bluuebunny/crossref_metadata_2025 huggingface dataset:
Gold Nanoparticles in Neurological Diseases: A Review of Neuroprotection
Authors: Chiang Ming-Chang , Yang Yu-Ping , Nicol Christopher J. B. , Wang Chieh-Ju
Published: February 2024

This review explores the diverse applications of gold nanoparticles (AuNPs) in neurological diseases, with a specific focus on Alzheimer’s disease (AD), Parkinson’s disease (PD), and stroke. The introduction highlights the pivotal role of neuroinflammation in these disorders and introduces the unique properties of AuNPs. The review’s core examines the mechanisms by which AuNPs exert neuroprotection and anti-neuro-inflammatory effects, elucidating various pathways through which they manifest these properties. The potential therapeutic applications of AuNPs in AD are discussed, shedding light on promising avenues for therapy. This review also explores the prospects of utilizing AuNPs in PD interventions, presenting a hopeful outlook for future treatments. Additionally, the review delves into the potential of AuNPs in providing neuroprotection after strokes, emphasizing their significance in mitigating cerebrovascular accidents’ aftermath. Experimental findings from cellular and animal models are consolidated to provide a comprehensive overview of AuNPs’ effectiveness, offering insights into their impact at both the cellular and in vivo levels. This review enhances our understanding of AuNPs’ applications in neurological diseases and lays the groundwork for innovative therapeutic strategies in neurology.
Special Issue “Peptides for Health Benefits 2021”
Authors: Martínez-Villaluenga Cristina , Hernández-Ledesma Blanca
Published: February 2024

In recent years, non-communicable diseases (NCDs) have increased in prevalence in our society and have become a serious burden of disease worldwide [...]
Special Issue “State-of-the-Art Molecular Plant Sciences in Japan”
Authors: Komatsu Setsuko , Uemura Matsuo
Published: February 2024

Food shortages are one of the most serious problems caused by global warming and population growth in this century [...]
NTRK Therapy among Different Types of Cancers, Review and Future Perspectives
Authors: Theik Nyein Wint Yee , Muminovic Meri , Alvarez-Pinzon Andres M. , Shoreibah Ahmed , Hussein Atif M. , Raez Luis E.
Published: February 2024

Neurotrophic tyrosine receptor kinase (NTRK) has been a remarkable therapeutic target for treating different malignancies, playing an essential role in oncogenic signaling pathways. Groundbreaking trials like NAVIGATE led to the approval of NTRK inhibitors by the Food and Drug Administration (FDA) to treat different malignancies, significantly impacting current oncology treatment. Accurate detection of NTRK gene fusion becomes very important for possible targeted therapy. Various methods to detect NTRK gene fusion have been applied widely based on sensitivity, specificity, and accessibility. The utility of different tests in clinical practice is discussed in this study by providing insights into their effectiveness in targeting patients who may benefit from therapy. Widespread use of NTRK inhibitors in different malignancies could remain limited due to resistance mechanisms that cause challenges to medication efficacy in addition to common side effects of the medications. This review provides a succinct overview of the application of NTRK inhibitors in various types of cancer by emphasizing the critical clinical significance of NTRK fusion gene detection. The discussion also provides a solid foundation for understanding the current challenges and potential changes for improving the efficacy of NTRK inhibitor therapy to treat different malignancies.
The Role of Cannabidiol in Liver Disease: A Systemic Review
Authors: Chen Si , Kim Jeon-Kyung
Published: February 2024

Cannabidiol (CBD), a non-psychoactive phytocannabinoid abundant in Cannabis sativa, has gained considerable attention for its anti-inflammatory, antioxidant, analgesic, and neuroprotective properties. It exhibits the potential to prevent or slow the progression of various diseases, ranging from malignant tumors and viral infections to neurodegenerative disorders and ischemic diseases. Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), alcoholic liver disease, and viral hepatitis stand as prominent causes of morbidity and mortality in chronic liver diseases globally. The literature has substantiated CBD’s potential therapeutic effects across diverse liver diseases in in vivo and in vitro models. However, the precise mechanism of action remains elusive, and an absence of evidence hinders its translation into clinical practice. This comprehensive review emphasizes the wealth of data linking CBD to liver diseases. Importantly, we delve into a detailed discussion of the receptors through which CBD might exert its effects, including cannabinoid receptors, CB1 and CB2, peroxisome proliferator-activated receptors (PPARs), G protein-coupled receptor 55 (GPR55), transient receptor potential channels (TRPs), and their intricate connections with liver diseases. In conclusion, we address new questions that warrant further investigation in this evolving field.
Efficacy of a Combination Therapy with Laronidase and Genistein in Treating Mucopolysaccharidosis Type I in a Mouse Model
Authors: Malinowska Marcelina , Nowicka Wioletta , Kloska Anna , Węgrzyn Grzegorz , Jakóbkiewicz-Banecka Joanna
Published: February 2024

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by α-L-iduronidase deficiency. The standard treatment, enzyme replacement therapy with laronidase, has limited effectiveness in treating neurological symptoms due to poor blood–brain barrier penetration. An alternative is substrate reduction therapy using molecules, such as genistein, which crosses this barrier. This study evaluated the effectiveness of a combination of laronidase and genistein in a mouse model of MPS I. Over 12 weeks, MPS I and wild-type mice received laronidase, genistein, or both. Glycosaminoglycan (GAG) storage in visceral organs and the brain, its excretion in urine, and the serum level of the heparin cofactor II–thrombin (HCII-T) complex, along with behavior, were assessed. The combination therapy resulted in reduced GAG storage in the heart and liver, whereas genistein alone reduced the brain GAG storage. Laronidase and combination therapy decreased liver and spleen weights and significantly reduced GAG excretion in the urine. However, this therapy negated some laronidase benefits in the HCII-T levels. Importantly, the combination therapy improved the behavior of female mice with MPS I. These findings offer valuable insights for future research to optimize MPS I treatments.
Statins—Their Role in Bone Tissue Metabolism and Local Applications with Different Carriers
Authors: Granat Marcin Mateusz , Eifler-Zydel Joanna , Kolmas Joanna
Published: February 2024

Statins, widely prescribed for lipid disorders, primarily target 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase competitively and reversibly, resulting in reduced low-density lipoprotein cholesterol (LDL-C). This mechanism proves effective in lowering the risk of lipid-related diseases such as ischemic cerebrovascular and coronary artery diseases. Beyond their established use, statins are under scrutiny for potential applications in treating bone diseases. The focus of research centers mainly on simvastatin, a lipophilic statin demonstrating efficacy in preventing osteoporosis and aiding in fracture and bone defect healing. Notably, these effects manifest at elevated doses (20 mg/kg/day) of statins, posing challenges for systematic administration due to their limited bone affinity. Current investigations explore intraosseous statin delivery facilitated by specialized carriers. This paper outlines various carrier types, characterizing their structures and underscoring various statins’ potential as local treatments for bone diseases.
In Silico Analysis of Genes Associated with the Pathogenesis of Odontogenic Keratocyst
Authors: Ramírez-Martínez Carla Monserrat , Legorreta-Villegas Itzel , Mejía-Velázquez Claudia Patricia , Portilla-Robertson Javier , Gaitán-Cepeda Luis Alberto , Paramo-Sánchez Jessica Tamara , Chanes-Cuevas Osmar Alejandro , Alonso-Moctezuma Alejandro , Jacinto-Alemán Luis Fernando
Published: February 2024

Odontogenic keratocyst (OK) is a benign intraosseous cystic lesion characterized by a parakeratinized stratified squamous epithelial lining with palisade basal cells. It represents 10–12% of odontogenic cysts. The changes in its classification as a tumor or cyst have increased interest in its pathogenesis. Objective: Identify key genes in the pathogenesis of sporadic OK through in silico analysis. Materials and methods: The GSE38494 technical sheet on OK was analyzed using GEOR2. Their functional and canonical signaling pathways were enriched in the NIH-DAVID bioinformatic platform. The protein–protein interaction network was constructed by STRING and analyzed with Cytoscape-MCODE software v 3.8.2 (score > 4). Post-enrichment analysis was performed by Cytoscape-ClueGO. Results: A total of 768 differentially expressed genes (DEG) with a fold change (FC) greater than 2 and 469 DEG with an FC less than 2 were identified. In the post-enrichment analysis of upregulated genes, significance was observed in criteria related to the organization of the extracellular matrix, collagen fibers, and endodermal differentiation, while the downregulated genes were related to defensive response mechanisms against viruses and interferon-gamma activation. Conclusions. Our in silico analysis showed a significant relationship with mechanisms of extracellular matrix organization, interferon-gamma activation, and response to viral infections, which must be validated through molecular assays.
Protein Translation in the Pathogenesis of Parkinson’s Disease
Authors: Ashraf Daniyal , Khan Mohammed Repon , Dawson Ted M. , Dawson Valina L.
Published: February 2024

In recent years, research into Parkinson’s disease and similar neurodegenerative disorders has increasingly suggested that these conditions are synonymous with failures in proteostasis. However, the spotlight of this research has remained firmly focused on the tail end of proteostasis, primarily aggregation, misfolding, and degradation, with protein translation being comparatively overlooked. Now, there is an increasing body of evidence supporting a potential role for translation in the pathogenesis of PD, and its dysregulation is already established in other similar neurodegenerative conditions. In this paper, we consider how altered protein translation fits into the broader picture of PD pathogenesis, working hand in hand to compound the stress placed on neurons, until this becomes irrecoverable. We will also consider molecular players of interest, recent evidence that suggests that aggregates may directly influence translation in PD progression, and the implications for the role of protein translation in our development of clinically useful diagnostics and therapeutics.
Expression Patterns and Molecular Mechanisms Regulating Drought Tolerance of Soybean [Glycine max (L.) Merr.] Conferred by Transcription Factor Gene GmNAC19
Authors: Cui Xiyan , Tang Minghao , Li Lei , Chang Jiageng , Yang Xiaoqin , Chang Hongli , Zhou Jiayu , Liu Miao , Wang Yan , Zhou Ying , Sun Fengjie , Chen Zhanyu
Published: February 2024

NAC transcription factors are commonly involved in the plant response to drought stress. A transcriptome analysis of root samples of the soybean variety ‘Jiyu47’ under drought stress revealed the evidently up-regulated expression of GmNAC19, consistent with the expression pattern revealed by quantitative real-time PCR analysis. The overexpression of GmNAC19 enhanced drought tolerance in Saccharomyces cerevisiae INVSc1. The seed germination percentage and root growth of transgenic Arabidopsis thaliana were improved in comparison with those of the wild type, while the transgenic soybean composite line showed improved chlorophyll content. The altered contents of physiological and biochemical indices (i.e., soluble protein, soluble sugar, proline, and malondialdehyde) related to drought stress and the activities of three antioxidant enzymes (i.e., superoxide dismutase, peroxidase, and catalase) revealed enhanced drought tolerance in both transgenic Arabidopsis and soybean. The expressions of three genes (i.e., P5CS, OAT, and P5CR) involved in proline synthesis were decreased in the transgenic soybean hairy roots, while the expression of ProDH involved in the breakdown of proline was increased. This study revealed the molecular mechanisms underlying drought tolerance enhanced by GmNAC19 via regulation of the contents of soluble protein and soluble sugar and the activities of antioxidant enzymes, providing a candidate gene for the molecular breeding of drought-tolerant crop plants.
Quantitative MRI Evaluation of Ferritin Overexpression in Non-Small-Cell Lung Cancer
Authors: Singhania Mekhla , Zaher Amira , Pulliam Casey F. , Bayanbold Khaliunaa , Searby Charles C. , Schoenfeld Joshua D. , Mapuskar Kranti A. , Fath Melissa A. , Allen Bryan G. , Spitz Douglas R. , Petronek Michael S.
Published: February 2024

Cancer cells frequently present elevated intracellular iron levels, which are thought to facilitate an enhanced proliferative capacity. Targeting iron metabolism within cancer cells presents an avenue to enhance therapeutic responses, necessitating the use of non-invasive models to modulate iron manipulation to predict responses. Moreover, the ubiquitous nature of iron necessitates the development of unique, non-invasive markers of metabolic disruptions to develop more personalized approaches and enhance the clinical utility of these approaches. Ferritin, an iron storage enzyme that is often upregulated as a response to iron accumulation, plays a central role in iron metabolism and has been frequently associated with unfavorable clinical outcomes in cancer. Herein, we demonstrate the successful utility, validation, and functionality of a doxycycline-inducible ferritin heavy chain (FtH) overexpression model in H1299T non-small-cell lung cancer (NSCLC) cells. Treatment with doxycycline increased the protein expression of FtH with a corresponding decrease in labile iron in vitro and in vivo, as determined by calcein-AM staining and EPR, respectively. Moreover, a subsequent increase in TfR expression was observed. Furthermore, T2* MR mapping effectively detected FtH expression in our in vivo model. These results demonstrate that T2* relaxation times can be used to monitor changes in FtH expression in tumors with bidirectional correlations depending on the model system. Overall, this study describes the development of an FtH overexpression NSCLC model and its correlation with T2* mapping for potential use in patients to interrogate iron metabolic alterations and predict clinical outcomes.
Holographic Brain Theory: Super-Radiance, Memory Capacity and Control Theory
Authors: Nishiyama Akihiro , Tanaka Shigenori , Tuszynski Jack A. , Tsenkova Roumiana
Published: February 2024

We investigate Quantum Electrodynamics corresponding to the holographic brain theory introduced by Pribram to describe memory in the human brain. First, we derive a super-radiance solution in Quantum Electrodynamics with non-relativistic charged bosons (a model of molecular conformational states of water) for coherent light sources of holograms. Next, we estimate memory capacity of a brain neocortex, and adopt binary holograms to manipulate optical information. Finally, we introduce a control theory to manipulate holograms involving biological water’s molecular conformational states. We show how a desired waveform in holography is achieved in a hierarchical model using numerical simulations.
Potential Candidate Molecule of Photosystem II Inhibitor Herbicide—Brassicanate A Sulfoxide
Authors: Wang Yu , Wang Dong , Dong Baozhu , Hao Jianxiu , Jia Xinyu , Zhou Hongyou
Published: February 2024

Brassicanate A sulfoxide, a secondary metabolite of broccoli, exhibited the inhibition of weed growth, but its mechanism of action on weeds remains unclear. To elucidate the mechanism by which brassicanate A sulfoxide suppresses weeds, this study explores the interaction between brassicanate A sulfoxide and the photosystem II D1 protein through molecular docking and molecular dynamics simulations. This research demonstrates that brassicanate A sulfoxide interacts with the photosystem II D1 protein by forming hydrogen bonds with Phe-261 and His-214. The successful expression of the photosystem II D1 protein in an insect cell/baculovirus system validated the molecular docking and dynamics simulations. Biolayer interferometry experiments elucidated that the affinity constant of brassicanate A sulfoxide with photosystem II was 2.69 × 10−3 M, suggesting that brassicanate A sulfoxide can stably bind to the photosystem II D1 protein. The findings of this study contribute to the understanding of the mode of action of brassicanate A sulfoxide and also aid in the development of natural-product-based photosynthesis-inhibiting herbicides.
Epidemiology of Wilson’s Disease and Pathogenic Variants of the ATP7B Gene Leading to Diversified Protein Disfunctions
Authors: Ovchinnikova Elena Vasilievna , Garbuz Mikhail Maksimovich , Ovchinnikova Anna Aleksandrovna , Kumeiko Vadim Vladimirovich
Published: February 2024

Wilson’s disease (WD) is an autosomal recessive disorder characterized by toxic accumulation of copper in the liver, brain, and other organs. The disease is caused by pathogenic variants in the ATP7B gene, which encodes a P-type copper transport ATPase. Diagnosing WD is associated with numerous difficulties due to the wide range of clinical manifestations and its unknown dependence on the physiological characteristics of the patient. This leads to a delay in the start of therapy and the subsequent deterioration of the patient’s condition. However, in recent years, molecular genetic testing of patients using next generation sequencing (NGS) has been gaining popularity. This immediately affected the detection speed of WD. If, previously, the frequency of this disease was estimated at 1:35,000–45,000 people, now, when conducting large molecular genetic studies, the frequency is calculated as 1:7026 people. This certainly points to the problem of identifying WD patients. This review provides an update on the performance of epidemiological studies of WD and describes normal physiological functions of the protein and diversified disfunctions depending on pathogenic variants of the ATP7B gene. Future prospects in the development of WD genetic diagnostics are also discussed.
Antioxidants in Photoaging: From Molecular Insights to Clinical Applications
Authors: Calvo María José , Navarro Carolina , Durán Pablo , Galan-Freyle Nataly J. , Parra Hernández Luis Alberto , Pacheco-Londoño Leonardo C , Castelanich Desiree , Bermúdez Valmore , Chacin Maricarmen
Published: February 2024

Photoaging (PA) is considered a silent disease affecting millions of people globally and is defined as skin damage due to prolonged exposure to ultraviolet radiation (UVR) from the sun. Physiologically, the skin is in a state of renewal and synthesis of components of the extracellular matrix (ECM). However, exposure to UVR affects the production of the ECM, and the functioning and response of skin cells to UVR begins to change, thus expressing clinical and phenotypic characteristics of PA. The primary mechanisms involved in PA are direct damage to the DNA of skin cells, increases in oxidative stress, the activation of cell signaling pathways responsible for the loss of skin integrity, and cytotoxicity. The medical and scientific community has been researching new therapeutic tools that counteract PA, considering that the damage caused by UVR exceeds the antioxidant defense mechanisms of the skin. Thus, in recent years, certain nutraceuticals and phytochemicals have been found to exhibit potential antioxidant and photoprotective effects. Therefore, the main objective of this review is to elucidate the molecular bases of PA and the latest pharmaceutical industry findings on antioxidant treatment against the progression of PA.
Aryl Hydrocarbon Receptor Regulates Muc2 Production Independently of IL-22 during Colitis
Authors: Saxena Archana , Mitchell Chandani , Bogdon Raymond , Roark Kasie , Wilson Kiesha , Staley Shanieka , Hailey Michelle , Williams Michal Claire , Rutkovsky Alex , Nagarkatti Prakash , Nagarkatti Mitzi , Busbee Philip Brandon
Published: February 2024

We previously reported that an aryl hydrocarbon receptor (AhR) ligand, indole-3-carbinol (I3C), was effective at reducing colitis severity through immune cell-mediated interleukin-22 (IL-22) production. Intestinal epithelial cells (IECs) are also involved in regulating colitis, so we investigated their AhR-mediated mechanisms in the current report. A transcriptome analysis of IECs in wildtype (WT) mice revealed that during colitis, I3C regulated select mucin proteins, which could be attributed to goblet cell development. To address this, experiments under in vivo colitis (mice) or in vitro colon organoid conditions were undertaken to determine how select mucin proteins were altered in the absence or presence of AhR in IECs during I3C treatment. Comparing WT to IEC-specific AhR knockout mice (AhRΔIEC), the results showed that AhR expression was essential in IECs for I3C-mediated protection during colitis. AhR-deficiency also impaired mucin protein expression, particularly mucin 2 (Muc2), independently of IL-22. Collectively, this report highlights the important role of AhR in direct regulation of Muc2. These results provide justification for future studies aimed at determining how AhR might regulate select mucins through mechanisms such as direct transcription binding to enhance production.
Special Issue “The Molecular and Cellular Pathophysiologic Mechanisms Underlying Ocular Diseases and Emerging Therapies”
Authors: Kaštelan Snježana
Published: February 2024

Visual impairment and ophthalmic diseases represent significant global public health concerns, and their prevalence continues to rise [...]
A Cross-Sectional Study of Protein Changes Associated with Dementia in Non-Obese Weight Matched Women with and without Polycystic Ovary Syndrome
Authors: Butler Alexandra E. , Moin Abu Saleh Md , Sathyapalan Thozhukat , Atkin Stephen L.
Published: February 2024

Dysregulated Alzheimer’s disease (AD)-associated protein expression is reported in polycystic ovary syndrome (PCOS), paralleling the expression reported in type 2 diabetes (T2D). We hypothesized, however, that these proteins would not differ between women with non-obese and non-insulin resistant PCOS compared to matched control subjects. We measured plasma amyloid-related proteins levels (Amyloid-precursor protein (APP), alpha-synuclein (SNCA), amyloid P-component (APCS), Pappalysin (PAPPA), Microtubule-associated protein tau (MAPT), apolipoprotein E (apoE), apoE2, apoE3, apoE4, Serum amyloid A (SAA), Noggin (NOG) and apoA1) in weight and aged-matched non-obese PCOS (n = 24) and control (n = 24) women. Dementia-related proteins fibronectin (FN), FN1.3, FN1.4, Von Willebrand factor (VWF) and extracellular matrix protein 1 (ECM1) were also measured. Protein levels were determined by Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement. Only APCS differed between groups, being elevated in non-obese PCOS women (p = 0.03) relative to the non-obese control women. This differed markedly from the elevated APP, APCS, ApoE, FN, FN1.3, FN1.4 and VWF reported in obese women with PCOS. Non-obese, non-insulin resistant PCOS subjects have a lower AD-associated protein pattern risk profile versus obese insulin resistant PCOS women, and are not dissimilar to non-obese controls, indicating that lifestyle management to maintain optimal body weight could be beneficial to reduce the long-term AD-risk in women with PCOS.
Immune Factors, Immune Cells and Inflammatory Diseases
Authors: Ward Alister C.
Published: February 2024

The immune system comprises distinct innate and adaptive arms, each of which contains many layers to provide a coordinated, sequential immune response to insults [...]
The Decellularized Cell-Derived Extracellular Matrix Enhances the Paracrine Function of Human Mesenchymal Stromal/Stem Cells
Authors: Ushakov Roman , Ratushnyy Andrey , Buravkova Ludmila , Tolkunova Elena , Burova Elena
Published: February 2024

The mesenchymal stromal/stem cells (MSCs) are known to secrete pleiotropic paracrine factors, contributing to tissue regeneration. This unique ability makes MSCs promising therapeutic tools for many diseases, including even those that were previously untreatable. Thus, the development of preconditioning approaches aimed at enhancing the paracrine function of MSCs attracts great interest. In the present work, we studied how the extracellular matrix, the essential part of the native tissue microenvironment, affects the secretory capacity of MSCs of various origins. The MSC-derived decellularized extracellular matrix (dECM), used as the cell culture substrate, triggered strong upregulation of FGF-2, MMP-1, HGF, GRO-α, GRO-β, CXCL-5, CXCL-6, IL-6, IL-8, G-CSF and MCP-1. Functional in vitro tests revealed that conditioned media derived from MSCs cultured on dECM significantly improved 3T3 fibroblast and HaCaT keratinocyte scratch wound healing, stimulated THP-1 monocyte migration and promoted capillary-like HUVEC-based tube formation compared to conditioned media from MSCs grown on plastic. In addition, we found that FAK inhibition promoted dECM-induced upregulation of paracrine factors, suggesting that this kinase participates in the MSCs’ paracrine response to dECM. Together, these findings demonstrate that dECM provides cues that considerably enhance the secretory function of MSCs. Thus, dECM usage as a cell culture substrate alone or in combination with a FAK inhibitor may be viewed as a novel MSC preconditioning technique.
Autism Spectrum Disorder: Brain Areas Involved, Neurobiological Mechanisms, Diagnoses and Therapies
Authors: Lamanna Jacopo , Meldolesi Jacopo
Published: February 2024

Autism spectrum disorder (ASD), affecting over 2% of the pre-school children population, includes an important fraction of the conditions accounting for the heterogeneity of autism. The disease was discovered 75 years ago, and the present review, based on critical evaluations of the recognized ASD studies from the beginning of 1990, has been further developed by the comparative analyses of the research and clinical reports, which have grown progressively in recent years up to late 2023. The tools necessary for the identification of the ASD disease and its related clinical pathologies are genetic and epigenetic mutations affected by the specific interaction with transcription factors and chromatin remodeling processes occurring within specific complexes of brain neurons. Most often, the ensuing effects induce the inhibition/excitation of synaptic structures sustained primarily, at dendritic fibers, by alterations of flat and spine response sites. These effects are relevant because synapses, established by specific interactions of neurons with glial cells, operate as early and key targets of ASD. The pathology of children is often suspected by parents and communities and then confirmed by ensuing experiences. The final diagnoses of children and mature patients are then completed by the combination of neuropsychological (cognitive) tests and electro-/magneto-encephalography studies developed in specialized centers. ASD comorbidities, induced by processes such as anxieties, depressions, hyperactivities, and sleep defects, interact with and reinforce other brain diseases, especially schizophrenia. Advanced therapies, prescribed to children and adult patients for the control of ASD symptoms and disease, are based on the combination of well-known brain drugs with classical tools of neurologic and psychiatric practice. Overall, this review reports and discusses the advanced knowledge about the biological and medical properties of ASD.
TGF-β1 Signaling Impairs Metformin Action on Glycemic Control
Authors: Pan Quan , Ai Weiqi , Guo Shaodong
Published: February 2024

Hyperglycemia is a hallmark of type 2 diabetes (T2D). Metformin, the first-line drug used to treat T2D, maintains blood glucose within a normal range by suppressing hepatic glucose production (HGP). However, resistance to metformin treatment is developed in most T2D patients over time. Transforming growth factor beta 1 (TGF-β1) levels are elevated both in the liver and serum of T2D humans and mice. Here, we found that TGF-β1 treatment impairs metformin action on suppressing HGP via inhibiting AMPK phosphorylation at Threonine 172 (T172). Hepatic TGF-β1 deficiency improves metformin action on glycemic control in high fat diet (HFD)-induced obese mice. In our hepatic insulin resistant mouse model (hepatic insulin receptor substrate 1 (IRS1) and IRS2 double knockout (DKO)), metformin action on glycemic control was impaired, which is largely improved by further deletion of hepatic TGF-β1 (TKObeta1) or hepatic Foxo1 (TKOfoxo1). Moreover, blockade of TGF-β1 signaling by chemical inhibitor of TGF-β1 type I receptor LY2157299 improves to metformin sensitivity in mice. Taken together, our current study suggests that hepatic TGF-β1 signaling impairs metformin action on glycemic control, and suppression of TGF-β1 signaling could serve as part of combination therapy with metformin for T2D treatment.
Comprehensive Analysis of the GRAS Gene Family in Paulownia fortunei and the Response of DELLA Proteins to Paulownia Witches’ Broom
Authors: Li Yixiao , Cao Yabing , Fan Yujie , Fan Guoqiang
Published: February 2024

The GRAS (GAI\RGA\SCL) gene family encodes plant-specific transcription factors that play crucial roles in plant growth and development, stress tolerance, and hormone network regulation. Plant dwarfing symptom is mainly regulated by DELLA proteins of the GRAS gene subfamily. In this study, the association between the GRAS gene family and Paulownia witches’ broom (PaWB) was investigated. A total of 79 PfGRAS genes were identified using bioinformatics methods and categorized into 11 groups based on amino acid sequences. Tandem duplication and fragment duplication were found to be the main modes of amplification of the PfGRAS gene family. Gene structure analysis showed that more than 72.1% of the PfGRASs had no introns. The genes PfGRAS12/18/58 also contained unique DELLA structural domains; only PfGRAS12, which showed significant response to PaWB phytoplasma infection in stems, showed significant tissue specificity and responded to gibberellin (GA3) in PaWB-infected plants. We found that the internodes were significantly elongated under 100 µmol·L−1 GA3 treatment for 30 days. The subcellular localization analysis indicated that PfGRAS12 is located in the nucleus and cell membrane. Yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC) assays confirmed that PfGRAS12 interacted with PfJAZ3 in the nucleus. Our results will lay a foundation for further research on the functions of the PfGRAS gene family and for genetic improvement and breeding of PaWB-resistant trees.
Inhibition of Biofilm Formation in Cutibacterium acnes, Staphylococcus aureus, and Candida albicans by the Phytopigment Shikonin
Authors: Kim Yong-Guy , Lee Jin-Hyung , Kim Sanghun , Park Sunyoung , Kim Yu-Jeong , Ryu Choong-Min , Seo Hwi Won , Lee Jintae
Published: February 2024

Skin microbiota, such as acne-related Cutibacterium acnes, Staphylococcus aureus, and fungal Candida albicans, can form polymicrobial biofilms with greater antimicrobial tolerance to traditional antimicrobial agents and host immune systems. In this study, the phytopigment shikonin was investigated against single-species and multispecies biofilms under aerobic and anaerobic conditions. Minimum inhibitory concentrations of shikonin were 10 µg/mL against C. acnes, S. aureus, and C. albicans, and at 1–5 µg/mL, shikonin efficiently inhibited single biofilm formation and multispecies biofilm development by these three microbes. Shikonin increased porphyrin production in C. acnes, inhibited cell aggregation and hyphal formation by C. albicans, decreased lipase production, and increased hydrophilicity in S. aureus. In addition, shikonin at 5 or 10 µg/mL repressed the transcription of various biofilm-related genes and virulence-related genes in C. acnes and downregulated the gene expression levels of the quorum-sensing agrA and RNAIII, α-hemolysin hla, and nuclease nuc1 in S. aureus, supporting biofilm inhibition. In addition, shikonin prevented multispecies biofilm development on porcine skin, and the antimicrobial efficacy of shikonin was recapitulated in a mouse infection model, in which it promoted skin regeneration. The study shows that shikonin inhibits multispecies biofilm development by acne-related skin microbes and might be useful for controlling bacterial infections.
Molecular Mechanism of Different Rooting Capacity between Two Clones of Taxodium hybrid ‘Zhongshanshan’
Authors: Liu Jiaqi , Xuan Lei , Yu Chaoguang , Hua Jianfeng , Wang Ziyang , Yin Yunlong , Wang Zhiquan
Published: February 2024

The conifer Taxodium hybrid ‘Zhongshanshan’ (T. hybrid ‘Zhongshanshan’) is characterized by rapid growth, strong stress resistance, and high ornamental value and has significant potential for use in afforestation, landscaping, and wood production. The main method of propagating T. hybrid ‘Zhongshanshan’ is tender branch cutting, but the cutting rooting abilities of different T. hybrid ‘Zhongshanshan’ clones differ significantly. To explore the causes of rooting ability differences at a molecular level, we analyzed the transcriptome data of cutting base and root tissues of T. hybrid ‘Zhongshanshan 149’ with a rooting rate of less than 5% and T. hybrid ‘Zhongshanshan 118’ with rooting rate greater than 60%, at the developmental time points in this study. The results indicated that differentially expressed genes between the two clones were mainly associated with copper ion binding, peroxidase, and oxidoreductase activity, response to oxidative stress, phenylpropanoid and flavonoid biosynthesis, and plant hormone signal transduction, among others. The expression pattern of ThAP2 was different throughout the development of the adventitive roots of the two clone cuttings. Therefore, this gene was selected for further study. It was shown that ThAP2 was a nuclear-localized transcription factor and demonstrated a positive feedback effect on rooting in transgenic Nicotiana benthamiana cuttings. Thus, the results of this study explain the molecular mechanism of cutting rooting and provide candidate gene resources for developing genetic breeding strategies for optimizing superior clones of T. hybrid ‘Zhongshanshan’.
Rapid Antibacterial Activity Assessment of Chimeric Lysins
Authors: Park Jin-Mi , Kim Jun-Hyun , Kim Gun , Sim Hun-Ju , Ahn Sun-Min , Choi Kang-Seuk , Kwon Hyuk-Joon
Published: February 2024

Various chimeric lysins have been developed as efficacious antibiotics against multidrug-resistant bacteria, but direct comparisons of their antibacterial activities have been difficult due to the preparation of multiple recombinant chimeric lysins. Previously, we reported an Escherichia coli cell-free expression method to better screen chimeric lysins against Staphylococcus aureus, but we still needed to increase the amounts of expressed proteins enough to be able to detect them non-isotopically for quantity comparisons. In this study, we improved the previous cell-free expression system by adding a previously reported artificial T7 terminator and reversing the different nucleotides between the T7 promoter and start codon to those of the T7 phage. The new method increased the expressed amount of chimeric lysins enough for us to detect them using Western blotting. Therefore, the qualitative comparison of activity between different chimeric lysins has become possible via the adjustment of the number of variables between samples without protein purification. We applied this method to select more active chimeric lysins derived from our previously reported chimeric lysin (ALS2). Finally, we compared the antibacterial activities of our selected chimeric lysins with reported chimeric lysins (ClyC and ClyO) and lysostaphin and determined the rank orders of antibacterial activities on different Staphylococcus aureus strains in our experimental conditions.
Transcriptome Analysis Reveals Coexpression Networks and Hub Genes Involved in Papillae Development in Lilium auratum
Authors: Zhu Yuntao , Yang Jie , Liu Xiaolin , Sun Tingting , Zhao Yiran , Xiang Fayun , Chen Feng , He Hengbin
Published: February 2024

Lilium is a genus of important ornamental plants with many colouring pattern variations. Lilium auratum is the parent of Oriental hybrid lilies. A typical feature of L. auratum is the presence of red-orange special raised spots named papillae on the interior tepals. Unlike the usual raised spots, the papillae are slightly rounded or connected into sheets and usually have hairy tips. To elucidate the potential genes regulating papillae development in L. auratum, we performed high-throughput sequencing of its tepals at different stages. Genes involved in the flavonoid biosynthesis pathway were significantly enriched during the colouration of the papillae, and CHS, F3H, F3′H, FLS, DFR, ANS, and UFGT were significantly upregulated. To identify the key genes involved in the papillae development of L. auratum, we performed weighted gene coexpression network analysis (WGCNA) and further analysed four modules. In total, 51, 24, 1, and 6 hub genes were identified in four WGCNA modules, MEbrown, MEyellow, MEpurple, and MEred, respectively. Then, the coexpression networks were constructed, and important genes involved in trichome development and coexpressed with anthocyanin biosynthesis genes, such as TT8, TTG1, and GEM, were identified. These results indicated that the papillae are essentially trichomes that accumulate anthocyanins. Finally, we randomly selected 12 hub genes for qRT-PCR analysis to verify the accuracy of our RNA-Seq analysis. Our results provide new insights into the papillae development in L. auratum flowers.
Genetic Mapping and Characterization of Verticillium Wilt Resistance in a Recombinant Inbred Population of Upland Cotton
Authors: Wilson Iain W. , Moncuquet Philippe , Yuan Yuman , Soliveres Melanie , Li Zitong , Stiller Warwick , Zhu Qian-Hao
Published: February 2024

Verticillium wilt (VW) is an important and widespread disease of cotton and once established is long-lived and difficult to manage. In Australia, the non-defoliating pathotype of Verticillium dahliae is the most common, and extremely virulent. Breeding cotton varieties with increased VW resistance is the most economical and effective method of controlling this disease and is greatly aided by understanding the genetics of resistance. This study aimed to investigate VW resistance in 240 F7 recombinant inbred lines (RIL) derived from a cross between MCU-5, which has good resistance, and Siokra 1–4, which is susceptible. Using a controlled environment bioassay, we found that resistance based on plant survival or shoot biomass was complex but with major contributions from chromosomes D03 and D09, with genomic prediction analysis estimating a prediction accuracy of 0.73 based on survival scores compared to 0.36 for shoot biomass. Transcriptome analysis of MCU-5 and Siokra 1–4 roots uninfected or infected with V. dahliae revealed that the two cultivars displayed very different root transcriptomes and responded differently to V. dahliae infection. Ninety-nine differentially expressed genes were located in the two mapped resistance regions and so are potential candidates for further identifying the genes responsible for VW resistance.
Potential Therapeutic Application and Mechanism of Action of Stem Cell-Derived Extracellular Vesicles (EVs) in Systemic Lupus Erythematosus (SLE)
Authors: Rajeev Kumar Sushmitha , Sakthiswary Rajalingham , Lokanathan Yogeswaran
Published: February 2024

Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease that affects nearly 3.41 million people globally, with 90% of the cases affecting women of childbearing age. SLE is a complex disease due to the interplay of various immunological pathways and mechanisms. This scoping review aims to highlight the latest research findings on the therapeutic mechanisms of action of EVs in SLE. Relevant research articles were identified using the PRISMA framework from databases such as PubMed/MEDLINE (National Library of Medicine), Scopus (Elsevier), and Web of Science: Core Collection (Clarivate Analytics) from July 2023 to October 2023. Eleven studies met the inclusion criteria and thus were included in this scoping review. The findings showed that EVs have therapeutic effects on ameliorating the disease progression of SLE. EVs can reduce the pro-inflammatory cytokines and increase the anti-inflammatory cytokines. Moreover, EVs can increase the levels of regulatory T cells, thus reducing inflammation. EVs also have the potential to regulate B cells to alleviate SLE and reduce its adverse effects. The scoping review has successfully analysed the therapeutic potential in ameliorating the disease progression of SLE. The review also includes prospects to improve the effects of EVs further to increase the therapeutic effects on SLE.
Strategic Approaches to Cybersecurity Learning: A Study of Educational Models and Outcomes
Authors: Mukherjee Madhav , Le Ngoc Thuy , Chow Yang-Wai , Susilo Willy
Published: February 2024

As the demand for cybersecurity experts in the industry grows, we face a widening shortage of skilled professionals. This pressing concern has spurred extensive research within academia and national bodies, who are striving to bridge this skills gap through refined educational frameworks, including the integration of innovative information applications like remote laboratories and virtual classrooms. Despite these initiatives, current higher education models for cybersecurity, while effective in some areas, fail to provide a holistic solution to the root causes of the skills gap. Our study conducts a thorough examination of established cybersecurity educational frameworks, with the goal of identifying crucial learning outcomes that can mitigate the factors contributing to this skills gap. Furthermore, by analyzing six different educational models, for each one that can uniquely leverage technology like virtual classrooms and online platforms and is suited to various learning contexts, we categorize these contexts into four distinct categories. This categorization introduces a holistic dimension of context awareness enriched by digital learning tools into the process, enhancing the alignment with desired learning outcomes, a consideration sparsely addressed in the existing literature. This thorough analysis further strengthens the framework for guiding education providers in selecting models that most effectively align with their targeted learning outcomes and implies practical uses for technologically enhanced environments. This review presents a roadmap for educators and institutions, offering insights into relevant teaching models, including the opportunities for the utilization of remote laboratories and virtual classrooms, and their contextual applications, thereby aiding curriculum designers in making strategic decisions.
Ambulatory Status at Discharge Predicts Six-Month Mortality in Patients with COVID-19: A Retrospective Cohort Study
Authors: Na Yoonju , Chung Chi Ryang , Suh Gee Young , Jeong Oksoon , Ko Ryoung-Eun , Do Jong Geol
Published: February 2024

This retrospective cohort study aimed to evaluate the association between ambulatory status at discharge and six-month post-discharge mortality among adults with coronavirus disease (COVID-19). We analyzed data from 398 patients aged over 18 admitted to a tertiary hospital in South Korea between December 2019 and June 2022. Patients were classified into two groups based on their ambulatory status at discharge: ambulatory (able to walk independently, n = 286) and non-ambulatory (unable to walk independently, requiring wheelchair or bed-bound, n = 112). Our analysis revealed that six-month survival rates were significantly higher in the ambulatory group (94.2%) compared to the non-ambulatory group (84.4%). Multivariate analysis identified ambulatory status at discharge (p = 0.047) and pre-existing malignancy (p = 0.007) as significant prognostic factors for post-discharge survival. This study highlights that the ability to walk independently at discharge is a crucial predictor of six-month survival in COVID-19 patients. These findings emphasize the need for interventions to improve the physical performance of non-ambulatory patients, potentially enhancing their survival prospects. This underscores the importance of targeted rehabilitation and physical therapy for the comprehensive care of COVID-19 survivors.
Risk Factor Analysis for Developing Major Complications Following Esophageal Surgery—A Two-Center Study
Authors: Stüben Björn-Ole , Plitzko Gabriel Andreas , Stern Louisa , Schmeding Rainer , Karstens Karl-Frederick , Reeh Matthias , Treckmann Jürgen Walter , Izbicki Jakob Robert , Saner Fuat Hakan , Neuhaus Jan Peter , Tachezy Michael , Hoyer Dieter Paul
Published: February 2024

Background: Esophagectomy carries a high risk of morbidity and mortality compared to other major surgeries. With the aim of creating an easy-to-use clinical preoperative risk assessment tool and to validate previously described risk factors for major complications following surgery, esophagectomies at two tertiary medical centers were analyzed. Methods: A total of 450 patients who underwent esophagectomy for esophageal carcinoma at the University Medical Centre, Hamburg, or at the Medical Center University Duisburg-Essen, Germany (January 2008 to January 2020) were retrospectively analyzed. Epidemiological and perioperative data were analyzed to identify the risk factors that impact major complication rates. The primary endpoint of this study was to determine the incidence of major complications. Results: The mean age of the patients was 63 years with a bimodal distribution. There was a male predominance across the cohort (81% vs. 19%, respectively). Alcohol abuse (p = 0.0341), chronic obstructive pulmonary disease (p = 0.0264), and cardiac comorbidity (p = 0.0367) were associated with a significantly higher risk of major complications in the multivariate analysis. Neoadjuvant chemotherapy significantly reduced the risk of major postoperative complications (p < 0.0001). Conclusions: Various patient-related risk factors increased the rate of major complications following esophagectomy. Patient-tailored prehabilitation programs before esophagectomy that focus on minimizing these risk factors may lead to better surgical outcomes and should be analyzed in further studies.