bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronically Radiation-Exposed Survivor Glioblastoma Cells Display Poor Response to Chk1 Inhibition under Hypoxia
Authors: Pinarbasi-Degirmenci Nareg , Sur-Erdem Ilknur , Akcay Vuslat , Bolukbasi Yasemin , Selek Ugur , Solaroglu Ihsan , Bagci-Onder Tugba
Published: June 2022

Glioblastoma is the most malignant primary brain tumor, and a cornerstone in its treatment is radiotherapy. However, tumor cells surviving after irradiation indicates treatment failure; therefore, better understanding of the mechanisms regulating radiotherapy response is of utmost importance. In this study, we generated clinically relevant irradiation-exposed models by applying fractionated radiotherapy over a long time and selecting irradiation-survivor (IR-Surv) glioblastoma cells. We examined the transcriptomic alterations, cell cycle and growth rate changes and responses to secondary radiotherapy and DNA damage response (DDR) modulators. Accordingly, IR-Surv cells exhibited slower growth and partly retained their ability to resist secondary irradiation. Concomitantly, IR-Surv cells upregulated the expression of DDR-related genes, such as CHK1, ATM, ATR, and MGMT, and had better DNA repair capacity. IR-Surv cells displayed downregulation of hypoxic signature and lower induction of hypoxia target genes, compared to naïve glioblastoma cells. Moreover, Chk1 inhibition alone or in combination with irradiation significantly reduced cell viability in both naïve and IR-Surv cells. However, IR-Surv cells’ response to Chk1 inhibition markedly decreased under hypoxic conditions. Taken together, we demonstrate the utility of combining DDR inhibitors and irradiation as a successful approach for both naïve and IR-Surv glioblastoma cells as long as cells are refrained from hypoxic conditions.
Biochemical, Enzymatic, and Computational Characterization of Recurrent Somatic Mutations of the Human Protein Tyrosine Phosphatase PTP1B in Primary Mediastinal B Cell Lymphoma
Authors: Liu Rongxing , Sun Yujie , Berthelet Jérémy , Bui Linh-Chi , Xu Ximing , Viguier Mireille , Dupret Jean-Marie , Deshayes Frédérique , Rodrigues Lima Fernando
Published: June 2022

Human protein tyrosine phosphatase 1B (PTP1B) is a ubiquitous non-receptor tyrosine phosphatase that serves as a major negative regulator of tyrosine phosphorylation cascades of metabolic and oncogenic importance such as the insulin, epidermal growth factor receptor (EGFR), and JAK/STAT pathways. Increasing evidence point to a key role of PTP1B-dependent signaling in cancer. Interestingly, genetic defects in PTP1B have been found in different human malignancies. Notably, recurrent somatic mutations and splice variants of PTP1B were identified in human B cell and Hodgkin lymphomas. In this work, we analyzed the molecular and functional levels of three PTP1B mutations identified in primary mediastinal B cell lymphoma (PMBCL) patients and located in the WPD-loop (V184D), P-loop (R221G), and Q-loop (G259V). Using biochemical, enzymatic, and molecular dynamics approaches, we show that these mutations lead to PTP1B mutants with extremely low intrinsic tyrosine phosphatase activity that display alterations in overall protein stability and in the flexibility of the active site loops of the enzyme. This is in agreement with the key role of the active site loop regions, which are preorganized to interact with the substrate and to enable catalysis. Our study provides molecular and enzymatic evidence for the loss of protein tyrosine phosphatase activity of PTP1B active-site loop mutants identified in human lymphoma.
Scorpion Neurotoxin Syb-prII-1 Exerts Analgesic Effect through Nav1.8 Channel and MAPKs Pathway
Authors: Bai Fei , Song Yongbo , Cao Yi , Ban Mengqi , Zhang Zhenyu , Sun Yang , Feng Yuan , Li Chunli
Published: June 2022

Trigeminal neuralgia (TN) is a common type of peripheral neuralgia in clinical practice, which is usually difficult to cure. Common analgesic drugs are difficult for achieving the desired analgesic effect. Syb-prII-1 is a β-type scorpion neurotoxin isolated from the scorpion venom of Buthus martensi Karsch (BmK). It has an important influence on the voltage-gated sodium channel (VGSCs), especially closely related to Nav1.8 and Nav1.9. To explore whether Syb-prII-1 has a good analgesic effect on TN, we established the Sprague Dawley (SD) rats’ chronic constriction injury of the infraorbital nerve (IoN-CCI) model. Behavioral, electrophysiological, Western blot, and other methods were used to verify the model. It was found that Syb-prII-1 could significantly relieve the pain behavior of IoN-CCI rats. After Syb-prII-1 was given, the phosphorylation level of the mitogen-activated protein kinases (MAPKs) pathway showed a dose-dependent decrease after IoN-CCI injury. Moreover, Syb-prII-1(4.0 mg/kg) could significantly change the steady-state activation and inactivation curves of Nav1.8. The steady-state activation and inactivation curves of Nav1.9 were similar to those of Nav1.8, but there was no significant difference. It was speculated that it might play an auxiliary role. The binding mode, critical residues, and specific interaction type of Syb-prII-1 and VSD2rNav1.8 were clarified with computational simulation methods. Our results indicated that Syb-prII-1 could provide a potential treatment for TN by acting on the Nav1.8 target.
Immunotherapy in NSCLC Patients with Brain Metastases
Authors: Buriolla Silvia , Pelizzari Giacomo , Corvaja Carla , Alberti Martina , Targato Giada , Bortolot Martina , Torresan Sara , Cortiula Francesco , Fasola Gianpiero , Follador Alessandro
Published: June 2022

Approximately 40% of unselected non-small cell lung cancer (NSCLC) patients develop brain metastases (BMs) during their disease, with considerable morbidity and mortality. The management of BMs in patients with NSCLC is a clinical challenge and requires a multidisciplinary approach to gain effective intracranial disease control. Over the last decade, immune checkpoint inhibitors (ICIs) have emerged as a game-changer in the treatment landscape of advanced NSCLC, with significant improvements in survival outcomes, although patients with BMs are mostly underrepresented in randomized clinical trials. Moreover, the safety and activity of ICIs and radiotherapy combinations compared with single-agent or sequential modalities is still under evaluation to establish the optimal management of these patients. The aim of this review is to summarize the state-of-the-art of clinical evidence of ICIs intracranial activity and the main challenges of incorporating these agents in the treatment armamentarium of NSCLC patients with BMs.
Molecular Basis Underlying the Therapeutic Potential of Vitamin D for the Treatment of Depression and Anxiety
Authors: Kouba Bruna R. , Camargo Anderson , Gil-Mohapel Joana , Rodrigues Ana Lúcia S.
Published: June 2022

Major depressive disorder and anxiety disorders are common and disabling conditions that affect millions of people worldwide. Despite being different disorders, symptoms of depression and anxiety frequently overlap in individuals, making them difficult to diagnose and treat adequately. Therefore, compounds capable of exerting beneficial effects against both disorders are of special interest. Noteworthily, vitamin D deficiency has been associated with an increased risk of developing depression and anxiety, and individuals with these psychiatric conditions have low serum levels of this vitamin. Indeed, in the last few years, vitamin D has gained attention for its many functions that go beyond its effects on calcium–phosphorus metabolism. Particularly, antioxidant, anti-inflammatory, pro-neurogenic, and neuromodulatory properties seem to contribute to its antidepressant and anxiolytic effects. Therefore, in this review, we highlight the main mechanisms that may underlie the potential antidepressant and anxiolytic effects of vitamin D. In addition, we discuss preclinical and clinical studies that support the therapeutic potential of this vitamin for the management of these disorders.
Role of Intrinsic Subtype Analysis with PAM50 in Hormone Receptors Positive HER2 Negative Metastatic Breast Cancer: A Systematic Review
Authors: Canino Fabio , Piacentini Federico , Omarini Claudia , Toss Angela , Barbolini Monica , Vici Patrizia , Dominici Massimo , Moscetti Luca
Published: June 2022

Endocrine therapy (ET), associated with CDK 4/6 inhibitors, represents the first choice of treatment for HR+/HER2- metastatic breast cancer (mBC). Primary or secondary endocrine resistance could develop; however validated biomarkers capable of predicting such a conditions are not available. Several studies have shown that HR+/HER2- mBC comprises five intrinsic subtypes. The purpose of this systematic review was to analyze the potential correlations between intrinsic subtype, efficacy of treatment, and patient outcome. Five papers that analyzed the intrinsic subtype with PAM50 assay in patients (pts) with HR+/HER2- mBC treated with ET (alone or in combination) within seven phase III clinical trials (EGF30008, BOLERO-2, PALOMA-2,3, MONALEESA-2,3,7) were identified. Non-luminal subtypes are more frequent in endocrine-resistant pts and in metastatic sites (vs. primary tumors), have less benefit from ET, and worse prognosis. Among these, HER2-enriched subtypes are similar to HER2+ tumors and benefit from the addition of anti-HER2 agents (lapatinib) and, for less clear reasons, of ribociclib (unconfirmed data for palbociclib and everolimus). Basal-like subtypes are similar to triple-negative tumors, making them more sensitive to chemotherapy. The intrinsic subtype is also not static but can vary over time with the evolution of the disease. Currently, the intrinsic subtype does not play a decisive role in the choice of treatment in clinical practice, but has potential prognostic and predictive value that should be further investigated.
Molecular Evolution and Functional Divergence of Stress-Responsive Cu/Zn Superoxide Dismutases in Plants
Authors: Zhou Guozhi , Liu Chaochao , Cheng Yuan , Ruan Meiying , Ye Qingjing , Wang Rongqing , Yao Zhuping , Wan Hongjian
Published: June 2022

Superoxide dismutases (SODs), a family of antioxidant enzymes, are the first line of defense against oxidative damage and are ubiquitous in every cell of all plant types. The Cu/Zn SOD, one of three types of SODs present in plant species, is involved in many of the biological functions of plants in response to abiotic and biotic stresses. Here, we carried out a comprehensive analysis of the Cu/Zn SOD gene family in different plant species, ranging from lower plants to higher plants, and further investigated their organization, sequence features, and expression patterns in response to biotic and abiotic stresses. Our results show that plant Cu/Zn SODs can be divided into two subfamilies (group I and group II). Group II appeared to be conserved only as single- or low-copy genes in all lineages, whereas group I genes underwent at least two duplication events, resulting in multiple gene copies and forming three different subgroups (group Ia, group Ib, and group Ic). We also found that, among these genes, two important events—the loss of introns and the loss of and variation in signal peptides—occurred over the long course of their evolution, indicating that they were involved in shifts in subcellular localization from the chloroplast to cytosol or peroxisome and underwent functional divergence. In addition, expression patterns of Cu/Zn SOD genes from Arabidopsis thaliana and Solanum lycopersicum were tested in different tissues/organs and developmental stages and under different abiotic stresses. The results indicate that the Cu/Zn SOD gene family possesses potential functional divergence and may play vital roles in ROS scavenging in response to various stresses in plants. This study will help establish a foundation for further understanding these genes’ function during stress responses.
Comparison of the Response to the CXCR4 Antagonist AMD3100 during the Development of Retinal Organoids Derived from ES Cells and Zebrafish Retina
Authors: Wu Yihui , Qiu Jin , Chen Shuilian , Chen Xi , Zhang Jing , Zhuang Jiejie , Liu Sian , Yang Meng , Zhou Pan , Chen Haoting , Yu Keming , Ge Jian , Zhuang Jing
Published: June 2022

Retinal organoids generated from human embryonic stem cells or iPSCs recreate the key structural and functional features of mammalian retinal tissue in vitro. However, the differences in the development of retinal organoids and normal retina in vivo are not well defined. Thus, in the present study, we analyzed the development of retinal organoids and zebrafish retina after inhibition of CXCR4, a key role in neurogenesis and optic nerve development, with the antagonist AMD3100. Our data indicated that CXCR4 was mainly expressed in ganglion cells in retinal organoids and was rarely expressed in amacrine or photoreceptor cells. AMD3100 treatment reduced the retinal organoid generation ratio, impaired differentiation, and induced morphological changes. Ganglion cells, amacrine cells, and photoreceptors were decreased and abnormal locations were observed in organoids treated with AMD3100. Neuronal axon outgrowth was also damaged in retinal organoids. Similarly, a decrease of ganglion cells, amacrine cells, and photoreceptors and the distribution of neural outgrowth was induced by AMD3100 treatment in zebrafish retina. However, abnormal photoreceptor ensembles induced by AMD3100 treatment in the organoids were not detected in zebrafish retina. Therefore, our study suggests that although retinal organoids might provide a reliable model for reproducing a retinal developmental model, there is a difference between the organoids and the retina in vivo.
Crosstalk between Schizophrenia and Metabolic Syndrome: The Role of Oxytocinergic Dysfunction
Authors: Goh Kah Kheng , Chen Cynthia Yi-An , Wu Tzu-Hua , Chen Chun-Hsin , Lu Mong-Liang
Published: June 2022

The high prevalence of metabolic syndrome in persons with schizophrenia has spurred investigational efforts to study the mechanism beneath its pathophysiology. Early psychosis dysfunction is present across multiple organ systems. On this account, schizophrenia may be a multisystem disorder in which one organ system is predominantly affected and where other organ systems are also concurrently involved. Growing evidence of the overlapping neurobiological profiles of metabolic risk factors and psychiatric symptoms, such as an association with cognitive dysfunction, altered autonomic nervous system regulation, desynchrony in the resting-state default mode network, and shared genetic liability, suggest that metabolic syndrome and schizophrenia are connected via common pathways that are central to schizophrenia pathogenesis, which may be underpinned by oxytocin system dysfunction. Oxytocin, a hormone that involves in the mechanisms of food intake and metabolic homeostasis, may partly explain this piece of the puzzle in the mechanism underlying this association. Given its prosocial and anorexigenic properties, oxytocin has been administered intranasally to investigate its therapeutic potential in schizophrenia and obesity. Although the pathophysiology and mechanisms of oxytocinergic dysfunction in metabolic syndrome and schizophrenia are both complex and it is still too early to draw a conclusion upon, oxytocinergic dysfunction may yield a new mechanistic insight into schizophrenia pathogenesis and treatment.
Melatonin and the Brain–Heart Crosstalk in Neurocritically Ill Patients—From Molecular Action to Clinical Practice
Authors: Bekała Artur , Płotek Włodzimierz , Siwicka-Gieroba Dorota , Sołek-Pastuszka Joanna , Bohatyrewicz Romuald , Biernawska Jowita , Kotfis Katarzyna , Bielacz Magdalena , Jaroszyński Andrzej , Dabrowski Wojciech
Published: June 2022

Brain injury, especially traumatic brain injury (TBI), may induce severe dysfunction of extracerebral organs. Cardiac dysfunction associated with TBI is common and well known as the brain–heart crosstalk, which broadly refers to different cardiac disorders such as cardiac arrhythmias, ischemia, hemodynamic insufficiency, and sudden cardiac death, which corresponds to acute disorders of brain function. TBI-related cardiac dysfunction can both worsen the brain damage and increase the risk of death. TBI-related cardiac disorders have been mainly treated symptomatically. However, the analysis of pathomechanisms of TBI-related cardiac dysfunction has highlighted an important role of melatonin in the prevention and treatment of such disorders. Melatonin is a neurohormone released by the pineal gland. It plays a crucial role in the coordination of the circadian rhythm. Additionally, melatonin possesses strong anti-inflammatory, antioxidative, and antiapoptotic properties and can modulate sympathetic and parasympathetic activities. Melatonin has a protective effect not only on the brain, by attenuating its injury, but on extracranial organs, including the heart. The aim of this study was to analyze the molecular activity of melatonin in terms of TBI-related cardiac disorders. Our article describes the benefits resulting from using melatonin as an adjuvant in protection and treatment of brain injury-induced cardiac dysfunction.
New Peptide Functionalized Nanostructured Lipid Carriers with CNS Drugs and Evaluation Anti-proliferative Activity
Authors: Silva Sara , Marto Joana , Gonçalves Lídia M. , Duarte Diana , Soares O. Salomé G. P. , Vasques-Nóvoa Francisco , Almeida António J. , Vale Nuno
Published: June 2022

Nanoparticulate systems have been widely investigated as delivery vectors for efficient drug delivery in different diseases. Nanostructured lipid carriers (NLC) are composed of both solid and liquid lipids (glyceryl dibehenate and diethylene glycol monoethyl ether) and have demonstrated enhanced biological compatibility and increased drug loading capability. Furthermore, the use of peptides, in particular cell-penetrating peptides, to functionalize nanoparticles and enhance cell membrane permeation was explored in this paper. In this paper, we described the synthesis of a new conjugated of tranylcypromine with MAP. In addition, taking into consideration our previous results, this study developed different NLCs loaded with three central nervous system (CNS) drugs (tacrine (TAC), rasagiline (RAS), and tranylcypromine (TCP)) functionalized with model amphipathic peptide (MAP) and evaluated their activity against cancer cells. Particle size analysis demonstrated NLC presented less than 200 nm and a polydispersity index less than 0.3. Moreover, in vitro results showed that conjugation of MAP with drugs led to a higher decrease in cell viability of a neuroblastoma cell line and Caco-2 cell line, more than MAP alone. Furthermore, NLC encapsulation contributed to higher cellular delivery and enhanced toxic activity at lower concentrations when compared with free or co-administration drug-MAP conjugate.
Sera of Neuromyelitis Optica Patients Increase BID-Mediated Apoptosis in Astrocytes
Authors: Zveik Omri , Rechtman Ariel , Haham Nitzan , Adini Irit , Canello Tamar , Lavon Iris , Brill Livnat , Vaknin-Dembinsky Adi
Published: June 2022

Neuromyelitis optica (NMO) is a rare disease usually presenting with bilateral or unilateral optic neuritis with simultaneous or sequential transverse myelitis. Autoantibodies directed against aquaporin-4 (AQP4-IgG) are found in most patients. They are believed to cross the blood–brain barrier, target astrocytes, activate complement, and eventually lead to astrocyte destruction, demyelination, and axonal damage. However, it is still not clear what the primary pathological event is. We hypothesize that the interaction of AQP4-IgG and astrocytes leads to DNA damage and apoptosis. We studied the effect of sera from seropositive NMO patients and healthy controls (HCs) on astrocytes’ immune gene expression and viability. We found that sera from seropositive NMO patients led to higher expression of apoptosis-related genes, including BH3-interacting domain death agonist (BID), which is the most significant differentiating gene (p < 0.0001), and triggered more apoptosis in astrocytes compared to sera from HCs. Furthermore, NMO sera increased DNA damage and led to a higher expression of immunological genes that interact with BID (TLR4 and NOD-1). Our findings suggest that sera of seropositive NMO patients might cause astrocytic DNA damage and apoptosis. It may be one of the mechanisms implicated in the primary pathological event in NMO and provide new avenues for therapeutic intervention.
Photoresponsive Metal-Organic Frameworks as Adjustable Scaffolds in Reticular Chemistry
Authors: Saura-Sanmartin Adrian
Published: June 2022

The easy and remote switching of light makes this stimulus an ideal candidate for a large number of applications, among which the preparation of photoresponsive materials stands out. The interest of several scientists in this area in order to achieve improved functionalities has increase parallel to the growth of the structural complexity of these materials. Thus, metal-organic frameworks (MOFs) turned out to be ideal scaffolds for light-responsive ligands. This review is focused on the integration of photoresponsive organic ligands inside MOF crystalline arrays to prepare enhanced functional materials. Besides the summary of the preparation, properties and applications of these materials, an overview of the future outlook of this research area is provided.
Effects of Compounds Isolated from Lindera erythrocarpa on Anti-Inflammatory and Anti-Neuroinflammatory Action in BV2 Microglia and RAW264.7 Macrophage
Authors: Yoon Chi-Su , Lee Hwan , Liu Zhiming , Lee Hyeong-Kyu , Lee Dong-Sung
Published: June 2022

Lindera erythrocarpa contains various constituents such as cyclopentenedione-, flavonoid-, and chalcone-type components. In this study, a novel bi-linderone derivative and 17 known compounds were isolated from the leaves of L. erythrocarpa by using various chromatographic methods. The structures of the components were determined from nuclear magnetic resonance and mass spectrometry data. All isolated compounds were tested for anti-inflammatory and anti-neuroinflammatory activities in lipopolysaccharide (LPS)-induced BV2 and RAW264.7 cells. Some of these compounds showed anti-inflammatory effects by inhibiting the nitric oxide (NO) produced by LPS. In particular, linderaspirone A (16), bi-linderone (17) and novel compound demethoxy-bi-linderone (18) showed significant inhibitory effects on the production of prostaglandin E2 (PGE2), tumor necrosis factor-α, and interleukin-6. The three compounds also inhibited the expression of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2), which are pro-inflammatory proteins, and the activation of nuclear factor κB (NF-κB). Therefore, linderaspirone A (16), bi-linderone (17), and demethoxy-bi-linderone (18) isolated from the leaves of L. erythrocarpa have therapeutic potential in neuroinflammatory diseases.
Catalase Inhibition by Aminoalkanol Derivatives with Potential Anti-Cancer Activity—In Vitro and In Silico Studies Using Capillary Electrophoresis Method
Authors: Grodner Błażej , Napiórkowska Mariola , Pisklak Dariusz Maciej
Published: June 2022

In this work, the investigation of type and inhibitory strength of catalase by two pairs of aminoalkanol derivatives (1,7 diEthyl- and 1,7-diMethyl-8,9-diphenyl-4-azatricyclo (5.2.1.02.6) dec-8-ene- 3,5,10-trione) has been presented. The obtained results allowed for the determination of all kinetic parameters (Km, Vmax, slope angles of Lineweaver–Burk plots, Ki and IC50) on the basis of which it was shown that all four aminoalkanol derivatives are competitive inhibitors of catalase. However, the strength of action of each of them depends on the type of substituents present in the main structure of the molecule. Subtle differences in the potency of individual derivatives were possible to detect thanks to the developed, sensitive method of capillary electrophoresis, which allowed simultaneous monitoring of the mutual changes in the concentrations of substrates and products of the reaction catalyzed by the enzyme. Detailed values of kinetic parameters showed that all derivatives are weak inhibitors of catalase, which in this case is a big advantage because each inhibition of catalase activity is associated with a greater amount of accumulated, harmful reactive oxygen species. The results of docking studies also show the convergence of the binding energies values of individual inhibitors with all kinetic parameters of the investigated catalase inhibition and thus additionally confirm the weak inhibitory strength of all four aminoalkanol derivatives.
The Dysregulation of MicroRNAs in the Development of Cervical Pre-Cancer—An Update
Authors: Choi Pui-Wah , Liu Tin Lun , Wong Chun Wai , Liu Sze Kei , Lum Yick-Liang , Ming Wai-Kit
Published: June 2022

Globally in 2020, an estimated ~600,000 women were diagnosed with and 340,000 women died from cervical cancer. Compared to 2012, the number of cases increased by 7.5% and the number of deaths increased by 17%. MiRNAs are involved in multiple processes in the pathogenesis of cervical cancer. Dysregulation of miRNAs in the pre-stage of cervical cancer is the focus of this review. Here we summarize the dysregulated miRNAs in clinical samples from cervical pre-cancer patients and relate them to the early transformation process owing to human papillomavirus (HPV) infection in the cervical cells. When HPV infects the normal cervical cells, the DNA damage response is initiated with the involvement of HPV’s E1 and E2 proteins. Later, cell proliferation and cell death are affected by the E6 and E7 proteins. We find that the expressions of miRNAs in cervical pre-cancerous tissue revealed by different studies seldom agreed with each other. The discrepancy in sample types, samples’ HPV status, expression measurement, and methods for analysis contributed to the non-aligned results across studies. However, several miRNAs (miR-34a, miR-9, miR-21, miR-145, and miR-375) were found to be dysregulated across multiple studies. In addition, there are hints that the DNA damage response and cell growth response induced by HPV during the early transformation of the cervical cells are related to these miRNAs. Currently, no review articles analyse the relationship between the dysregulated miRNAs in cervical pre-cancerous tissue and their possible roles in the early processes involving HPV’s protein encoded by the early genes and DNA damage response during normal cell transformation. Our review provides insight on spotting miRNAs involved in the early pathogenic processes and pointing out their potential as biomarker targets of cervical pre-cancer.
Advancements in Activating Transcription Factor 5 Function in Regulating Cell Stress and Survival
Authors: Paerhati Pameila , Liu Jing , Jin Zhedong , Jakoš Tanja , Zhu Shunyin , Qian Lan , Zhu Jianwei , Yuan Yunsheng
Published: June 2022

Activating transcription factor 5 (ATF5) belongs to the activating transcription factor/cyclic adenosine monophosphate (cAMP) response element-binding protein family of basic region leucine zipper transcription factors. ATF5 plays an important role in cell stress regulation and is involved in cell differentiation and survival, as well as centrosome maintenance and development. Accumulating evidence demonstrates that ATF5 plays an oncogenic role in cancer by regulating gene expressions involved in tumorigenesis and tumor survival. Recent studies have indicated that ATF5 may also modify the gene expressions involved in other diseases. This review explores in detail the regulation of ATF5 expression and signaling pathways and elucidates the role of ATF5 in cancer biology. Furthermore, an overview of putative therapeutic strategies that can be used for restoring aberrant ATF5 activity in different cancer types is provided.
Isolation and Characterization of Urinary Extracellular Vesicles from Healthy Donors and Patients with Castration-Resistant Prostate Cancer
Authors: Lee Haneul , Kang Su Jin , Lee Jimin , Park Kyong Hwa , Rhee Won Jong
Published: June 2022

Prostate cancer (PCa) is the most commonly diagnosed malignancy among men in developed countries. The five-year survival rate for men diagnosed with early-stage PCa is approximately 100%, while it is less than 30% for castration-resistant PCa (CRPC). Currently, the detection of prostate-specific antigens as biomarkers for the prognosis of CRPC is criticized because of its low accuracy, high invasiveness, and high false-positive rate. Therefore, it is important to identify new biomarkers for prediction of CRPC progression. Extracellular vesicles (EVs) derived from tumors have been highlighted as potential markers for cancer diagnosis and prognosis. Specifically, urinary EVs directly reflect changes in the pathophysiological conditions of the urogenital system because it is exposed to prostatic secretions. Thus, detecting biomarkers in urinary EVs provides a promising approach for performing an accurate and non-invasive liquid biopsy for CPRC. In this study, we effectively isolated urinary EVs with low protein impurities using size-exclusion chromatography combined with ultrafiltration. After EV isolation and characterization, we evaluated the miRNAs in urinary EVs from healthy donors and patients with CRPC. The results indicated that miRNAs (miR-21-5p, miR-574-3p, and miR-6880-5p) could be used as potential biomarkers for the prognosis of CRPC. This analysis of urinary EVs contributes to the fast and convenient prognosis of diseases, including CRPC, in the clinical setting.
Ciliary Proteins Repurposed by the Synaptic Ribbon: Trafficking Myristoylated Proteins at Rod Photoreceptor Synapses
Authors: Suiwal Shweta , Dembla Mayur , Schwarz Karin , Katiyar Rashmi , Jung Martin , Carius Yvonne , Maxeiner Stephan , Lauterbach Marcel A. , Lancaster C. Roy D. , Schmitz Frank
Published: June 2022

The Unc119 protein mediates transport of myristoylated proteins to the photoreceptor outer segment, a specialized primary cilium. This transport activity is regulated by the GTPase Arl3 as well as by Arl13b and Rp2 that control Arl3 activation/inactivation. Interestingly, Unc119 is also enriched in photoreceptor synapses and can bind to RIBEYE, the main component of synaptic ribbons. In the present study, we analyzed whether the known regulatory proteins, that control the Unc119-dependent myristoylated protein transport at the primary cilium, are also present at the photoreceptor synaptic ribbon complex by using high-resolution immunofluorescence and immunogold electron microscopy. We found Arl3 and Arl13b to be enriched at the synaptic ribbon whereas Rp2 was predominantly found on vesicles distributed within the entire terminal. These findings indicate that the synaptic ribbon could be involved in the discharge of Unc119-bound lipid-modified proteins. In agreement with this hypothesis, we found Nphp3 (Nephrocystin-3), a myristoylated, Unc119-dependent cargo protein enriched at the basal portion of the ribbon in close vicinity to the active zone. Mutations in Nphp3 are known to be associated with Senior–Løken Syndrome 3 (SLS3). Visual impairment and blindness in SLS3 might thus not only result from ciliary dysfunctions but also from malfunctions of the photoreceptor synapse.
Characterization of the MicroRNA Cargo of Extracellular Vesicles Isolated from a Pulmonary Tumor-Draining Vein Identifies miR-203a-3p as a Relapse Biomarker for Resected Non-Small Cell Lung Cancer
Authors: Han Bing , Molins Laureano , He Yangyi , Viñolas Nuria , Sánchez-Lorente David , Boada Marc , Guirao Angela , Díaz Tania , Martinez Daniel , Ramirez Jose , Moisés Jorge , Acosta-Plasencia Melissa , Monzo Mariano , Marrades Ramón M. , Navarro Alfons
Published: June 2022

In resected non-small cell lung cancer (NSCLC), post-surgical recurrence occurs in around 40% of patients, highlighting the necessity to identify relapse biomarkers. An analysis of the extracellular vesicle (EV) cargo from a pulmonary tumor-draining vein (TDV) can grant biomarker identification. We studied the pulmonary TDV EV-miRNAome to identify relapse biomarkers in a two-phase study (screening and validation). In the screening phase, a 17-miRNA relapse signature was identified in 18 selected patients by small RNAseq. The most expressed miRNA from the signature (EV-miR-203a-3p) was chosen for further validation. Pulmonary TDV EV-miR-203a-3p was studied by qRT-PCR in a validation cohort of 70 patients, where it was found to be upregulated in relapsed patients (p = 0.0194) and in patients with cancer spread to nearby lymph nodes (N+ patients) (p = 0.0396). The ROC curve analysis showed that TDV EV-miR-203a-3p was able to predict relapses with a sensitivity of 88% (AUC: 0.67; p = 0.022). Moreover, patients with high TDV EV-miR-203a-3p had a shorter time to relapse than patients with low levels (43.6 vs. 97.6 months; p = 0.00703). The multivariate analysis showed that EV-miR-203a-3p was an independent, predictive and prognostic post-surgical relapse biomarker. In conclusion, pulmonary TDV EV-miR-203a-3p is a promising new relapse biomarker for resected NSCLC patients.
Effects of Ferroptosis on Male Reproduction
Authors: Liu Yang , Cao Xuanhong , He Chen , Guo Xinrui , Cai Hui , Aierken Aili , Hua Jinlian , Peng Sha
Published: June 2022

Ferroptosis is a relatively novel form of regulated cell death that was discovered in 2012. With the increasing research related to the mechanisms of ferroptosis, previous studies have demonstrated that the inactive of the intracellular antioxidant system and iron overload can result in the accumulation of reactive oxygen species (ROS), which can ultimately cause lipid peroxidation in the various cell types of the body. ROS accumulation can cause sperm damage by attacking the plasma membrane and damaging DNA. Acute ferroptosis causes oxidative damage to sperm DNA and testicular oxidative stress, thereby causing male reproductive dysfunction. This review aims to discuss the metabolic network of ferroptosis, summarize and analyze the relationship between male reproductive diseases caused by iron overload as well as lipid peroxidation, and provide a novel direction for the research and prevention of various male reproductive diseases.
Blocking of SGLT2 to Eliminate NADPH-Induced Oxidative Stress in Lenses of Animals with Fructose-Induced Diabetes Mellitus
Authors: Chen Ying-Ying , Wu Tsung-Tien , Ho Chiu-Yi , Yeh Tung-Chen , Sun Gwo-Ching , Tseng Ching-Jiunn , Cheng Pei-Wen
Published: June 2022

Chronic hyperglycemia triggers an abnormal rise in reactive oxygen species (ROS) that leads to blindness in patients with diabetes mellitus (DM) and cataracts. In this study, the effects of dapagliflozin, metformin and resveratrol on ROS production were investigated in lens epithelial cells (LECs) of animals with fructose-induced DM. LECs were isolated from patients without DM, or with DM devoid of diabetic retinopathy. Animals were treated with 10% fructose for 8 weeks to induce DM, which was verified by monitoring blood pressure and serum parameters. For drug treatments, 1.2 mg/day of dapagliflozin was given for 2 weeks, 500 mg/kg/day of metformin was given, and 10 mg/kg/day of resveratrol was given. Dihydroethidium was used to stain endogenous O2˙− production in vivo of the LECs. Superoxide production was expressed in the cataract of DM, or patients without DM. Sodium–glucose cotransporter 2 (SGLT2), glucose transporter 1 (GLUT1), GLUT5, the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p47/p67-phox, NOX4 and RAGE were significantly increased in LECs with DM. In addition, the dapagliflozin treatment reduced GLUT5, p47/p67-phox, NADPH oxidase 4 (NOX4) and receptor for advanced glycation end products (RAGE) expressions. On the contrary, metformin or resveratrol inhibited p47-phox, GLUT5, and SGLT2 expressions, but not nuclear factor erythroid 2–related factor 2 (NRF2). In summary, dapagliflozin, metformin or resveratrol down-regulated p47-phox expression through SGLT2 inactivation and ROS reduction. These important findings imply that SGLT2 can be blocked to ameliorate oxidative stress in the cataracts of DM patients.
MGMT and Whole-Genome DNA Methylation Impacts on Diagnosis, Prognosis and Therapy of Glioblastoma Multiforme
Authors: Della Monica Rosa , Cuomo Mariella , Buonaiuto Michela , Costabile Davide , Franca Raduan Ahmed , Del Basso De Caro Marialaura , Catapano Giuseppe , Chiariotti Lorenzo , Visconti Roberta
Published: June 2022

Epigenetic changes in DNA methylation contribute to the development of many diseases, including cancer. In glioblastoma multiforme, the most prevalent primary brain cancer and an incurable tumor with a median survival time of 15 months, a single epigenetic modification, the methylation of the O6-Methylguanine-DNA Methyltransferase (MGMT) gene, is a valid biomarker for predicting response to therapy with alkylating agents and also, independently, prognosis. More recently, the progress from single gene to whole-genome analysis of DNA methylation has allowed a better subclassification of glioblastomas. Here, we review the clinically relevant information that can be obtained by studying MGMT gene and whole-genome DNA methylation changes in glioblastomas, also highlighting benefits, including those of liquid biopsy, and pitfalls of the different detection methods. Finally, we discuss how changes in DNA methylation, especially in glioblastomas bearing mutations in the Isocitrate Dehydrogenase (IDH) 1 and 2 genes, can be exploited as targets for tailoring therapy.
Newly Discovered Alleles of the Tomato Antiflorigen Gene SELF PRUNING Provide a Range of Plant Compactness and Yield
Authors: Kang Min-Sung , Kim Yong Jun , Heo Jung , Rajendran Sujeevan , Wang Xingang , Bae Jong Hyang , Lippman Zachary , Park Soon Ju
Published: June 2022

In tomato cultivation, a rare natural mutation in the flowering repressor antiflorigen gene SELF-PRUNING (sp-classic) induces precocious shoot termination and is the foundation in determinate tomato breeding for open field production. Heterozygous single flower truss (sft) mutants in the florigen SFT gene in the background of sp-classic provide a heterosis-like effect by delaying shoot termination, suggesting the subtle suppression of determinacy by genetic modification of the florigen–antiflorigen balance could improve yield. Here, we isolated three new sp alleles from the tomato germplasm that show modified determinate growth compared to sp-classic, including one allele that mimics the effect of sft heterozygosity. Two deletion alleles eliminated functional transcripts and showed similar shoot termination, determinate growth, and yields as sp-classic. In contrast, amino acid substitution allele sp-5732 showed semi-determinate growth with more leaves and sympodial shoots on all shoots. This translated to greater yield compared to the other stronger alleles by up to 42%. Transcriptome profiling of axillary (sympodial) shoot meristems (SYM) from sp-classic and wild type plants revealed six mis-regulated genes related to the floral transition, which were used as biomarkers to show that the maturation of SYMs in the weaker sp-5732 genotype is delayed compared to sp-classic, consistent with delayed shoot termination and semi-determinate growth. Assessing sp allele frequencies from over 500 accessions indicated that one of the strong sp alleles (sp-2798) arose in early breeding cultivars but was not selected. The newly discovered sp alleles are potentially valuable resources to quantitatively manipulate shoot growth and yield in determinate breeding programs, with sp-5732 providing an opportunity to develop semi-determinate field varieties with higher yields.
Identifying the Early Signs of Preterm Birth from U.S. Birth Records Using Machine Learning Techniques
Authors: Ebrahimvandi Alireza , Hosseinichimeh Niyousha , Kong Zhenyu James
Published: June 2022

Preterm birth (PTB) is the leading cause of infant mortality in the U.S. and globally. The goal of this study is to increase understanding of PTB risk factors that are present early in pregnancy by leveraging statistical and machine learning (ML) techniques on big data. The 2016 U.S. birth records were obtained and combined with two other area-level datasets, the Area Health Resources File and the County Health Ranking. Then, we applied logistic regression with elastic net regularization, random forest, and gradient boosting machines to study a cohort of 3.6 million singleton deliveries to identify generalizable PTB risk factors. The response variable is preterm birth, which includes spontaneous and indicated PTB, and we performed a binary classification. Our results show that the most important predictors of preterm birth are gestational and chronic hypertension, interval since last live birth, and history of a previous preterm birth, which explains 10.92, 5.98, and 5.63% of the predictive power, respectively. Parents’ education is one of the influential variables in predicting PTB, explaining 7.89% of the predictive power. The relative importance of race declines when parents are more educated or have received adequate prenatal care. The gradient boosting machines outperformed with an AUC of 0.75 (sensitivity: 0.64, specificity: 0.73) for the validation dataset. In this study, we compare our results with seminal and most related studies to demonstrate the superiority of our results. The application of ML techniques improved the performance measures in the prediction of preterm birth. The results emphasize the importance of socioeconomic factors such as parental education as one of the most important indicators of preterm birth. More research is needed on these mechanisms through which socioeconomic factors affect biological responses.
“We Will Let You Know”: An Assessment of Digital vs. Face-to-Face Job Interviews via EEG Connectivity Analysis
Authors: Balconi Michela , Crivelli Davide , Cassioli Federico
Published: June 2022

We focused on job interviews as critical examples of complex social interaction in organizational contexts. We aimed at investigating the effect of face-to-face vs. computer-mediated interaction, of role (candidate, recruiter), and of the interview phase (introductory, attitudinal, technical, conclusive) on intra-brain and inter-brain connectivity measures and autonomic synchronization. Twenty expert recruiters and potential candidates took part in a hyperscanning investigation. Namely, electroencephalography (delta, theta, alpha, beta bands) and autonomic (skin-conductance, heart-rate) data were collected in candidate-recruiter dyads during a simulated job interview and then concurrently analyzed. Analyses highlighted a link between face-to-face condition and greater intra-/inter-brain connectivity indices in delta and theta bands. Furthermore, intra-brain and inter-brain connectivity measures were higher for delta and theta bands in the final interview phases compared to the first ones. Consistently, autonomic synchronization was higher during the final interview phases, specifically in the face-to-face condition. Finally, recruiters showed higher intra-brain connectivity in the delta range over frontal and temporoparietal areas, while candidates showed higher intra-brain connectivity in the theta range over frontal areas. Findings highlight the value of hyperscanning investigations in exploring social attunement in professional contexts and hint at their potential to foster neuroscience-informed practices in human resource management processes.
An Improved Complete Coverage Path Planning Method for Intelligent Agricultural Machinery Based on Backtracking Method
Authors: Han Yonglian , Shao Min , Wu Yunzhi , Zhang Xiaoming
Published: June 2022

The advancement of society and technology has promoted the development of modern agriculture. It has become a trend to replace traditional manpower with intelligent agricultural machinery that operates independently. As the core technology of intelligent agricultural machinery, complete coverage path planning technology has become more important. At present, the complete coverage path planning algorithms still suffer from problems such as sacrificing the coverage rate to obtain the minimum energy consumption, taking a long time to calculate the algorithm, and destroying crops across the covered region. In view of the above problems, an improved complete coverage path planning algorithms based on backtracking is proposed combined with the actual needs of intelligent agricultural machinery for planting seedlings to improve four aspects: repeated coverage, search efficiency, path planning, and sub-regional crossing. Firstly, the Morse decomposition method is used to divide a complex farmland region into simple sub-regions. Then an improved backtracking method based on a greedy algorithm is proposed in order to reduce the computational efficiency of the current region connection algorithms. The priority principle and the strategy of moving along the boundary are used to solve the problems of region crossing and sacrificing the coverage rate, thereby improving the performance of the current complete coverage path planning method. Compared with the traditional backtracking method, the experimental results show that the number of backtracking points is decreased by about 70% and the occurrence of crossing sub-regions has been significantly reduced. This proposed method can improve the coverage and operating efficiency of intelligent agricultural machinery operations and provide technical support for agricultural operations such as sowing, tillage, and harvesting, thus improving the quality and efficiency of agricultural production.
An Effective Ensemble Automatic Feature Selection Method for Network Intrusion Detection
Authors: Zhang Yang , Zhang Hongpo , Zhang Bo
Published: June 2022

The mass of redundant and irrelevant data in network traffic brings serious challenges to intrusion detection, and feature selection can effectively remove meaningless information from the data. Most current filtered and embedded feature selection methods use a fixed threshold or ratio to determine the number of features in a subset, which requires a priori knowledge. In contrast, wrapped feature selection methods are computationally complex and time-consuming; meanwhile, individual feature selection methods have a bias in evaluating features. This work designs an ensemble-based automatic feature selection method called EAFS. Firstly, we calculate the feature importance or ranks based on individual methods, then add features to subsets sequentially by importance and evaluate subset performance comprehensively by designing an NSOM to obtain the subset with the largest NSOM value. When searching for a subset, the subset with higher accuracy is retained to lower the computational complexity by calculating the accuracy when the full set of features is used. Finally, the obtained subsets are ensembled, and by comparing the experimental results on three large-scale public datasets, the method described in this study can help in the classification, and also compared with other methods, we discover that our method outperforms other recent methods in terms of performance.