bluuebunny/crossref_metadata_2025 huggingface dataset:
COVID-19′s Psychological Impact on Chronic Disease Patients Seeking Medical Care
Authors: Salah Hager , Ibrahim Rabie AL Shaimaa , Said Amira S. A. , AlAhmad Mohammad M. , Shaaban Ahmed Hassan , Khalil Doaa Mahmoud , Hussein Raghda R. S. , Khodary Azza
Published: March 2023

Background: The outbreak has harmed patients with multiple comorbidities and chronic conditions. The pandemic’s psychological impact is thought to change their routine of seeking medical care. Research Question or Hypothesis: During COVID-19, patients with chronic conditions may experience anxiety, depression, and stress, and their pattern of seeking medical care may change. Materials and Methods: In May 2021, a cross-sectional, web-based study of patients with chronic diseases was conducted. Eligible patients (1036) were assessed for psychological disorders, primarily depression, stress, and anxiety, using the DASS-21 scale, and their pattern of receiving medical care during COVID-19. Results: During the pandemic, 52.5% of the patients with chronic diseases were depressed, 57.9% were anxious, and 35.6% were stressed. Patients with chronic diseases who had moderate to severe depression (34.9% versus 45.1%, p = 0.001), moderate to severe anxiety (43.6% versus 53.8%, p = 0.001), or moderate to severe stress (14.9% versus 34.8%, p = 0.001) were significantly more likely to have no follow-up for their chronic conditions. Conclusions: Patients with chronic conditions experienced significant anxiety, depression, and stress during COVID-19, which changed their pattern of seeking medical care, and the majority of them did not receive follow-up for their chronic conditions.
Effects of Pelvic-Tilt Imbalance on Disability, Muscle Performance, and Range of Motion in Office Workers with Non-Specific Low-Back Pain
Authors: Kim Won-Deuk , Shin Doochul
Published: March 2023

Imbalance in the pelvic tilt is considered to be a major variable in low back pain. The purpose of this study was to investigate the effects of pelvic-tilt imbalance on trunk- and hip-muscle performance, range of motion, low-back pain, and the degree of disability in office workers. This was a cross-sectional study conducted in a physical therapy clinic on forty-one office workers diagnosed with non-specific low-back pain. Among the office workers with non-specific low-back pain, 25 were assigned to the pelvic-tilt-imbalance group and 16 to the normal group without pelvic-tilt imbalance. In order to determine the differences according to the imbalance in pelvic tilt, the pain intensity and disability indices were compared between the groups. In addition, the muscle performance and range of motion of the trunk and hip joints and foot pressure were measured and compared. There were differences between the groups in the disability indices and the ratio of internal and external rotation of the hip joint. However, there were no differences in the other variables. Pelvic-tilt imbalance in office workers with non-specific chronic low-back pain may exacerbate the degree of disability and be related to hip-joint rotational range of motion.
Saddar Bazar Quarter in Karachi: A Case of British-Era Protected Heritage Based on the Literature Review and Fieldwork
Authors: Akbar Syed Hamid , Iqbal Naveed , Van Cleempoel Koenraad
Published: March 2023

On the international level, heritage is considered an essential element for the sustainable development of a country. In South Asian countries such as Pakistan, India, and Bangladesh, historic cities struggle to preserve their built heritage, due to rapid urbanisation and changing contemporary urban and architectural requirements. This contribution elaborates on the effects of urbanisation, and city development on the protected heritage of Karachi, Pakistan. The city developed in the 19th century from a mud-fortified small town along the Lyari river to become one of the busiest ports of the Indian subcontinent under British rule. Karachi has now become a metropolitan city with more than sixteen million inhabitants. Due to the accelerated rate of urbanisation and trade activities, Karachi has become Pakistan’s economic capital, resulting in the oblivion of its historical sites. Most of the city’s historic sites are in a state of dereliction, from over- or under-programming, or even under the threat of demolition. The paper focuses on the present condition of a British-era protected-heritage site through a literature review and fieldwork (mapping, drawing, archival research, interviews, photographic surveys, etc.), carried out during 2019 and 2020. The first author conducted site visits to photograph buildings and interview their users to gather feedback on how they perceive the current state of these buildings. The data were analysed to investigate how many buildings from Karachi’s British era with protected status have been demolished or are at risk of demolition. At the heart of the article is the Saddar Bazar Quarter in Karachi and its historical, social, cultural, and economic importance in the city from the British period until the present. The analysis will lead the discussion on what potential these sites/buildings hold, and how to make their preservation possible and withstand the uncurbed urbanisation and the threat of land development. Through discussion, we will focus on the social, cultural and economic aspects which the area and the buildings from the British period hold, and which can be useful in the future for the continuation of the Saddar Bazaar Quarter (SBQ), the historic urban landscape (HUL) and the heritage buildings.
Reasearch on Kiwi Fruit Flower Recognition for Efficient Pollination Based on an Improved YOLOv5 Algorithm
Authors: Zhou Haili , Ou Junlang , Meng Penghao , Tong Junhua , Ye Hongbao , Li Zhen
Published: March 2023

A close relationship has been observed between the growth and development of kiwi fruit and the pollination of the kiwi flower. Flower overlap, flower tilt, and other problems will affect this plant’s pollination success rate. A pollination model based on YOLOv5 was developed to improve the pollination of kiwi flowers. The K-means++ clustering method was used to cluster the anchors closer to the target size, which improved the speed of the algorithm. A convolutional block module attention mechanism was incorporated to improve the extraction accuracy with respect to kiwi flower features and effectively reduce the missed detection and error rates. The optimization of the detection function improves the recognition of flower overlap and the accuracy of flower tilt angle calculation and accurately determines flower coordinates, pollination point coordinates, and pollination angles. The experimental results show that the predicted value of the YOLOv5s model is 96.7% and that its recognition accuracy is the highest. Its mean average precision value is up to 89.1%, its F1 score ratio is 90.12%, and its memory requirements are the smallest (only 20 MB). The YOLOv5s model achieved the highest recognition accuracy as determined through a comparison experiment of the four sets of analysed models, thereby demonstrating its ability to facilitate the efficient target pollination of kiwi flowers.
Farmers’ Intention to Adopt Agronomic Biofortification: The Case of Iodine Biofortified Vegetables in Uganda
Authors: Aparo Nathaline Onek , Olum Solomon , Atimango Alice Onek , Odongo Walter , Aloka Bonny , Ongeng Duncan , Gellynck Xavier , De Steur Hans
Published: March 2023

Agronomic biofortification, the application of fertilizer to increase micronutrient concentrations in staple food crops, has been increasingly promoted as a valuable approach to alleviate micronutrient deficiencies, but its success inevitably depends on farmers’ acceptance and adoption. By using iodine fertilizers as a case, this study aimed to understand vegetable farmers’ intentions to adopt agronomic biofortification. Therefore, the focus is on the potential role of socio-psychological factors, derived from two well-established theoretical models in explaining adoption intentions. Data from a cross-sectional survey of 465 cowpea and cabbage farmers from a high-risk region of Uganda were analyzed using binary logistic regression. The findings show that 75% of the farmers are likely to adopt agronomic iodine biofortification and are willing to devote a substantial part of their land to this innovation. Farmers’ intention to adopt strongly depends on their attitude and control beliefs regarding iodine biofortification, vegetable type, access to extension services, and farmland size. This study highlights the crucial role that behavioral and attitude factors play in communities at risk for nutritional disorders’ potential acceptance and sustained implementation of vegetable biofortification. To reinforce the observed positive inclination towards iodine biofortification among vegetable farmers, it is essential to increase awareness of the benefits, potential risks, and consequences of iodine deficiency, accompanied by motivational strategies to enhance farmers’ inherent beliefs in their ability to implement this innovation.
Radiation from UV-A to Red Light Induces ROS-Dependent Release of Neutrophil Extracellular Traps
Authors: Arzumanyan Grigory , Mamatkulov Kahramon , Arynbek Yersultan , Zakrytnaya Darya , Jevremović Anka , Vorobjeva Nina
Published: March 2023

Neutrophils release decondensed chromatin or extracellular traps (NETs) in response to various physiological and pharmacological stimuli. Apart from host defensive functions, NETs play an essential role in the pathogenesis of various autoimmune, inflammatory, and malignant diseases. In recent years, studies have been performed on photo-induced NET formation, mainly activated by UV radiation. Understanding the mechanisms of NET release under the influence of UV and visible light is important to control the consequences of the damaging effects of electromagnetic radiation. Raman spectroscopy was applied to record characteristic Raman frequencies of various reactive oxygen species (ROS) and low-frequency lattice vibrational modes for citrulline. NETosis was induced by irradiation with wavelength-switchable LED sources. Fluorescence microscopy was used to visualize and quantify NET release. The ability of five wavelengths of radiation, from UV-A to red light, to induce NETosis was investigated at three different energy doses. We demonstrated, for the first time, that NET formation is activated not only by UV-A but also by three spectra of visible light: blue, green, and orange, in a dose-dependent manner. Using inhibitory analysis, we established that light-induced NETosis proceeds through NADPH oxidase and PAD4. The development of new drugs designed to suppress NETosis, especially when induced by exposure to intense UV and visible light, can help to mitigate light-induced photoaging and other damaging effects of electromagnetic radiation.
A Novel Strategy to Identify Endolysins with Lytic Activity against Methicillin-Resistant Staphylococcus aureus
Authors: Kim Hanbeen , Seo Jakyeom
Published: March 2023

The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in the dairy industry has become a fundamental concern. Endolysins are bacteriophage-derived peptidoglycan hydrolases that induce the rapid lysis of host bacteria. Herein, we evaluated the lytic activity of endolysin candidates against S. aureus and MRSA. To identify endolysins, we used a bioinformatical strategy with the following steps: (1) retrieval of genetic information, (2) annotation, (3) selection of MRSA, (4) selection of endolysin candidates, and (5) evaluation of protein solubility. We then characterized the endolysin candidates under various conditions. Approximately 67% of S. aureus was detected as MRSA, and 114 putative endolysins were found. These 114 putative endolysins were divided into three groups based on their combinations of conserved domains. Considering protein solubility, we selected putative endolysins 117 and 177. Putative endolysin 117 was the only successfully overexpressed endolysin, and it was renamed LyJH1892. LyJH1892 showed potent lytic activity against both methicillin-susceptible S. aureus and MRSA and showed broad lytic activity against coagulase-negative staphylococci. In conclusion, this study demonstrates a rapid strategy for the development of endolysin against MRSA. This strategy could also be used to combat other antibiotic-resistant bacteria.
Discovery of 1,2,4-Oxadiazole Derivatives Containing Haloalkyl as Potential Acetylcholine Receptor Nematicides
Authors: Luo Ling , Ou Yuqin , Zhang Qi , Gan Xiuhai
Published: March 2023

Plant-parasitic nematodes pose a serious threat to crops and cause substantial financial losses due to control difficulties. Tioxazafen (3-phenyl-5-thiophen-2-yl-1,2,4-oxadiazole) is a novel broad-spectrum nematicide developed by the Monsanto Company, which shows good prevention effects on many kinds of nematodes. To discover compounds with high nematocidal activities, 48 derivatives of 1,2,4-oxadiazole were obtained by introducing haloalkyl at the 5-position of tioxazafen, and their nematocidal activities were systematically evaluated. The bioassays revealed that most of 1,2,4-oxadiazole derivatives showed remarkable nematocidal activities against Bursaphelenchus xylophilus, Aphelenchoides besseyi, and Ditylenchus dipsaci. Notably, compound A1 showed excellent nematocidal activity against B. xylophilus with LC50 values of 2.4 μg/mL, which was superior to that of avermectin (335.5 μg/mL), tioxazafen (>300 μg/mL), and fosthiazate (436.9 μg/mL). The transcriptome and enzyme activity results indicate that the nematocidal activity of compound A1 was mainly related to the compound which affected the acetylcholine receptor of B. xylophilus.
Antibiotics and Bacterial Resistance—A Short Story of an Endless Arms Race
Authors: Baran Aleksandra , Kwiatkowska Aleksandra , Potocki Leszek
Published: March 2023

Despite the undisputed development of medicine, antibiotics still serve as first-choice drugs for patients with infectious disorders. The widespread use of antibiotics results from a wide spectrum of their actions encompassing mechanisms responsible for: the inhibition of bacterial cell wall biosynthesis, the disruption of cell membrane integrity, the suppression of nucleic acids and/or proteins synthesis, as well as disturbances of metabolic processes. However, the widespread availability of antibiotics, accompanied by their overprescription, acts as a double-edged sword, since the overuse and/or misuse of antibiotics leads to a growing number of multidrug-resistant microbes. This, in turn, has recently emerged as a global public health challenge facing both clinicians and their patients. In addition to intrinsic resistance, bacteria can acquire resistance to particular antimicrobial agents through the transfer of genetic material conferring resistance. Amongst the most common bacterial resistance strategies are: drug target site changes, increased cell wall permeability to antibiotics, antibiotic inactivation, and efflux pumps. A better understanding of the interplay between the mechanisms of antibiotic actions and bacterial defense strategies against particular antimicrobial agents is crucial for developing new drugs or drug combinations. Herein, we provide a brief overview of the current nanomedicine-based strategies that aim to improve the efficacy of antibiotics.
A Dynamic Recurrent Neural Network for Predicting Higher Heating Value of Biomass
Authors: Aghel Babak , Yahya Salah I. , Rezaei Abbas , Alobaid Falah
Published: March 2023

The higher heating value (HHV) is the main property showing the energy amount of biomass samples. Several linear correlations based on either the proximate or the ultimate analysis have already been proposed for predicting biomass HHV. Since the HHV relationship with the proximate and ultimate analyses is not linear, nonlinear models might be a better alternative. Accordingly, this study employed the Elman recurrent neural network (ENN) to anticipate the HHV of different biomass samples from both the ultimate and proximate compositional analyses as the model inputs. The number of hidden neurons and the training algorithm were determined in such a way that the ENN model showed the highest prediction and generalization accuracy. The single hidden layer ENN with only four nodes, trained by the Levenberg–Marquardt algorithm, was identified as the most accurate model. The proposed ENN exhibited reliable prediction and generalization performance for estimating 532 experimental HHVs with a low mean absolute error of 0.67 and a mean square error of 0.96. In addition, the proposed ENN model provides a ground to clearly understand the dependency of the HHV on the fixed carbon, volatile matter, ash, carbon, hydrogen, nitrogen, oxygen, and sulfur content of biomass feedstocks.
The Drp1-Mediated Mitochondrial Fission Protein Interactome as an Emerging Core Player in Mitochondrial Dynamics and Cardiovascular Disease Therapy
Authors: Zerihun Mulate , Sukumaran Surya , Qvit Nir
Published: March 2023

Mitochondria, the membrane-bound cell organelles that supply most of the energy needed for cell function, are highly regulated, dynamic organelles bearing the ability to alter both form and functionality rapidly to maintain normal physiological events and challenge stress to the cell. This amazingly vibrant movement and distribution of mitochondria within cells is controlled by the highly coordinated interplay between mitochondrial dynamic processes and fission and fusion events, as well as mitochondrial quality-control processes, mainly mitochondrial autophagy (also known as mitophagy). Fusion connects and unites neighboring depolarized mitochondria to derive a healthy and distinct mitochondrion. In contrast, fission segregates damaged mitochondria from intact and healthy counterparts and is followed by selective clearance of the damaged mitochondria via mitochondrial specific autophagy, i.e., mitophagy. Hence, the mitochondrial processes encompass all coordinated events of fusion, fission, mitophagy, and biogenesis for sustaining mitochondrial homeostasis. Accumulated evidence strongly suggests that mitochondrial impairment has already emerged as a core player in the pathogenesis, progression, and development of various human diseases, including cardiovascular ailments, the leading causes of death globally, which take an estimated 17.9 million lives each year. The crucial factor governing the fission process is the recruitment of dynamin-related protein 1 (Drp1), a GTPase that regulates mitochondrial fission, from the cytosol to the outer mitochondrial membrane in a guanosine triphosphate (GTP)-dependent manner, where it is oligomerized and self-assembles into spiral structures. In this review, we first aim to describe the structural elements, functionality, and regulatory mechanisms of the key mitochondrial fission protein, Drp1, and other mitochondrial fission adaptor proteins, including mitochondrial fission 1 (Fis1), mitochondrial fission factor (Mff), mitochondrial dynamics 49 (Mid49), and mitochondrial dynamics 51 (Mid51). The core area of the review focuses on the recent advances in understanding the role of the Drp1-mediated mitochondrial fission adaptor protein interactome to unravel the missing links of mitochondrial fission events. Lastly, we discuss the promising mitochondria-targeted therapeutic approaches that involve fission, as well as current evidence on Drp1-mediated fission protein interactions and their critical roles in the pathogeneses of cardiovascular diseases (CVDs).
Elucidation of OSW-1-Induced Stress Responses in Neuro2a Cells
Authors: Oh-hashi Kentaro , Nakamura Hibiki , Ogawa Hirotaka , Hirata Yoko , Sakurai Kaori
Published: March 2023

OSW-1, a steroidal saponin isolated from the bulbs of Ornithogalum saundersiae, is a promising compound for an anticancer drug; however, its cytotoxic mechanisms have not been fully elucidated. Therefore, we analyzed the stress responses triggered by OSW-1 in the mouse neuroblastoma cell line Neuro2a by comparing it with brefeldin A (BFA), a Golgi apparatus-disrupting reagent. Among the Golgi stress sensors TFE3/TFEB and CREB3, OSW-1 induced dephosphorylation of TFE3/TFEB but not cleavage of CREB3, and induction of the ER stress-inducible genes GADD153 and GADD34 was slight. On the other hand, the induction of LC3-II, an autophagy marker, was more pronounced than the BFA stimulation. To elucidate OSW-1-induced gene expression, we performed a comprehensive gene analysis using a microarray method and observed changes in numerous genes involved in lipid metabolism, such as cholesterol, and in the regulation of the ER–Golgi apparatus. Abnormalities in ER–Golgi transport were also evident in the examination of secretory activity using NanoLuc-tag genes. Finally, we established Neuro2a cells lacking oxysterol-binding protein (OSBP), which were severely reduced by OSW-1, but found OSBP deficiency had little effect on OSW-1-induced cell death and the LC3-II/LC3-I ratio in Neuro2a cells. Future work to elucidate the relationship between OSW-1-induced atypical Golgi stress responses and autophagy induction may lead to the development of new anticancer agents.
Molecular Mechanisms Underlying TNFα-Induced Mitochondrial Biogenesis in Human Airway Smooth Muscle
Authors: Dasgupta Debanjali , Mahadev Bhat Sanjana , Price Alexis L. , Delmotte Philippe , Sieck Gary C.
Published: March 2023

Proinflammatory cytokines such as TNFα mediate airway inflammation. Previously, we showed that TNFα increases mitochondrial biogenesis in human ASM (hASM) cells, which is associated with increased PGC1α expression. We hypothesized that TNFα induces CREB and ATF1 phosphorylation (pCREBS133 and pATF1S63), which transcriptionally co-activate PGC1α expression. Primary hASM cells were dissociated from bronchiolar tissue obtained from patients undergoing lung resection, cultured (one–three passages), and then differentiated by serum deprivation (48 h). hASM cells from the same patient were divided into two groups: TNFα (20 ng/mL) treated for 6 h and untreated controls. Mitochondria were labeled using MitoTracker green and imaged using 3D confocal microscopy to determine mitochondrial volume density. Mitochondrial biogenesis was assessed based on relative mitochondrial DNA (mtDNA) copy number determined by quantitative real-time PCR (qPCR). Gene and/or protein expression of pCREBS133, pATF1S63, PCG1α, and downstream signaling molecules (NRFs, TFAM) that regulate transcription and replication of the mitochondrial genome, were determined by qPCR and/or Western blot. TNFα increased mitochondrial volume density and mitochondrial biogenesis in hASM cells, which was associated with an increase in pCREBS133, pATF1S63 and PCG1α expression, with downstream transcriptional activation of NRF1, NRF2, and TFAM. We conclude that TNFα increases mitochondrial volume density in hASM cells via a pCREBS133/pATF1S63/PCG1α-mediated pathway.
Intracellular Membrane Transport in Vascular Endothelial Cells
Authors: Mironov Alexander A. , Mironov Anna , Sanavio Barbara , Krol Silke , Beznoussenko Galina V.
Published: March 2023

The main component of blood and lymphatic vessels is the endothelium covering their luminal surface. It plays a significant role in many cardiovascular diseases. Tremendous progress has been made in deciphering of molecular mechanisms involved into intracellular transport. However, molecular machines are mostly characterized in vitro. It is important to adapt this knowledge to the situation existing in tissues and organs. Moreover, contradictions have accumulated within the field related to the function of endothelial cells (ECs) and their trans-endothelial pathways. This has induced necessity for the re-evaluation of several mechanisms related to the function of vascular ECs and intracellular transport and transcytosis there. Here, we analyze available data related to intracellular transport within ECs and re-examine several hypotheses about the role of different mechanisms in transcytosis across ECs. We propose a new classification of vascular endothelium and hypotheses related to the functional role of caveolae and mechanisms of lipid transport through ECs.
Neuroinflammation in Parkinson’s Disease: From Gene to Clinic: A Systematic Review
Authors: Castillo-Rangel Carlos , Marin Gerardo , Hernández-Contreras Karla Aketzalli , Vichi-Ramírez Micheel Merari , Zarate-Calderon Cristofer , Torres-Pineda Osvaldo , Diaz-Chiguer Dylan L. , De la Mora González David , Gómez Apo Erick , Teco-Cortes Javier Alejandro , Santos-Paez Flor de María , Coello-Torres María de los Ángeles , Baldoncini Matías , Reyes Soto Gervith , Aranda-Abreu Gonzalo Emiliano , García Luis I.
Published: March 2023

Parkinson’s disease is a neurodegenerative disease whose progression and clinical characteristics have a close bidirectional and multilevel relationship with the process of neuroinflammation. In this context, it is necessary to understand the mechanisms involved in this neuroinflammation–PD link. This systematic search was, hereby, conducted with a focus on the four levels where alterations associated with neuroinflammation in PD have been described (genetic, cellular, histopathological and clinical-behavioral) by consulting the PubMed, Google Scholar, Scielo and Redalyc search engines, including clinical studies, review articles, book chapters and case studies. Initially, 585,772 articles were included, and, after applying the inclusion and exclusion criteria, 84 articles were obtained that contained information about the multilevel association of neuroinflammation with alterations in gene, molecular, cellular, tissue and neuroanatomical expression as well as clinical-behavioral manifestations in PD.
A Single Nucleotide Variation of CRS2 Affected the Establishment of Photosynthetic System in Rice
Authors: Chen Hongwei , Wang Qi , Fan Mingqian , Zhang Xijuan , Feng Pulin , Zhu Lin , Wu Jiayi , Cheng Xiaoyi , Wang Jiayu
Published: March 2023

Chloroplasts are essential sites for plant photosynthesis, and the biogenesis of the photosynthetic complexes involves the interaction of nuclear genes and chloroplast genes. In this study, we identified a rice pale green leaf mutant, crs2. The crs2 mutant showed different degrees of low chlorophyll phenotypes at different growth stages, especially at the seedling stage. Fine mapping and DNA sequencing of crs2 revealed a single nucleotide substitution (G4120A) in the eighth exons of CRS2, causing a G-to-R mutation of the 229th amino acid of CRS2 (G229R). The results of complementation experiments confirmed that this single-base mutation in crs2 is responsible for the phenotype of the crs2 mutant. CRS2 encodes a chloroplast RNA splicing 2 protein localized in the chloroplast. Western blot results revealed an abnormality in the abundance of the photosynthesis-related protein in crs2. However, the mutation of CRS2 leads to the enhancement of antioxidant enzyme activity, which could reduce ROS levels. Meanwhile, with the release of Rubisco activity, the photosynthetic performance of crs2 was improved. In summary, the G229R mutation in CRS2 causes chloroplast protein abnormalities and affects photosystem performance in rice; the above findings facilitate the elucidation of the physiological mechanism of chloroplast proteins affecting photosynthesis.
Landscape of BCL2 Resistance Mutations in a Real-World Cohort of Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia Treated with Venetoclax
Authors: Kotmayer Lili , László Tamás , Mikala Gábor , Kiss Richárd , Lévay Luca , Hegyi Lajos László , Gróf Stefánia , Nagy Tibor , Barna Gábor , Farkas Péter , Weisinger Júlia , Nagy Zsolt , Balogh Alexandra , Masszi Tamás , Demeter Judit , Sulák Adrienn , Kohl Zoltán , Alizadeh Hussain , Egyed Miklós , Pettendi Piroska , Gergely Lajos , Plander Márk , Pauker Zsolt , Masszi András , Matolcsy András , Szász Róbert , Bödör Csaba , Alpár Donát
Published: March 2023

The oral, highly selective Bcl2 inhibitor venetoclax has substantially improved the therapeutic landscape of chronic lymphocytic leukemia (CLL). Despite the remarkable response rates in patients with relapsed/refractory (R/R) disease, acquired resistance is the leading cause of treatment failure, with somatic BCL2 mutations being the predominant genetic drivers underpinning venetoclax resistance. To assess the correlation between disease progression and the most common BCL2 mutations G101V and D103Y, sensitive (10−4) screening for the most common BCL2 mutations G101V and D103Y was performed in 67 R/R CLL patients during venetoclax single-agent or venetoclax–rituximab combination therapy. With a median follow-up time of 23 months, BCL2 G101V and D103Y were detected in 10.4% (7/67) and 11.9% (8/67) of the cases, respectively, with four patients harboring both resistance mutations. Ten out of eleven patients carrying BCL2 G101V and/or D103Y experienced relapse during the follow-up period, representing 43.5% of the cases (10/23) showing clinical signs of disease progression. All BCL2 G101V or D103Y variants were detected in patients receiving venetoclax as a continuous single-agent treatment while these mutations were not observed during or after fixed-duration venetoclax therapy. Targeted ultra-deep sequencing of BCL2 uncovered three additional variants in four patient samples obtained at relapse, suggesting convergent evolution and implying a cooperating role of BCL2 mutations in driving venetoclax resistance. This cohort is the largest R/R CLL patient population reported to date in which BCL2 resistance mutations were investigated. Our study demonstrates the feasibility and clinical value of sensitive screening for BCL2 resistance mutations in R/R CLL.
Circulating miRNA-451a and miRNA-328-3p as Potential Markers of Coronary Artery Aneurysmal Disease
Authors: Iwańczyk Sylwia , Lehmann Tomasz , Cieślewicz Artur , Malesza Katarzyna , Woźniak Patrycja , Hertel Agnieszka , Krupka Grzegorz , Jagodziński Paweł P. , Grygier Marek , Lesiak Maciej , Araszkiewicz Aleksander
Published: March 2023

MicroRNAs (miRNAs) are currently investigated as crucial regulatory factors which may serve as a potential therapeutic target. Reports on the role of miRNA in patients with coronary artery aneurysmal disease (CAAD) are limited. The present analysis aims to confirm the differences in the expression of previously preselected miRNAs in larger study groups and evaluate their usefulness as potential markers of CAAD. The study cohort included 35 consecutive patients with CAAD (Group 1), and two groups of 35 patients matched Group 1 regarding sex and age from the overall cohort of 250 patients (Group 2 and Group 3). Group 2 included patients with angiographically documented coronary artery disease (CAD), while Group 3 enrolled patients with normal coronary arteries (NCA) assessed during coronary angiography. We applied the RT-qPCR method using the custom plates for the RT-qPCR array. We confirmed that the level of five preselected circulating miRNAs was different in patients with CAAD compared to Group 2 and Group 3. We found that miR-451a and miR-328 significantly improved the CAAD prediction. In conclusion, miR-451a is a significant marker of CAAD compared to patients with CAD. In turn, miR-328-3p is a significant marker of CAAD compared to patients with NCA.
Track Structure of Light Ions: The Link to Radiobiology
Authors: Conte Valeria , Bianchi Anna , Selva Anna
Published: March 2023

It is generally recognized that the biological response to irradiation by light ions is initiated by complex damages at the DNA level. In turn, the occurrence of complex DNA damages is related to spatial and temporal distribution of ionization and excitation events, i.e., the particle track structure. It is the aim of the present study to investigate the correlation between the distribution of ionizations at the nanometric scale and the probability to induce biological damage. By means of Monte Carlo track structure simulations, the mean ionization yield M1 and the cumulative probabilities F1, F2, and F3 of at least one, two and three ionizations, respectively, were calculated in spherical volumes of water-equivalent diameters equal to 1, 2, 5 and 10 nm. When plotted as a function of M1, the quantities F1, F2 and F3 are distributed along almost unique curves, largely independent of particle type and velocity. However, the shape of the curves depends on the size of the sensitive volume. When the site size is 1 nm, biological cross sections are strongly correlated to combined probabilities of F2 and F3 calculated in the spherical volume, and the proportionality factor is the saturation value of biological cross sections.
Gene Structure, Expression and Function Analysis of MEF2 in the Pacific White Shrimp Litopenaeus vannamei
Authors: Xia Yanting , Zhong Xiaoyun , Zhang Xiaoxi , Zhang Xiaojun , Yuan Jianbo , Liu Chengzhang , Sha Zhenxia , Li Fuhua
Published: March 2023

The Pacific white shrimp Litopenaeus vannamei is the most economically important crustacean in the world. The growth and development of shrimp muscle has always been the focus of attention. Myocyte Enhancer Factor 2 (MEF2), a member of MADS transcription factor, has an essential influence on various growth and development programs, including myogenesis. In this study, based on the genome and transcriptome data of L. vannamei, the gene structure and expression profiles of MEF2 were characterized. We found that the LvMEF2 was widely expressed in various tissues, mainly in the Oka organ, brain, intestine, heart, and muscle. Moreover, LvMEF2 has a large number of splice variants, and the main forms are the mutually exclusive exon and alternative 5′ splice site. The expression profiles of the LvMEF2 splice variants varied under different conditions. Interestingly, some splice variants have tissue or developmental expression specificity. After RNA interference into LvMEF2, the increment in the body length and weight decreased significantly and even caused death, suggesting that LvMEF2 can affect the growth and survival of L. vannamei. Transcriptome analysis showed that after LvMEF2 was knocked down, the protein synthesis and immune-related pathways were affected, and the associated muscle protein synthesis decreased, indicating that LvMEF2 affected muscle formation and the immune system. The results provide an important basis for future studies of the MEF2 gene and the mechanism of muscle growth and development in shrimp.
Light, Water, and Melatonin: The Synergistic Regulation of Phase Separation in Dementia
Authors: Loh Doris , Reiter Russel J.
Published: March 2023

The swift rise in acceptance of molecular principles defining phase separation by a broad array of scientific disciplines is shadowed by increasing discoveries linking phase separation to pathological aggregations associated with numerous neurodegenerative disorders, including Alzheimer’s disease, that contribute to dementia. Phase separation is powered by multivalent macromolecular interactions. Importantly, the release of water molecules from protein hydration shells into bulk creates entropic gains that promote phase separation and the subsequent generation of insoluble cytotoxic aggregates that drive healthy brain cells into diseased states. Higher viscosity in interfacial waters and limited hydration in interiors of biomolecular condensates facilitate phase separation. Light, water, and melatonin constitute an ancient synergy that ensures adequate protein hydration to prevent aberrant phase separation. The 670 nm visible red wavelength found in sunlight and employed in photobiomodulation reduces interfacial and mitochondrial matrix viscosity to enhance ATP production via increasing ATP synthase motor efficiency. Melatonin is a potent antioxidant that lowers viscosity to increase ATP by scavenging excess reactive oxygen species and free radicals. Reduced viscosity by light and melatonin elevates the availability of free water molecules that allow melatonin to adopt favorable conformations that enhance intrinsic features, including binding interactions with adenosine that reinforces the adenosine moiety effect of ATP responsible for preventing water removal that causes hydrophobic collapse and aggregation in phase separation. Precise recalibration of interspecies melatonin dosages that account for differences in metabolic rates and bioavailability will ensure the efficacious reinstatement of the once-powerful ancient synergy between light, water, and melatonin in a modern world.
Bioactive Peptides in Human Health and Disease
Authors: Martini Serena , Tagliazucchi Davide
Published: March 2023

Bioactive peptides are defined as short amino acid sequences that may have specific physiological functions, ultimately affecting human health and protecting against the development of several diseases [...]
Dioleoylphosphatidylglycerol Inhibits Heat Shock Protein B4 (HSPB4)-Induced Inflammatory Pathways In Vitro
Authors: Fowler Teresa E. , Choudhary Vivek , Melnyk Samuel , Farsi Mishma , Chang Luke Y. , Fortingo Nyemkuna , Chen Xunsheng , Watsky Mitchell A. , Bollag Wendy B.
Published: March 2023

Our previous work shows that dioleoylphosphatidylglycerol (DOPG) accelerates corneal epithelial healing in vitro and in vivo by unknown mechanisms. Prior data demonstrate that DOPG inhibits toll-like receptor (TLR) activation and inflammation induced by microbial components (pathogen-associated molecular patterns, PAMPs) and by endogenous molecules upregulated in psoriatic skin, which act as danger-associated molecular patterns (DAMPs) to activate TLRs and promote inflammation. In the injured cornea, sterile inflammation can result from the release of the DAMP molecule, heat shock protein B4 (HSPB4), to contribute to delayed wound healing. Here, we show in vitro that DOPG inhibits TLR2 activation induced in response to HSPB4, as well as DAMPs that are elevated in diabetes, a disease that also slows corneal wound healing. Further, we show that the co-receptor, cluster of differentiation-14 (CD14), is necessary for PAMP/DAMP-induced activation of TLR2, as well as of TLR4. Finally, we simulated the high-glucose environment of diabetes to show that elevated glucose levels enhance TLR4 activation by a DAMP known to be upregulated in diabetes. Together, our results demonstrate the anti-inflammatory actions of DOPG and support further investigation into its development as a possible therapy for corneal injury, especially in diabetic patients at high risk of vision-threatening complications.
Palmitic Acid Inhibits Myogenic Activity and Expression of Myosin Heavy Chain MHC IIb in Muscle Cells through Phosphorylation-Dependent MyoD Inactivation
Authors: Matsuba Izumi , Fujita Rikako , Iida Kaoruko
Published: March 2023

Sarcopenia associated with aging and obesity is characterized by the atrophy of fast-twitch muscle fibers and an increase in intramuscular fat deposits. However, the mechanism of fast-twitch fiber-specific atrophy remains unclear. In this study, we aimed to assess the effect of palmitic acid (PA), the most common fatty acid component of human fat, on muscle fiber type, focusing on the expression of fiber-type-specific myosin heavy chain (MHC). Myotubes differentiated from C2C12 myoblasts were treated with PA. The PA treatment inhibited myotube formation and hypertrophy while reducing the gene expression of MHC IIb and IIx, specific isoforms of fast-twitch fibers. Consistent with this, a significant suppression of MHC IIb protein expression in PA-treated cells was observed. A reporter assay using plasmids containing the MHC IIb gene promoter revealed that the PA-induced reduction in MHC IIb gene expression was caused by the suppression of MyoD transcriptional activity through its phosphorylation. Treatment with a specific protein kinase C (PKC) inhibitor recovered the reduction in MHC IIb gene expression levels in PA-treated cells, suggesting the involvement of the PA-induced activation of PKC. Thus, PA selectively suppresses the mRNA and protein expression of fast-twitch MHC by modulating MyoD activity. This finding provides a potential pathogenic mechanism for age-related sarcopenia.
Local Liver Irradiation Concurrently Versus Sequentially with Cabozantinib on the Pharmacokinetics and Biodistribution in Rats
Authors: Huang Yu-Chuen , Hsieh Pei-Ying , Wang Li-Ying , Tsai Tung-Hu , Chen Yu-Jen , Hsieh Chen-Hsi
Published: March 2023

The aim of this study was to evaluate the radiotherapy (RT)-pharmacokinetics (PK) effect of cabozantinib in concurrent or sequential regimens with external beam radiotherapy (EBRT) or stereotactic body radiation therapy (SBRT). Concurrent and sequential regimens involving RT and cabozantinib were designed. The RT–drug interactions of cabozantinib under RT were confirmed in a free-moving rat model. The drugs were separated on an Agilent ZORBAX SB-phenyl column with a mobile phase consisting of 10 mM potassium dihydrogen phosphate (KH2PO4)–methanol solution (27:73, v/v) for cabozantinib. There were no statistically significant differences in the concentration versus time curve of cabozantinib (AUCcabozantinib) between the control group and the RT2Gy×3 f’x and RT9Gy×3 f’x groups in the concurrent and the sequential regimens. However, compared to those in the control group, the Tmax, T1/2 and MRT decreased by 72.8% (p = 0.04), 49.0% (p = 0.04) and 48.5% (p = 0.04) with RT2Gy×3 f’x in the concurrent regimen, respectively. Additionally, the T1/2 and MRT decreased by 58.8% (p = 0.01) and 57.8% (p = 0.01) in the concurrent RT9Gy×3 f’x group when compared with the control group, respectively. The biodistribution of cabozantinib in the heart increased by 271.4% (p = 0.04) and 120.0% (p = 0.04) with RT2Gy×3 f’x in the concurrent and sequential regimens compared to the concurrent regimen, respectively. Additionally, the biodistribution of cabozantinib in the heart increased by 107.1% (p = 0.01) with the RT9Gy×3 f’x sequential regimen. Compared to the RT9Gy×3 f’x concurrent regimen, the RT9Gy×3 f’x sequential regimen increased the biodistribution of cabozantinib in the heart (81.3%, p = 0.02), liver (110.5%, p = 0.02), lung (125%, p = 0.004) and kidneys (87.5%, p = 0.048). No cabozantinib was detected in the brain in any of the groups. The AUC of cabozantinib is not modulated by irradiation and is not affected by treatment strategies. However, the biodistribution of cabozantinib in the heart is modulated by off-target irradiation and SBRT doses simultaneously. The impact of the biodistribution of cabozantinib with RT9Gy×3 f’x is more significant with the sequential regimen than with the concurrent regimen.
New Drugs and Therapies in Pulmonary Arterial Hypertension
Authors: Shah Aangi J. , Beckmann Taylor , Vorla Mounica , Kalra Dinesh K.
Published: March 2023

Pulmonary arterial hypertension is a chronic, progressive disorder of the pulmonary vasculature with associated pulmonary and cardiac remodeling. PAH was a uniformly fatal disease until the late 1970s, but with the advent of targeted therapies, the life expectancy of patients with PAH has now considerably improved. Despite these advances, PAH inevitably remains a progressive disease with significant morbidity and mortality. Thus, there is still an unmet need for the development of new drugs and other interventional therapies for the treatment of PAH. One shortcoming of currently approved vasodilator therapies is that they do not target or reverse the underlying pathogenesis of the disease process itself. A large body of evidence has evolved in the past two decades clarifying the role of genetics, dysregulation of growth factors, inflammatory pathways, mitochondrial dysfunction, DNA damage, sex hormones, neurohormonal pathways, and iron deficiency in the pathogenesis of PAH. This review focuses on newer targets and drugs that modify these pathways as well as novel interventional therapies in PAH.
Effects of GRP78 on Endoplasmic Reticulum Stress and Inflammatory Response in Macrophages of Large Yellow Croaker (Larimichthys crocea)
Authors: Sun Jie , Mai Kangsen , Ai Qinghui
Published: March 2023

Endoplasmic reticulum (ER) homeostasis plays a vital role in cell physiological functions. Various factors can destroy the homeostasis of the ER and cause ER stress. Moreover, ER stress is often related to inflammation. Glucose-regulated protein 78 (GRP78) is an ER chaperone, which plays a vital role in maintaining cellular homeostasis. Nevertheless, the potential effects of GRP78 on ER stress and inflammation is still not fully elucidated in fish. In the present study, ER stress and inflammation was induced by tunicamycin (TM) or palmitic acid (PA) in the macrophages of large yellow croakers. GRP78 was treated with an agonist/inhibitor before or after the TM/PA treatment. The results showed that the TM/PA treatment could significantly induce ER stress and an inflammatory response in the macrophages of large yellow croakers whereas the incubation of the GRP78 agonist could reduce TM/PA-induced ER stress and an inflammatory response. Moreover, the incubation of the GRP78 inhibitor could further induce TM/PA-induced ER stress and an inflammatory response. These results provide an innovative idea to explain the relationship between GRP78 and TM/PA-induced ER stress or inflammation in large yellow croakers.
Extracellular Vesicles Produced by the Cardiac Microenvironment Carry Functional Enzymes to Produce Lipid Mediators In Situ
Authors: Ong-Meang Varravaddheay , Blanzat Muriel , Savchenko Lesia , Perquis Lucie , Guardia Mégane , Pizzinat Nathalie , Poinsot Verena
Published: March 2023

The impact of the polyunsaturated fatty acids (PUFAs) at physiological concentrations on the composition of eicosanoids transported within the extracellular vesicles (EVs) of rat bone marrow mesenchymal stem cells and cardiomyoblasts was reported by our group in 2020. The aim of this article was to extend this observation to cells from the cardiac microenvironment involved in the processes of inflammation, namely mouse J774 macrophages and rat heart mesenchymal stem cells cMSCs. Moreover, to enhance our capacity to understand the paracrine exchange between these orchestrators of cardiac inflammation, we investigated some machinery involved in the eicosanoid’s synthesis transported by the EVs produced by these cells (including the two formerly described cells: bone marrow mesenchymal stem cells BM-MSC and cardiomyoblasts H9c2). We analyzed the oxylipin and the enzymatic content of the EVs collected from cell cultures supplemented (or not) with PUFAs. We prove that large eicosanoid profiles are exported in the EVs by the cardiac microenvironment cells, but also that these EVs carry some critical and functional biosynthetic enzymes, allowing them to synthesize inflammation bioactive compounds by sensing their environment. Moreover, we demonstrate that these are functional. This observation reinforces the hypothesis that EVs are key factors in paracrine signaling, even in the absence of the parent cell. We also reveal a macrophage-specific behavior, as we observed a radical change in the lipid mediator profile when small EVs derived from J774 cells were exposed to PUFAs. To summarize, we prove that the EVs, due to the carried functional enzymes, can alone produce bioactive compounds, in the absence of the parent cell, by sensing their environment. This makes them potential circulating monitoring entities.