bluuebunny/crossref_metadata_2025 huggingface dataset:
Intraurban Geographic and Socioeconomic Inequalities of Mortality in Four Cities in Colombia
Authors: Rodriguez-Villamizar Laura A. , Marín Diana , Piñeros-Jiménez Juan Gabriel , Rojas-Sánchez Oscar Alberto , Serrano-Lomelin Jesus , Herrera Victor
Published: January 2023

Mortality inequalities have been described across Latin American countries, but less is known about inequalities within cities, where most populations live. We aimed to identify geographic and socioeconomic inequalities in mortality within the urban areas of four main cities in Colombia. We analyzed mortality due to non-violent causes of diseases in adults between 2015 and 2019 using census sectors as unit of analysis in Barranquilla, Bogotá, Cali, and Medellín. We calculated smoothed Bayesian mortality rates as main health outcomes and used concentration indexes (CInd) for assessing inequalities using the multidimensional poverty index (MPI) as the socioeconomic measure. Moran eigenvector spatial filters were calculated to capture the spatial patterns of mortality and then used in multivariable models of the association between mortality rates and quintiles of MPI. Social inequalities were evident but not consistent across cities. The most disadvantaged groups showed the highest mortality rates in Cali. Geographic inequalities in mortality rates, regardless of the adults and poverty distribution, were identified in each city, suggesting that other social, environmental, or individual conditions are impacting the spatial distribution of mortality rates within the four cities.
A Cross-Sectional Study: Determining Factors of Functional Independence and Quality of Life of Patients One Month after Having Suffered a Stroke
Authors: González-Santos Josefa , Rodríguez-Fernández Paula , Pardo-Hernández Rocío , González-Bernal Jerónimo J. , Fernández-Solana Jessica , Santamaría-Peláez Mirian
Published: January 2023

(1) Background: loss of quality of life (QoL) and functional independence are two of the most common consequences of suffering a stroke. The main objective of this research is to study which factors are the greatest determinants of functional capacity and QoL a month after suffering a stroke so that they can be considered in early interventions. (2) Methods: a cross-sectional study was conducted which sample consisted of 81 people who had previously suffered a stroke. The study population was recruited at the time of discharge from the Neurology Service and Stroke Unit of the hospitals of Burgos and Córdoba, Spain, through a consecutive sampling. Data were collected one month after participants experienced a stroke, and the main study variables were quality of life, measured with the Stroke-Specific Quality of Life Measure (NEWSQOL), and functional independence, measured with the Functional Independence Measure-Functional Assessment Measure (FIM-FAM). (3) Results: the factors associated with a worse QoL and functional capacity one month after having suffered a stroke were living in a different dwelling than the usual flat or house (p < 0.05), a worse cognitive capacity (p < 0.001) and a worse functional capacity of the affected upper limb (p < 0.001). A higher age was related to a worse functional capacity one month after suffering a stroke (p = 0.048). (4) Conclusions: the type of dwelling, age, cognitive ability and functional capacity of the affected upper limb are determining aspects in functional independence and QoL during the first weeks after a stroke.
Implementation of A Year-Long Antimicrobial Stewardship Program in A 227-Bed Community Hospital in Southern Italy
Authors: Albano Giuseppe Davide , Midiri Mauro , Zerbo Stefania , Matteini Emanuele , Passavanti Giulia , Curcio Rosario , Curreri Lidia , Albano Salvatore , Argo Antonina , Cadelo Marcello
Published: January 2023

Background: Healthcare-Acquired Infections (HAIs) are serious healthcare complications affecting hospital stay, in-hospital mortality, and costs. Root cause analysis has identified the inappropriate use of antibiotics as the main causative factor in the expansion of multi-drug-resistant organisms (MDRO) in our hospital. An Antimicrobial Stewardship (AMS) program was implemented to optimize antibiotic use, limit the development of resistance, improve therapeutic efficacy and clinical outcomes, and reduce costs. Methods: The stewardship strategies were: antimicrobial oversight on “critical” antibiotics; the development of hospital guidelines on antibiotic selection with the production of a consensus document; the implementation of clinical and management control algorithms with visual impact and Business Intelligence methods; training and updating; and the monitoring of outcome measures and process indicators. Results: Clinical outcomes: length of stay reduced by 0.23 days, hospital readmission/first month rates decreased by 19%, and mortality for infections reduced by 8.8%. Microbiological Outcomes: Clostridium Difficile colitis incidence reduced by 9.1%.Economic Outcomes: Reduction in antimicrobial costs by 35% on average fee/discharged patient. Conclusions: The systematic application of the AMS program in a small hospital led to multiple improvements in clinical, microbiological, and economic outcome measures. The analysis of the core indicators for our hospital AMS program showed a significant adherence to the model and hospital recommendations.
The Adaptive Dynamics of the Halloween Effect: Evidence from a 120-Year Sample from a Small European Market
Authors: Lobão Júlio , Costa Ana C.
Published: January 2023

The Halloween effect predicts that stock markets in the winter months (November through April) generate significantly higher returns than in the summer months (May through October). This paper examines the time-varying behavior of the Halloween effect within a new historical dataset that covers about 120 years of Portuguese stock market history. We combine subsample analysis with rolling window analysis to show that the performance of the anomaly has varied in an adaptive fashion over time. The anomaly existed during the first four decades of the 20th century. Afterward, it vanished for 60 years, reappearing only at the beginning of the 21st century. However, in the first two decades of the new century, the effect seems to be a mere reflection of the excess return generated in January. Overall, the time-varying performance of the Halloween effect supports the adaptive market hypothesis for the Portuguese stock market.
The Induction of Antigen 85B-Specific CD8+ T Cells by Recombinant BCG Protects against Mycobacterial Infection in Mice
Authors: Komine-Aizawa Shihoko , Mizuno Satoru , Kawano Akira , Hayakawa Satoshi , Matsuo Kazuhiro , Honda Mitsuo
Published: January 2023

Mycobacterium tuberculosis (Mtb) infection remains a major health problem worldwide. Although the Bacillus Calmette-Guérin (BCG) vaccine is the most widely used vaccination for preventing tuberculosis (TB), its efficacy is limited. We previously developed a new recombinant BCG (rBCG)-based vaccine encoding the Ag85B protein of M. kansasii (Mkan85B), termed rBCG-Mkan85B, and its administration is followed by boosting with plasmid DNA expressing the Ag85B gene (DNA-Mkan85B). Previously, we identified MHC-I (H2-Kd)-restricted epitopes that highly cross-react with those of Mtb in BALB/c (H2d) and CB6F1 (H2b/d) mice. We also reported that the rBCG-Mkan85B/DNA-Mkan85B prime–boost vaccination protocol protected CB6F1 mice against M. kansasii infection. In this study, to investigate the protective effect of our novel rBCG against Mtb infection, CB6F1 mice were either left unimmunized or immunized with the BCG, rBCG-Mkan85B, or rBCG-Mkan85B/DNA-Mkan85B vaccine for 10 weeks prior to inhalation exposure to the virulent Mtb Erdman strain for another 6 weeks. Compared with the BCG and rBCG-Mkan85B vaccinations, the rBCG-Mkan85B/DNA-Mkan85B prime–boost vaccination protocol significantly reduced the numbers of pulmonary colony-forming units (CFUs). Moreover, the rBCG-Mkan85B/DNA-Mkan85B prime–boost vaccination induced antigen-specific polyfunctional CD4+ and CD8+ T cells. These results suggest that CD8+ T-cell immunity to immunodominant epitopes of Mtb is enhanced by rBCG vector-based immunization. Thus, rBCG vector-based vaccinations may overcome the limited ability of the current BCG vaccine to elicit TB immunity.
Paricalcitol Ameliorates Acute Kidney Injury in Mice by Suppressing Oxidative Stress and Inflammation via Nrf2/HO-1 Signaling
Authors: Wang Shuang , Huang Siqi , Liu Xingyao , He Yanjun , Liu Yun
Published: January 2023

Effective and targeted prevention and treatment methods for acute kidney injury (AKI), a common clinical complication, still needs to be explored. Paricalcitol is a biologically active chemical that binds to vitamin D receptors in the body to exert anti-oxidant and anti-inflammatory effects. However, the molecular mechanism of the effect of paricalcitol on AKI remains unclear. The current study uses a paricalcitol pretreatment with a mouse AKI model induced by cisplatin to detect changes in renal function, pathology and ultrastructure. Results showed that paricalcitol significantly improved renal function in mice and reduced inflammatory cell infiltration and mitochondrial damage in renal tissue. Furthermore, paricalcitol markedly suppressed reactive oxygen species and malondialdehyde levels in the kidneys of AKI mice and increased the levels of glutathione, superoxide dismutase, Catalase and total anti-oxidant capacity. In addition, we detected renal necrosis and inflammation-related proteins in AKI mice by immunofluorescence and Western blot, and found that their levels were markedly decreased after paricalcitol pretreatment. Moreover, paricalcitol promotes nuclear factor erythroid 2-related factor 2 (Nrf2) in the nucleus and activates the Nrf2/heme oxygenase-1 (HO-1) signaling pathway; while HO-1 is inhibited, the protective effect of paricalcitol on the kidney is attenuated. In conclusion, paricalcitol exerts a renoprotective effect by decreasing renal oxidative injury and inflammation through Nrf2/HO-1 signaling, providing a new insight into AKI prevention.
The Role of Italy in the Use of Advanced Plant Genomic Techniques on Fruit Trees: State of the Art and Future Perspectives
Authors: Nerva Luca , Dalla Costa Lorenza , Ciacciulli Angelo , Sabbadini Silvia , Pavese Vera , Dondini Luca , Vendramin Elisa , Caboni Emilia , Perrone Irene , Moglia Andrea , Zenoni Sara , Michelotti Vania , Micali Sabrina , La Malfa Stefano , Gentile Alessandra , Tartarini Stefano , Mezzetti Bruno , Botta Roberto , Verde Ignazio , Velasco Riccardo , Malnoy Mickael Arnaud , Licciardello Concetta
Published: January 2023

Climate change is deeply impacting the food chain production, lowering quality and yield. In this context, the international scientific community has dedicated many efforts to enhancing resilience and sustainability in agriculture. Italy is among the main European producers of several fruit trees; therefore, national research centers and universities undertook several initiatives to maintain the specificity of the ‘Made in Italy’ label. Despite their importance, fruit crops are suffering from difficulties associated with the conventional breeding approaches, especially in terms of financial commitment, land resources availability, and long generation times. The ‘new genomic techniques’ (NGTs), renamed in Italy as ‘technologies for assisted evolution’ (TEAs), reduce the time required to obtain genetically improved cultivars while precisely targeting specific DNA sequences. This review aims to illustrate the role of the Italian scientific community in the use of NGTs, with a specific focus on Citrus, grapevine, apple, pear, chestnut, strawberry, peach, and kiwifruit. For each crop, the key genes and traits on which the scientific community is working, as well as the technological improvements and advancements on the regeneration of local varieties, are presented. Lastly, a focus is placed on the legal aspects in the European and in Italian contexts.
IGFL2-AS1, a Long Non-Coding RNA, Is Associated with Radioresistance in Colorectal Cancer
Authors: Lee Jeeyong , Kim Da Yeon , Kim Younjoo , Shin Ui Sup , Kim Kwang Seok , Kim Eun Ju
Published: January 2023

Precise prediction of radioresistance is an important factor in the treatment of colorectal cancer (CRC). To discover genes that regulate the radioresistance of CRCs, we analyzed an RNA sequencing dataset of patient-originated samples. Among various candidates, IGFL2-AS1, a long non-coding RNA (lncRNA), exhibited an expression pattern that was well correlated with radioresistance. IGFL2-AS1 is known to be highly expressed in various cancers and functions as a competing endogenous RNA. To further investigate the role of IGFL2-AS1 in radioresistance, which has not yet been studied, we assessed the amount of IGFL2-AS1 transcripts in CRC cell lines with varying degrees of radioresistance. This analysis showed that the more radioresistant the cell line, the higher the level of IGFL2-AS1 transcripts—a similar trend was observed in CRC samples. To directly assess the relationship between IGFL2-AS1 and radioresistance, we generated a CRC cell line stably expressing a small hairpin RNA (shRNA) targeting IGFL2-AS1. shRNA-mediated knockdown of IGFL2-AS1 decreased radioresistance and cell migration in vitro, establishing a functional role for IGFL2-AS1 in radioresistance. We also showed that downstream effectors of the AKT pathway played crucial roles. These data suggest that IGFL2-AS1 contributes to the acquisition of radioresistance by regulating the AKT pathway.
On Associations between Fear-Induced Aggression, Bdnf Transcripts, and Serotonin Receptors in the Brains of Norway Rats: An Influence of Antiaggressive Drug TC-2153
Authors: Moskaliuk Vitalii S. , Kozhemyakina Rimma V. , Khomenko Tatyana M. , Volcho Konstantin P. , Salakhutdinov Nariman F. , Kulikov Alexander V. , Naumenko Vladimir S. , Kulikova Elizabeth A.
Published: January 2023

The Bdnf (brain-derived neurotrophic factor) gene contains eight regulatory exons (I–VIII) alternatively spliced to the protein-coding exon IX. Only exons I, II, IV, and VI are relatively well studied. The BDNF system and brain serotonergic system are tightly interconnected and associated with aggression. The benzopentathiepine TC-2153 affects both systems and exerts antiaggressive action. Our aim was to evaluate the effects of TC-2153 on the Bdnf exons I–IX’s expressions and serotonin receptors’ mRNA levels in the brain of rats featuring high aggression toward humans (aggressive) or its absence (tame). Aggressive and tame adult male rats were treated once with vehicle or 10 or 20 mg/kg of TC-2153. mRNA was quantified in the cortex, hippocampus, hypothalamus, and midbrain with real-time PCR. Selective breeding for high aggression or its absence affected the serotonin receptors’ and Bdnf exons’ transcripts differentially, depending on the genotype (strain) and brain region. TC-2153 had comprehensive effects on the Bdnf exons’ expressions. The main trend was downregulation in the hypothalamus and midbrain. TC-2153 increased 5-HT1B receptor hypothalamusc mRNA expression. For the first time, an influence of TC-2153 on the expressions of Bdnf regulatory exons and the 5-HT1B receptor was shown, as was an association between Bdnf regulatory exons and fear-induced aggression involving genetic predisposition.
Protective Effects of Hexarelin and JMV2894 in a Human Neuroblastoma Cell Line Expressing the SOD1-G93A Mutated Protein
Authors: Meanti Ramona , Licata Martina , Rizzi Laura , Bresciani Elena , Molteni Laura , Coco Silvia , Locatelli Vittorio , Omeljaniuk Robert J. , Torsello Antonio
Published: January 2023

Amyotrophic lateral sclerosis (ALS) is an incurable motor neuron disease whose etiology remains unresolved; nonetheless, mutations of superoxide dismutase 1 (SOD1) have been associated with several variants of ALS. Currently available pharmacologic interventions are only symptomatic and palliative in effect; therefore, there is a pressing demand for more effective drugs. This study examined potential therapeutic effects of growth hormone secretagogues (GHSs), a large family of synthetic compounds, as possible candidates for the treatment of ALS. Human neuroblastoma cells expressing the SOD1-G93A mutated protein (SH-SY5Y SOD1G93A cells) were incubated for 24 h with H2O2 (150 µM) in the absence, or presence, of GHS (1 µM), in order to study the protective effect of GHS against increased oxidative stress. The two GHSs examined in this study, hexarelin and JMV2894, protected cells from H2O2-induced cytotoxicity by activating molecules that regulate apoptosis and promote cell survival processes. These findings suggest the possibility of developing new GHS-based anti-oxidant and neuroprotective drugs with improved therapeutic potential. Further investigations are required for the following: (i) to clarify GHS molecular mechanisms of action, and (ii) to envisage the development of new GHSs that may be useful in ALS therapy.
Bromodomain (BrD) Family Members as Regulators of Cancer Stemness—A Comprehensive Review
Authors: Czerwinska Patrycja , Mackiewicz Andrzej Adam
Published: January 2023

Epigenetic mechanisms involving DNA methylation and chromatin modifications have emerged as critical facilitators of cancer heterogeneity, substantially affecting cancer development and progression, modulating cell phenotypes, and enhancing or inhibiting cancer cell malignant properties. Not surprisingly, considering the importance of epigenetic regulators in normal stem cell maintenance, many chromatin-related proteins are essential to maintaining the cancer stem cell (CSC)-like state. With increased tumor-initiating capacities and self-renewal potential, CSCs promote tumor growth, provide therapy resistance, spread tumors, and facilitate tumor relapse after treatment. In this review, we characterized the epigenetic mechanisms that regulate the acquisition and maintenance of cancer stemness concerning selected epigenetic factors belonging to the Bromodomain (BrD) family of proteins. An increasing number of BrD proteins reinforce cancer stemness, supporting the maintenance of the cancer stem cell population in vitro and in vivo via the utilization of distinct mechanisms. As bromodomain possesses high druggable potential, specific BrD proteins might become novel therapeutic targets in cancers exhibiting de-differentiated tumor characteristics.
Sperm DNA Fragmentation and Sperm-Borne miRNAs: Molecular Biomarkers of Embryo Development?
Authors: Conflitti Anna Chiara , Cicolani Gaia , Buonacquisto Alessandra , Pallotti Francesco , Faja Fabiana , Bianchini Serena , Blaconà Giovanna , Bruno Sabina Maria , Linari Antonella , Lucarelli Marco , Montanino Diletta , Muzii Ludovico , Lenzi Andrea , Lombardo Francesco , Paoli Donatella
Published: January 2023

The evaluation of morpho-functional sperm characteristics alone is not enough to explain infertility or to predict the outcome of Assisted Reproductive Technologies (ART): more sensitive diagnostic tools are needed in clinical practice. The aim of the present study was to analyze Sperm DNA Fragmentation (SDF) and sperm-borne miR-34c-5p and miR-449b-5p levels in men of couples undergoing ART, in order to investigate any correlations with fertilization rate, embryo quality and development. Male partners (n = 106) were recruited. Semen analysis, SDF evaluation and molecular profiling analysis of miR-34c-5p and miR-449b-5p (in 38 subjects) were performed. Sperm DNA Fragmentation evaluation- a positive correlation between SDF post sperm selection and the percentage of low-quality embryos and a negative correlation with viable embryo were found. SDF > 2.9% increased the risk of obtaining a non-viable embryo by almost 4-fold. Sperm miRNAs profile—we found an association with both miRNAs and sperm concentration, while miR-449b-5p is positively associated with SDF. Moreover, the two miRNAs are positively correlated. Higher levels of miR-34c-5p compared to miR-449b-5p increases by 14-fold the probability of obtaining viable embryos. This study shows that SDF, sperm miR-34c-5p, and miR-449b-5p have a promising role as biomarkers of semen quality and ART outcome.
The Human Pre-miRNA Distance Distribution for Exploring Disease Association
Authors: Wang Hsiuying , Ho Ching
Published: January 2023

MicroRNAs (miRNAs), playing an important role in cell differentiation, development, gene regulation, and apoptosis, have attracted much attention in recent years. miRNAs were shown to be involved in the mechanisms of various diseases, and certainly, they can be employed as useful disease biomarkers. The phylogenetic tree analysis of miRNA biomarkers is a useful tool to investigate the association between various diseases as well as the association between viruses and disease. In addition to the phylogenetic tree analysis, a more advanced study is to use the miRNA distance distribution to evaluate the similarity of the miRNA biomarkers. The mature miRNA distance distribution based on mature miRNA sequences has been derived. The averages of the pairwise distances of miRNA biomarkers for several associated diseases were shown to be smaller than the overall mean of all miRNAs, which indicates the high similarity of miRNA biomarkers for associated diseases. In addition to the mature miRNA, the precursor miRNA (pre-miRNA) may be more useful to explore the similarity of miRNAs because the mature miRNA duplex is released from the pre-miRNA. Therefore, in this study, the distance distributions based on human pre-miRNA stem–loop sequences were derived. The 1917 human miRNA stem-loop sequences in the miRBase dataset were used to derive the pre-miRNA distance distribution, and this is the first study to provide the distance distribution based on the human pre-miRNAs. The similarity of miRNA biomarkers for several associated diseases or vaccines was examined using the derived distribution, and the results show that the similarity of pre-miRNA biomarkers may be a feasible way to help explore the disease association.
Toll-like Receptors and Thrombopoiesis
Authors: Tang Xiaoqin , Xu Qian , Yang Shuo , Huang Xinwu , Wang Long , Huang Feihong , Luo Jiesi , Zhou Xiaogang , Wu Anguo , Mei Qibing , Zhao Chunling , Wu Jianming
Published: January 2023

Platelets are the second most abundant blood component after red blood cells and can participate in a variety of physiological and pathological functions. Beyond its traditional role in hemostasis and thrombosis, it also plays an indispensable role in inflammatory diseases. However, thrombocytopenia is a common hematologic problem in the clinic, and it presents a proportional relationship with the fatality of many diseases. Therefore, the prevention and treatment of thrombocytopenia is of great importance. The expression of Toll-like receptors (TLRs) is one of the most relevant characteristics of thrombopoiesis and the platelet inflammatory function. We know that the TLR family is found on the surface or inside almost all cells, where they perform many immune functions. Of those, TLR2 and TLR4 are the main stress-inducing members and play an integral role in inflammatory diseases and platelet production and function. Therefore, the aim of this review is to present and discuss the relationship between platelets, inflammation and the TLR family and extend recent research on the influence of the TLR2 and TLR4 pathways and the regulation of platelet production and function. Reviewing the interaction between TLRs and platelets in inflammation may be a research direction or program for the treatment of thrombocytopenia-related and inflammatory-related diseases.
Activation of Early Proinflammatory Responses by TBEV NS1 Varies between the Strains of Various Subtypes
Authors: Starodubova Elizaveta , Tuchynskaya Ksenia , Kuzmenko Yulia , Latanova Anastasia , Tutyaeva Vera , Karpov Vadim , Karganova Galina
Published: January 2023

Tick-borne encephalitis (TBE) is an emerging zoonosis that may cause long-term neurological sequelae or even death. Thus, there is a growing interest in understanding the factors of TBE pathogenesis. Viral genetic determinants may greatly affect the severity and consequences of TBE. In this study, nonstructural protein 1 (NS1) of the tick-borne encephalitis virus (TBEV) was tested as such a determinant. NS1s of three strains with similar neuroinvasiveness belonging to the European, Siberian and Far-Eastern subtypes of TBEV were studied. Transfection of mouse cells with plasmids encoding NS1 of the three TBEV subtypes led to different levels of NS1 protein accumulation in and secretion from the cells. NS1s of TBEV were able to trigger cytokine production either in isolated mouse splenocytes or in mice after delivery of NS1 encoding plasmids. The profile and dynamics of TNF-α, IL-6, IL-10 and IFN-γ differed between the strains. These results demonstrated the involvement of TBEV NS1 in triggering an immune response and indicated the diversity of NS1 as one of the genetic factors of TBEV pathogenicity.
Stem Cells for Cancer Therapy: Translating the Uncertainties and Possibilities of Stem Cell Properties into Opportunities for Effective Cancer Therapy
Authors: Aldoghachi Ahmed Faris , Chong Zhi Xiong , Yeap Swee Keong , Cheong Soon Keng , Ho Wan Yong , Ong Alan Han Kiat
Published: January 2023

Cancer recurrence and drug resistance following treatment, as well as metastatic forms of cancer, are trends that are commonly encountered in cancer management. Amidst the growing popularity of personalized medicine and targeted therapy as effective cancer treatment, studies involving the use of stem cells in cancer therapy are gaining ground as promising translational treatment options that are actively pursued by researchers due to their unique tumor-homing activities and anti-cancer properties. Therefore, this review will highlight cancer interactions with commonly studied stem cell types, namely, mesenchymal stroma/stem cells (MSC), induced pluripotent stem cells (iPSC), iPSC-derived MSC (iMSC), and cancer stem cells (CSC). A particular focus will be on the effects of paracrine signaling activities and exosomal miRNA interaction released by MSC and iMSCs within the tumor microenvironment (TME) along with their therapeutic potential as anti-cancer delivery agents. Similarly, the role of exosomal miRNA released by CSCs will be further discussed in the context of its role in cancer recurrence and metastatic spread, which leads to a better understanding of how such exosomal miRNA could be used as potential forms of non-cell-based cancer therapy.
Alternative Splicing of TaHsfA2-7 Is Involved in the Improvement of Thermotolerance in Wheat
Authors: Ma Zhenyu , Li Mingyue , Zhang Huaning , Zhao Baihui , Liu Zihui , Duan Shuonan , Meng Xiangzhao , Li Guoliang , Guo Xiulin
Published: January 2023

High temperature has severely affected plant growth and development, resulting in reduced production of crops worldwide, especially wheat. Alternative splicing (AS), a crucial post-transcriptional regulatory mechanism, is involved in the growth and development of eukaryotes and the adaptation to environmental changes. Previous transcriptome data suggested that heat shock transcription factor (Hsf) TaHsfA2-7 may form different transcripts by AS. However, it remains unclear whether this post-transcriptional regulatory mechanism of TaHsfA2-7 is related to thermotolerance in wheat (Triticum aestivum). Here, we identified a novel splice variant, TaHsfA2-7-AS, which was induced by high temperature and played a positive role in thermotolerance regulation in wheat. Moreover, TaHsfA2-7-AS is predicted to encode a small truncated TaHsfA2-7 isoform, retaining only part of the DNA-binding domain (DBD). TaHsfA2-7-AS is constitutively expressed in various tissues of wheat. Notably, the expression level of TaHsfA2-7-AS is significantly up-regulated by heat shock (HS) during flowering and grain-filling stages in wheat. Further studies showed that TaHsfA2-7-AS was localized in the nucleus but lacked transcriptional activation activity. Ectopic expression of TaHsfA2-7-AS in yeast exhibited improved thermotolerance. Compared to non-transgenic plants, overexpression of TaHsfA2-7-AS in Arabidopsis results in enhanced tolerance to heat stress. Simultaneously, we also found that TaHsfA1 is directly involved in the transcriptional regulation of TaHsfA2-7 and TaHsfA2-7-AS. In summary, our findings demonstrate the function of TaHsfA2-7-AS splicing variant in response to heat stress and establish a link between regulatory mechanisms of AS and the improvement of thermotolerance in wheat.
A Mulberry Diels-Alder-Type Adduct, Kuwanon M, Triggers Apoptosis and Paraptosis of Lung Cancer Cells through Inducing Endoplasmic Reticulum Stress
Authors: Ma Mengjiao , Luan Xiaoyi , Zheng Hao , Wang Xiaoning , Wang Shuqi , Shen Tao , Ren Dongmei
Published: January 2023

The mulberry tree (Morus alba) has been cultivated in China for thousands of years. Mulberry Diels-Alder-type adducts (MDAAs) are characteristic constituents of the genus Morus. The unique structure and diverse bioactivities of MDAAs have attracted the attention of researchers. Kuwanon M (KWM) is an MDAA isolated from the root bark of Morus alba. This research reports the growth inhibitory effects of KWM on human lung cancer cells and its possible mechanism. In A549 and NCI-H292 cells, KWM treatment induced suppression of cell proliferation and migration. The appearance of chromatin condensation, phosphatidyl serine exposure and caspase cleavage indicated the arising of apoptosis. The loss of mitochondrial membrane potential (MMP), release of cytochrome c and dysregulation of Bax/Bcl-2 demonstrated that the KWM-induced apoptosis was through the mitochondrial pathway. Paraptosis was simultaneously detected under KWM treatment, as evidenced by the exhibition of cytoplasmic vacuolation, down-regulation of Alix and up-regulation of endoplasmic reticulum (ER) stress-related proteins. Mechanistically, ER stress induced activation of unfolded protein response (UPR) pathways and activation of the MAPK (JNK and ERK) pathway, all of which were critical for KWM-induced apoptosis and paraptosis. These findings suggested the possibility that KWM might be considered as a potential lung cancer therapeutic agent.
Bacteriobiota of the Cave Church of Sts. Peter and Paul in Serbia—Culturable and Non-Culturable Communities’ Assessment in the Bioconservation Potential of a Peculiar Fresco Painting
Authors: Dimkić Ivica , Ćopić Milica , Petrović Marija , Stupar Miloš , Savković Željko , Knežević Aleksandar , Subakov Simić Gordana , Ljaljević Grbić Milica , Unković Nikola
Published: January 2023

The principal aim of this study was to determine bacterial diversity within the Cave Church of Sts. Peter and Paul, via culturable and non-culturable approaches, and elucidate the antifungal potential of autochthonous antagonistic bacterial isolates against biodeteriogenic fungi. Furthermore, whole-genome sequencing of selected bacterial antagonists and the analysis of genes included in the synthesis of secondary metabolites were performed. With the highest RA values, determined in metabarcoding analysis, phyla Actinobacteriota (12.08–54.00%) and Proteobacteria (25.34–44.97%) dominated most of the samples. A total of 44 different species, out of 96 obtained isolates, were determined as part of the culturable bacteriobiota, with the predominance of species from the genus Bacillus. Bacillus simplex was the only isolated species simultaneously present in all investigated substrata within the church. The best antagonistic activity against 10 biodeteriogenic fungi was documented for Streptomyces anulatus, followed by Bacillus altitudinis, Chryseobacterium viscerum, and Streptomyces sp. with their highest PGI% values ranging of from 55.9% to 80.9%. These promising results indicate that characterized bacteria are excellent candidates for developing biocontrol strategies for suppressing deteriogenic fungi responsible for the deterioration of investigated fresco painting. Finally, isolate 11-11MM, characterized as Streptomyces sp., represents a new species for science prompting the need for further study.
Theophylline Attenuates BLM-Induced Pulmonary Fibrosis by Inhibiting Th17 Differentiation
Authors: Park Soo-Jin , Hahn Hwa-Jeong , Oh Sei-Ryang , Lee Hyun-Jun
Published: January 2023

Idiopathic pulmonary fibrosis (IPF) is a chronic and refractory interstitial lung disease. Although there are two approved drugs for IPF, they were not able to completely cure the disease. Therefore, the development of new drugs is required for the effective treatment of IPF. In this study, we investigated the effect of theophylline, which has long been used for the treatment of asthma, on pulmonary fibrosis. The administration of theophylline attenuated the fibrotic changes of lung tissues and improved mechanical pulmonary functions in bleomycin (BLM)-induced pulmonary fibrosis. Theophylline treatment suppressed IL-17 production through inhibiting cytokines controlling Th17 differentiation; TGF-β, IL-6, IL-1β, and IL-23. The inhibition of IL-6 and IL-1β by theophylline is mediated by suppressing BLM-induced ROS production and NF-κB activation in epithelial cells. We further demonstrated that theophylline inhibited TGF-β-induced epithelial-to-mesenchymal transition in epithelial cells through suppressing the phosphorylation of Smad2/3 and AKT. The inhibitory effects of theophylline on the phosphorylation of Smad2/3 and AKT were recapitulated in BLM-treated lung tissues. Taken together, these results demonstrated that theophylline prevents pulmonary fibrosis by inhibiting Th17 differentiation and TGF-β signaling.
Silent Death by Sound: C60 Fullerene Sonodynamic Treatment of Cancer Cells
Authors: Radivoievych Aleksandar , Kolp Benjamin , Grebinyk Sergii , Prylutska Svitlana , Ritter Uwe , Zolk Oliver , Glökler Jörn , Frohme Marcus , Grebinyk Anna
Published: January 2023

The acoustic pressure waves of ultrasound (US) not only penetrate biological tissues deeper than light, but they also generate light emission, termed sonoluminescence. This promoted the idea of its use as an alternative energy source for photosensitizer excitation. Pristine C60 fullerene (C60), an excellent photosensitizer, was explored in the frame of cancer sonodynamic therapy (SDT). For that purpose, we analyzed C60 effects on human cervix carcinoma HeLa cells in combination with a low-intensity US treatment. The time-dependent accumulation of C60 in HeLa cells reached its maximum at 24 h (800 ± 66 ng/106 cells). Half of extranuclear C60 is localized within mitochondria. The efficiency of the C60 nanostructure’s sonoexcitation with 1 MHz US was tested with cell-based assays. A significant proapoptotic sonotoxic effect of C60 was found for HeLa cells. C60′s ability to induce apoptosis of carcinoma cells after sonoexcitation with US provides a promising novel approach for cancer treatment.
A Systemic Investigation of Genetic Architecture and Gene Resources Controlling Kernel Size-Related Traits in Maize
Authors: Wang Cheng , Li Huangai , Long Yan , Dong Zhenying , Wang Jianhui , Liu Chang , Wei Xun , Wan Xiangyuan
Published: January 2023

Grain yield is the most critical and complex quantitative trait in maize. Kernel length (KL), kernel width (KW), kernel thickness (KT) and hundred-kernel weight (HKW) associated with kernel size are essential components of yield-related traits in maize. With the extensive use of quantitative trait locus (QTL) mapping and genome-wide association study (GWAS) analyses, thousands of QTLs and quantitative trait nucleotides (QTNs) have been discovered for controlling these traits. However, only some of them have been cloned and successfully utilized in breeding programs. In this study, we exhaustively collected reported genes, QTLs and QTNs associated with the four traits, performed cluster identification of QTLs and QTNs, then combined QTL and QTN clusters to detect consensus hotspot regions. In total, 31 hotspots were identified for kernel size-related traits. Their candidate genes were predicted to be related to well-known pathways regulating the kernel developmental process. The identified hotspots can be further explored for fine mapping and candidate gene validation. Finally, we provided a strategy for high yield and quality maize. This study will not only facilitate causal genes cloning, but also guide the breeding practice for maize.
Evaluating lncRNA Expression Patterns during HIV-1 Treatment Interruption
Authors: Schynkel Tinus , van Snippenberg Willem , Van Hecke Clarissa , Vandekerckhove Linos , Trypsteen Wim
Published: January 2023

Lately, the interest in long non-coding RNAs (lncRNAs) as potential drug targets and predictive markers in the context of HIV-1 has peaked, but their in vivo expression and regulation remains largely unexplored. Therefore, the present study examined lncRNA expression patterns during a clinical antiretroviral treatment interruption (ATI) trial. Peripheral blood mononuclear cells were isolated from ten patients at four timepoints: prior to ATI, 7–15 days after stop, at viral rebound and 3 months post antiretroviral therapy re-initiation. RNA was extracted and RT-qPCR on five known HIV-1-related lncRNAs (HEAL, MALAT1, NEAT1, GAS5 and NRON) was performed and correlated with HIV-1 and host marker expression. All lncRNAs correlated stronger with interferon stimulated genes (ISGs) than with HIV-1 reservoir and replication markers. However, one lncRNA, HEAL, showed significant upregulation at viral rebound during ATI compared to baseline and re-initiation of therapy (p = 0.0010 and p = 0.0094, respectively), following a similar viral-load-driven expression pattern to ISGs. In vitro knockdown of HEAL caused a significant reduction in HIV-1 infection levels, validating HEAL’s importance for HIV-1 replication. We conclude that the HIV-1-promoting lncRNA HEAL is upregulated at viral rebound during ATI, most likely induced by viral cues.
Diversity and Biosynthetic Potential of Fungi Isolated from St. John’s Island, Singapore
Authors: Munusamy Madhaiyan , Tan Kenneth , Nge Choy Eng , Gakuubi Martin Muthee , Crasta Sharon , Kanagasundaram Yoganathan , Ng Siew Bee
Published: January 2023

Adaptation to a wide variety of habitats allows fungi to develop unique abilities to produce diverse secondary metabolites with diverse bioactivities. In this study, 30 Ascomycetes fungi isolated from St. John’s Island, Singapore were investigated for their general biosynthetic potential and their ability to produce antimicrobial secondary metabolites (SMs). All the 30 fungal isolates belong to the Phylum Ascomycota and are distributed into 6 orders and 18 genera with Order Hypocreales having the highest number of representative (37%). Screening for polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) genes using degenerate PCR led to the identification of 23 polyketide synthases (PKSs) and 5 nonribosomal peptide synthetases (NRPSs) grouped into nine distinct clades based on their reduction capabilities. Some of the identified PKSs genes share high similarities between species and known reference genes, suggesting the possibility of conserved biosynthesis of closely related compounds from different fungi. Fungal extracts were tested for their antimicrobial activity against S. aureus, Methicillin-resistant S. aureus (MRSA), and Candida albicans. Bioassay-guided fractionation of the active constituents from two promising isolates resulted in the isolation of seven compounds: Penilumamides A, D, and E from strain F4335 and xanthomegnin, viomellein, pretrichodermamide C and vioxanthin from strain F7180. Vioxanthin exhibited the best antibacterial activity with IC50 values of 3.0 μM and 1.6 μM against S. aureus and MRSA respectively. Viomellein revealed weak antiproliferative activity against A549 cells with an IC50 of 42 μM. The results from this study give valuable insights into the diversity and biosynthetic potential of fungi from this unique habitat and forms a background for an in-depth analysis of the biosynthetic capability of selected strains of interest with the aim of discovering novel fungal natural products.
A New Face of the Old Gene: Deletion of the PssA, Encoding Monotopic Inner Membrane Phosphoglycosyl Transferase in Rhizobium leguminosarum, Leads to Diverse Phenotypes That Could Be Attributable to Downstream Effects of the Lack of Exopolysaccharide
Authors: Marczak Małgorzata , Żebracki Kamil , Koper Piotr , Horbowicz Aleksandra , Wójcik Magdalena , Mazur Andrzej
Published: January 2023

The biosynthesis of subunits of rhizobial exopolysaccharides is dependent on glycosyltransferases, which are usually encoded by large gene clusters. PssA is a member of a large family of phosphoglycosyl transferases catalyzing the transfer of a phosphosugar moiety to polyprenol phosphate; thus, it can be considered as priming glycosyltransferase commencing synthesis of the EPS repeating units in Rhizobium leguminosarum. The comprehensive analysis of PssA protein features performed in this work confirmed its specificity for UDP-glucose and provided evidence that PssA is a monotopic inner membrane protein with a reentrant membrane helix rather than a transmembrane segment. The bacterial two-hybrid system screening revealed interactions of PssA with some GTs involved in the EPS octasaccharide synthesis. The distribution of differentially expressed genes in the transcriptome of the ΔpssA mutant into various functional categories indicated complexity of cell response to the deletion, which can mostly be attributed to the lack of exopolysaccharide and downstream effects caused by such deficiency. The block in the EPS biosynthesis at the pssA step, potentially leading to an increased pool of UDP-glucose, is likely to be filtered through to other pathways, and thus the absence of EPS may indirectly affect the expression of proteins involved in these pathways.
Expression of pH-Sensitive TRPC4 in Common Skin Tumors
Authors: Kurz Bernadett , Michael Hannah Philine , Förch Antonia , Wallner Susanne , Zeman Florian , Decking Sonja-Maria , Ugele Ines , Hintschich Constantin , Haubner Frank , Ettl Tobias , Renner Kathrin , Brochhausen Christoph , Schreml Stephan
Published: January 2023

TRPCs (transient receptor potential classical or cation channels) play a crucial role in tumor biology, especially in the Ca2+ homeostasis in cancer cells. TRPC4 is a pH-sensitive member of this family of proteins. As solid tumors exhibit an inversed pH-gradient with lowered extracellular and increased intracellular pH, both contributing to tumor progression, TRPC4 might be a signaling molecule in the altered tumor microenvironment. This is the first study to investigate the expression profiles of TRPC4 in common skin cancers such as basal cell carcinoma (BCC), squamous cell carcinoma (SCC), malignant melanoma (MM) and nevus cell nevi (NCN). We found that all SCCs, NCNs, and MMs show positive TRPC4-expression, while BCCs do only in about half of the analyzed samples. These data render TRPC4 an immunohistochemical marker to distinguish SCC and BCC, and this also gives rise to future studies investigating the role of TRPC4 in tumor progression, and especially metastasis as BCCs very rarely spread and are mostly negative for TRPC4.
A Novel Form of Arginine-Chitosan as Nanoparticles Efficient for siRNA Delivery into Mouse Leukemia Cells
Authors: Luo Jixian , Chen Jiangfeng , Liu Yan , He Yongji , Dong Wenjuan
Published: January 2023

The modification of chitosan (CS) has greatly expanded its application in the field of medicine. In this study, low-molecular-weight chitosan was modified with arginine (Arg) by a simple method. The identification by the Fourier transform infrared spectra (FTIR) showed that Arg was successfully covalently attached to the CS. Interestingly, Arg-CS was identified as nanoparticles by atomic force microscopy (AFM) and transmission electron microscopy (TEM), whose particle size was 75.76 ± 12.07 nm based on Dynamic Light Scattering (DLS) characterization. Then, whether the prepared Arg-CS nanoparticles could encapsulate and deliver siRNA safely was investigated. Arg-CS was found to be able to encapsulate siRNAs in vitro via electrostatic interaction with siRNA; the Arg-CS/siRNA complex was safe for L1210 leukemia cells. Therefore, modification of chitosan by Arg produces novel nanoparticles to deliver siRNA into leukemia cells. This is the first time to identify Arg-CS as nanoparticles and explore their ability to deliver Rhoa siRNA into T-cell acute lymphoblastic leukemia (T-ALL) cells to advance therapies targeting Rhoa in the future.
The Histone Chaperone Network Is Highly Conserved in Physarum polycephalum
Authors: Poulet Axel , Rousselot Ellyn , Téletchéa Stéphane , Noirot Céline , Jacob Yannick , van Wolfswinkel Josien , Thiriet Christophe , Duc Céline
Published: January 2023

The nucleosome is composed of histones and DNA. Prior to their deposition on chromatin, histones are shielded by specialized and diverse proteins known as histone chaperones. They escort histones during their entire cellular life and ensure their proper incorporation in chromatin. Physarum polycephalum is a Mycetozoan, a clade located at the crown of the eukaryotic tree. We previously found that histones, which are highly conserved between plants and animals, are also highly conserved in Physarum. However, histone chaperones differ significantly between animal and plant kingdoms, and this thus probed us to further study the conservation of histone chaperones in Physarum and their evolution relative to animal and plants. Most of the known histone chaperones and their functional domains are conserved as well as key residues required for histone and chaperone interactions. Physarum is divergent from yeast, plants and animals, but PpHIRA, PpCABIN1 and PpSPT6 are similar in structure to plant orthologues. PpFACT is closely related to the yeast complex, and the Physarum genome encodes the animal-specific APFL chaperone. Furthermore, we performed RNA sequencing to monitor chaperone expression during the cell cycle and uncovered two distinct patterns during S-phase. In summary, our study demonstrates the conserved role of histone chaperones in handling histones in an early-branching eukaryote.
BREVIPEDICELLUS Positively Regulates Salt-Stress Tolerance in Arabidopsis thaliana
Authors: Cai Huixian , Xu Yang , Yan Kang , Zhang Shizhong , Yang Guodong , Wu Changai , Zheng Chengchao , Huang Jinguang
Published: January 2023

Salt stress is one of the major environmental threats to plant growth and development. However, the mechanisms of plants responding to salt stress are not fully understood. Through genetic screening, we identified and characterized a salt-sensitive mutant, ses5 (sensitive to salt 5), in Arabidopsis thaliana. Positional cloning revealed that the decreased salt-tolerance of ses5 was caused by a mutation in the transcription factor BP (BREVIPEDICELLUS). BP regulates various developmental processes in plants. However, the biological function of BP in abiotic stress-signaling and tolerance are still not clear. Compared with wild-type plants, the bp mutant exhibited a much shorter primary-root and lower survival rate under salt treatment, while the BP overexpressors were more tolerant. Further analysis showed that BP could directly bind to the promoter of XTH7 (xyloglucan endotransglucosylase/hydrolase 7) and activate its expression. Resembling the bp mutant, the disruption of XTH7 gave rise to salt sensitivity. These results uncovered novel roles of BP in positively modulating salt-stress tolerance, and illustrated a putative working mechanism.