RPB1 assembly and translocation. Control vessels showed predominant cytoplasmic RPB1 localization. Despite adaptive responses, Sm endothelial cells exhibited significant damage, indicated by markers like Poly(ADP-ribose) polymerase-1. Ex vivo metal treatment on control vessels mirrored Sm sample alterations, emphasizing marker roles in cell survival under toxic exposure. Maternal smoking induces specific molecular adaptations in UC vessels, affecting mRNA condensate formation, transcriptional regulation, and DNA damage response pathways. Understanding these intricate molecular mechanisms could inform interventions to improve neonatal health outcomes and mitigate adverse effects of toxic exposure during pregnancy.
Reprogramming Chromosome Ends by Functional Histone Acetylation
Authors: Meltzer W. Alex , Gupta Aditi , Lin Phyo Nay , Brown Robert A. , Benyamien-Roufaeil Daniel S. , Khatri Raju , Mahurkar Anup A. , Song Yang , Taylor Rodney J. , Zalzman Michal
Published: March 2024

Cancers harness embryonic programs to evade aging and promote survival. Normally, sequences at chromosome ends called telomeres shorten with cell division, serving as a countdown clock to limit cell replication. Therefore, a crucial aspect of cancerous transformation is avoiding replicative aging by activation of telomere repair programs. Mouse embryonic stem cells (mESCs) activate a transient expression of the gene Zscan4, which correlates with chromatin de-condensation and telomere extension. Head and neck squamous cell carcinoma (HNSCC) cancers reactivate ZSCAN4, which in turn regulates the phenotype of cancer stem cells (CSCs). Our study reveals a new role for human ZSCAN4 in facilitating functional histone H3 acetylation at telomere chromatin. Next-generation sequencing indicates ZSCAN4 enrichment at telomere chromatin. These changes correlate with ZSCAN4-induced histone H3 acetylation and telomere elongation, while CRISPR/Cas9 knockout of ZSCAN4 leads to reduced H3 acetylation and telomere shortening. Our study elucidates the intricate involvement of ZSCAN4 and its significant contribution to telomere chromatin remodeling. These findings suggest that ZSCAN4 induction serves as a novel link between ‘stemness’ and telomere maintenance. Targeting ZSCAN4 may offer new therapeutic approaches to effectively limit or enhance the replicative lifespan of stem cells and cancer cells.
Association between Parkinson’s Disease and Cancer: New Findings and Possible Mediators
Authors: Surguchov Andrei , Surguchev Alexei A.
Published: March 2024

Epidemiological evidence points to an inverse association between Parkinson’s disease (PD) and almost all cancers except melanoma, for which this association is positive. The results of multiple studies have demonstrated that patients with PD are at reduced risk for the majority of neoplasms. Several potential biological explanations exist for the inverse relationship between cancer and PD. Recent results identified several PD-associated proteins and factors mediating cancer development and cancer-associated factors affecting PD. Accumulating data point to the role of genetic traits, members of the synuclein family, neurotrophic factors, the ubiquitin–proteasome system, circulating melatonin, and transcription factors as mediators. Here, we present recent data about shared pathogenetic factors and mediators that might be involved in the association between these two diseases. We discuss how these factors, individually or in combination, may be involved in pathology, serve as links between PD and cancer, and affect the prevalence of these disorders. Identification of these factors and investigation of their mechanisms of action would lead to the discovery of new targets for the treatment of both diseases.
Design, Synthesis and Biological Evaluation of Novel Phenyl-Substituted Naphthoic Acid Ethyl Ester Derivatives as Strigolactone Receptor Inhibitor
Authors: Du Lin , Li Xingjia , Ding Yimin , Ma Dengke , Yu Chunxin , Zhao Hanqing , Wang Ye , Liu Ziyan , Duan Liusheng
Published: March 2024

Strigolactones (SLs) are plant hormones that regulate several key agronomic traits, including shoot branching, leaf senescence, and stress tolerance. The artificial regulation of SL biosynthesis and signaling has been considered as a potent strategy in regulating plant architecture and combatting the infection of parasitic weeds to help improve crop yield. DL1b is a previously reported SL receptor inhibitor molecule that significantly promotes shoot branching. Here, we synthesized 18 novel compounds based on the structure of DL1b. We performed rice tillering activity assay and selected a novel small molecule, C6, as a candidate SL receptor inhibitor. In vitro bioassays demonstrated that C6 possesses various regulatory functions as an SL inhibitor, including inhibiting germination of the root parasitic seeds Phelipanche aegyptiaca, delaying leaf senescence and promoting hypocotyl elongation of Arabidopsis. ITC analysis and molecular docking experiments further confirmed that C6 can interact with SL receptor proteins, thereby interfering with the binding of SL to its receptor. Therefore, C6 is considered a novel SL receptor inhibitor with potential applications in plant architecture control and prevention of root parasitic weed infestation.
Hinokitiol Inhibits Breast Cancer Cells In Vitro Stemness-Progression and Self-Renewal with Apoptosis and Autophagy Modulation via the CD44/Nanog/SOX2/Oct4 Pathway
Authors: Chiang Yi-Fen , Huang Ko-Chieh , Chen Hsin-Yuan , Hamdy Nadia M. , Huang Tsui-Chin , Chang Hsin-Yi , Shieh Tzong-Ming , Huang Yun-Ju , Hsia Shih-Min
Published: March 2024

Breast cancer (BC) represents one of the most prevalent malignant threats to women globally. Tumor relapse or metastasis is facilitated by BC stemness progression, contributing to tumorigenicity. Therefore, comprehending the characteristics of stemness progression and the underlying molecular mechanisms is pivotal for BC advancement. Hinokitiol (β-thujaplicin), a tropolone-related compound abundant in the heartwood of cupressaceous plants, exhibits antimicrobial activity. In our study, we employed three BC cell lines (MDA-MB-231, MCF-7, and T47D) to assess the expression of stemness-, apoptosis-, and autophagy-related proteins. Hinokitiol significantly reduced the viability of cancer cells in a dose-dependent manner. Furthermore, we observed that hinokitiol enhances apoptosis by increasing the levels of cleaved poly-ADP-ribose polymerase (PARP) and phospho-p53. It also induces dysfunction in autophagy through the upregulation of LC3B and p62 protein expression. Additionally, hinokitiol significantly suppressed the number and diameter of cancer cell line spheres by reducing the expression of cluster of differentiation44 (CD44) and key transcription factors. These findings underscore hinokitiol’s potential as a therapeutic agent for breast cancer, particularly as a stemness-progression inhibitor. Further research and clinical studies are warranted to explore the full therapeutic potential of hinokitiol in the treatment of breast cancer.
Leaf Senescence Regulation Mechanism Based on Comparative Transcriptome Analysis in Foxtail Millet
Authors: Zhen Xiaoxi , Liu Chao , Guo Yajun , Yu Zirui , Han Yuanhuai , Zhang Bin , Liang Yinpei
Published: March 2024

Leaf senescence, a pivotal process in plants, directly influences both crop yield and nutritional quality. Foxtail millet (Setaria italica) is a C4 model crop renowned for its exceptional nutritional value and stress tolerance characteristics. However, there is a lack of research on the identification of senescence-associated genes (SAGs) and the underlying molecular regulatory mechanisms governing this process. In this study, a dark-induced senescence (DIS) experimental system was applied to investigate the extensive physiological and transcriptomic changes in two foxtail millet varieties with different degrees of leaf senescence. The physiological and biochemical indices revealed that the light senescence (LS) variety exhibited a delayed senescence phenotype, whereas the severe senescence (SS) variety exhibited an accelerated senescence phenotype. The most evident differences in gene expression profiles between these two varieties during DIS included photosynthesis, chlorophyll, and lipid metabolism. Comparative transcriptome analysis further revealed a significant up-regulation of genes related to polysaccharide and calcium ion binding, nitrogen utilization, defense response, and malate metabolism in LS. In contrast, the expression of genes associated with redox homeostasis, carbohydrate metabolism, lipid homeostasis, and hormone signaling was significantly altered in SS. Through WGCNA and RT-qPCR analyses, we identified three SAGs that exhibit potential negative regulation towards dark-induced leaf senescence in foxtail millet. This study establishes the foundation for a further comprehensive examination of the regulatory network governing leaf senescence and provides potential genetic resources for manipulating senescence in foxtail millet.
Personalized, Precision Medicine to Cure Alzheimer’s Dementia: Approach #1
Authors: Fessel Jeffrey
Published: March 2024

The goal of the treatment for Alzheimer’s dementia (AD) is the cure of dementia. A literature review revealed 18 major elements causing AD and 29 separate medications that address them. For any individual with AD, one is unlikely to discern which major causal elements produced dementia. Thus, for personalized, precision medicine, all causal elements must be treated so that each individual patient will have her or his causal elements addressed. Twenty-nine drugs cannot concomitantly be administered, so triple combinations of drugs taken from that list are suggested, and each triple combination can be administered sequentially, in any order. Ten combinations given over 13 weeks require 2.5 years, or if given over 26 weeks, they require 5.0 years. Such sequential treatment addresses all 18 elements and should cure dementia. In addition, any comorbid risk factors for AD whose first presence or worsening was within ±1 year of when AD first appeared should receive appropriate, standard treatment together with the sequential combinations. The article outlines a randomized clinical trial that is necessary to assess the safety and efficacy of the proposed treatments; it includes a triple-drug Rx for equipoise. Clinical trials should have durations of both 2.5 and 5.0 years unless the data safety monitoring board (DSMB) determines earlier success or futility since it is uncertain whether three or six months of treatment will be curative in humans, although studies in animals suggest that the briefer duration of treatment might be effective and restore defective neural tracts.
Intramolecular Hydrogen Bonds Assisted Construction of Planar Tricyclic Structures for Insensitive and Highly Thermostable Energetic Materials
Authors: Liu Yubing , Li Jie , Cai Jinxiong , Zhang Xun , Hu Lu , Pang Siping , He Chunlin
Published: March 2024

Safety is fundamental for the practical development and application of energetic materials. Three tricyclic energetic compounds, namely, 1,3-di(1H-tetrazol-5-yl)-1H-1,2,4-triazol-5-amine (ATDT), 5′-nitro-3-(1H-tetrazol-5-yl)-2′H-[1,3′-bi(1,2,4-triazol)]-5-amine (ATNT), and 1-(3,4-dinitro-1H-pyrazol-5-yl)-3-(1H-tetrazol-5-yl)-1H-1,2,4-triazol-5-amine (ATDNP), were effectively synthesized through a simple two-step synthetic route. The introduction of intramolecular hydrogen bonds resulted in excellent molecular planarity for the three new compounds. Additionally, they exhibit regular crystal packing, leading to numerous intermolecular hydrogen bonds and π–π interactions. Benefiting from planar tricyclic structural features, ATDT, ATNT, and ATDNP are insensitive (IS > 60 J, FS = 360 N) when exposed to external stimuli. Furthermore, ATNT (Td = 361.1 °C) and ATDNP (Td = 317.0 °C) exhibit high decomposition temperatures and satisfying detonation performance. The intermolecular hydrogen bonding that produced this planar tricyclic molecular structure serves as a model for the creation of innovative multiple heterocycle energetic materials with excellent stability.
The Predictive Role of Serum Lipid Levels, p53 and ki-67, According to Molecular Subtypes in Breast Cancer: A Randomized Clinical Study
Authors: Faur Ionut Flaviu , Dobrescu Amadeus , Clim Ioana Adelina , Pasca Paul , Prodan-Barbulescu Catalin , Tarta Cristi , Neamtu Andreea-Adriana , Brebu Dan , Neamtu Carmen , Rosu Mihai , Duta Ciprian , Clim Andreea , Lazar Gabriel , Totolici Bogdan
Published: March 2024

Dyslipidemia is a component of metabolic syndrome, having an important role in the carcinogenesis of different tumor types, such as prostate, ovarian, or renal cancer. The number of studies on the predictive potential of the different components of the lipid profile with a predictive potential in breast cancer is quite low. The evaluation of the lipid profile was carried out for the 142 patients who benefited from neoadjuvant therapy (NAC) in order to identify a potential predictive biomarker. The serological sample collection was performed sequentially according to a standardized protocol, pre-NAC, post-NAC and 6 months post-NAC after a 6-h pre-collection fast. We also investigated in the general group the presence or absence of the p53 mutation (TP53) and of the mitotic index ki-67, respectively, in relation to the molecular subtypes. The menopausal status, tumor size, family history, grading, Ki-67, p53 and LN metastases have a predictive nature regarding overall survival (OS) (p < 0.05), while for disease free survival (DFS), only tumor size, tumor grading, Ki-67 > 14, and p53+ are of predictive nature. The genetic and molecular analysis carried out in our group indicates that 71.67% have a Ki-67 score higher than 14%, and 39% of the patients have the positive P53 mutation. The multivariate analysis in the case of patients included in the TNBC subtype showed that the increased tumor volume (p = 0.002) and increased level of HDL (p = 0.004) represent predictive factors for the tumor response rate to NAC. High HDL-C levels before NAC and increased LDL-C levels after NAC were associated with the better treatment response in ER-positive and HER2+ breast cancer patients. Increased HDL-C values and tumor volume represent predictive factors as to the response rate to NAC in the case of patients included in the TNBC subtype. Regarding the ER+ and HER2+ subtypes, increased levels of HDL-C pre-NAC and increased levels of LDL-C post-NAC were associated with a better therapeutic response rate. Tumor grading, Ki-67, p53, and LN metastases have a predictive nature for OS, while tumor size, tumor grading, and Ki-67 > 14, and p53+ are predictive for DFS.
Effects of Regulating Hippo and Wnt on the Development and Fate Differentiation of Bovine Embryo
Authors: Zhang Peipei , Zhang Hang , Li Chongyang , Yang Baigao , Feng Xiaoyi , Cao Jianhua , Du Weihua , Shahzad Muhammad , Khan Adnan , Sun Shao-Chen , Zhao Xueming
Published: March 2024

The improvement of in vitro embryo development is a gateway to enhance the output of assisted reproductive technologies. The Wnt and Hippo signaling pathways are crucial for the early development of bovine embryos. This study investigated the development of bovine embryos under the influence of a Hippo signaling agonist (LPA) and a Wnt signaling inhibitor (DKK1). In this current study, embryos produced in vitro were cultured in media supplemented with LPA and DKK1. We comprehensively analyzed the impact of LPA and DKK1 on various developmental parameters of the bovine embryo, such as blastocyst formation, differential cell counts, YAP fluorescence intensity and apoptosis rate. Furthermore, single-cell RNA sequencing (scRNA-seq) was employed to elucidate the in vitro embryonic development. Our results revealed that LPA and DKK1 improved the blastocyst developmental potential, total cells, trophectoderm (TE) cells and YAP fluorescence intensity and decreased the apoptosis rate of bovine embryos. A total of 1203 genes exhibited differential expression between the control and LPA/DKK1-treated (LD) groups, with 577 genes upregulated and 626 genes downregulated. KEGG pathway analysis revealed significant enrichment of differentially expressed genes (DEGs) associated with TGF-beta signaling, Wnt signaling, apoptosis, Hippo signaling and other critical developmental pathways. Our study shows the role of LPA and DKK1 in embryonic differentiation and embryo establishment of pregnancy. These findings should be helpful for further unraveling the precise contributions of the Hippo and Wnt pathways in bovine trophoblast formation, thus advancing our comprehension of early bovine embryo development.
Protein Disulfide Isomerase 4 Is an Essential Regulator of Endothelial Function and Survival
Authors: Bu Shuhan , Singh Aman , Nguyen Hien C. , Peddi Bharatsinai , Bhatt Kriti , Ravendranathan Naresh , Frisbee Jefferson C. , Singh Krishna K.
Published: March 2024

Endothelial autophagy plays an important role in the regulation of endothelial function. The inhibition of endothelial autophagy is associated with the reduced expression of protein disulfide isomerase 4 (PDIA-4); however, its role in endothelial cells is not known. Here, we report that endothelial cell-specific loss of PDIA-4 leads to impaired autophagic flux accompanied by loss of endothelial function and apoptosis. Endothelial cell-specific loss of PDIA-4 also induced marked changes in endothelial cell architecture, accompanied by the loss of endothelial markers and the gain of mesenchymal markers consistent with endothelial-to-mesenchymal transition (EndMT). The loss of PDIA-4 activated TGFβ-signaling, and inhibition of TGFβ-signaling suppressed EndMT in PDIA-4-silenced endothelial cells in vitro. Our findings help elucidate the role of PDIA-4 in endothelial autophagy and endothelial function and provide a potential target to modulate endothelial function and/or limit autophagy and EndMT in (patho-)physiological conditions.
Association between PD-L1 Expression and the Prognosis and Clinicopathologic Features of Non-Clear Cell Renal Cell Carcinoma
Authors: Chrabańska Magdalena , Szweda-Gandor Nikola , Rynkiewicz Magdalena , Hraboš Dominik , Drozdzowska Bogna
Published: March 2024

PD-L1 is one of the two programmed cell death 1 (PD-1) ligands and a part of an immune checkpoint system (PD-1/PD-L1) with widespread clinical application. The aim of this study was to investigate PD-L1 expression and its association with clinicopathological and prognostic significance in non-clear cell renal cell carcinoma (non-ccRCC) patients. A total of 41 papillary (pRCC) and 20 chromophobe (chRCC) RCC tumors were examined for PD-L1 expression by immunohistochemistry in the cancer cells and tumor-infiltrating mononuclear cells (TIMCs). PD-L1 positivity was detected in 36.6% pRCC and 85.0% chRCC cancer cells, while PD-L1 positivity was observed in 73.2% pRCC and 50.0% chRCC TIMCs. PD-L1 positivity in both pRCC and chRCC tumor cells was not correlated with any of the examined clinicopathological features, while PD-L1 positivity in TIMCs was associated with the age of patients with pRCC. During follow-up, the death was documented among 6 patients with pRCC. Papillary RCC patients with PD-L1-positive tumor cells were significantly associated with an increased risk of death compared with patients with PD-L1-negative cancer cells. A similar trend was observed when comparing PD-L1 expression in TIMCs. However, no differences in overall survival for PD-L1-positive pRCC patients with compared to PD-L1-negative patients were observed in tumor cells or TIMCs.
Genetic Structure and Diversity of Hatchery and Wild Populations of Yellow Catfish Tachysurus fulvidraco (Siluriformes: Bagridae) from Korea
Authors: Kim Kang-Rae , Kim Keun-Yong , Song Ha Yoon
Published: March 2024

Yellow catfish Tachysurus fulvidraco is an important commercial fish species in South Korea. However, due to their current declines in its distribution area and population size, it is being released from hatchery populations into wild populations. Hatchery populations also produced from wild broodstocks are used for its captive breeding. We reported 15 new microsatellite DNA markers of T. fulvidraco to identify the genetic diversity and structure of its hatchery and wild populations, providing baseline data for useful resource development strategies. The observed heterozygosity of the hatchery populations ranged from 0.816 to 0.873, and that of the wild populations ranged from 0.771 to 0.840. Their inbreeding coefficient ranged from −0.078 to 0.024. All populations experienced a bottleneck (p < 0.05), with effective population sizes ranging from 21 to infinity. Their gene structure was divided into two groups with STRUCTURE results of K = 2. It was confirmed that each hatchery population originated from a different wild population. This study provides genetic information necessary for the future development and conservation of fishery resources for T. fulvidraco.
S-YOLOv5: A Lightweight Model for Detecting Objects Thrown from Tall Buildings in Communities
Authors: Shi Yuntao , Luo Qi , Zhou Meng , Guo Wei , Li Jie , Li Shuqin , Ding Yu
Published: March 2024

Objects thrown from tall buildings in communities are characterized by their small size, inconspicuous features, and high speed. Existing algorithms for detecting such objects face challenges, including excessive parameters, overly complex models that are difficult to implement, and insufficient detection accuracy. This study proposes a lightweight detection model for objects thrown from tall buildings in communities, named S-YOLOv5, to address these issues. The model is based on the YOLOv5 algorithm, and a lightweight convolutional neural network, Enhanced ShuffleNet (ESNet), is chosen as the backbone network to extract image features. On this basis, the initial stage of the backbone network is enhanced and the simplified attention module (SimAM) attention mechanism is added to utilize the rich position information and contour information in the shallow feature map to improve the detection of small targets. For feature fusion, the sparsely connected Path Aggregation Network (SCPANet) module is designed to use sparsely connected convolution (SCConv) instead of the regular convolution of the Path Aggregation Network (PANet) to fuse features efficiently. In addition, the model uses the normalized Wasserstein distance (NWD) loss function to reduce the sensitivity of positional bias. The accuracy of the model is further improved. Test results from the self-built objects thrown from tall buildings dataset show that S-YOLOv5 can detect objects thrown from tall buildings quickly and accurately, with an accuracy of 90.2% and a detection rate of 34.1 Fps/s. Compared with the original YOLOv5 model, the parameters are reduced by 87.3%, and the accuracy and rate are improved by 0.8% and 63%, respectively.
Generally Applicable Q-Table Compression Method and Its Application for Constrained Stochastic Graph Traversal Optimization Problems
Authors: Kegyes Tamás , Kummer Alex , Süle Zoltán , Abonyi János
Published: March 2024

We analyzed a special class of graph traversal problems, where the distances are stochastic, and the agent is restricted to take a limited range in one go. We showed that both constrained shortest Hamiltonian pathfinding problems and disassembly line balancing problems belong to the class of constrained shortest pathfinding problems, which can be represented as mixed-integer optimization problems. Reinforcement learning (RL) methods have proven their efficiency in multiple complex problems. However, researchers concluded that the learning time increases radically by growing the state- and action spaces. In continuous cases, approximation techniques are used, but these methods have several limitations in mixed-integer searching spaces. We present the Q-table compression method as a multistep method with dimension reduction, state fusion, and space compression techniques that project a mixed-integer optimization problem into a discrete one. The RL agent is then trained using an extended Q-value-based method to deliver a human-interpretable model for optimal action selection. Our approach was tested in selected constrained stochastic graph traversal use cases, and comparative results are shown to the simple grid-based discretization method.
An Incremental Mutual Information-Selection Technique for Early Ransomware Detection
Authors: Gazzan Mazen , Sheldon Frederick T.
Published: March 2024

Ransomware attacks have emerged as a significant threat to critical data and systems, extending beyond traditional computers to mobile and IoT/Cyber–Physical Systems. This study addresses the need to detect early ransomware behavior when only limited data are available. A major step for training such a detection model is choosing a set of relevant and non-redundant features, which is challenging when data are scarce. Therefore, this paper proposes an incremental mutual information-selection technique as a method for selecting the relevant features at the early stages of ransomware attacks. It introduces an adaptive feature-selection technique that processes data in smaller, manageable batches. This approach lessens the computational load and enhances the system’s ability to quickly adapt to new data arrival, making it particularly suitable for ongoing attacks during the initial phases of the attack. The experimental results emphasize the importance of the proposed technique in estimating feature significance in limited data scenarios. Such results underscore the significance of the incremental approach as a proactive measure in addressing the escalating challenges posed by ransomware.
Key Industry 4.0 Organisational Capability Prioritisation towards Organisational Transformation
Authors: Smuts Stefan , van der Merwe Alta
Published: April 2024

Industry 4.0 aids organisational transformation powered by innovative technologies and connectivity. In addition to navigating complex Industry 4.0 concepts and characteristics, organisations must also address organisational consequences related to fast-paced organisational transformation and resource efficacy. The optimal allocation of organisational resources and capabilities to large transformational programs, as well as the significant capital investment associated with digital transformation, compel organisations to prioritize their efforts. Hence, this study investigates how key Industry 4.0 organisational capabilities could be prioritized towards organisational digital transformation. Data were collected from 49 participants who had completed a questionnaire containing 26 statement actions aligned to sensing, seizing, transforming and supporting organisational capability domains. By analysing the data, statement actions were prioritized and operationalized into a prototyped checklist. Two organisations applied the prototyped checklist, illustrating unique profiles and transformative actions. The operationalisation of the checklist highlighted its utility in establishing where an organisation operates in terms of digital transformation, as well as what additional steps might be followed to improve its capability prioritisation based on low checklist scores. By understanding the prioritisation of Industry 4.0 capabilities, organisations could ensure that resources are allocated optimally for business value creation based on organisational capabilities prioritisation.
Room-Temperature Entanglement of the Nickel-Radical Molecular Complex (Et3NH)[Ni(hfac)2L] Reinforced by the Magnetic Field
Authors: Strečka Jozef , Shahrabadi Elham Shahhosseini
Published: March 2024

Bipartite entanglement is comprehensively investigated in the mononuclear molecular complex (Et3NH)[Ni(hfac)2L], where HL denotes 2-(2-hydroxy-3-methoxy-5-nitrophenyl)-4,4,5,5-tetramethyl-4,5-dihydro-1H-imidazol-3-oxide-1-oxyl and hfacH stands for hexafluoroacetylacetone. From the magnetic point of view, the molecular compound (Et3NH)[Ni(hfac)2L] consists of an exchange-coupled spin-1 Ni2+ magnetic ion and a spin-12 nitronyl-nitroxide radical substituted nitrophenol. The nickel-radical molecular complex affords an experimental realization of a mixed spin-(12, 1) Heisenberg dimer with a strong antiferromagnetic exchange coupling, J/kB = 505 K, and two distinct g-factors, gRad = 2.005 and gNi = 2.275. By adopting this set of magnetic parameters, we demonstrate that the Zeeman splitting of a quantum ferrimagnetic ground-state doublet due to a weak magnetic field may substantially reinforce the strength of bipartite entanglement at low temperatures. The molecular compound (Et3NH)[Ni(hfac)2L] maintains sufficiently strong thermal entanglement, even at room temperature, vanishing only above 546 K. Specifically, the thermal entanglement in the nickel-radical molecular complex retains approximately 40% of the maximum value, corresponding to perfectly entangled Bell states at room temperature, which implies that this magnetic compound provides a suitable platform of a molecular qubit with potential implications for room-temperature quantum computation and quantum information processing.
miRNA Dynamics for Pest Management: Implications in Insecticide Resistance
Authors: Mahalle Rashmi Manohar , Mota-Sanchez David , Pittendrigh Barry R. , Kim Young Ho , Seong Keon Mook
Published: March 2024

Utilizing chemical agents in pest management in modern agricultural practices has been the predominant approach since the advent of synthetic insecticides. However, insecticide resistance is an emerging issue, as pest populations evolve to survive exposure to chemicals that were once effective in controlling them, underlining the need for advanced and innovative approaches to managing pests. In insects, microRNAs (miRNAs) serve as key regulators of a wide range of biological functions, characterized by their dynamic expression patterns and the ability to target genes. Recent studies are increasingly attributed to the significance of miRNAs in contributing to the evolution of insecticide resistance in numerous insect species. Abundant miRNAs have been discovered in insects using RNA sequencing and transcriptome analysis and are known to play vital roles in regulation at both the transcriptional and post-transcriptional levels. Globally, there is growing research interest in the characterization and application of miRNAs, especially for their potential role in managing insecticide resistance. This review focuses on how miRNAs contribute to regulating insecticide resistance across various insect species. Furthermore, we discuss the gain and loss of functions of miRNAs and the techniques for delivering miRNAs into the insect system. The review emphasizes the application of miRNA-based strategies to studying their role in diminishing insecticide resistance, offering a more efficient and lasting approach to insect management.
Effects of Carbohydrate Intake on Anopheles darlingi and Anopheles deaneorum Fitness under Lab-Reared Conditions
Authors: Santos Najara A. C. , Martins Mirilene M. , Andrade Alice O. , Bastos Alessandra S. , Pontual José D. C. , Araújo Jéssica E. , Rocha Marina L. , Medeiros Jansen F. , Araujo Maisa S.
Published: March 2024

The maintenance of a highly productive colony of anopheline mosquitoes requires standardized methods in order to obtain a sufficient number of homogeneous individuals for malaria research. In this context, nutritional status may affect survival, fecundity, and the capacity to support pathogen development. Here we assess the effects of carbohydrate sources on fecundity, survival, and susceptibility to Plasmodium vivax infection in colonies of Anopheles darlingi and Anopheles deaneorum mosquitoes. Newly emerged females from each species were fed either 10% sugar or 15% honey solutions until the end of each experiment. The type of carbohydrate meal did not impact any entomological parameters for An. deaneorum, except for survival. For both species, honey meal significantly increased median survival post-emergence by three to four days, probably due to its nutritional value. For An. darlingi fed with honey, a higher mean frequency in stage 5 was observed at 48 h post-blood-meal, which could indicate a delay in the digestion process. However, no effects on fecundity parameters were observed. Regarding susceptibility, An. darlingi fed with sugar exhibited a low intensity of sporozoites, although any negative effects of sucrose on sporozoites invasions in the salivary glands are unknown. Based on the increase in mosquito survival, a carbohydrate source composed of 15% honey solution could be better for maintaining An. darlingi and An. deaneorum in the lab-rearing context.
Biomarkers and Proteomics in Sarcomeric Hypertrophic Cardiomyopathy in the Young—FGF-21 Highly Associated with Overt Disease
Authors: Österberg Anna Wålinder , Östman-Smith Ingegerd , Green Henrik , Gunnarsson Cecilia , Fredrikson Mats , Liuba Petru , Fernlund Eva
Published: March 2024

Background: Any difference in biomarkers between genotype-positive individuals with overt hypertrophic cardiomyopathy (HCM), and genotype-positive but phenotype-negative individuals (G+P-) in HCM-associated pathways might shed light on pathophysiological mechanisms. We studied this in young HCM patients. Methods: 29 HCM patients, 17 G+P--individuals, and age- and sex-matched controls were prospectively included. We analyzed 184 cardiovascular disease-associated proteins by two proximity extension assays, categorized into biological pathways, and analyzed with multivariate logistic regression analysis. Significant proteins were dichotomized into groups above/below median concentration in control group. Results: Dichotomized values of significant proteins showed high odds ratio (OR) in overt HCMphenotype for Fibroblast growth factor-21 (FGF-21) 10 (p = 0.001), P-selectin glycoprotein ligand-1 (PSGL-1) OR 8.6 (p = 0.005), and Galectin-9 (Gal-9) OR 5.91 (p = 0.004). For G+P-, however, angiopoietin-1 receptor (TIE2) was notably raised, OR 65.5 (p = 0.004), whereas metalloproteinase inhibitor 4 (TIMP4) involved in proteolysis, in contrast, had reduced OR 0.06 (p = 0.013). Conclusions: This study is one of the first in young HCM patients and G+P- individuals. We found significantly increased OR for HCM in FGF-21 involved in RAS-MAPK pathway, associated with cardiomyocyte hypertrophy. Upregulation of FGF-21 indicates involvement of the RAS-MAPK pathway in HCM regardless of genetic background, which is a novel finding.
Differential Development of the Chordae Tendineae and Anterior Leaflet of the Bovine Mitral Valve
Authors: Martin Meghan , Chen Chih-Ying , McCowan Timothy , Wells Sarah
Published: March 2024

There is increasing evidence that some adult mitral valve pathologies may have developmental origins involving errors in cell signaling and protein deposition during valvulogenesis. While early and late gestational stages are well-documented in zebrafish, chicks, and small mammalian models, longitudinal studies in large mammals with a similar gestational period to humans are lacking. Further, the mechanism of chordae tendineae formation and multiplication remains unclear. The current study presents a comprehensive examination of mitral anterior leaflet and chordae tendineae development in a bovine model (a large mammal with the same gestational period as humans). Remarkably distinct from small mammals, bovine development displayed early branched chordae, with increasing attachments only until birth, while the anterior leaflet grew both during gestation and postnatally. Chordae also exhibited accelerated collagen deposition, maturation, and crimp development during gestation. These findings suggest that the bovine anterior leaflet and chordae tendineae possess unique processes of development despite being a continuous collagenous structure and could provide greater insight into human valve development.
Ex Vivo Antiplatelet Effects of Oral Anticoagulants
Authors: Renda Giulia , Bucciarelli Valentina , Barbieri Giulia , Lanuti Paola , Berteotti Martina , Malatesta Gelsomina , Cesari Francesca , Salvatore Tanya , Giusti Betti , Gori Anna Maria , Marcucci Rossella , De Caterina Raffaele
Published: March 2024

Background: The impact of non-vitamin K antagonist oral anticoagulants (NOACs) on platelet function is still unclear. We conducted a comprehensive ex vivo study aimed at assessing the effect of the four currently marketed NOACs on platelet function. Methods: We incubated blood samples from healthy donors with concentrations of NOACs (50, 150 and 250 ng/mL), in the range of those achieved in the plasma of patients during therapy. We evaluated generation of thrombin; light transmittance platelet aggregation (LTA) in response to adenosine diphosphate (ADP), thrombin receptor-activating peptide (TRAP), human γ-thrombin (THR) and tissue factor (TF); generation of thromboxane (TX)B2; and expression of protease-activated receptor (PAR)-1 and P-selectin on the platelet surface. Results: All NOACs concentration-dependently reduced thrombin generation compared with control. THR-induced LTA was suppressed by the addition of dabigatran at any concentration, while TF-induced LTA was reduced by factor-Xa inhibitors. ADP- and TRAP-induced LTA was not modified by NOACs. TXB2 generation was reduced by all NOACs, particularly at the highest concentrations. We found a concentration-dependent increase in PAR-1 expression after incubation with dabigatran, mainly at the highest concentrations, but not with FXa inhibitors; P-selectin expression was not changed by any drugs. Conclusions: Treatment with the NOACs is associated with measurable ex vivo changes in platelet function, arguing for antiplatelet effects beyond the well-known anticoagulant activities of these drugs. There are differences, however, among the NOACs, especially between dabigatran and the FXa inhibitors.