bluuebunny/crossref_metadata_2025 huggingface dataset:
Combined Metabolomics and Transcriptomics Analysis of the Distribution of Flavonoids in the Fibrous Root and Taproot of Polygonatum kingianum Coll.et Hemsl
Authors: Mo Xinchun , Wang Ling , Yu Chenghua , Kou Can
Published: June 2024

Polygonati rhizoma, known for its distinct yellow rhizomes, is a common therapeutic and culinary plant in Far East Asia. The hue of medicinal plants is closely tied to the flavonoid biosynthesis and content levels. In this research, the fibrous root and taproot of Polygonatum kingianum Coll.et Hemsl. were studied to explore the secondary metabolite expression and flavonoid biosynthesis mechanisms using transcriptomics and metabolomics. Metabolic analysis identified that the differentially accumulated metabolites (DAMs) in the fibrous root and taproot were predominantly flavonoids, steroids, alkaloids, and phenolic acids. Overall, 200 flavonoids were identified in P. kingianum Coll.et Hemsl., with 170 exhibiting variances between the fibrous root and taproot. The transcriptome analysis revealed that a total of 289 unigenes encoding 32 enzymes were annotated into four flavonoid biosynthesis pathways, which include phenylpropanoid biosynthesis pathway, flavonoid biosynthesis pathway, isoflavonoid biosynthesis pathway, and flavone and flavonol biosynthesis pathway. The integration of transcriptomic and metabolomic data elucidated that the 76 differentially expressed genes (DEGs) encoding 13 enzyme genes (HCT, CCOMT, C4H, C3′H, CHI, PGT1, FLS, F3′H, CHS, ANR, DFR, F3′5′H, and LAR) and 15 DAMs preferred to be regulated in the flavonoid biosynthesis pathway. The expression of 10 DEGs was validated by qRT-PCR, agreeing with the same results by RNA-Seq. These findings shed light into the biosynthesis of secondary metabolites in P. kingianum Coll.et Hemsl., offering valuable information for the sustainable utilization and enhancement of this plant species.
Complete Mitochondrial Genome and Phylogenetic Analysis of the Blue Whistling Thrush (Myophonus caeruleus)
Authors: Yuan Zhenfeng , Liu Peng , Lu Xi , Zhu Dong , Liu Jun , Guo Qiang , Zhang Wenping , Duan Yubao
Published: June 2024

The blue whistling thrush (Myophonus caeruleus) is a bird belonging to the order Passeriformes and family Muscicapidae. M. caeruleus is widely distributed in China, Pakistan, India, and Myanmar and is a resident bird in the southern part of the Yangtze River in China and summer migratory bird in the northern part of the Yangtze River. At present, there are some controversies about the classification of M. caeruleus. We use complete mitochondrial genomes to provide insights into the phylogenetic position of M. caeruleus and its relationships among Muscicapidae. The mitochondrial genome (GenBank: MN564936) is 16,815 bp long and contains 13 protein-coding genes (PCGs), 2 rRNA genes, 22 tRNA genes, and a non-coding control region (D-loop). The thirteen PCGs started with GTG and ATG and ended with five types of stop codons. The nucleotide composition of T was 23.71%, that of C was 31.45%, that of A was 30.06%, and that of G was 14.78%. The secondary structures of 22 tRNAs were predicted, all of which could form typical cloverleaf structures. There were 24 mismatches, mainly G–U mismatches. Through phylogenetic tree reconstruction, it was found that Saxicola, Monticola, Oenanthe, and Phoenicurus were clustered into one clade, together with the sister group of Myophonus.
Association between Subjective Cognitive Complaints and Sleep Disturbance among Community-Dwelling Elderly Individuals in Japan
Authors: Goda Akio , Nakano Hideki , Kikuchi Yuki , Mori Kohei , Mitsumaru Nozomi , Murata Shin
Published: June 2024

Subjective cognitive complaints (SCCs) are a crucial modifiable risk factor for dementia. There is increasing interest in the association between SCC and sleep disturbance; however, the effects of sleep disturbance on SCC development among community-dwelling elderly individuals in Japan remain unclear. We aimed to cross-sectionally investigate the association between SCC and sleep disturbance, with adjustment for multiple factors related to cognitive decline, among 241 community-dwelling elderly persons without cognitive impairment. The measures were SCCs (Kihon Checklist-Cognitive Function, KCL-CF), sleep disturbance (Japanese version of the Athens Insomnia Scale, AIS-J), general cognitive function (Mini-Mental State Examination), and depressive symptoms (five-item version of the Geriatric Depression Scale [GDS-5]). The following data were collected: sex, age, educational history, whether the participants had visited a medical institution for diseases (hypertension, diabetes, hyperlipidemia, heart disease), and the presence/absence of established risk factors (hearing loss, history of head injury, drinking habits, smoking habits, social isolation, and physical inactivity and activity). Based on the KCL-CF, 96 and 145 participants were considered to have and lack SCCs, respectively. On logistic regression analysis, the AIS-J score and smoking history were significantly associated with SCCs. Our findings suggest that sleep disturbance is associated with SCC development among community-dwelling elderly people in Japan. Evaluating and managing sleep disturbances can be important in preventing SCCs and dementia.
Inflammatory Status in Trained and Untrained Mice at Different Pollution Levels
Authors: Foster Roberta , Veras Mariana Matera , Bachi Andre Luis Lacerda , Amaral Jonatas Bussador do , Yariwake Victor Yuji , Waked Dunia , Rodrigues Ana Clara Bastos , Farrajota Marilia , Pires Robério Pereira , Pantaleão Karina , dos Santos Juliana de Melo Batista , Damian Francys Helen , Saldiva Paulo Hilário , Vaisberg Mauro Walter
Published: June 2024

Atmospheric pollution can be defined as a set of changes that occur in the composition of the air, making it unsuitable and/or harmful and thereby generating adverse effects on human health. The regular practice of physical exercise (PE) is associated with the preservation and/or improvement of health; however, it can be influenced by neuroimmunoendocrine mechanisms and external factors such as air pollution, highlighting the need for studies involving the practice of PE in polluted environments. Herein, 24 male C57BL/6 mice were evaluated, distributed into four groups (exposed to a high concentration of pollutants/sedentary, exposed to a high concentration of pollutants/exercised, exposed to ambient air/sedentary, and exposed to ambient air/exercised). The exposure to pollutants occurred in the environmental particle concentrator (CPA) and the physical training was performed on a treadmill specially designed for use within the CPA. Pro- and anti-inflammatory markers in blood and bronchoalveolar lavage (BALF), BALF cellularity, and lung tissue were evaluated. Although the active group exposed to a high concentration of pollution showed a greater inflammatory response, both the correlation analysis and the ratio between pro- and anti-inflammatory cytokines demonstrated that the exercised group presented greater anti-inflammatory activity, suggesting a protective/adaptative effect of exercise when carried out in a polluted environment.
Rainfall and Temperature Influences on Childhood Diarrhea and the Effect Modification Role of Water and Sanitation Conditions: A Systematic Review and Meta-Analysis
Authors: Geremew Gorfu , Cumming Oliver , Haddis Alemayehu , Freeman Matthew C. , Ambelu Argaw
Published: June 2024

The latest report from the Intergovernmental Panel on Climate Change (IPCC) highlighted the worsening impacts of climate change. Two climate factors—temperature and rainfall uncertainties—influence the risk of childhood diarrhea, which remains a significant cause of morbidity and mortality in low- and middle-income countries. They create a conducive environment for diarrhea-causing pathogens and overwhelm environmental prevention measures. This study aimed to produce comprehensive evidence on the association of temperature and rainfall variability with the risk of childhood diarrhea and the influence of water and sanitation conditions on those associations. We conducted a systematic review and meta-analysis using the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) approach. Records published in English from 2006 to 2023 were searched on 8 January 2024 via PubMed, EMBASE, ScienceDirect, Scopus, the Cochrane Library, and Google/Google Scholar using comprehensive search terms. We assessed studies for any risk of bias using the Navigation Guide and rated the quality of the evidence using the GRADE approach. The heterogeneity among estimates was assessed using I-squared statistics (I2). The findings of the analysis were presented with forest plots using an incidence rate ratio (IRR). A meta-analysis was conducted on effect modifiers (water supply and sanitation conditions) using a random effects model with a 95% confidence interval (CI). The statistical analyses were conducted using R 4.3.2 software and Review Manager 5.3. A total of 2017 records were identified through searches, and only the 36 articles that met the inclusion criteria were included. The analysis suggests a small positive association between increased temperature and the occurrence of under-five diarrhea, with the pooled IRR = 1.04; 95% CI [1.03, 1.05], at I2 = 56% and p-value < 0.01, and increased rainfall and U5 diarrhea, with IRR = 1.14; 95% CI [1.03, 1.27], at I2 = 86% and p-value < 0.01. The meta-analysis indicated a positive association between unimproved latrine facilities and drinking water sources with a rainfall-modified effect on U5 diarrhea, with IRR = 1.21; 95% CI [0.95, 1.53], at I2 = 62% and p-value = 0.03. We found that an increase in mean temperature and rainfall was associated with an increased risk of childhood diarrhea. Where there were unimproved latrine facilities and drinking water sources, the increase in mean rainfall or temperature would increase the incidence of childhood diarrhea. The results of this review help in assessing the effectiveness of current intervention programs, making changes as needed, or creating new initiatives to lower the prevalence of childhood diarrhea.
Screening of the Skin-Regenerative Potential of Antimicrobial Peptides: Clavanin A, Clavanin-MO, and Mastoparan-MO
Authors: Alencar-Silva Thuany , Díaz-Martín Rubén D , Sousa dos Santos Mickelly , Saraiva Rivaldo Varejão Pasqual , Leite Michel Lopes , de Oliveira Rodrigues Maria Tereza , Pogue Robert , Andrade Rosângela , Falconi Costa Fabrício , Brito Nicolau , Dias Simoni Campos , Carvalho Juliana Lott
Published: June 2024

Skin wound healing is coordinated by a delicate balance between proinflammatory and anti-inflammatory responses, which can be affected by opportunistic pathogens and metabolic or vascular diseases. Several antimicrobial peptides (AMPs) possess immunomodulatory properties, suggesting their potential to support skin wound healing. Here, we evaluated the proregenerative activity of three recently described AMPs (Clavanin A, Clavanin-MO, and Mastoparan-MO). Human primary dermal fibroblasts (hFibs) were used to determine peptide toxicity and their capacity to induce cell proliferation and migration. Furthermore, mRNA analysis was used to investigate the modulation of genes associated with skin regeneration. Subsequently, the regenerative potential of the peptides was further confirmed using an ex vivo organotypic model of human skin (hOSEC)-based lesion. Our results indicate that the three molecules evaluated in this study have regenerative potential at nontoxic doses (i.e., 200 μM for Clavanin-A and Clavanin-MO, and 6.25 μM for Mastoparan-MO). At these concentrations, all peptides promoted the proliferation and migration of hFibs during in vitro assays. Such processes were accompanied by gene expression signatures related to skin regenerative processes, including significantly higher KI67, HAS2 and CXCR4 mRNA levels induced by Clavanin A and Mastoparan-MO. Such findings translated into significantly accelerated wound healing promoted by both Clavanin A and Mastoparan-MO in hOSEC-based lesions. Overall, the data demonstrate the proregenerative properties of these peptides using human experimental skin models, with Mastoparan-MO and Clavanin A showing much greater potential for inducing wound healing compared to Clavanin-MO.
Idiosyncratic Drug-Induced Liver Injury and Amoxicillin–Clavulanate: Spotlight on Gut Microbiota, Fecal Metabolome and Bile Acid Profile in Patients
Authors: Román-Sagüillo Sara , Quiñones Castro Raisa , Juárez-Fernández María , Soluyanova Polina , Stephens Camilla , Robles-Díaz Mercedes , Jorquera Plaza Francisco , González-Gallego Javier , Martínez-Flórez Susana , García-Mediavilla María Victoria , Nistal Esther , Jover Ramiro , Sánchez-Campos Sonia
Published: June 2024

Several hepatic disorders are influenced by gut microbiota, but its role in idiosyncratic drug-induced liver injury (iDILI), whose main causative agent is amoxicillin–clavulanate, remains unknown. This pioneering study aims to unravel particular patterns of gut microbiota composition and associated metabolites in iDILI and iDILI patients by amoxicillin–clavulanate (iDILI-AC). Thus, serum and fecal samples from 46 patients were divided into three study groups: healthy controls (n = 10), non-iDILI acute hepatitis (n = 12) and iDILI patients (n = 24). To evaluate the amoxicillin–clavulanate effect, iDILI patients were separated into two subgroups: iDILI non-caused by amoxicillin–clavulanate (iDILI-nonAC) (n = 18) and iDILI-AC patients (n = 6). Gut microbiota composition and fecal metabolome plus serum and fecal bile acid (BA) analyses were performed, along with correlation analyses. iDILI patients presented a particular microbiome profile associated with reduced fecal secondary BAs and fecal metabolites linked to lower inflammation, such as dodecanedioic acid and pyridoxamine. Moreover, certain taxa like Barnesiella, Clostridia UCG-014 and Eubacterium spp. correlated with significant metabolites and BAs. Additionally, comparisons between iDILI-nonAC and iDILI-AC groups unraveled unique features associated with iDILI when caused by amoxicillin–clavulanate. In conclusion, specific gut microbiota profiles in iDILI and iDILI-AC patients were associated with particular metabolic and BA status, which could affect disease onset and progression.
Biochemical and Histological Differences between Longitudinal and Vertical Fibres of Dupuytren’s Palmar Aponeurosis and Innovative Clinical Implications
Authors: Fede Caterina , Coldebella Ludovico , Petrelli Lucia , Bassetto Franco , Tiengo Cesare , Stecco Carla
Published: June 2024

Dupuytren’s disease, a chronic and progressive fibroproliferative lesion of the hand, which affects the palmar fascia, has a recurrence rate after selective aponeurotomy of 20–40% at 5 years. This study focused, for the first time, on the microanatomical and histopathological characteristics of the longitudinal and vertical fibres (usually spared during surgery) in the aponeurosis with Dupuytren’s disease, in different stages of the Tubiana’s classification. Twelve human samples were collected and analysed by immunostaining, Total Collagen Assay, ELISA Immunoassay, and immunoblotting for the Von Willebrand factor, α-Sma, D2-40, CD-68, Total Collagen, Collagen-I and III, IL1β, TNF-α to analyse the blood and lymphatic vascularization, the amount and distribution of collagen, and the inflammation. The results show a progressive increase in the arterial vascularization in the vertical fibres (from 8.8/mm2 in the early stage to 21.4/mm2 in stage 3/4), and a parallel progressive decrease in the lymphatic drainage (from 6.2/mm2 to 2.8/mm2), correlated with a local inflammatory context (increase in IL-1β and TNF-α until the stage 2) in both the longitudinal and vertical fibres. The acute inflammation after stage 2 decreased, in favour of a fibrotic action, with the clear synthesis of new collagen (up to ~83 µg/mg), especially Collagen-I. These results clearly demonstrate the involvement of the septa of Legueu and Juvara in the disease pathology and the modifications with the disease’s progression. A greater understanding of the pathology becomes fundamental for staging and the adequate therapeutic timing, to obtain the best morpho-functional result and the lowest risk of complications.
Expanding Knowledge about the Influence of Citral on Cognitive Functions—In Vitro, In Vivo and Ex Vivo Studies
Authors: Wojtunik-Kulesza Karolina , Rudkowska Monika , Klimek Katarzyna , Agacka-Mołdoch Monika , Mołdoch Jarosław , Michalak Agnieszka
Published: June 2024

Citral, a common monoterpene found in numerous plants, is an interesting compound that has been shown to have various biological activities. Although it is widely distributed in nature and there are many studies presenting its biological activities, its anti-neurodegenerative activity, especially under in vivo conditions, is very poorly understood. Thus, this paper aimed to deepen knowledge about citral activity towards factors and symptoms of neurodegeneration. To accomplish this, several comprehensive tests were conducted, including the estimation of butyrylcholinesterase inhibition, the evaluation of hepatotoxicity and the detection of oxidative stress and lipid peroxidation in vitro, as well as an in vivo behavioral assessment using mice models. Additionally, ex vivo determination of level of the compound in the brain and blood of a tested animal was undertaken. The results obtained revealed that citral is able to inhibit butyrylcholinesterase activity and protect hepatic cells against oxidative stress and lipid peroxidation in vitro. Moreover, behavioral tests in vivo indicated that citral (50 mg/kg) improves memory processes associated with acquisition (passive avoidance test), both in acute and subchronic administration. Additionally, we found that the administration of citral at 25 mg/kg and 50 mg/kg did not significantly affect the locomotor activity. Beyond the aforementioned, gas chromatography-mass spectrometry analysis revealed the presence of the compound in the blood and brain after subchronic administration of citral. Taken together, the results obtained in vitro, in vivo and ex vivo clearly indicate that citral is a promising monoterpene that can potentially be used towards cognition improvement.
Functional and Structural Properties of Cytoplasmic Tropomyosin Isoforms Tpm1.8 and Tpm1.9
Authors: Lapshina Ksenia K. , Nefedova Victoria V. , Nabiev Salavat R. , Roman Svetlana G. , Shchepkin Daniil V. , Kopylova Galina V. , Kochurova Anastasia M. , Beldiia Evgenia A. , Kleymenov Sergey Y. , Levitsky Dmitrii I. , Matyushenko Alexander M.
Published: June 2024

The actin cytoskeleton is one of the most important players in cell motility, adhesion, division, and functioning. The regulation of specific microfilament formation largely determines cellular functions. The main actin-binding protein in animal cells is tropomyosin (Tpm). The unique structural and functional diversity of microfilaments is achieved through the diversity of Tpm isoforms. In our work, we studied the properties of the cytoplasmic isoforms Tpm1.8 and Tpm1.9. The results showed that these isoforms are highly thermostable and differ in the stability of their central and C-terminal fragments. The properties of these isoforms were largely determined by the 6th exons. Thus, the strength of the end-to-end interactions, as well as the affinity of the Tpm molecule for F-actin, differed between the Tpm1.8 and Tpm1.9 isoforms. They were determined by whether an alternative internal exon, 6a or 6b, was included in the Tpm isoform structure. The strong interactions of the Tpm1.8 and Tpm1.9 isoforms with F-actin led to the formation of rigid actin filaments, the stiffness of which was measured using an optical trap. It is quite possible that the structural and functional features of the Tpm isoforms largely determine the appearance of these isoforms in the rigid actin structures of the cell cortex.
In Silico Electrophysiological Investigation of Transient Receptor Potential Melastatin-4 Ion Channel Biophysics to Study Detrusor Overactivity
Authors: Mahapatra Chitaranjan , Thakkar Ravindra
Published: June 2024

Enhanced electrical activity in detrusor smooth muscle (DSM) cells is a key factor in detrusor overactivity which causes overactive bladder pathological disorders. Transient receptor potential melastatin-4 (TRPM4) channels, which are calcium-activated cation channels, play a role in regulating DSM electrical activities. These channels likely contribute to depolarizing the DSM cell membrane, leading to bladder overactivity. Our research focuses on understanding TRPM4 channel function in the DSM cells of mice, using computational modeling. We aimed to create a detailed computational model of the TRPM4 channel based on existing electrophysiological data. We employed a modified Hodgkin-Huxley model with an incorporated TRP-like current to simulate action potential firing in response to current and synaptic stimulus inputs. Validation against experimental data showed close agreement with our simulations. Our model is the first to analyze the TRPM4 channel’s role in DSM electrical activity, potentially revealing insights into bladder overactivity. In conclusion, TRPM4 channels are pivotal in regulating human DSM function, and TRPM4 channel inhibitors could be promising targets for treating overactive bladder.
Regrettable Substitutes and the Brain: What Animal Models and Human Studies Tell Us about the Neurodevelopmental Effects of Bisphenol, Per- and Polyfluoroalkyl Substances, and Phthalate Replacements
Authors: Morales-Grahl Elena , Hilz Emily N. , Gore Andrea C.
Published: June 2024

In recent decades, emerging evidence has identified endocrine and neurologic health concerns related to exposure to endocrine-disrupting chemicals (EDCs), including bisphenol A (BPA), certain per- and polyfluoroalkyl compounds (PFASs), and phthalates. This has resulted in consumer pressure to remove these chemicals from the market, especially in food-contact materials and personal care products, driving their replacement with structurally or functionally similar substitutes. However, these “new-generation” chemicals may be just as or more harmful than their predecessors and some have not received adequate testing. This review discusses the research on early-life exposures to new-generation bisphenols, PFASs, and phthalates and their links to neurodevelopmental and behavioral alterations in zebrafish, rodents, and humans. As a whole, the evidence suggests that BPA alternatives, especially BPAF, and newer PFASs, such as GenX, can have significant effects on neurodevelopment. The need for further research, especially regarding phthalate replacements and bio-based alternatives, is briefly discussed.
Network Models of BACE-1 Inhibitors: Exploring Structural and Biochemical Relationships
Authors: Akgüller Ömer , Balcı Mehmet Ali , Cioca Gabriela
Published: June 2024

This study investigates the clustering patterns of human β-secretase 1 (BACE-1) inhibitors using complex network methodologies based on various distance functions, including Euclidean, Tanimoto, Hamming, and Levenshtein distances. Molecular descriptor vectors such as molecular mass, Merck Molecular Force Field (MMFF) energy, Crippen partition coefficient (ClogP), Crippen molar refractivity (MR), eccentricity, Kappa indices, Synthetic Accessibility Score, Topological Polar Surface Area (TPSA), and 2D/3D autocorrelation entropies are employed to capture the diverse properties of these inhibitors. The Euclidean distance network demonstrates the most reliable clustering results, with strong agreement metrics and minimal information loss, indicating its robustness in capturing essential structural and physicochemical properties. Tanimoto and Hamming distance networks yield valuable clustering outcomes, albeit with moderate performance, while the Levenshtein distance network shows significant discrepancies. The analysis of eigenvector centrality across different networks identifies key inhibitors acting as hubs, which are likely critical in biochemical pathways. Community detection results highlight distinct clustering patterns, with well-defined communities providing insights into the functional and structural groupings of BACE-1 inhibitors. The study also conducts non-parametric tests, revealing significant differences in molecular descriptors, validating the clustering methodology. Despite its limitations, including reliance on specific descriptors and computational complexity, this study offers a comprehensive framework for understanding molecular interactions and guiding therapeutic interventions. Future research could integrate additional descriptors, advanced machine learning techniques, and dynamic network analysis to enhance clustering accuracy and applicability.
The Role of CD4+T Cells in Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma
Authors: Miao Yadi , Li Ziyong , Feng Juan , Lei Xia , Shan Juanjuan , Qian Cheng , Li Jiatao
Published: June 2024

Hepatocellular carcinoma (HCC) has become the fourth leading cause of cancer-related deaths worldwide; annually, approximately 830,000 deaths related to liver cancer are diagnosed globally. Since early-stage HCC is clinically asymptomatic, traditional treatment modalities, including surgical ablation, are usually not applicable or result in recurrence. Immunotherapy, particularly immune checkpoint blockade (ICB), provides new hope for cancer therapy; however, immune evasion mechanisms counteract its efficiency. In addition to viral exposure and alcohol addiction, nonalcoholic steatohepatitis (NASH) has become a major cause of HCC. Owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance, NASH-associated HCC patients respond much less efficiently to ICB treatment than do patients with other etiologies. In addition, abnormal inflammation contributes to NASH progression and NASH–HCC transition, as well as to HCC immune evasion. Therefore, uncovering the detailed mechanism governing how NASH-associated immune cells contribute to NASH progression would benefit HCC prevention and improve HCC immunotherapy efficiency. In the following review, we focused our attention on summarizing the current knowledge of the role of CD4+T cells in NASH and HCC progression, and discuss potential therapeutic strategies involving the targeting of CD4+T cells for the treatment of NASH and HCC.
To Erase or Not to Erase: Non-Canonical Catalytic Functions and Non-Catalytic Functions of Members of Histone Lysine Demethylase Families
Authors: Di Nisio Elena , Manzini Valeria , Licursi Valerio , Negri Rodolfo
Published: June 2024

Histone lysine demethylases (KDMs) play an essential role in biological processes such as transcription regulation, RNA maturation, transposable element control, and genome damage sensing and repair. In most cases, their action requires catalytic activities, but non-catalytic functions have also been shown in some KDMs. Indeed, some strictly KDM-related proteins and some KDM isoforms do not act as histone demethylase but show other enzymatic activities or relevant non-enzymatic functions in different cell types. Moreover, many studies have reported on functions potentially supported by catalytically dead mutant KDMs. This is probably due to the versatility of the catalytical core, which can adapt to assume different molecular functions, and to the complex multi-domain structure of these proteins which encompasses functional modules for targeting histone modifications, promoting protein–protein interactions, or recognizing nucleic acid structural motifs. This rich modularity and the availability of multiple isoforms in the various classes produced variants with enzymatic functions aside from histone demethylation or variants with non-catalytical functions during the evolution. In this review we will catalog the proteins with null or questionable demethylase activity and predicted or validated inactive isoforms, summarizing what is known about their alternative functions. We will then go through some experimental evidence for the non-catalytical functions of active KDMs.
Comprehensive Overview of Alzheimer’s Disease: Etiological Insights and Degradation Strategies
Authors: Singh Manish Kumar , Shin Yoonhwa , Ju Songhyun , Han Sunhee , Kim Sung Soo , Kang Insug
Published: June 2024

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and affects millions of individuals globally. AD is associated with cognitive decline and memory loss that worsens with aging. A statistical report using U.S. data on AD estimates that approximately 6.9 million individuals suffer from AD, a number projected to surge to 13.8 million by 2060. Thus, there is a critical imperative to pinpoint and address AD and its hallmark tau protein aggregation early to prevent and manage its debilitating effects. Amyloid-β and tau proteins are primarily associated with the formation of plaques and neurofibril tangles in the brain. Current research efforts focus on degrading amyloid-β and tau or inhibiting their synthesis, particularly targeting APP processing and tau hyperphosphorylation, aiming to develop effective clinical interventions. However, navigating this intricate landscape requires ongoing studies and clinical trials to develop treatments that truly make a difference. Genome-wide association studies (GWASs) across various cohorts identified 40 loci and over 300 genes associated with AD. Despite this wealth of genetic data, much remains to be understood about the functions of these genes and their role in the disease process, prompting continued investigation. By delving deeper into these genetic associations, novel targets such as kinases, proteases, cytokines, and degradation pathways, offer new directions for drug discovery and therapeutic intervention in AD. This review delves into the intricate biological pathways disrupted in AD and identifies how genetic variations within these pathways could serve as potential targets for drug discovery and treatment strategies. Through a comprehensive understanding of the molecular underpinnings of AD, researchers aim to pave the way for more effective therapies that can alleviate the burden of this devastating disease.
Assessing the Potential of an Enzymatically Liberated Salmon Oil to Support Immune Health Recovery from Acute SARS-CoV-2 Infection via Change in the Expression of Cytokine, Chemokine and Interferon-Related Genes
Authors: Currie Crawford , Myklebust Tor Åge , Bjerknes Christian , Framroze Bomi
Published: June 2024

Cytokines, chemokines, and interferons are released in response to viral infection with the ultimate aim of viral clearance. However, in SARS-CoV-2 infection, there is an imbalanced immune response, with raised cytokine levels but only a limited interferon response with inefficient viral clearance. Furthermore, the inflammatory response can be exaggerated, which risks both acute and chronic sequelae. Several observational studies have suggested a reduced risk of progression to severe COVID-19 in subjects with a higher omega-3 index. However, randomized studies of omega-3 supplementation have failed to replicate this benefit. Omega-3 fats provide important anti-inflammatory effects; however, fatty fish contains many other fatty acids that provide health benefits distinct from omega-3. Therefore, the immune health benefit of whole salmon oil (SO) was assessed in adults with mild to moderate COVID-19. Eleven subjects were randomized to best supportive care (BSC) with or without a full spectrum, enzymatically liberated SO, dosed at 4g daily, for twenty-eight days. Nasal swabs were taken to measure the change in gene expression of markers of immune response and showed that the SO provided both broad inflammation-resolving effects and improved interferon response. The results also suggest improved lung barrier function and enhanced immune memory, although the clinical relevance needs to be assessed in longer-duration studies. In conclusion, the salmon oil was well tolerated and provided broad inflammation-resolving effects, indicating a potential to enhance immune health.
The Therapeutic Role of NPS-1034 in Pancreatic Ductal Adenocarcinoma as Monotherapy and in Combination with Chemotherapy
Authors: Luan Yu-Ze , Wang Chi-Chih , Yu Chia-Ying , Chang Ya-Chuan , Sung Wen-Wei , Tsai Ming-Chang
Published: June 2024

Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge in terms of diagnosis and treatment, with limited therapeutic options and a poor prognosis. This study explored the potential therapeutic role of NPS-1034, a kinase inhibitor targeting MET and AXL, in PDAC. The investigation included monotherapy with NPS-1034 and its combination with the commonly prescribed chemotherapy agents, fluorouracil and oxaliplatin. Our study revealed that NPS-1034 induces cell death and reduces the viability and clonogenicity of PDAC cells in a dose-dependent manner. Furthermore, NPS-1034 inhibits the migration of PDAC cells by suppressing MET/PI3K/AKT axis-induced epithelial-to-mesenchymal transition (EMT). The combination of NPS-1034 with fluorouracil or oxaliplatin demonstrated a synergistic effect, significantly reducing cell viability and inducing tumor cell apoptosis compared to monotherapies. Mechanistic insights provided by next-generation sequencing indicated that NPS-1034 modulates immune responses by inducing type I interferon and tumor necrosis factor production in PDAC cells. This suggests a broader role for NPS-1034 beyond MET and AXL inhibition, positioning it as a potential immunity modulator. Overall, these findings highlight the anticancer potential of NPS-1034 in PDAC treatment in vitro, both as a monotherapy and in combination with traditional chemotherapy, offering a promising avenue for further in vivo investigation before clinical exploration.
Synthesis, Characterization, and Cytotoxicity of a Ga(III) Complex with Warfarin
Authors: Joe Hubert , Atanasova Venceslava , Mojžiš Jan , Kostova Irena
Published: June 2024

The gallium(III) complex of warfarin was synthesized, and its structure was determined by means of theoretical, analytical, and spectral analyses. Significant differences in the IR and Raman spectra of the complex were observed as compared to the spectra of the ligand and confirmed the suggested metal-ligand binding mode. The theoretical study of the Ga(III) complex of warfarin has been done to elucidate the structure-activity relation, inter- and intra-molecular interactions, and frontier molecular orbital energy analysis based on DFT computations. A molecular docking study has been performed to predict the biological activity of the molecule. In this paper, we report preliminary results about the cytotoxicity of the investigated compounds. The cytotoxic effects of the ligand and its Ga(III) complex were determined using the MTT method on different tumor cell lines. The screening performed revealed that the tested compounds exerted cytotoxic activity on the evaluated cell lines.
Advancing Fingertip Regeneration: Outcomes from a New Conservative Treatment Protocol
Authors: Kang Daihun
Published: June 2024

Background Fingertip injuries with volar pulp tissue defects present a significant challenge in management. This study aimed to evaluate the efficacy of a conservative treatment protocol using artificial dermis and semi-occlusive dressings for these injuries. Methods A single-center, prospective study was conducted on 31 patients with fingertip injuries involving volar pulp defects. The treatment protocol included wound debridement, application of artificial dermis (Pelnac®), and a semi-occlusive dressing (IV3000®). The outcomes were assessed using subjective questionnaires and objective measures, including fingerprint regeneration, sensory function, pain, and cosmetic appearance. Results The mean treatment duration was 45.29 days (SD = 17.53). Complications were minimal, with only one case (3.22%) directly attributable to the treatment. Fingerprint regeneration was considerable (mean score = 2.58, SD = 0.67). The sensory disturbances were minimal, with no significant differences across injury types. Post-treatment pain was low (mean = 0.45, SD = 0.67), and cosmetic satisfaction was high (mean = 4.09, SD = 0.94). The overall patient satisfaction was high (mean = 4.41, SD = 0.67), regardless of injury severity. Conclusions The conservative treatment protocol using artificial dermis and semi-occlusive dressings is a promising strategy for managing fingertip injuries with volar pulp defects. This approach minimizes surgical morbidity and achieves excellent functional and aesthetic outcomes.
Implications of Serum IgG4 Levels for Pancreatobiliary Disorders and Cancer
Authors: Tseng Ching-Tang , Liao Yi-Jun , Lin Cheng-Li , Peng Yen-Chun
Published: June 2024

Background/Objectives: Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated disorder presenting as mass-like lesions with obstructions. An elevated serum IgG4 level is identified in more than half of affected patients and is considered a diagnostic criterion. IgG4-RD is still easily misdiagnosed as neoplastic or infectious disease. We aimed to conduct a hospital-based study to illuminate the association between serum IgG4 levels and pancreatobiliary disorders and cancer. Methods: In this study, serum IgG4 levels were assessed at our hospital’s immunology laboratory, utilizing data from the hospital’s computer center, and the diagnostic codes used were based on ICD-9-CM. We analyzed IgG4 level data collected between April 2013 and April 2020, including patients’ age, gender, and diseases, but excluding the rationale for IgG4 level assessment. Employing propensity score matching (PSM) at a 1:1 ratio to mitigate age and gender confounding, we analyzed 759 patients divided into groups by IgG4 levels (≤140 and >140 mg/dL; and ≤140, 141–280, >280 mg/dL). We explored associations between IgG4 levels and conditions such as pancreatobiliary cancer (the group included cholangiocarcinoma, pancreatic cancer, and ampullary cancer), cholangitis, cholangiocarcinoma, pancreatitis, pancreatic cancer, and ampullary cancer. Results: Our study analyzed the demographics, characteristics, and serum IgG4 levels of participants and found no significant differences in serum IgG4 levels across various pancreatobiliary conditions. Nevertheless, the crude odds ratios (ORs) suggested a nuanced association between a higher IgG4 level > 280 mg/dL and increased risks of cancer and pancreatitis, with crude ORs of 1.52 (p = 0.03) and 1.49 (p = 0.008), respectively. After PSM matching, the further analysis of 759 matched patients showed no significant differences in IgG4 levels > 140 mg/dL between cancerous and non-cancerous groups, nor across other pancreatobiliary conditions. A higher serum IgG4 level > 280 mg/dL was significantly associated with pancreatobiliary cancer and cholangiocarcinoma, with crude ORs of 1.61 (p = 0.026) and 1.62 (p = 0.044), respectively. In addition, IgG4 > 280 mg/dL showed a greater association with pancreatic cancer compared with 141–280 mg/dL, with crude OR of 2.18 (p = 0.038). Conclusions: Our study did not find a clear association between serum IgG4 levels (>140 mg/dL) and pancreatobiliary cancer. We observed that higher IgG4 levels (>280 mg/dL) may be associated with cholangiocarcinoma and pancreatic cancer, as indicated by crude ORs. However, the adjusted analysis did not demonstrate the significant association between IgG4 level > 280 mg/dL and cancer. Considering IgG4-RD as a chronic and persistent inflammatory status, it is more closely associated with inflammatory diseases than with cancer. Therefore, further long-term cohort studies are necessary to evaluate the potential role of IgG4 levels in cancer risk among these patients.
Hemochromatosis—How Not to Overlook and Properly Manage “Iron People”—A Review
Authors: Szczerbinska Agnieszka , Kasztelan-Szczerbinska Beata , Rycyk-Bojarzynska Anna , Kocki Janusz , Cichoz-Lach Halina
Published: June 2024

Hemochromatosis (HC) is the main genetic disorder of iron overload and is regarded as metal-related human toxicosis. HC may result from HFE and rare non-HFE gene mutations, causing hepcidin deficiency or, sporadically, hepcidin resistance. This review focuses on HFE-related HC. The illness presents a strong biochemical penetrance, but its prevalence is low. Unfortunately, the majority of patients with HC remain undiagnosed at their disease-curable stage. The main aim of HC management is to prevent iron overload in its early phase and remove excess iron from the body by phlebotomy in its late stage. Raising global awareness of HC among health staff, teaching them how not to overlook early HC manifestations, and paying attention to careful patient monitoring remain critical management strategies for preventing treatment delays, upgrading its efficacy, and improving patient prognosis.
Thoracic Ultrasound as an Alternative to Chest X-ray in Thoracic Surgery Patients: A Single-Center Experience
Authors: Lione Luigi , Busetto Alberto , Verzeletti Vincenzo , Cannone Giorgio , Bonis Alessandro , Berni Alessandro , Gasparini Daniele , Mammana Marco , Rebusso Alessandro , Nicotra Samuele , Gregori Dario , Dell’Amore Andrea , Rea Federico
Published: June 2024

Background/Objectives: Chest X-ray (CXR) is currently the most used investigation for clinical follow-up after major noncardiac thoracic surgery. This study explores the use of lung ultrasound (LUS) as an alternative to CXR in the postoperative management of patients who undergo major thoracic procedures. Methods: The patients in our cohort were monitored with both a CXR and a lung ultrasonography after surgery and the day after chest drain removal. The LUS was performed by a member of the medical staff of our unit who was blinded to both the images and the radiologist’s report of the CXR. Findings were compared between the two methods. Results: In the immediate postoperative evaluation, 280 patients were compared, finding general agreement between the two procedures at 84% (kappa statistic, 0.603). The LUS showed a sensibility of 84.1%, a specificity of 84.3%, a positive predictive value (PPV) of 60.9%, and a negative predictive value (NPV) of 94.8%. We evaluated 219 out of 280 patients in the postdrainage-removal setting due to technical issues. Concordance between the methods in the postdrainage-removal setting was 89% (kappa statistic, 0.761) with the LUS demonstrating an 82.2% sensibility, a 93.2% specificity, a PPV of 85.7%, and an NPV of 91.3%. Conclusions: The results of this study showed a substantial agreement between LUS and CXR, suggesting that the LUS could reduce the number of X rays in certain conditions. The high NPV allows for the exclusion of PNX and pleural effusion without the need to expose patients to radiation. Discrepancies were noted in cases of mild pneumothorax or modest pleural effusion, without altering the clinical approach.
Silicone Arthroplasty as an Alternative to Arthrodesis in the Metatarsophalangeal Degenerative Disease of Hallux Valgus—A 5-Year Observational Study
Authors: Lesman Jędrzej , Wojna Joanna , Szkutnik Patrycja , Tomasik Bartłomiej , Domżalski Marcin , Łaganowski Przemysław
Published: June 2024

Background: Arthroplasty is gaining more and more popularity in the treatment of osteoarthritis (OA) of the metatarsophalangeal I joint (MTP1). The aim of our study was to evaluate the early and long-term objective clinical and radiographic results, as well as the subjective results, of MTP1 arthroplasty in comparison to MTP1 arthrodesis among patients with OA and a valgus deformity of their MTP 1 joint. Methods: Patients with OA MTP1 were examined before surgery and in the 5-year period after surgery. The inclusion criteria for the study were OA of the MTP1 joint and a non-axial position of the toe in valgus between 20 and 40 degrees. Prostheses were created for the patients with higher demands for mobility of their MTP 1 joint and arthrodesis was carried out for those with lower expectations. The treatment outcomes were assessed by clinical examination, radiography, the AOFAS scale, the SEFAS scale, and using patient-related outcome measures (PROM). Results: A total of 39 people, 37 women and 2 men, aged 55 to 67 years old (average, 61 years old) participated in the study. During the follow-up period, there were no complications in the form of infection or a loosening of the implant after both arthroplasty and arthrodesis. The follow-up examination 60 months after the surgery showed an improvement in scores (>20 points) on both the AOFAS and SEFAS scales. All patients, after surgery, reported reduced pain. Conclusions: The use of a silicone prosthesis in the surgical treatment of degenerative changes in the MTPI joint, with appropriate indications and excluding cases with large hallux valgus, gives better results than arthrodesis.
Overturning Children’s Misconceptions about Ruler Measurement: The Power of Disconfirming Evidence
Authors: Kwon Mee-Kyoung , Congdon Eliza , Ping Raedy , Levine Susan C.
Published: June 2024

Children have persistent difficulty with foundational measurement concepts, which may be linked to the instruction they receive. Here, we focus on testing various ways to support their understanding that rulers comprise spatial interval units. We examined whether evidence-based learning tools—disconfirming evidence and/or structural alignment—enhance their understanding of ruler units. Disconfirming evidence, in this context, involves having children count the spatial interval units under an object that is not aligned with the origin of a ruler. Structural alignment, in this context, involves highlighting what a ruler unit is by overlaying plastic unit chips on top of ruler units when an object is aligned with the origin of a ruler. In three experiments employing a pre-test/training/post-test design, a total of 120 second graders were randomly assigned to one of six training conditions (two training conditions per experiment). The training conditions included different evidence-based learning principles or “business-as-usual” instruction (control), with equal allocation to each (N = 20 for each condition). In each experiment, children who did not perform above chance level on the pre-test were selected to continue with training, which resulted in a total of 88 students for the analysis of improvement. The children showed significant improvement in training conditions that included disconfirming evidence, but not in the structural alignment or control conditions. However, an exploratory analysis suggests that improvement occurred more rapidly and was retained better when structural alignment was combined with disconfirming evidence compared to disconfirming evidence alone.