bluuebunny/crossref_metadata_2025 huggingface dataset:
A Rare De Novo Mutation in the TRIM8 Gene in a 17-Year-Old Boy with Steroid-Resistant Nephrotic Syndrome: Case Report
Authors: Badeńska Marta , Pac Małgorzata , Badeński Andrzej , Rutkowska Karolina , Czubilińska-Łada Justyna , Płoski Rafał , Bohynikova Nadezda , Szczepańska Maria
Published: April 2024

Idiopathic nephrotic syndrome is the most common chronic glomerular disease in children. Treatment with steroids is usually successful; however, in a small percentage of patients, steroid resistance is observed. The most frequent histologic kidney feature of steroid-resistant nephrotic syndrome (SRNS) is focal segmental glomerulosclerosis (FSGS). Genetic testing has become a valuable diagnostic tool in defining the etiology of SRNS, leading to the identification of a genetic cause. The TRIM8 gene is expressed in various tissues, including kidney cells and the central nervous system (CNS). An association between a mutation in the TRIM8 gene and an early onset of FSGS has been proposed but is not well described. We present a 17-year-old boy with epilepsy, early mild developmental delay, a low IgG serum level, and proteinuria, secondary to FSGS. A Next-Generation Sequencing (NGS)-based analysis revealed a heterozygous de novo pathogenic variant in the TRIM8 gene (c.1200C>G, p.Tyr400Ter). TRIM8 gene sequencing should be considered in individuals with early onset of FSGS, particularly accompanied by symptoms of cortical dysfunction, such as epilepsy and intellectual disability.
Analysis and Characterization of the Extracellular Vesicles Released in Non-Cancer Diseases Using Matrix-Assisted Laser Desorption Ionization/Mass Spectrometry
Authors: Aresta Antonella Maria , De Vietro Nicoletta , Zambonin Carlo
Published: April 2024

The extracellular vesicles (EVs) released by cells play a crucial role in intercellular communications and interactions. The direct shedding of EVs from the plasma membrane represents a fundamental pathway for the transfer of properties and information between cells. These vesicles are classified based on their origin, biogenesis, size, content, surface markers, and functional features, encompassing a variety of bioactive molecules that reflect the physiological state and cell type of origin. Such molecules include lipids, nucleic acids, and proteins. Research efforts aimed at comprehending EVs, including the development of strategies for their isolation, purification, and characterization, have led to the discovery of new biomarkers. These biomarkers are proving invaluable for diagnosing diseases, monitoring disease progression, understanding treatment responses, especially in oncology, and addressing metabolic, neurological, infectious disorders, as well as advancing vaccine development. Matrix-Assisted Laser Desorption Ionization (MALDI)/Mass Spectrometry (MS) stands out as a leading tool for the analysis and characterization of EVs and their cargo. This technique offers inherent advantages such as a high throughput, minimal sample consumption, rapid and cost-effective analysis, and user-friendly operation. This review is mainly focused on the primary applications of MALDI–time-of-flight (TOF)/MS in the analysis and characterization of extracellular vesicles associated with non-cancerous diseases and pathogens that infect humans, animals, and plants.
Mitochondrial Kinase Signaling for Cardioprotection
Authors: Boengler Kerstin , Eickelmann Chantal , Kleinbongard Petra
Published: April 2024

Myocardial ischemia/reperfusion injury is reduced by cardioprotective adaptations such as local or remote ischemic conditioning. The cardioprotective stimuli activate signaling cascades, which converge on mitochondria and maintain the function of the organelles, which is critical for cell survival. The signaling cascades include not only extracellular molecules that activate sarcolemmal receptor-dependent or -independent protein kinases that signal at the plasma membrane or in the cytosol, but also involve kinases, which are located to or within mitochondria, phosphorylate mitochondrial target proteins, and thereby modify, e.g., respiration, the generation of reactive oxygen species, calcium handling, mitochondrial dynamics, mitophagy, or apoptosis. In the present review, we give a personal and opinionated overview of selected protein kinases, localized to/within myocardial mitochondria, and summarize the available data on their role in myocardial ischemia/reperfusion injury and protection from it. We highlight the regulation of mitochondrial function by these mitochondrial protein kinases.
The Role of Extracellular Vesicles in Allergic Sensitization: A Systematic Review
Authors: Tucis Davis , Hopkins Georgina , Browne William , James Victoria , Onion David , Fairclough Lucy C.
Published: April 2024

Allergies affect approximately 10–30% of people worldwide, with an increasing number of cases each year; however, the underlying mechanisms are still poorly understood. In recent years, extracellular vesicles (EVs) have been suggested to play a role in allergic sensitization and skew to a T helper type 2 (Th2) response. The aim of this review is to highlight the existing evidence of EV involvement in allergies. A total of 22 studies were reviewed; 12 studies showed EVs can influence a Th2 response, while 10 studies found EVs promoted a Th1 or Treg response. EVs can drive allergic sensitization through up-regulation of pro-Th2 cytokines, such as IL-4 and IL-13. In addition, EVs from MRSA can induce IgE hypersensitivity in mice towards MRSA. On the other hand, EVs can induce tolerance in the immune system; for example, pre-exposing OVA-loaded EVs prevented OVA sensitization in mice. The current literature thus suggests that EVs play an essential role in allergy. Further research utilizing human in vitro models and clinical studies is needed to give a reliable account of the role of EVs in allergy.
NF-κB in the Radiation Response of A549 Non-Small Cell Lung Cancer Cells to X-rays and Carbon Ions under Hypoxia
Authors: Nisar Hasan , Sanchidrián González Paulina Mercedes , Labonté Frederik M. , Schmitz Claudia , Roggan Marie Denise , Kronenberg Jessica , Konda Bikash , Chevalier François , Hellweg Christine E.
Published: April 2024

Cellular hypoxia, detectable in up to 80% of non-small cell lung carcinoma (NSCLC) tumors, is a known cause of radioresistance. High linear energy transfer (LET) particle radiation might be effective in the treatment of hypoxic solid tumors, including NSCLC. Cellular hypoxia can activate nuclear factor κB (NF-κB), which can modulate radioresistance by influencing cancer cell survival. The effect of high-LET radiation on NF-κB activation in hypoxic NSCLC cells is unclear. Therefore, we compared the effect of low (X-rays)- and high (12C)-LET radiation on NF-κB responsive genes’ upregulation, as well as its target cytokines’ synthesis in normoxic and hypoxic A549 NSCLC cells. The cells were incubated under normoxia (20% O2) or hypoxia (1% O2) for 48 h, followed by irradiation with 8 Gy X-rays or 12C ions, maintaining the oxygen conditions until fixation or lysis. Regulation of NF-κB responsive genes was evaluated by mRNA sequencing. Secretion of NF-κB target cytokines, IL-6 and IL-8, was quantified by ELISA. A greater fold change increase in expression of NF-κB target genes in A549 cells following exposure to 12C ions compared to X-rays was observed, regardless of oxygenation status. These genes regulate cell migration, cell cycle, and cell survival. A greater number of NF-κB target genes was activated under hypoxia, regardless of irradiation status. These genes regulate cell migration, survival, proliferation, and inflammation. X-ray exposure under hypoxia additionally upregulated NF-κB target genes modulating immunosurveillance and epithelial-mesenchymal transition (EMT). Increased IL-6 and IL-8 secretion under hypoxia confirmed NF-κB-mediated expression of pro-inflammatory genes. Therefore, radiotherapy, particularly with X-rays, may increase tumor invasiveness in surviving hypoxic A549 cells.
Recent Advances in the Use of Stem Cells in Tissue Engineering and Adjunct Therapies for Tendon Reconstruction and Future Perspectives
Authors: Dec Paweł , Żyłka Małgorzata , Burszewski Piotr , Modrzejewski Andrzej , Pawlik Andrzej
Published: April 2024

Due to their function, tendons are exposed to acute injuries. This type of damage to the musculoskeletal system represents a challenge for clinicians when natural regeneration and treatment methods do not produce the expected results. Currently, treatment is long and associated with long-term complications. In this review, we discuss the use of stem cells in the treatment of tendons, including how to induce appropriate cell differentiation based on gene therapy, growth factors, tissue engineering, proteins involved in regenerative process, drugs and three-dimensional (3D) structures. A multidirectional approach as well as the incorporation of novel components of the therapy will improve the techniques used and benefit patients with tendon injuries in the future.
Cross-Domain Text Mining of Pathophysiological Processes Associated with Diabetic Kidney Disease
Authors: Patidar Krutika , Deng Jennifer H. , Mitchell Cassie S. , Ford Versypt Ashlee N.
Published: April 2024

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide. This study’s goal was to identify the signaling drivers and pathways that modulate glomerular endothelial dysfunction in DKD via artificial intelligence-enabled literature-based discovery. Cross-domain text mining of 33+ million PubMed articles was performed with SemNet 2.0 to identify and rank multi-scalar and multi-factorial pathophysiological concepts related to DKD. A set of identified relevant genes and proteins that regulate different pathological events associated with DKD were analyzed and ranked using normalized mean HeteSim scores. High-ranking genes and proteins intersected three domains—DKD, the immune response, and glomerular endothelial cells. The top 10% of ranked concepts were mapped to the following biological functions: angiogenesis, apoptotic processes, cell adhesion, chemotaxis, growth factor signaling, vascular permeability, the nitric oxide response, oxidative stress, the cytokine response, macrophage signaling, NFκB factor activity, the TLR pathway, glucose metabolism, the inflammatory response, the ERK/MAPK signaling response, the JAK/STAT pathway, the T-cell-mediated response, the WNT/β-catenin pathway, the renin–angiotensin system, and NADPH oxidase activity. High-ranking genes and proteins were used to generate a protein–protein interaction network. The study results prioritized interactions or molecules involved in dysregulated signaling in DKD, which can be further assessed through biochemical network models or experiments.
Neutrophil Extracellular Traps and Respiratory Disease
Authors: King Paul T. , Dousha Lovisa
Published: April 2024

Extracellular traps made by neutrophils (NETs) and other leukocytes such as macrophages and eosinophils have a key role in the initial immune response to infection but are highly inflammatory and may contribute to tissue damage. They are particularly relevant to lung disease, with the pulmonary anatomy facilitating their ability to fully extend into the airways/alveolar space. There has been a rapid expansion in the number of published studies demonstrating their role in a variety of important respiratory diseases including chronic obstructive pulmonary disease, cystic fibrosis, bronchiectasis, asthma, pneumonia, COVID-19, rhinosinusitis, interstitial lung disease and lung cancer. The expression of NETs and other traps is a specific process, and diagnostic tests need to differentiate them from other inflammatory pathways/causes of cell death that are also characterised by the presence of extracellular DNA. The specific targeting of this pathway by relevant therapeutics may have significant clinical benefit; however, current clinical trials/evidence are at a very early stage. This review will provide a broad overview of the role of NETs and their possible treatment in respiratory disease.
Molecular Phylogenetic and Comparative Genomic Analysis of Pleurocordyceps fusiformispora sp. nov. and Perennicordyceps elaphomyceticola in the Family Polycephalomycetaceae
Authors: Liu Zuoheng , Lu Yingling , Tang Dexiang , Zhu Juye , Luo Lijun , Chen Yue , Yu Hong
Published: April 2024

Several Pleurocordyceps species have been reported as hyperparasitic fungi. A new species, Pleurocordyceps fusiformispora, and a known species, Perennicordyceps elaphomyceticola, are described here based on morphology and phylogenetic evidence from six genes (ITS, SSU, LSU, TET1-α, RPB1, and RPB2). Pl. fusiformispora differed from the other Pleurocordyceps species by producing flaky colonies, ovoid or elliptic α-conidia, and fusiform or long fusiform β-conidia. Both full genomes of Pe. elaphomyceticola and Pl. fusiformispora were sequenced, annotated, and compared. The antiSMASH and local BLAST analyses revealed significant differences in the number and types of putative secondary metabolite biosynthetic gene clusters, i.e., NPPS, PKS, and hybrid PKS–NRPS domains, between the two species. In addition, the putative BGCs of six compounds, namely ε-poly lysine, 4-epi-15-epi-brefeldin A, Monorden D/monocillin IV/monocillin VII/pochonin M/monocillin V/monocillin II, Tolypyridone, Piperazine, and Triticone DABFC, were excavated in the present study. This study motivates the use of heterologous expression and gene knockout methods to discover novel biologically active SMs from Polycephalomycetaceae.
Improving the Electroluminescence Properties of New Chrysene Derivatives with High Color Purity for Deep-Blue OLEDs
Authors: Park Sunwoo , Lee Changyu , Lee Hayoon , Lee Kiho , Kwon Hyukmin , Park Sangwook , Park Jongwook
Published: April 2024

Two blue-emitting materials, 4-(12-([1,1′:3′,1″-terphenyl]-5′-yl)chrysen-6-yl)-N,N-diphenylaniline (TPA-C-TP) and 6-([1,1′:3′,1″-terphenyl]-5′-yl)-12-(4-(1,2,2-triphenylvinyl)phenyl)chrysene (TPE-C-TP), were prepared with the composition of a chrysene core moiety and terphenyl (TP), triphenyl amine (TPA), and tetraphenylethylene (TPE) moieties as side groups. The maximum photoluminescence (PL) emission wavelengths of TPA-C-TP and TPE-C-TP were 435 and 369 nm in the solution state and 444 and 471 nm in the film state. TPA-C-TP effectively prevented intermolecular packing through the introduction of TPA, a bulky aromatic amine group, and it showed an excellent photoluminescence quantum yield (PLQY) of 86% in the film state. TPE-C-TP exhibited aggregation-induced emission; the PLQY increased dramatically from 0.1% to 78% from the solution state to the film state. The two synthesized materials had excellent thermal stability, with a high decomposition temperature exceeding 460 °C. The two compounds were used as emitting layers in a non-doped device. The TPA-C-TP device achieved excellent electroluminescence (EL) performance, with Commission Internationale de L′Eclairage co-ordinates of (0.15, 0.07) and an external quantum efficiency of 4.13%, corresponding to an EL peak wavelength of 439 nm.
Research and Optimization of Extrusion Tap Structure Based on Numerical Simulation and Experimental Analysis
Authors: Tao Yi , Wan Nian , Xu Daoming , He Qiang
Published: April 2024

In order to enhance the quality of thread processing by tap, a systematic analysis of its forming mechanism and factors affecting forming quality is conducted. Effects of the number of edges, the amount of shovel back, the extrusion cone, the calibration part and the extrusion cone angle on the torque and temperature are achieved by finite element analysis and experiments. From the perspective of reducing torque and temperature during the forming process, the optimal combination of tap structural parameters for machining M22×2 internal threads on 42CrMo4 high-strength steel are further obtained through orthogonal optimization. The results show that, unlike the cutting process of threads, the extrusion forming process of threads is a net forming process in which metal undergoes plastic deformation in a limited space, and the metal material continuously flows along the edge of the V-shaped groove of the tap, gradually piling up to form the thread tooth shape. This also caused a noticeable lack of flesh at the top of the extruded thread teeth. Better quality threads can be obtained by machining with optimized structural parameters. The maximum torque and temperature during the machining process are reduced by 22.86% and 20.31%, respectively. The depth of the hardened layer increased by 0.05 mm, and the root and top hardness of the teeth increased by 10 HV0.2 and 5 HV0.2, respectively.
Creep and Shrinkage Properties of Nano-SiO2-Modified Recycled Aggregate Concrete
Authors: Zhou Yingwu , Zhuang Jiahao , Lin Wenwei , Xu Wenzhuo , Hu Rui
Published: April 2024

The poor performance of recycled concrete aggregate (RCA) leads to greater creep in recycled aggregate concrete (RAC) compared to natural aggregate concrete (NAC). To enhance the quality of RCA, this paper utilizes a 2% concentration of a nano-SiO2 (NS) solution for pre-soaking RCA. This study aims to replace natural aggregate (NA) with NS-modified recycled aggregate (SRCA) and investigate the creep and shrinkage properties of NS-modified recycled aggregate concrete (SRAC) at various SRCA replacement rates. Subsequently, the creep and shrinkage strains of NAC, SRAC, and RAC are simulated using the finite element method. Finally, a comparative analysis is conducted with the predicted creep and shrinkage strains from CEB-FIP, ACI, B3, and GL2000 models. The experimental results indicate that the creep and shrinkage deformation of SRAC increases with the SRCA replacement rate. Compared to NAC, the creep and shrinkage deformation of SRAC at replacement rates of 30%, 50%, 70%, and 100% increased by 2%, 7%, 13%, and 30%, respectively. However, when 100% of the natural aggregate is replaced with SRCA, the creep and shrinkage deformation decreases by 7% compared to RAC. Moreover, the CEB-FIP and ACI models can predict the creep and shrinkage deformation of concrete reasonably well.
Effect of Ni Doping on the Thermoelectric Properties of YbCo2Zn20
Authors: Galeano-Cabral Jorge R. , Schundelmier Benny , Oladehin Olatunde , Feng Keke , Ordonez Juan C. , Baumbach Ryan E. , Wei Kaya
Published: April 2024

Thermoelectric devices are both solid-state heat pumps and energy generators. Having a reversible process without moving parts is of high importance for applications in remote locations or under extreme conditions. Yet, most thermoelectric devices have a rather limited energy conversion efficiency due to the natural competition between high electrical conductivity and low thermal conductivity, both being essential conditions for achieving a high energy conversion efficiency. Heavy-fermion compounds YbT2Zn20 (T = Co, Rh, Ir) have been reported to be potential candidate materials for thermoelectric applications at low temperatures. Motivated by this result, we applied chemical substitution studies on the transition metal site in order to optimize the charge carrier concentration as well as promote more efficient phonon scatterings. Here, we present the latest investigation on the Ni-doped specimens YbCo2−xNixZn20, where enhanced thermoelectric figure of merit values have been obtained.
Meroterpenoids from Marine Sponge Hyrtios sp. and Their Anticancer Activity against Human Colorectal Cancer Cells
Authors: Wang Jie , Yan Yue-Lu , Yu Xin-Yi , Pan Jia-Yan , Liu Xin-Lian , Hong Li-Li , Wang Bin
Published: April 2024

Two new meroterpenoids, hyrtamide A (1) and hyrfarnediol A (2), along with two known ones, 3-farnesyl-4-hydroxybenzoic acid methyl ester (3) and dictyoceratin C (4), were isolated from a South China Sea sponge Hyrtios sp. Their structures were elucidated by NMR and MS data. Compounds 2–4 exhibited weak cytotoxicity against human colorectal cancer cells (HCT-116), showing IC50 values of 41.6, 45.0, and 37.3 μM, respectively. Furthermore, compounds 3 and 4 significantly suppressed the invasion of HCT-116 cells while also downregulating the expression of vascular endothelial growth factor receptor 1 (VEGFR-1) and vimentin proteins, which are key markers associated with angiogenesis and epithelial–mesenchymal transition (EMT). Our findings suggest that compounds 3 and 4 may exert their anti-invasive effects on tumor cells by inhibiting the expression of VEGFR-1 and impeding the process of EMT.
Zeaxanthin epoxidase 3 Knockout Mutants of the Model Diatom Phaeodactylum tricornutum Enable Commercial Production of the Bioactive Carotenoid Diatoxanthin
Authors: Græsholt Cecilie , Brembu Tore , Volpe Charlotte , Bartosova Zdenka , Serif Manuel , Winge Per , Nymark Marianne
Published: April 2024

Carotenoids are pigments that have a range of functions in human health. The carotenoid diatoxanthin is suggested to have antioxidant, anti-inflammatory and chemo-preventive properties. Diatoxanthin is only produced by a few groups of microalgae, where it functions in photoprotection. Its large-scale production in microalgae is currently not feasible. In fact, rapid conversion into the inactive pigment diadinoxanthin is triggered when cells are removed from a high-intensity light source, which is the case during large-scale harvesting of microalgae biomass. Zeaxanthin epoxidase (ZEP) 2 and/or ZEP3 have been suggested to be responsible for the back-conversion of high-light accumulated diatoxanthin to diadinoxanthin in low-light in diatoms. Using CRISPR/Cas9 gene editing technology, we knocked out the ZEP2 and ZEP3 genes in the marine diatom Phaeodactylum tricornutum to investigate their role in the diadinoxanthin–diatoxanthin cycle and determine if one of the mutant strains could function as a diatoxanthin production line. Light-shift experiments proved that ZEP3 encodes the enzyme converting diatoxanthin to diadinoxanthin in low light. Loss of ZEP3 caused the high-light-accumulated diatoxanthin to be stable for several hours after the cultures had been returned to low light, suggesting that zep3 mutant strains could be suitable as commercial production lines of diatoxanthin.
Retrospective Evaluation of the Efficacy of Total Neoadjuvant Therapy and Chemoradiotherapy Neoadjuvant Treatment in Relation to Surgery in Patients with Rectal Cancer
Authors: Bratu Lucian Dragoș , Schenker Michael , Stovicek Puiu Olivian , Schenker Ramona Adriana , Mehedințeanu Alina Maria , Berisha Tradian Ciprian , Donoiu Andreas , Mogoantă Stelian Ștefăniță
Published: April 2024

Background and Objective: In the therapeutic strategy of rectal cancer, radiotherapy has consolidated its important position and frequent use in current practice due to its indications as neoadjuvant, adjuvant, definitive, or palliative treatment. In recent years, total neoadjuvant therapy (TNT) has been established as the preferred regimen compared to concurrent neoadjuvant chemoradiotherapy (CRT). In relation to better outcomes, the percentage of patients who achieved pathological complete response (pCR) after neoadjuvant treatment is higher in the case of TNT. This study aimed to analyze the response to TNT compared to neoadjuvant CRT regarding pCR rate and the change in staging after surgical intervention. Materials and Methods: We performed a retrospective study on 323 patients with rectal cancer and finally analyzed the data of 201 patients with neoadjuvant treatment, selected based on the inclusion and exclusion criteria. Patients received CRT neoadjuvant therapy or TNT neoadjuvant therapy with FOLFOX or CAPEOX. Results: Out of 157 patients who underwent TNT treatment, 19.74% had pathological complete response, whereas in the group with CRT (n = 44), those with pCR were 13.64%. After neoadjuvant treatment, the most frequent TNM classifications were ypT2 (40.30%) and ypN0 (79.10%). The statistical analysis of the postoperative disease stage, after neoadjuvant therapy, showed that the most frequent changes were downstaging (71.14%) and complete response (18.41%). Only four patients (1.99%) had an upstaging change. The majority of patients (88.56%) initially presented clinical evidence of nodal involvement whereas only 20.9% of the patients still presented regional disease at the time of surgical intervention. Conclusions: By using TNT, a higher rate of stage reduction is obtained compared to the neoadjuvant CRT treatment. The post-neoadjuvant-treatment imagistic evaluation fails to accurately evaluate the response. A better response to TNT was observed in young patients.
Human Papillomavirus Is Rare and Does Not Correlate with p16INK4A Expression in Non-Small-Cell Lung Cancer in a Jordanian Subpopulation
Authors: Abu Al Karsaneh Ola , Al Anber Arwa , AlMustafa Sahar , AlMa’aitah Hussien , AlQadri Batool , Igbaria Abir , Tayem Rama , Khasawneh Mustafa , Batayha Shaima , Saleh Tareq , ALQudah Mohammad , Sughayer Maher
Published: April 2024

Background and Objectives: Human papillomavirus (HPV) was previously investigated in lung cancer with wide inter-geographic discrepancies. p16INK4a has been used as a surrogate for detecting high-risk HPV (HR-HPV) in some cancer types. This study assessed the evidence of HPV in non-small-cell lung cancer (NSCLC) among Jordanian patients, investigated the expression of p16INK4a, and evaluated its prognostic value and association with HPV status. Materials and Methods: The archived samples of 100 patients were used. HPV DNA detection was performed by real-time polymerase chain reaction (RT-PCR). p16INK4a expression was assessed by immunohistochemistry (IHC). The Eighth American Joint Committee on Cancer protocol (AJCC) of head and neck cancer criteria were applied to evaluate p16INK4a positivity considering a moderate/strong nuclear/cytoplasmic expression intensity with a distribution in ≥75% of cells as positive. Results: HPV DNA was detected in 5% of NSCLC cases. Three positive cases showed HR-HPV subtypes (16, 18, 52), and two cases showed the probable HR-HPV 26 subtype. p16INK4a expression was positive in 20 (20%) NSCLC cases. None of the HPV-positive tumors were positive for p16INK4a expression. A statistically significant association was identified between p16INK4a expression and the pathological stage (p = 0.029) but not with other variables. No survival impact of p16INK4a expression was detected in NSCLC cases as a group; however, it showed a statistically significant association with overall survival (OS) in squamous cell carcinoma (SqCC) cases (p = 0.033). Conclusions: This is the first study to assess HPV and p16INK4a expression in a Jordanian population. HPV positivity is rare in NSCLC among a Jordanian subpopulation. P16 INK4a reliability as a surrogate marker for HPV infection in lung cancer must be revisited.
Conditions and Mechanism of Crystallization of Hydrous W-Fe Oxides with a Pyrochlore-Type of Structure (Elsmoreite Group) in the Oxidation Zone of Ore Deposits
Authors: Tarassov Mihail , Tarassova Eugenia
Published: April 2024

The purpose of the article is to elucidate the conditions and mechanism of crystallization of W-Fe oxide minerals with a pyrochlore-type structure (formerly ferritungstite, now elsmoreite group minerals) based on (1) a study of representative samples of secondary tungsten minerals from the oxidation zone of the Grantcharitsa tungsten deposit (Bulgaria) and (2) laboratory experiments under conditions suggested by the study of natural samples. It has been shown that crystallization of W-Fe pyrochlores occurs easily and effectively when treating WO3·xFe2O3·nH2O compounds (meymacite and tungstite) with W-Fe-containing solutions with pH 2.5–6.5 (70 °C); at the same time, direct crystallization (direct low-temperature hydrothermal synthesis) of these phases from aqueous solutions is unlikely. The crystallization of W-Fe pyrochlores under natural and laboratory conditions occurs through the oriented attachment of their nanocrystals to the {111} faces of growing crystals. The nucleation of such nanocrystals occurs in the bulk of the solution as a result of the interaction of the W-Fe solution with the W-(Fe) oxide hydrate precursor. The Fe/W ratio in the resulting W-Fe pyrochlore phase depends on the Fe/W ratio in the solution and precursor, as well as on the pH of the solution.
A Systematic Review of Statins for the Treatment of Nonalcoholic Steatohepatitis: Safety, Efficacy, and Mechanism of Action
Authors: Zhang Shiqin , Ren Xiaoling , Zhang Bingzheng , Lan Tian , Liu Bing
Published: April 2024

Nonalcoholic fatty liver disease (NAFLD) is the liver component of a cluster of conditions, while its subtype, nonalcoholic steatohepatitis (NASH), emerges as a potentially progressive liver disorder that harbors the risk of evolving into cirrhosis and culminating in hepatocellular carcinoma (HCC). NASH and cardiovascular disease (CVD) have common risk factors, but compared to liver-related causes, the most common cause of death in NASH patients is CVD. Within the pharmacological armamentarium, statins, celebrated for their lipid-modulating prowess, have now garnered attention for their expansive therapeutic potential in NASH. Evidence from a plethora of studies suggests that statins not only manifest anti-inflammatory and antifibrotic properties but also impart a multifaceted beneficial impact on hepatic health. In this review, we used “statin”, “NAFLD”, “NASH”, and “CVD” as the major keywords and conducted a literature search using the PubMed and Web of Science databases to determine the safety and efficacy of statins in patients and animals with NASH and NAFLD, and the mechanism of statin therapy for NASH. Simultaneously, we reviewed the important role of the intestinal microbiota in statin therapy for NASH, as it is hoped that statins will provide new insights into modulating the harmful inflammatory microbiota in the gut and reducing systemic inflammation in NASH patients.
A Study on the Efficient Preparation of α-Ketoglutarate with L-Glutamate Oxidase
Authors: Niu Shuhui , Liu Fang , Wang Yaping , Rao Ben , Wang Yueying
Published: April 2024

Alpha-ketoglutaric acid (α-KG), as an intermediate product of the tricarboxylic acid cycle, plays a crucial role in peptide and amino acid synthesis. In order to reduce costs and improve efficiency in the oxidative production of α-ketoglutaric acid, this study successfully synthesized and expressed L-glutamate oxidase (LGOXStr) from Streptomyces viridosporus R111 and catalase (KatGEsc) from Escherichia coli H736. Two immobilization methods and the conditions for one-step whole-cell catalysis of α-ketoglutaric acid were investigated. α-Ketoglutaric acid has broad applications in the pharmaceutical, food, and chemical industries. The specific research results are as follows: (1) By fusing the sfGFP tag, L-glutamate oxidase (LGOXStr r) and catalase (KatGEsc) were successfully anchored to the outer membrane of Escherichia coli cells, achieving one-step whole-cell catalysis of α-ketoglutaric acid with a conversion efficiency of up to 75%. (2) Through the co-immobilization of LGOXStr and KatGEsc, optimization of the preparation parameters of immobilized cells, and exploration of the immobilization method using E.coli@ZIF-8, immobilized cells with conversion rates of over 60% were obtained even after 10 cycles of reuse. Under the optimal conditions, the production rate of α-ketoglutaric acid reached 96.7% in a 12 h reaction, which is 1.1 times that of E. coli@SA and 1.29 times that of free cells.
Evaluation of Physicochemical Properties of Ipsapirone Derivatives Based on Chromatographic and Chemometric Approaches
Authors: Nisterenko Wiktor , Kułaga Damian , Woziński Mateusz , Singh Yash Raj , Judzińska Beata , Jagiello Karolina , Greber Katarzyna Ewa , Sawicki Wiesław , Ciura Krzesimir
Published: April 2024

Drug discovery is a challenging process, with many compounds failing to progress due to unmet pharmacokinetic criteria. Lipophilicity is an important physicochemical parameter that affects various pharmacokinetic processes, including absorption, metabolism, and excretion. This study evaluated the lipophilic properties of a library of ipsapirone derivatives that were previously synthesized to affect dopamine and serotonin receptors. Lipophilicity indices were determined using computational and chromatographic approaches. In addition, the affinity to human serum albumin (HSA) and phospholipids was assessed using biomimetic chromatography protocols. Quantitative Structure–Retention Relationship (QSRR) methodologies were used to determine the impact of theoretical descriptors on experimentally determined properties. A multiple linear regression (MLR) model was calculated to identify the most important features, and genetic algorithms (GAs) were used to assist in the selection of features. The resultant models showed commendable predictive accuracy, minimal error, and good concordance correlation coefficient values of 0.876, 0.149, and 0.930 for the validation group, respectively.
Influence of the Nitrogen Fertilization on the Yield, Biometric Characteristics and Chemical Composition of Stevia rebaudiana Bertoni Grown in Poland
Authors: Śniegowska Joanna , Biesiada Anita , Gasiński Alan
Published: April 2024

Stevia rebaudiana Bertoni is a plant native to South America that has gathered much interest in recent decades thanks to diterpene glycosides, called steviosides, which it produces. These compounds are characterised by their sweetness, which is 250–300 times higher than saccharose, and they contain almost no caloric value. Stevia is currently also grown outside the South American continent, in various countries characterised by warm weather. This research aimed to determine whether it is viable to grow Stevia rebaudiana plants in Poland, a country characterised by a cooler climate than the native regions for stevia plants. Additionally, the impact of adding various dosages and forms of nitrogen fertiliser was analysed. It was determined that Stevia rebaudiana grown in Poland is characterised by a rather low concentration of steviosides, although proper nitrogen fertilisation can improve various characteristics of the grown plants. The addition of 100 kg or 150 kg of nitrogen per hectare of the field in the form of urea or ammonium nitrate increased the yield of the stevia plants. The stevioside content can be increased by applying fertilisation using 100 kg or 150 kg of nitrogen per hectare in the form of ammonium sulfate. The total yield of the stevia plants grown in Poland was lower than the yield typically recorded in warmer countries, and the low concentration of steviosides in the plant suggests that more research about growing Stevia rebaudiana in Poland would be needed to develop profitable methods of stevia cultivation.
Sesquiterpene Lactones Containing an α-Methylene-γ-Lactone Moiety Selectively Down-Regulate the Expression of Tumor Necrosis Factor Receptor 1 by Promoting Its Ectodomain Shedding in Human Lung Adenocarcinoma A549 Cells
Authors: Vu Quy Van , Sayama Shinsei , Ando Masayoshi , Kataoka Takao
Published: April 2024

Alantolactone is a eudesmane-type sesquiterpene lactone containing an α-methylene-γ-lactone moiety. Previous studies showed that alantolactone inhibits the nuclear factor κB (NF-κB) signaling pathway by targeting the inhibitor of NF-κB (IκB) kinase. However, in the present study, we demonstrated that alantolactone selectively down-regulated the expression of tumor necrosis factor (TNF) receptor 1 (TNF-R1) in human lung adenocarcinoma A549 cells. Alantolactone did not affect the expression of three adaptor proteins recruited to TNF-R1. The down-regulation of TNF-R1 expression by alantolactone was suppressed by an inhibitor of TNF-α-converting enzyme. Alantolactone increased the soluble forms of TNF-R1 that were released into the culture medium as an ectodomain. The structure–activity relationship of eight eudesmane derivatives revealed that an α-methylene-γ-lactone moiety was needed to promote TNF-R1 ectodomain shedding. In addition, parthenolide and costunolide, two sesquiterpene lactones with an α-methylene-γ-lactone moiety, increased the amount of soluble TNF-R1. Therefore, the present results demonstrate that sesquiterpene lactones with an α-methylene-γ-lactone moiety can down-regulate the expression of TNF-R1 by promoting its ectodomain shedding in A549 cells.
NIMO: A Natural Product-Inspired Molecular Generative Model Based on Conditional Transformer
Authors: Shen Xiaojuan , Zeng Tao , Chen Nianhang , Li Jiabo , Wu Ruibo
Published: April 2024

Natural products (NPs) have diverse biological activity and significant medicinal value. The structural diversity of NPs is the mainstay of drug discovery. Expanding the chemical space of NPs is an urgent need. Inspired by the concept of fragment-assembled pseudo-natural products, we developed a computational tool called NIMO, which is based on the transformer neural network model. NIMO employs two tailor-made motif extraction methods to map a molecular graph into a semantic motif sequence. All these generated motif sequences are used to train our molecular generative models. Various NIMO models were trained under different task scenarios by recognizing syntactic patterns and structure–property relationships. We further explored the performance of NIMO in structure-guided, activity-oriented, and pocket-based molecule generation tasks. Our results show that NIMO had excellent performance for molecule generation from scratch and structure optimization from a scaffold.
Catalytically Active SiO2 Aerogels Comprising Chelate Complexes of Palladium
Authors: Sipyagina Nataliya A. , Vlasenko Nikita E. , Malkova Alena N. , Kopitsa Gennady P. , Gorshkova Yulia E. , Kottsov Sergey Yu. , Lermontov Sergey A.
Published: April 2024

A series of silica-based aerogels comprising novel bifunctional chelating ligands was prepared. To produce target aerogels, two aminosilanes, namely (3-aminopropyl)trimethoxysilane (APTMS) and N-(2-aminoethyl)-3-aminopropyltrimethoxysilane (AEAPTMS), were acylated by natural amino acids ((S)-(+)-2-phenylglycine or L-phenylalanine), followed by gelation and supercritical drying (SCD). Lithium tetrachloropalladate was used as the metal ion source to prepare strong complexes of Pd2+ with amino acids covalently bonded to a silica matrix. Aerogels bearing chelate complexes retain the Pd2+ oxidation state after supercritical drying in CO2, but the Pd ion is reduced to Pd metal after SCD in isopropanol. Depending on the structure of amino complexes, Pd-containing aerogels showed catalytic activity and selectivity in the hydrogenation reactions of C=C, C≡C and C=O bonds.
Synthesis of ω-Chloroalkyl Aryl Ketones via C–C Bond Cleavage of tert-Cycloalkanols with Tetramethylammonium Hypochlorite
Authors: Hanazawa Natsumi , Kuriyama Masami , Yamamoto Kosuke , Onomura Osamu
Published: April 2024

An oxidative C–C bond cleavage of tert-cycloalkanols with tetramethylammonium hypochlorite (TMAOCl) has been developed. TMAOCl is easy to prepare from tetramethylammonium hydroxide, and the combination of TMAOCl and AcOH effectively promoted the C–C bond cleavage in a two-phase system without additional phase-transfer reagents. Unstrained tert-cycloalkanols were transformed into ω-chloroalkyl aryl ketones in moderate to excellent yields under metal-free and mild reaction conditions.
The Recognition Pathway of the SARS-CoV-2 Spike Receptor-Binding Domain to Human Angiotensin-Converting Enzyme 2
Authors: Peng Can , Lv Xinyue , Zhang Zhiqiang , Lin Jianping , Li Dongmei
Published: April 2024

COVID-19 caused by SARS-CoV-2 has spread around the world. The receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 is a critical component that directly interacts with host ACE2. Here, we simulate the ACE2 recognition processes of RBD of the WT, Delta, and OmicronBA.2 variants using our recently developed supervised Gaussian accelerated molecular dynamics (Su-GaMD) approach. We show that RBD recognizes ACE2 through three contact regions (regions I, II, and III), which aligns well with the anchor–locker mechanism. The higher binding free energy in State d of the RBDOmicronBA.2-ACE2 system correlates well with the increased infectivity of OmicronBA.2 in comparison with other variants. For RBDDelta, the T478K mutation affects the first step of recognition, while the L452R mutation, through its nearby Y449, affects the RBDDelta-ACE2 binding in the last step of recognition. For RBDOmicronBA.2, the E484A mutation affects the first step of recognition, the Q493R, N501Y, and Y505H mutations affect the binding free energy in the last step of recognition, mutations in the contact regions affect the recognition directly, and other mutations indirectly affect recognition through dynamic correlations with the contact regions. These results provide theoretical insights for RBD-ACE2 recognition and may facilitate drug design against SARS-CoV-2.
Promising Antileishmanial Activity of Micromeria nervosa Essential Oil: In Vitro and In Silico Studies
Authors: Essid Rym , Kefi Sarra , Damergi Bilel , Abid Ghassen , Fares Nadia , Jallouli Selim , Abid Islem , Hussein Dina , Tabbene Olfa , Limam Ferid
Published: April 2024

The present study aimed to evaluate the leishmanicidal potential of the essential oil (EO) of Micromeria (M.) nervosa and to investigate its molecular mechanism of action by qPCR. Furthermore, in silicointeraction study of the major M. nervosa EO compounds with the enzyme cytochrome P450 sterol 14α-demethylase (CYP51) was also performed. M. nervosa EO was analyzed by gas chromatography-mass spectrometry (GC-MS). Results showed that α-pinene (26.44%), t-cadinol (26.27%), caryophyllene Oxide (7.73 ± 1.04%), and α-Cadinene (3.79 ± 0.12%) are the major compounds of M. nervosa EO. However, limited antioxidant activity was observed, as this EO was ineffective in neutralizing DPPH free radicals and in inhibiting β-carotene bleaching. Interestingly, it displayed effective leishmanicidal potential against promastigote (IC50 of 6.79 and 5.25 μg/mL) and amastigote (IC50 of 8.04 and 7.32 μg/mL) forms of leishmania (L.) infantum and L. major, respectively. Molecular mechanism investigation showed that M. nervosa EO displayed potent inhibition on the thiol regulatory pathway. Furthermore, a docking study of the main components of the EO with cytochrome P450 sterol 14α-demethylase (CYP51) enzyme revealed that t-cadinol exhibited the best binding energy values (−7.5 kcal/mol), followed by α-cadinene (−7.3 kcal/mol) and caryophyllene oxide (−7 kcal/mol). These values were notably higher than that of the conventional drug fluconazole showing weaker binding energy (−6.9 kcal/mol). These results suggest that M. nervosa EO could serve as a potent and promising candidate for the development of alternative antileishmanial agent in the treatment of leishmaniasis.
Graphene-Tuned, Tightly Coupled Hybrid Plasmonic Meta-Atoms
Authors: Chen Kai , Li Ke , Wang Yiming , Zhang Zihao , Shi Yanpeng , Song Aimin , Zhang Yifei
Published: April 2024

Tightly coupled meta-atoms (TCMAs) are densely packed metamaterials with unnatural refractive indexes. Actively modulated TCMAs with tunable optical properties have found many applications in beam shaping, holography, and enhanced light–matter interactions. Typically, TCMAs are studied in the classic Bloch theory. Here, tightly coupled H-shaped meta-atoms are proposed with an ultra-high permittivity of ~6000, and their active modulation with graphene is designed by using the tightly coupled dipole array (TCDA) theory. The H-shaped meta-atoms are used as dipole arms, and the graphene strips function as the dipole loads. By tuning the chemical potential of graphene, the resonant amplitude, frequency, and permittivity are dynamically modulated. The simulations indicate that the real and imaginary parts of permittivity change from 6854 to 1522 and from 7356 to 2870, respectively. The experimental validation demonstrates a modulation depth of 11.6% in the resonant frequency, i.e., from 219.4 to 195 GHz, and a substantial 52.5% modulation depth in transmittance under a bias voltage of less than 1.5 V.
The Role of Social Media Advertisement and Physical Activity on Eating Behaviors among the General Population in Saudi Arabia
Authors: Aleid Sara , Alshahrani Najim Z. , Alsedrah Safa , Carvalho Ana Branca , Lima Maria João , Teixeira-Lemos Edite , Raposo António
Published: April 2024

Over the past few decades, people in Saudi Arabia have become less inclined to adopt active lifestyles and healthy eating habits due to the increasing use of digital technologies such as social media. The objective of this online-based cross-sectional study was to assess the role of social media food advertisements and physical activity on eating behaviors among the general population in Saudi Arabia (n = 471). Data were collected through a structured questionnaire, which consisted of four parts: (i) sociodemographic information, (ii) attitude towards social media, (iii) eating behaviors-related information, and (iv) exposure to and engagement with social media advertisements. The study’s outcome variable, eating behaviors (healthy vs. unhealthy), was assessed using the following question: “Are you on a healthy diet (such as a balanced diet, keto, or low carb)?” A multiple binary logistic regression analysis was performed to investigate the factors that influence unhealthy eating behaviors. Approximately 79.6% of the participants had unhealthy eating behaviors. Participants who were not involved in daily physical activity were more likely to have unhealthy eating behaviors compared to their counterparts (adjusted odds ratio, AOR = 4.86). Participants who watched food ads on social media channels 1–3 times a week (AOR = 2.58) or daily (AOR = 3.49) were more likely to have unhealthy eating behaviors than their counterparts. Participants whose appetite to try foods increases always (AOR = 1.42) or usually (AOR = 2.88) after viewing ads on social media were more likely to have unhealthy eating behaviors. These findings suggest that policymakers should take immediate action to regulate food advertising policy to promote a healthy food environment across the country. Saudis should be encouraged to engage in more physical activity, which could support the maintenance of healthy eating patterns and lifestyles.
Histamine Intolerance: Symptoms, Diagnosis, and Beyond
Authors: Jochum Christoph
Published: April 2024

Histamine intolerance is a condition characterized by the accumulation of histamine to a point that exceeds the body’s capacity to eliminate it. Researchers have attributed several reasons to this condition, such as genetic factors, alcohol, and dietary deficiencies, among other elements. Symptoms of histamine intolerance have been found to extend beyond the gastrointestinal tract and to the whole body, with these symptoms being sporadic and non-specific. This review will explore various aspects related to histamine intolerance, such as its causes, symptoms, diagnosis, and information related to management.
Diabetic Rats Induced Using a High-Fat Diet and Low-Dose Streptozotocin Treatment Exhibit Gut Microbiota Dysbiosis and Osteoporotic Bone Pathologies
Authors: Huang Kuo-Chin , Chuang Po-Yao , Yang Tien-Yu , Tsai Yao-Hung , Li Yen-Yao , Chang Shun-Fu
Published: April 2024

Type 2 diabetes mellitus (T2DM) presents a challenge for individuals today, affecting their health and life quality. Besides its known complications, T2DM has been found to contribute to bone/mineral abnormalities, thereby increasing the vulnerability to bone fragility/fractures. However, there is still a need for appropriate diagnostic approaches and targeted medications to address T2DM-associated bone diseases. This study aims to investigate the relationship between changes in gut microbiota, T2DM, and osteoporosis. To explore this, a T2DM rat model was induced by combining a high-fat diet and low-dose streptozotocin treatment. Our findings reveal that T2DM rats have lower bone mass and reduced levels of bone turnover markers compared to control rats. We also observe significant alterations in gut microbiota in T2DM rats, characterized by a higher relative abundance of Firmicutes (F) and Proteobacteria (P), but a lower relative abundance of Bacteroidetes (B) at the phylum level. Further analysis indicates a correlation between the F/B ratio and bone turnover levels, as well as between the B/P ratio and HbA1c levels. Additionally, at the genus level, we observe an inverse correlation in the relative abundance of Lachnospiraceae. These findings show promise for the development of new strategies to diagnose and treat T2DM-associated bone diseases.