bluuebunny/crossref_metadata_2025 huggingface dataset:
Joking Around, Seriously: Freud, Derrida, and the Irrepressible Wit of Heinrich Heine
Authors: Rottenberg Elizabeth
Published: October 2023

This essay sets out to explore the unexpected but amusing entanglement of three Jewish writers—Harry (“Heinrich”) Heine, Sigismund (“Sigmund”) Freud, and Jackie (“Jacques”) Derrida. You will not often find a reference to Heine in the work of Jacques Derrida, but you will find a Heine joke in Derrida’s discussion of forgiveness in Le parjure et le pardon (1998–1999), where the name Heine is invoked precisely in order to recall the scandalous automaticity, the machine-like quality of forgiveness. Beginning with Derrida’s surprising reference to the man George Eliot called a “unique German wit”, this essay will begin by arguing that there is something about Heine’s jokes, his Witze, his mots d’esprit, that not only plays up, but also paradoxically takes seriously, what Derrida, echoing Nietzsche in Of Grammatology, describes as the “play of the world.” The second part of this essay will engage Freud’s particular and quite special relation to Heine: Heine is the third most cited German writer in all of Freud’s work (after Goethe and Schiller). Neither Homer nor Sophocles is cited more often than Heine. Indeed, a bon mot from Heine is always ready-to-hand in the face of theoretical obstacles (e.g., “Observations on Transference Love”, “On Narcissism”, etc.). But perhaps nowhere is Freud’s affinity with Heine more apparent and more striking than in Jokes and Their Relation to the Unconscious (1905), where Heine’s witticisms offer the best and most canonical examples of jokes. In conclusion, this essay will argue that Heine’s wit can be read as a playbook—not only for psychoanalysis’s economic understanding of jokes, but also, more radically, for deconstruction’s thinking of play.
Interactions between Metabolic Syndrome, MASLD, and Arterial Stiffening: A Single-Center Cross-Sectional Study
Authors: Solomon Adelaida , Negrea Mihai Octavian , Cipăian Călin Remus , Boicean Adrian , Mihaila Romeo , Rezi Cristina , Cristinescu Bianca Andreea , Berghea-Neamtu Cristian Stefan , Popa Mirela Livia , Teodoru Minodora , Stoia Oana , Neamtu Bogdan
Published: October 2023

Metabolic-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), has emerged as a prominent global cause of chronic liver disease and is increasingly recognized as associated with atherosclerotic vascular illness, consolidating its position along traditional cardiovascular risk factors. Individuals with MASLD exhibit a combination of metabolic syndrome risk factors, carotid atherosclerosis, and increased arterial stiffness, hinting at shared pathogenesis. In this study, we aim to explore liver involvement and arterial stiffness within metabolic syndrome. We enrolled 75 patients (30 male and 45 female) with either liver steatosis on conventional ultrasound, altered liver function tests, or the presence of cardiometabolic risk factors after excluding liver pathology other than MASLD. Clinical evaluation, laboratory measurements, abdominal and carotid ultrasounds, vibration-controlled transient elastography (VCTE, Fibroscan), and assessment with the Arteriograph (Tensiomed) were performed. The 26 patients diagnosed with MetS had significantly higher liver involvement as quantified via the hepatic steatosis index (HSI), Fibrosis-4 (FIB4), aspartate aminotransferase to platelet ratio index (APRI) category, and VCTE measurements, as well as Agile 3+ and Agile 4 scores which use a combination of clinical and laboratory parameters together with results obtained from VCTE to reflect the probability of advanced liver fibrosis or cirrhosis. Patients with MetS also exhibited more pronounced vascular involvement as quantified via arterial stiffness measurements and CIMT (carotid intima–media thickness). We applied a two-step clustering algorithm to enhance our analysis, which gave us pertinent insight into the interplay between metabolic syndrome elements and typologies of hepatic steatosis and arterial stiffness degrees. Notably, of the three obtained clusters, the cluster showing increased levels of hepatic steatosis and arterial stiffness also exhibited the highest prevalence of metabolic syndrome and its constituting components. The results have significant clinical implications, advocating for a comprehensive diagnostic approach when MetS or MASLD is suspected.
Assessing the Impact of the 2023 Kahramanmaras Earthquake on Cultural Heritage Sites Using High-Resolution SAR Images
Authors: Boyoğlu Cem Sönmez , Chike Ifeanyi , Caspari Gino , Balz Timo
Published: October 2023

Earthquakes are hard to predict, and the destruction caused by the events far outstrip the monetary damage. Important cultural heritage sites functioning as places of community and identity have a value which evades pure pecuniary calculation. This makes understanding the complete economic and social impact of earthquakes a difficult and daunting task. We use high-resolution TerraSAR-X data acquired after the 2023 earthquake in Turkey to assess its impact on selected cultural heritage sites. Leveraging different orbit and incidence angles of image acquisition allow us to show the difficulties in interpreting high-resolution SAR data. While large impacts, like the complete collapse of structures, can be detected successfully, small-scale damage and partial collapses are often difficult to detect from single SAR images. We find that single SAR scene interpretation for damage assessment of cultural heritage is not a viable option. While contextualizing data might help to understand the situation, SAR is only helpful if data of the intact cultural heritage sites have been obtained before the event.
Resilience, Positivity and Social Support as Perceived Stress Predictors among University Students
Authors: Litwic-Kaminska Kamila , Błachnio Aleksandra , Kapsa Izabela , Brzeziński Łukasz , Kopowski Jakub , Stojković Milica , Hinić Darko , Krsmanović Ivana , Ragni Benedetta , Sulla Francesco , Limone Pierpaolo
Published: October 2023

Since the COVID-19 pandemic, researchers have been trying to identify which personal resources can contribute to minimizing the mental health costs in students incurred due to the restrictions that disrupted safety and predictability in their academic lives. The aim of the study was to verify if and how individual factors (resilience and positivity) and socio-environmental factors (social support and nationality) allow prediction of the level of perceived stress. University students (n = 559) from Poland, Serbia, and Italy were surveyed using the Perceived Stress Scale (PSS-10), the Brief Resilience Scale (BRS), the Positivity Scale (PS), and the Interpersonal Support Evaluation List (ISEL-12). Personal resources—positivity, resilience, and support—were found to be positively interrelated and significantly associated with stress levels. Additionally, gender and nationality differentiated stress levels. A general linear model (GLM) showed that levels of perceived stress are best explained by resilience, positivity, tangible support, and gender. The results obtained can strengthen students’ awareness of personal resources and their protective role in maintaining mental health, as well as contribute to the creation of prevention-oriented educational activities. Nationality was not a significant predictor of the level of perceived stress, which highlights the universality of examined predictors among university students from different countries and suggests that interventions aimed at enhancing these resources could benefit students across different cultural contexts.
Data-Sparse Prediction of High-Risk Schools for Lead Contamination in Drinking Water: Examples from Four U.S. States
Authors: Shrivatsa Samyukta , Lobo Gabriel , Gadgil Ashok
Published: October 2023

Childhood lead exposure through drinking water has long-term effects on cognition and development, and is a significant public health concern. The comprehensive lead testing of public schools entails high expense and time. In prior work, random forest modeling was used successfully to predict the likelihood of lead contamination in the drinking water from schools in the states of California and Massachusetts. In those studies, data from 70% of the schools was used to predict the probability of unsafe water lead levels (WLLs) in the remaining 30%. This study explores how the model predictions degrade, as the training dataset forms a progressively smaller proportion of schools. The size of the training set was varied from 80% to 10% of the total samples in four US states: California, Massachusetts, New York, and New Hampshire. The models were evaluated using the precision-recall area under curve (PR AUC) and area under the receiver operating characteristic curve (ROC AUC). While some states required as few as 10% of the schools to be included in the training set for an acceptable ROC AUC, all four states performed within an acceptable ROC AUC range when at least 50% of the schools were included. The results in New York and New Hampshire were consistent with the prior work that found the most significant predictor in the modeling to be the Euclidean distance to the closest school in the training set demonstrating unsafe WLLs. This study further supports the efficacy of predictive modeling in identifying the schools at a high risk of lead contamination in their drinking water supply, even when the survey data is incomplete on WLLs in all schools.
Healthcare Stakeholders’ Perspectives on Challenges in the Provision of Quality Primary Healthcare for People with Disabilities in Three Regions of Guatemala: A Qualitative Study
Authors: Hashemi Goli , Santos Ana Leticia , Wickenden Mary , Kuper Hannah , Shea Chi-Kwan , Hameed Shaffa
Published: October 2023

It is estimated that 3.75 billion people worldwide lack access to healthcare services. Marginalized populations, such as people with disabilities, are at greater risk of exclusion. People with disabilities not only face the same barriers as people without disabilities, but also experience a range of additional barriers in accessing healthcare due to a variety of discriminatory and inaccessible environments. These extra barriers exist despite their greater need for general healthcare, as well as specialized healthcare related to their impairment. Few studies have focused on healthcare providers and the challenges they face in caring for this group. This paper describes the perspectives of healthcare stakeholders and reported challenges to the provision of quality primary healthcare for people with disabilities. In-depth interviews with 11 healthcare stakeholders were conducted in three regions of Guatemala. Data were analyzed using thematic analysis. Five sub-themes emerged from the above theme: infrastructure and availability of resources, impairment-based challenges, need for special attention and empathy, opportunity to provide services to people with disabilities, and gaps in training. The results could contribute to the development and implementation of strategies that can improve primary care provision and ultimately access to services for people with disabilities in low- and middle-income countries.
Comment on Balwierz et al. Potential Carcinogens in Makeup Cosmetics. Int. J. Environ. Res. Public Health 2023, 20, 4780
Authors: Chaudhuri Ishrat , Ngiewih Yufanyi , Levy Len , McCunney Robert J.
Published: October 2023

We read with interest the article by Balwierz et al. [...]
Evaluating the Usability of a Gaze-Adaptive Approach for Identifying and Comparing Raster Values between Multilayers
Authors: Zhang Changbo , Liao Hua , Huang Yongbo , Dong Weihua
Published: October 2023

Raster maps provide intuitive visualizations of remote sensing data representing various phenomena on the Earth’s surface. Reading raster maps with intricate information requires a high cognitive workload, especially when it is necessary to identify and compare values between multiple layers. In traditional methods, users need to repeatedly move their mouse and switch their visual focus between the map content and legend to interpret various grid value meanings. Such methods are ineffective and may lead to the loss of visual context for users. In this research, we aim to explore the potential benefits and drawbacks of gaze-adaptive interactions when interpreting raster maps. We focus on the usability of the use of low-cost eye trackers on gaze-based interactions. We designed two gaze-adaptive methods, gaze fixed and gaze dynamic adaptations, for identifying and comparing raster values between multilayers. In both methods, the grid content of different layers is adaptively adjusted depending on the user’s visual focus. We then conducted a user experiment by comparing such adaptation methods with a mouse dynamic adaptation method and a traditional method. Thirty-one participants (n = 31) were asked to complete a series of single-layer identification and multilayer comparison tasks. The results indicated that although gaze interaction with adaptive legends confused participants in single-layer identification, it improved multilayer comparison efficiency and effectiveness. The gaze-adaptive approach was well received by the participants overall, but was also perceived to be distracting and insensitive. By analyzing the participants’ eye movement data, we found that different methods exhibited significant differences in visual behaviors. The results are helpful for gaze-driven adaptation research in (geo)visualization in the future.
Metabolite Profiling of Conifer Needles: Tracing Pollution and Climate Effects
Authors: Miricioiu Marius Gheorghe , Ionete Roxana Elena , Simova Svetlana , Gerginova Dessislava , Botoran Oana Romina
Published: October 2023

In the face of escalating environmental challenges, understanding the intricate relationship between plant metabolites, pollution stress, and climatic conditions is of paramount importance. This study aimed to conduct a comprehensive analysis of metabolic variations generated through 1H and 13C NMR measurements in evergreen needles collected from different regions with varying pollution levels. Multivariate analyses were employed to identify specific metabolites responsive to pollution stress and climatic factors. Air pollution indicators were assessed through ANOVA and Pearson correlation analyses. Our results revealed significant metabolic changes attributed to geographical origin, establishing these conifer species as potential indicators for both air pollution and climatic conditions. High levels of air pollution correlated with increased glucose and decreased levels of formic acid and choline. Principal component analysis (PCA) unveiled a clear species separation, largely influenced by succinic acid and threonine. Discriminant analysis (DA) confirmed these findings, highlighting the positive correlation of glucose with pollution grade. Beyond pollution assessment, these metabolic variations could have ecological implications, impacting interactions and ecological functions. Our study underscores the dynamic interplay between conifer metabolism, environmental stressors, and ecological systems. These findings not only advance environmental monitoring practices but also pave the way for holistic research encompassing ecological and physiological dimensions, shedding light on the multifaceted roles of metabolites in conifer responses to environmental challenges.
Three-Dimensional Modeling of CpG DNA Binding with Matrix Lumican Shows Leucine-Rich Repeat Motif Involvement as in TLR9-CpG DNA Interactions
Authors: Choi Tansol , Maiti George , Chakravarti Shukti
Published: October 2023

Lumican is an extracellular matrix proteoglycan known to regulate toll-like receptor (TLR) signaling in innate immune cells. In experimental settings, lumican suppresses TLR9 signaling by binding to and sequestering its synthetic ligand, CpG-DNA, in non-signal permissive endosomes. However, the molecular details of lumican interactions with CpG-DNA are obscure. Here, the 3-D structure of the 22 base-long CpG-DNA (CpG ODN_2395) bound to lumican or TLR9 were modeled using homology modeling and docking methods. Some of the TLR9-CpG ODN_2395 features predicted by our model are consistent with the previously reported TLR9-CpG DNA crystal structure, substantiating our current analysis. Our modeling indicated a smaller buried surface area for lumican-CpG ODN_2395 (1803 Å2) compared to that of TLR9-CpG ODN_2395 (2094 Å2), implying a potentially lower binding strength for lumican and CpG-DNA than TLR9 and CpG-DNA. The docking analysis identified 32 amino acids in lumican LRR1–11 interacting with CpG ODN_2395, primarily through hydrogen bonding, salt-bridges, and hydrophobic interactions. Our study provides molecular insights into lumican and CpG-DNA interactions that may lead to molecular targets for modulating TLR9-mediated inflammation and autoimmunity.
MicroRNA as Possible Mediators of the Synergistic Effect of Celecoxib and Glucosamine Sulfate in Human Osteoarthritic Chondrocyte Exposed to IL-1β
Authors: Cheleschi Sara , Veronese Nicola , Carta Serafino , Collodel Giulia , Bottaro Maria , Moretti Elena , Corsaro Roberta , Barbarino Marcella , Fioravanti Antonella
Published: October 2023

This study investigated the role of a pattern of microRNA (miRNA) as possible mediators of celecoxib and prescription-grade glucosamine sulfate (GS) effects in human osteoarthritis (OA) chondrocytes. Chondrocytes were treated with celecoxib (1.85 µM) and GS (9 µM), alone or in combination, for 24 h, with or without interleukin (IL)-1β (10 ng/mL). Cell viability was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, apoptosis and reactive oxygen species (ROS) by cytometry, nitric oxide (NO) by Griess method. Gene levels of miRNA, antioxidant enzymes, nuclear factor erythroid (NRF)2, and B-cell lymphoma (BCL)2 expressions were analyzed by quantitative real time polymerase chain reaction (real time PCR). Protein expression of NRF2 and BCL2 was also detected at immunofluorescence and western blot. Celecoxib and GS, alone or in combination, significantly increased viability, reduced apoptosis, ROS and NO production and the gene expression of miR-34a, -146a, -181a, -210, in comparison to baseline and to IL-1β. The transfection with miRNA specific inhibitors significantly counteracted the IL-1β activity and potentiated the properties of celecoxib and GS on viability, apoptosis and oxidant system, through nuclear factor (NF)-κB regulation. The observed effects were enhanced when the drugs were tested in combination. Our data confirmed the synergistic anti-inflammatory and chondroprotective properties of celecoxib and GS, suggesting microRNA as possible mediators.
Effects of Nanosecond Pulsed Electric Field (nsPEF) on a Multicellular Spheroid Tumor Model: Influence of Pulse Duration, Pulse Repetition Rate, Absorbed Energy, and Temperature
Authors: Orlacchio Rosa , Kolosnjaj-Tabi Jelena , Mattei Nicolas , Lévêque Philippe , Rols Marie Pierre , Arnaud-Cormos Delia , Golzio Muriel
Published: October 2023

Cellular response upon nsPEF exposure depends on different parameters, such as pulse number and duration, the intensity of the electric field, pulse repetition rate (PRR), pulsing buffer composition, absorbed energy, and local temperature increase. Therefore, a deep insight into the impact of such parameters on cellular response is paramount to adaptively optimize nsPEF treatment. Herein, we examined the effects of nsPEF ≤ 10 ns on long-term cellular viability and growth as a function of pulse duration (2–10 ns), PRR (20 and 200 Hz), cumulative time duration (1–5 µs), and absorbed electrical energy density (up to 81 mJ/mm3 in sucrose-containing low-conductivity buffer and up to 700 mJ/mm3 in high-conductivity HBSS buffer). Our results show that the effectiveness of nsPEFs in ablating 3D-grown cancer cells depends on the medium to which the cells are exposed and the PRR. When a medium with low-conductivity is used, the pulses do not result in cell ablation. Conversely, when the same pulse parameters are applied in a high-conductivity HBSS buffer and high PRRs are applied, the local temperature rises and yields either cell sensitization to nsPEFs or thermal damage.
MicroRNAs in Endometriosis: Insights into Inflammation and Progesterone Resistance
Authors: Hon Jing-Xian , Wahab Norhazlina Abdul , Karim Abdul Kadir Abdul , Mokhtar Norfilza Mohd , Mokhtar Mohd Helmy
Published: October 2023

Endometriosis, a non-malignant gynecological disorder influenced by estrogen, involves the growth of endometrial tissue outside the uterus. Its development includes processes such as inflammation, progesterone resistance, angiogenesis, and cell proliferation. Epigenetic factors, particularly the dysregulation of microRNAs (miRNAs), have emerged as key factors in these mechanisms in endometriosis. This review aims to unveil the intricate molecular processes that control inflammation, progesterone resistance, and miRNA functions in endometriosis. In addition, it provides a comprehensive overview of the current understanding regarding the involvement of miRNAs in the inflammatory aspects of this condition. This synthesis encompasses research investigating the molecular underpinnings of inflammation, along with the biogenesis and roles of miRNAs in endometriosis. Furthermore, it examines human studies and functional analyses to establish the intricate connection between miRNAs, inflammation, and progesterone resistance in the context of endometriosis. The results highlight the significant impact of dysregulated miRNAs on the inflammatory pathways and hormonal imbalances characteristic of endometriosis. Consequently, miRNAs hold promise as potential non-invasive biomarkers and targeted therapeutic agents aimed at addressing inflammation and enhancing the response to progesterone treatment in individuals with endometriosis.
Unveiling the Genetic Complexity of Teratozoospermia: Integrated Genomic Analysis Reveals Novel Insights into lncRNAs’ Role in Male Infertility
Authors: Kyrgiafini Maria-Anna , Giannoulis Themistoklis , Chatziparasidou Alexia , Christoforidis Nikolaos , Mamuris Zissis
Published: October 2023

Male infertility is a global health issue, affecting over 20 million men worldwide. Genetic factors are crucial in various male infertility forms, including teratozoospermia. Nonetheless, the genetic causes of male infertility remain largely unexplored. In this study, we employed whole-genome sequencing and RNA expression analysis to detect differentially expressed (DE) long-noncoding RNAs (lncRNAs) in teratozoospermia, along with mutations that are exclusive to teratozoospermic individuals within these DE lncRNAs regions. Bioinformatic tools were used to assess variants’ impact on lncRNA structure, function, and lncRNA–miRNA interactions. Our analysis identified 1166 unique mutations in teratozoospermic men within DE lncRNAs, distinguishing them from normozoospermic men. Among these, 64 variants in 23 lncRNAs showed potential regulatory roles, 7 variants affected 4 lncRNA structures, while 37 variants in 17 lncRNAs caused miRNA target loss or gain. Pathway Enrichment and Gene Ontology analyses of the genes targeted by the affected miRNAs revealed dysregulated pathways in teratozoospermia and a link between male infertility and cancer. This study lists novel variants and lncRNAs associated for the first time with teratozoospermia. These findings pave the way for future studies aiming to enhance diagnosis and therapy in the field of male infertility.
An Investigation of the JAZ Family and the CwMYC2-like Protein to Reveal Their Regulation Roles in the MeJA-Induced Biosynthesis of β-Elemene in Curcuma wenyujin
Authors: Liu Yuyang , Wu Shiyi , Lan Kaer , Wang Qian , Ye Tingyu , Jin Huanan , Hu Tianyuan , Xie Tian , Wei Qiuhui , Yin Xiaopu
Published: October 2023

β-Elemene (C15H24), a sesquiterpenoid compound isolated from the volatile oil of Curcuma wenyujin, has been proven to be effective for multiple cancers and is widely used in clinical treatment. Unfortunately, the β-elemene content in C. wenyujin is very low, which cannot meet market demands. Our previous research showed that methyl jasmonate (MeJA) induced the accumulation of β-elemene in C. wenyujin. However, the regulatory mechanism is unclear. In this study, 20 jasmonate ZIM-domain (JAZ) proteins in C. wenyujin were identified, which are the core regulatory factors of the JA signaling pathway. Then, the conservative domains, motifs composition, and evolutionary relationships of CwJAZs were analyzed comprehensively and systematically. The interaction analysis indicated that CwJAZs can form homodimers or heterodimers. Fifteen out of twenty CwJAZs were significantly induced via MeJA treatment. As the master switch of the JA signaling pathway, the CwMYC2-like protein has also been identified and demonstrated to interact with CwJAZ2/3/4/5/7/15/17/20. Further research found that the overexpression of the CwMYC2-like gene increased the accumulation of β-elemene in C. wenyujin leaves. Simultaneously, the expressions of HMGR, HMGS, DXS, DXR, MCT, HDS, HDR, and FPPS related to β-elemene biosynthesis were also up-regulated by the CwMYC2-like protein. These results indicate that CwJAZs and the CwMYC2-like protein respond to the JA signal to regulate the biosynthesis of β-elemene in C. wenyujin.
Genome-Wide Evolutionary Characterization and Expression Analysis of Major Latex Protein (MLP) Family Genes in Tomato
Authors: Sun Zhengliang , Meng Liangzhe , Yao Yuhe , Zhang Yanhong , Cheng Baohui , Liang Yan
Published: October 2023

Major latex proteins (MLPs) play a key role in plant response to abiotic and biotic stresses. However, little is known about this gene family in tomatoes (Solanum lycopersicum). In this paper, we perform a genome-wide evolutionary characterization and gene expression analysis of the MLP family in tomatoes. We found a total of 34 SlMLP members in the tomato genome, which are heterogeneously distributed on eight chromosomes. The phylogenetic analysis of the SlMLP family unveiled their evolutionary relationships and possible functions. Furthermore, the tissue-specific expression analysis revealed that the tomato MLP members possess distinct biological functions. Crucially, multiple cis-regulatory elements associated with stress, hormone, light, and growth responses were identified in the promoter regions of these SlMLP genes, suggesting that SlMLPs are potentially involved in plant growth, development, and various stress responses. Subcellular localization demonstrated that SlMLP1, SlMLP3, and SlMLP17 are localized in the cytoplasm. In conclusion, these findings lay a foundation for further dissecting the functions of tomato SlMLP genes and exploring the evolutionary relationships of MLP homologs in different plants.
Synthesis and Antiviral and Antitumor Activities of Novel 18β-Glycyrrhetinic Acid Derivatives
Authors: Pan Bo-Wen , Zheng Liang-Liang , Shi Yang , Dong Zhang-Chao , Feng Ting-Ting , Yang Jian , Wei Ying , Zhou Ying
Published: October 2023

A series of novel derivatives of 18β-glycyrrhetinic acid (GA) were synthesized by introducing aromatic or heterocyclic structures to extend the side chain, thereby enhancing their interaction with amino acid residues in the active pocket of the target protein. These compounds were structurally characterized using 1H NMR, 13C NMR, and HRMS. The compounds were subsequently evaluated for their inhibitory effects on HIV-1 protease and cell viability in the human cancer cell lines K562 and HeLa and the mouse cancer cell line CT26. Towards HIV-1 protease, compounds 28 and 32, which featured the introduction of heterocyclic moieties at the C3 position of GA, exhibited the highest inhibition, with inhibition rates of 76% and 70.5%, respectively, at 1 mg/mL concentration. Further molecular docking suggests that a 3-substituted polar moiety would be likely to enhance the inhibitory activity against HIV-1 protease. As for the anti-proliferative activities of the GA derivatives, incorporation of a thiazole heterocycle at the C3- position in compound 29 significantly enhanced the effect against K562 cells with an IC50 value of 8.86 ± 0.93 µM. The introduction of electron-withdrawing substituents on the C3-substituted phenyl ring augmented the anti-proliferative activity against Hela and CT26 cells. Compound 13 exhibited the highest inhibitory activity against Hela cells with an IC50 value of 9.89 ± 0.86 µM, whereas compound 7 exerted the strongest inhibition against CT26 cells with an IC50 value of 4.54 ± 0.37 µM. These findings suggest that further modification of GA is a promising path for developing potent novel anti-HIV and anticancer therapeutics.
Combined Omics Approaches Reveal Distinct Mechanisms of Resistance and/or Susceptibility in Sugar Beet Double Haploid Genotypes at Early Stages of Beet Curly Top Virus Infection
Authors: Galewski Paul J. , Majumdar Rajtilak , Lebar Matthew D. , Strausbaugh Carl A. , Eujayl Imad A.
Published: October 2023

Sugar beet is susceptible to Beet curly top virus (BCTV), which significantly reduces yield and sugar production in the semi-arid growing regions worldwide. Sources of genetic resistance to BCTV is limited and control depends upon insecticide seed treatments with neonicotinoids. Through double haploid production and genetic selection, BCTV resistant breeding lines have been developed. Using BCTV resistant (R) [KDH13; Line 13 and KDH4-9; Line 4] and susceptible (S) [KDH19-17; Line 19] lines, beet leafhopper mediated natural infection, mRNA/sRNA sequencing, and metabolite analyses, potential mechanisms of resistance against the virus and vector were identified. At early infection stages (2- and 6-days post inoculation), examples of differentially expressed genes highly up-regulated in the ‘R’ lines (vs. ‘S’) included EL10Ac5g10437 (inhibitor of trypsin and hageman factor), EL10Ac6g14635 (jasmonate-induced protein), EL10Ac3g06016 (ribosome related), EL10Ac2g02812 (probable prolyl 4-hydroxylase 10), etc. Pathway enrichment analysis showed differentially expressed genes were predominantly involved with peroxisome, amino acids metabolism, fatty acid degradation, amino/nucleotide sugar metabolism, etc. Metabolite analysis revealed significantly higher amounts of specific isoflavonoid O-glycosides, flavonoid 8-C glycosides, triterpenoid, and iridoid-O-glycosides in the leaves of the ‘R’ lines (vs. ‘S’). These data suggest that a combination of transcriptional regulation and production of putative antiviral metabolites might contribute to BCTV resistance. In addition, genome divergence among BCTV strains differentially affects the production of small non-coding RNAs (sncRNAs) and small peptides which may potentially affect pathogenicity and disease symptom development.
Proenkephalin Levels and Its Determinants in Patients with End-Stage Kidney Disease Treated with Hemodialysis and Peritoneal Dialysis
Authors: Grycuk Wiktoria , Jakubowska Zuzanna , Małyszko Jolanta
Published: October 2023

Recently, proenkephalin A (PENK A) has been shown to reflect glomerular dysfunction and to predict new-onset acute kidney injury and heart failure. While previous studies have investigated PENK A as a biomarker in individuals with preserved renal function, PENK A concentration in patients with end-stage kidney disease (ESKD) was not investigated. Plasma PENK A concentration was assessed in 88 patients with ESKD treated with hemodialysis (HD) or peritoneal dialysis (PD), and its associations with kidney function and heart failure indicators were investigated. In HD patients, the difference in PENK A levels before and after hemodialysis, was measured and further assessed for an association with the type of HD membrane used. PENK A levels did not differ significantly between HD and PD patients. In HD patients, the median PENK A concentration was significantly higher before than after hemodialysis (1.368 vs. 2.061, p = 0.003). No correlation was found between PENK A level and urea (p = 0.192), eGFR (p = 0.922), dialysis vintage (p = 0.637), and residual urine output (p = 0.784). Heart failure (p = 0.961), EF (p = 0.361), and NT-proBNP (p = 0.949) were not associated with increased PENK A concentration. PENK A does not reflect renal function and cardiac status in patients with ESKD. Further research is required to establish the clinical utility of the new biomarker in patients with impaired kidney function.
Enhancing the Heterologous Expression of a Thermophilic Endoglucanase and Its Cost-Effective Production in Pichia pastoris Using Multiple Strategies
Authors: Dai Wuling , Dong Haofan , Zhang Zhaokun , Wu Xin , Bao Tongtong , Gao Le , Chen Xiaoyi
Published: October 2023

Although Pichia pastoris was successfully used for heterologous gene expression for more than twenty years, many factors influencing protein expression remain unclear. Here, we optimized the expression of a thermophilic endoglucanase from Thermothielavioides terrestris (TtCel45A) for cost-effective production in Pichia pastoris. To achieve this, we established a multifactorial regulation strategy that involved selecting a genome-editing system, utilizing neutral loci, incorporating multiple copies of the heterologous expression cassette, and optimizing high-density fermentation for the co-production of single-cell protein (SCP). Notably, even though all neutral sites were used, there was still a slight difference in the enzymatic activity of heterologously expressed TtCel45A. Interestingly, the optimal gene copy number for the chromosomal expression of TtCel45A was found to be three, indicating limitations in translational capacity, post-translational processing, and secretion, ultimately impacting protein yields in P. pastoris. We suggest that multiple parameters might influence a kinetic competition between protein elongation and mRNA degradation. During high-density fermentation, the highest protein concentration and endoglucanase activity of TtCel45A with three copies reached 15.8 g/L and 9640 IU/mL, respectively. At the same time, the remaining SCP of P. pastoris exhibited a crude protein and amino acid content of up to 59.32% and 46.98%, respectively. These findings suggested that SCP from P. pastoris holds great promise as a sustainable and cost-effective alternative for meeting the global protein demand, while also enabling the production of thermophilic TtCel45A in a single industrial process.
Robust AMBER Force Field Parameters for Glutathionylated Cysteines
Authors: Elftmaoui Zineb , Bignon Emmanuelle
Published: October 2023

S-glutathionylation is an oxidative post-translational modification, which is involved in the regulation of many cell signaling pathways. Increasing amounts of studies show that it is crucial in cell homeostasis and deregulated in several pathologies. However, the effect of S-glutathionylation on proteins’ structure and activity is poorly understood, and a drastic lack of structural information at the atomic scale remains. Studies based on the use of molecular dynamics simulations, which can provide important information about modification-induced modulation of proteins’ structure and function, are also sparse, and there is no benchmarked force field parameters for this modified cysteine. In this contribution, we provide robust AMBER parameters for S-glutathionylation, which we tested extensively against experimental data through a total of 33 μs molecular dynamics simulations. We show that our parameter set efficiently describes the global and local structural properties of S-glutathionylated proteins. These data provide the community with an important tool to foster new investigations into the effect of S-glutathionylation on protein dynamics and function, in a common effort to unravel the structural mechanisms underlying its critical role in cellular processes.
Development of Novel Class of Phenylpyrazolo[3,4-d]pyrimidine-Based Analogs with Potent Anticancer Activity and Multitarget Enzyme Inhibition Supported by Docking Studies
Authors: Aljohani Ahmed K. B. , El Zaloa Waheed Ali Zaki , Alswah Mohamed , Seleem Mohamed A. , Elsebaei Mohamed M. , Bayoumi Ashraf H. , El-Morsy Ahmed M. , Almaghrabi Mohammed , Awaji Aeshah A. , Hammad Ali , Alsulaimany Marwa , Ahmed Hany E. A.
Published: October 2023

Phenylpyrazolo[3,4-d]pyrimidine is considered a milestone scaffold known to possess various biological activities such as antiparasitic, antifungal, antimicrobial, and antiproliferative activities. In addition, the urgent need for selective and potent novel anticancer agents represents a major route in the drug discovery process. Herein, new aryl analogs were synthesized and evaluated for their anticancer effects on a panel of cancer cell lines: MCF-7, HCT116, and HePG-2. Some of these compounds showed potent cytotoxicity, with variable degrees of potency and cell line selectivity in antiproliferative assays with low resistance. As the analogs carry the pyrazolopyrimidine scaffold, which looks structurally very similar to tyrosine and receptor kinase inhibitors, the potent compounds were evaluated for their inhibitory effects on three essential cancer targets: EGFRWT, EGFRT790M, VGFR2, and Top-II. The data obtained revealed that most of these compounds were potent, with variable degrees of target selectivity and dual EGFR/VGFR2 inhibitors at the IC50 value range, i.e., 0.3–24 µM. Among these, compound 5i was the most potent non-selective dual EGFR/VGFR2 inhibitor, with inhibitory concentrations of 0.3 and 7.60 µM, respectively. When 5i was tested in an MCF-7 model, it effectively inhibited tumor growth, strongly induced cancer cell apoptosis, inhibited cell migration, and suppressed cell cycle progression leading to DNA fragmentation. Molecular docking studies were performed to explore the binding mode and mechanism of such compounds on protein targets and mapped with reference ligands. The results of our studies indicate that the newly discovered phenylpyrazolo[3,4-d]pyrimidine-based multitarget inhibitors have significant potential for anticancer treatment.
Imidazo-Pyrazole-Loaded Palmitic Acid and Polystyrene-Based Nanoparticles: Synthesis, Characterization and Antiproliferative Activity on Chemo-Resistant Human Neuroblastoma Cells
Authors: Valenti Giulia Elda , Marengo Barbara , Milanese Marco , Zuccari Guendalina , Brullo Chiara , Domenicotti Cinzia , Alfei Silvana
Published: October 2023

Neuroblastoma (NB) is a childhood cancer, commonly treated with drugs, such as etoposide (ETO), whose efficacy is limited by the onset of resistance. Here, aiming at identifying new treatments for chemo-resistant NB, the effects of two synthesized imidazo-pyrazoles (IMPs) (4G and 4I) were investigated on ETO-sensitive (HTLA-230) and ETO-resistant (HTLA-ER) NB cells, detecting 4I as the more promising compound, that demonstrated IC50 values lower than those of ETO on HTLA ER. Therefore, to further improve the activity of 4I, we developed 4I-loaded palmitic acid (PA) and polystyrene-based (P5) cationic nanoparticles (P5PA-4I NPs) with high drug loading (21%) and encapsulation efficiency (97%), by a single oil-in-water emulsification technique. Biocompatible PA was adopted as an emulsion stabilizer, while synthesized P5 acted as an encapsulating agent, solubilizer and hydrophilic–lipophilic balance (HLB) improver. Optic microscopy and cytofluorimetric analyses were performed to investigate the micromorphology, size and complexity distributions of P5PA-4I NPs, which were also structurally characterized by chemometric-assisted Fourier transform infrared spectroscopy (FTIR). Potentiometric titrations allowed us to estimate the milliequivalents of PA and basic nitrogen atoms present in NPs. P5PA-4I NPs afforded dispersions in water with excellent buffer capacity, essential to escape lysosomal degradation and promote long residence time inside cells. They were chemically stable in an aqueous medium for at least 40 days, while in dynamic light scattering (DLS) analyses, P5PA-4I showed a mean hydrodynamic diameter of 541 nm, small polydispersity (0.194), and low positive zeta potentials (+8.39 mV), assuring low haemolytic toxicity. Biological experiments on NB cells, demonstrated that P5PA-4I NPs induced ROS-dependent cytotoxic effects significantly higher than those of pristine 4I, showing a major efficacy compared to ETO in reducing cell viability in HTLA-ER cells. Collectively, this 4I-based nano-formulation could represent a new promising macromolecular platform to develop a new delivery system able to increase the cytotoxicity of the anticancer drugs.
The Complex Network of ADP-Ribosylation and DNA Repair: Emerging Insights and Implications for Cancer Therapy
Authors: Li Ziyuan , Luo Aiqin , Xie Bingteng
Published: October 2023

ADP-ribosylation is a post-translational modification of proteins that plays a key role in various cellular processes, including DNA repair. Recently, significant progress has been made in understanding the mechanism and function of ADP-ribosylation in DNA repair. ADP-ribosylation can regulate the recruitment and activity of DNA repair proteins by facilitating protein–protein interactions and regulating protein conformations. Moreover, ADP-ribosylation can influence additional post-translational modifications (PTMs) of proteins involved in DNA repair, such as ubiquitination, methylation, acetylation, phosphorylation, and SUMOylation. The interaction between ADP-ribosylation and these additional PTMs can fine-tune the activity of DNA repair proteins and ensure the proper execution of the DNA repair process. In addition, PARP inhibitors have been developed as a promising cancer therapeutic strategy by exploiting the dependence of certain cancer types on the PARP-mediated DNA repair pathway. In this paper, we review the progress of ADP-ribosylation in DNA repair, discuss the crosstalk of ADP-ribosylation with additional PTMs in DNA repair, and summarize the progress of PARP inhibitors in cancer therapy.
The Relationship between Clock Genes, Sirtuin 1, and Mitochondrial Activity in Head and Neck Squamous Cell Cancer: Effects of Melatonin Treatment
Authors: Rodríguez-Santana César , López-Rodríguez Alba , Martinez-Ruiz Laura , Florido Javier , Cela Olga , Capitanio Nazzareno , Ramírez-Casas Yolanda , Acuña-Castroviejo Darío , Escames Germaine
Published: October 2023

The circadian clock is a regulatory system, with a periodicity of approximately 24 h, which generates rhythmic changes in many physiological processes, including mitochondrial activity. Increasing evidence links chronodisruption with aberrant functionality in clock gene expression, resulting in multiple diseases such as cancer. Melatonin, whose production and secretion oscillates according to the light–dark cycle, is the principal regulator of clock gene expression. In addition, the oncostatic effects of melatonin correlate with an increase in mitochondrial activity. However, the direct links between circadian clock gene expression, mitochondrial activity, and the antiproliferative effects of melatonin in cancers, including head and neck squamous cell carcinoma (HNSCC), remain largely unknown. In this study, we analyzed the effects of melatonin on HNSCC cell lines (Cal-27 and SCC9), which were treated with 500 and 1000 µM melatonin. We found that the antiproliferative effect of melatonin is not mediated by the Bmal1 clock gene. Additionally, high doses of melatonin were observed to result in resynchronization of oscillatory circadian rhythm genes (Per2 and Sirt1). Surprisingly, the resynchronizing effect of melatonin on Per2 and Sirt1 did not produce alterations in the oscillation of mitochondrial respiratory activity. These results increase our understanding of the possible antiproliferative mechanisms in melatonin in the treatment of head and neck squamous cell carcinoma and suggest that its antiproliferative effects are independent of clock genes but are directly related to mitochondrial activity.
Multi-Omics Profiling of Human Endothelial Cells from the Coronary Artery and Internal Thoracic Artery Reveals Molecular but Not Functional Heterogeneity
Authors: Frolov Alexey , Lobov Arseniy , Kabilov Marsel , Zainullina Bozhana , Tupikin Alexey , Shishkova Daria , Markova Victoria , Sinitskaya Anna , Grigoriev Evgeny , Markova Yulia , Kutikhin Anton
Published: October 2023

Major adverse cardiovascular events occurring upon coronary artery bypass graft surgery are typically accompanied by endothelial dysfunction. Total arterial revascularisation, which employs both left and right internal thoracic arteries instead of the saphenous vein to create a bypass, is associated with better mid- and long-term outcomes. We suggested that molecular profiles of human coronary artery endothelial cells (HCAECs) and human internal mammary artery endothelial cells (HITAECs) are coherent in terms of transcriptomic and proteomic signatures, which were then investigated by RNA sequencing and ultra-high performance liquid chromatography-mass spectrometry, respectively. Both HCAECs and HITAECs overexpressed molecules responsible for the synthesis of extracellular matrix (ECM) components, basement membrane assembly, cell-ECM adhesion, organisation of intercellular junctions, and secretion of extracellular vesicles. HCAECs were characterised by higher enrichment with molecular signatures of basement membrane construction, collagen biosynthesis and folding, and formation of intercellular junctions, whilst HITAECs were notable for augmented pro-inflammatory signaling, intensive synthesis of proteins and nitrogen compounds, and enhanced ribosome biogenesis. Despite HCAECs and HITAECs showing a certain degree of molecular heterogeneity, no specific markers at the protein level have been identified. Coherence of differentially expressed molecular categories in HCAECs and HITAECs suggests synergistic interactions between these ECs in a bypass surgery scenario.
Unveiling the Anti-Cancer Potential of Onoceranoid Triterpenes from Lansium domesticum Corr. cv. kokosan: An In Silico Study against Estrogen Receptor Alpha
Authors: Hardianto Ari , Mardetia Sarah Syifa , Destiarani Wanda , Budiman Yudha Prawira , Kurnia Dikdik , Mayanti Tri
Published: October 2023

Breast cancer is a significant global concern, with tamoxifen, the standard treatment, raising long-term safety issues due to side effects. In this study, we evaluated the potential of five onoceranoid triterpenes from Lansium domesticum Corr. cv. kokosan against estrogen receptor alpha (ERα) using in silico techniques. Utilizing molecular docking, Lipinski’s rule of five, in silico ADMET, and molecular dynamics simulations, we assessed the potency of five onoceranoid triterpenes against ERα. Molecular docking indicated competitive binding energies for these triterpenes relative to the active form of tamoxifen (4OHT) and estradiol, an ERα native ligand. Three triterpenes met drug-likeness criteria with favorable ADMET profiles. Notably, 2 demonstrated superior binding affinity in molecular dynamics simulations, outperforming estradiol, closely followed by 3 and 4. Hierarchical clustering on principal components (HCPC) and the spatial distribution of contact surface area (CSA) analyses suggest that these triterpenes, especially 2, may act as antagonist ligands akin to 4OHT. These findings highlight the potential of onoceranoid triterpenes in treating ERα-related breast cancer.