bluuebunny/crossref_metadata_2025 huggingface dataset:
Chronotope of the border in the story of A. N. Tolstoy "The Viper"
Authors: Anisimova Alexandra Naumovna , Efremova Yulia Ivanovna
Published: July 2024

The article is devoted to the analysis of the novel by A. N. Tolstoy "The Viper" (1928). The purpose of the study is to reveal the features of the chronotope of the boundary of the work. The scientific novelty of this work lies in the fact that despite the focus on the story, which was explored through the heroic events of the civil war and hagiographic elements, there were aspects that were not fully explored from a gender perspective and through the theme of love. In particular, the authors have identified for the first time the types of chronotope boundaries in this work. The results showed that chronotopic values of various degrees and volumes, such as existential, social, personal and gender boundaries, become the most striking and important. The heroine of the story overcomes these thresholds, going through the initiation process and making sacrifices associated with the loss of home, parents, love, freedom, self-identity, human essence. The writer identifies the opposition of the "I" – "Other", associating it with the opposition of the human – animal and demonstrating the dominance of the second principle at a crucial moment for the country of the destruction of the old order and the formation of a new one. The main functions of the chronotope of the boundaries of this work are plot-forming, spatial, psychological and integrating.
The role of musical ecphrasis in the works of A. I. Kuprin in the late 80s - early 90s of the 19th century
Authors: Darenskaya Natalia Alexandrovna
Published: July 2024

The purpose of the study is to find out the role of musical ecphrasis in the early stories of A. I. Kuprin (works of 1889-1896). The scientific novelty of the work lies in the fact that for the first time a detailed sequential analysis of the precedents of musical citation and references to musical sources is given, their role in the narrative structure is analyzed. The identification and analysis of cases of verbal representation of musical works in Kuprin's texts gives an idea of the writer's search and formation of his own unique artistic handwriting. The significance of this research is generally associated with the little-studied phenomenon of the game poetics of Kuprin's early prose, especially the earliest stories, which for a long time were considered as learnedly immature, therefore not deserving any serious literary attention. As a result of the study, it was shown that the innovation of the young Kuprin consisted in a bold experimental attempt to combine fiction with related art forms, for example, musical opera, romance, to create precedents for "musical citation" as a complex genre symbiosis. Such syncretism is explained by the desire of the young writer to develop his "corporate" style by creating centonic texts in which musical allusions and quotations take on the role of a complex language of allegory and form new semantic connections. Musical ecphrasis in the analyzed works serves as a tool for encoding meanings, sets the axial points of the unfolding of the plot, programs the fate of the characters, motivates their behavior.
Anatomy of the sonnet "Don Juan" by N. S. Gumilev
Authors: Pogrebnaya Yana Vsevolodovna
Published: July 2024

The purpose of the study is to establish the concept of the image of Don Juan in the works of N. S. Gumilev through the prism of affirming and clarifying the aesthetics of acmeism and the dynamics of the poet's axiology and ontology. The scientific novelty of this research lies in two main aspects: firstly, we identify the image of Don Juan in N. S. Gumilev's work and place it in the context of various interpretations of the eternal image; secondly, we apply the methodology of level analysis of a poem, which was proposed by Gumilev himself in his article "Anatomy of a Poem," to our interpretation of the eternal image in the sonnet "Don Juan." This approach serves as a starting point for further readings of the image in other forms of literature, such as lyrics, drama (in the case of "Don Juan in Egypt"), and journalism (as seen in "The Reader"). The mythological genesis of the image of Don Juan actualizes the diachronic decoding of archaic meanings in the interpretation of N. S. Gumilev, which are harmoniously embedded in the architecture of the classical sonnet. At the same time, Don Juan, in accordance with the role concept of the collection "Pearls", acts as one of the hypostases of a person in general, which dictates the need for an ethical assessment of the hero's life path. As a result of the study, it was found that the grammatical structure and poetic language of the sonnet "Don Juan" form the concept of an image polemically opposed to both the romantic rehabilitation of Don Juan and his acmeistic interpretation in the one-act drama in verse "Don Juan in Egypt".
An Autoethnography on the Survival Strategies of a Beginning Elementary School Teacher
Authors: Yang Yeontae , Lee Dongsung ,   Korean Association for Qualitative Inquiry
Published: July 2024

The aim of this paper is to describe a beginning teacher’s teaching socialization process with a focus on survival strategies, based on the theoretical premise of dramaturgy and the methodological premise of autoethnography, which explores the social self. The research results are briefly presented as follows. Firstly, as a novice elementary school teacher, I did impression management by putting on the mask of a weak ‘chick’ to appear compliant to the teaching staff. Secondly, as a novice teacher, I managed to give the impression of wearing a cozy ‘puppy’ mask in order to become a teacher recognized by elementary school students. Thirdly, I managed to give the impression of wearing the mask of a patient ‘bear’ to gain trust and respect from parents. These three types of impression management were survival strategies to instill a professional image of a competent teacher among school members. The results of this paper will deepen understanding of the professional life of beginning elementary school teacher by representing professional survival strategies for teaching socialization from an insider’s perspective, and provide a policy perspective that can support the teaching socialization process of beginning elementary school teacher.
Analisis Pengaruh Motivasi, Pengetahuan, dan Aspek Syariah terhadap Kesiapan UMKM Memasuki Era Digital
Authors: Abimanyu Andika Putra  , Achmad Syamsul Huda
Published: July 2024

Tujuan dari penelitian ini untuk mencari tau pengaruh motivasi, pengetahuan, dan aspek syariah terhadap kesiapan pelaku UMKM dalam memasuki era digital, terkhususnya para pelaku usaha mikro di wilayah Kabupaten Bogor. Pada penelitian ini metode yang digunakan adalah metode kuantitatif, dengan teknik pengambilan sample Cluster Random Sampling. Penelitian dilakukan dengan menyebar angket yang berisikan beberapa pernyataan terkait variabelvariabel yang ditentukan yang kemudian dijawab oleh pelaku UMKM dengan pernyataan sangat tidak setuju, tidak setuju, setuju, dan sangat setuju. Pada penelitian ini ditemukan bahwa: (1) variabel motivasi berpengaruh positif dan signifikan terhadap variabel kesiapan, (2) variabel pengetahuan berpengaruh positif dan signifikan terhadap variabel kesiapan, (3) variabel aspek syariah berpengaruh positif dan signifikan terhadap kesiapan variabel.
Pengaruh Faktor Makroekonomi terhadap Nilai Outstanding Sukuk Korporasi di Indonesia Tahun 2016-2021
Authors: Diana Dina
Published: July 2024

This study aims to This study aims to analyze the effect of macroeconomic factors on the outstanding corporate sukuk in Indonesia. This study uses a quantitative approach. The data used is secondary data, in the form of a time series from January 2016 to October 2021. The method used is Multiple Linear Regression Analysis with an error rate of 5%. From this study, it was found that macroeconomic factors that have a significant influence on the outstanding value of corporate sukuk in Indonesia are the BI Rate, money supply, and exports variables. Factors that have no effect on the outstanding value of corporate sukuk in Indonesia are inflation variable and the USD exchange rate. Inflation, BI Rate, money supply, USD exchange rate and exports simultaneously affect the outstanding value of corporate sukuk in Indonesia.
Effect of High Serum Estradiol Levels and Duration of Vaginal Estradiol Administration on Reproductive Outcomes in Frozen-Thawed Embryo Transfer Cycles
Authors: Zhang Xiaolei , Wang Minglei , Chen Yongqian , Li Linan
Published: July 2024

Background: The purpose of this study is to assess the effects of high serum estradiol (E2) levels on reproductive outcomes as well as to compare pregnancy outcomes of duration of vaginal E2 administration after the day of progesterone (P4) initiation in frozen-thawed embryo transfer (FET) hormonal replacement cycles. Methods: We performed a retrospective cohort study on 627 patients ≤40 years old that underwent a FET cycle. The patients were grouped based on the serum E2 level on the P4 initiation day as follows: E2 ≤600 pg/mL (n = 471); E2 ≥900 pg/mL (n = 151); the group of E2 600–900 pg/mL (n = 5) was not included in the analysis due to too small sample size. A total of 151 patients with E2 ≥900 pg/mL were grouped based on the duration of vaginal E2 administration after the day of P4 initiation: withdrawal before transfer (n = 53); constant administration (n = 98). Results: There was no significant difference in implantation rate, clinical pregnancy rate, spontaneous abortion rate, premature birth rate, live birth rate and multiple pregnancy rate between the two E2 level groups. The logistic regression analysis demonstrated that age was the only variable that significantly affected clinical pregnancy rate and live birth rate. There were no fetal malformations in either group. Baseline characteristics of patients with different duration of vaginal E2 administration were similar. The pregnancy outcomes showed no significant difference between the withdrawal before transfer group and the constant administration group. Conclusions: In FET cycles, high E2 level on the embryo transfer day did not reduce the clinical pregnancy and live birth rates. In addition, vaginal E2 could be stopped on the embryo transfer day since we found no benefit in continuing E2 until the pregnancy testing day.
Role of Neoadjuvant Chemotherapy in High-Grade Neuroendocrine Carcinoma of the Uterine Cervix
Authors: Eum Hyerim , Shin Yoon-Kyung , Kim Ju-Hyun , Kim Yong Man , Kim Jong-Hyeok , Suh Dae-Shik , Kim Dae-Yeon , Park Jeong-Yeol
Published: July 2024

Background: This study aimed to assess the feasibility and efficacy of neoadjuvant chemotherapy (NACT) in treating patients with high-grade neuroendocrine carcinoma of the uterine cervix (HGNEC). Methods: We performed a retrospective case-control study at Asan Medical Center, Seoul, Republic of Korea, from January 1993 to December 2017, involving 60 patients with surgically treated HGNEC. Thirteen patients (21.7%) received NACT before undergoing surgery. Regarding the comparison between the group that underwent NACT and the group that did not, we used a propensity score-matched analysis, matching 22 patients in the primary radical surgery group with 11 patients in the neoadjuvant chemotherapy followed by radical hysterectomy group. Results: In the entire cohort, primary open surgery was more common in the primary surgery group compared to the NACT group (p = 0.004). After propensity score matching (PSM), the median tumor size was 3.5 cm in the primary surgery group and 2.4 cm in the NACT group (p = 0.078). After matching, there was no significant difference in the recurrence rate between the two groups (63.6% in the primary surgery group vs. 63.6% in the neoadjuvant chemotherapy group, p = 0.782). After PSM, the primary surgery group exhibited a lower intraoperative transfusion rate (10%) than the NACT group (45.5%, p = 0.052). Conclusions: While NACT was feasible in patients with HGNEC, it did not significantly improve the survival rate over primary radical surgery.
Inflammatory Response of Monocytes/Macrophages in Patients with Systemic Sclerosis
Authors: Kirichenko Tatiana V. , Bogatyreva Anastasia I. , Gerasimova Elena V. , Popkova Tatiana V. , Markina Yuliya V. , Markin Alexander M. , Gerasimova Daria A. , Orekhov Alexander N.
Published: July 2024

Background: Investigation of the inflammatory response of immune cells is a current focus of research on autoimmune disorders. The aim of this study was to evaluate the inflammatory status of monocytes/macrophages in systemic sclerosis (SSc). Methods: The study included 35 SSc and 25 healthy participants. The secretion of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), monocyte chemoattractant protein-1 (MCP-1), interleukin-8 (IL-8), interleukin-6 (IL-6) was measured by enzyme-linked immunosorbent assay (ELISA) in primary cultures of monocytes/macrophages after stimulation with lipopolysaccharide (LPS) on day 1 and on day 6 of incubation. Impaired tolerance of the immune response was characterized by increased secretion of the inflammatory mediators in response to restimulation. Results: Basal secretion of all cytokines was significantly higher in SSc patients compared to healthy individuals. The secretion of TNF-α, IL-1β and IL-6 after the initial LPS stimulation, and secretion of IL-1β, MCP-1, IL-6, IL-8 after LPS restimulation, was significantly higher in the SSc group. Eleven SSc patients (31%) showed impaired immune tolerance in terms of MCP-1 secretion. These patients were significantly younger and had a higher level of anti-topoisomerase I (anti-Scl70) antibodies compared to SSc patients with immune tolerance. Conclusions: This study revealed pro-inflammatory activation and impaired immune tolerance in monocytes/macrophages from SSc patients. The violation of immune response in terms of MCP-1 secretion may be an important factor in the development of chronic inflammation in SSc. MCP-1 may thus be a potential therapeutic target for novel SSc treatment strategies.
SMARCA2 and SMARCA4 Participate in DNA Damage Repair
Authors: Yu Lily , Wu Duo
Published: July 2024

Background: The switching/sucrose non-fermentable (SWI/SNF) Related, Matrix Associated, Actin Dependent Regulator Of Chromatin, Subfamily A (SMARCA) member 2 and member 4 (SMARCA2/4) are paralogs and act as the key enzymatic subunits in the SWI/SNF complex for chromatin remodeling. However, the role of SMARCA2/4 in DNA damage response remains unclear. Methods: Laser microirradiation assays were performed to examine the key domains of SMARCA2/4 for the relocation of the SWI/SNF complex to DNA lesions. To examine the key factors that mediate the recruitment of SMARCA2/4, the relocation of SMARCA2/4 to DNA lesions was examined in HeLa cells treated with inhibitors of Ataxia-telangiectasia-mutated (ATM), Ataxia telangiectasia and Rad3-related protein (ATR), CREB-binding protein (CBP) and its homologue p300 (p300/CBP), or Poly (ADP-ribose) polymerase (PARP) 1/2 as well as in H2AX-deficient HeLa cells. Moreover, by concomitantly suppressing SMARCA2/4 with the small molecule inhibitor FHD286 or Compound 14, the function of SMARCA2/4 in Radiation sensitive 51 (RAD51) foci formation and homologous recombination repair was examined. Finally, using a colony formation assay, the synergistic effect of PARP inhibitors and SMARCA2/4 inhibitors on the suppression of tumor cell growth was examined. Results: We show that SMARCA2/4 relocate to DNA lesions in response to DNA damage, which requires their ATPase activities. Moreover, these ATPase activities are also required for the relocation of other subunits in the SWI/SNF complex to DNA lesions. Interestingly, the relocation of SMARCA2/4 is independent of γH2AX, ATM, ATR, p300/CBP, or PARP1/2, indicating that it may directly recognize DNA lesions as a DNA damage sensor. Lacking SMARCA2/4 prolongs the retention of γH2AX, Ring Finger Protein 8 (RNF8) and Breast cancer susceptibility gene 1 (BRCA1) at DNA lesions and impairs RAD51-dependent homologous recombination repair. Furthermore, the treatment of an SMARCA2/4 inhibitor sensitizes tumor cells to PARP inhibitor treatment. Conclusions: This study reveals SMARCA2/4 as a DNA damage repair factor for double-strand break repair.
Microglia Involvement into Acute and Chronic Brain Damage in Diabetic Rats: Impact of GLP-1RA and SGLT-2i
Authors: Simanenkova Anna , Fuks Oksana , Timkina Natalya , Islamova Alina , Sufieva Dina , Kirik Оlga , Korzhevskii Dmitrii , Vlasov Timur , Karonova Tatiana
Published: July 2024

Background: Acute and chronic brain damage in type 2 diabetes mellitus (DM) determines the need to investigate the neuroprotective potential of glucose-lowering drugs. The purpose was to directly compare the neuroprotective effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) with different duration of action and sodium-glucose cotransporter-2 inhibitors (SGLT-2i) in type 2 diabetic rats with and without stroke. Methods: DM was modelled using high-fat diet and nicotinamide+streptozotocin protocol. The following groups (n = 15 each) were formed: DM without treatment, treatment with liraglutide, dulaglutide, canagliflozin as well as control group without DM and treatment. After 8 weeks, 10 rats from each group underwent middle cerebral artery occlusion. In the reperfusion period neurological deficit, neuroglial damage markers and brain necrosis were evaluated. Brain slices from the remaining 5 animals in each group were histologically examined for microglial activation and neuronal damage. Results: Brain damage was similar in “DM” and “Control” (17.53 [14.23; 26.58] and 15.87 [13.40; 22.68] % of total brain volume, respectively). All study drugs diminished damage volume comparing with “DM” and “Control” whereas the necrosis volume in “DM+Liraglutide” was smaller than in “DM+Canagliflozin” and did not significantly differ from “DM+Dulaglutide” (2.9 [1.83; 4.71], 6.17 [3.88; 8.88] and 4.57 [3.27; 7.90] %). The neurological deficit was more prominent in “DM” than in “Control”, while all the drugs demonstrated similar positive effect. Neurofilament light chains (NLC) did not differ between “DM” and “Control”. Dulaglutide and canagliflozin caused a marked decrease in NLC. Protein S100BB level was similar in “DM” and “Control”. Liraglutide caused the largest S100BB decrease, while canagliflozin did not influence it. In chronic brain ischaemia, all drugs increased the number of normal neurons, but GLP-1RAs had a more pronounced effect. DM was accompanied by increased number of activated microglial cells in Cornu Ammonis (CA)1 hippocampal region. Both GLP-1RAs reduced the number of Iba-1-positive cells, with dulaglutide being more effective than liraglutide, whereas canagliflozin did not affect this parameter. Conclusions: GLP-1RAs and SGLT-2i have neuroprotective properties against acute and chronic brain damage in diabetic rats, although the infarct-limiting effect of GLP-1RAs may be more pronounced. GLP-1RAs and SGLT-2i exert their protective effects by directly influencing neuronal survival, whereas GLP-1RAs also affect microglia.
Based on NF-κB and Notch1/Hes1 Signaling Pathways, the Mechanism of Artesunate on Inflammation in Osteoporosis in Ovariectomized Rats was Investigated
Authors: Wang Guangwei , Tan Jun , Huang Chongbo , Xu Yidong , Yang Zhong , Huo Liwei
Published: July 2024

Background: Artesunate (ART) has the potential to modulate the nuclear factor kappa B (NF-κB) and Notch1/Hes1 signaling pathways, which play crucial roles in the pathogenesis of osteoporosis. This study aims to explore whether ART participates in the progression of osteoporosis by regulating these signaling pathways. Methods: In the in vitro experiments, we treated bone marrow mesenchymal stem cells (BMSCs) with different concentrations of ART (0, 3, 6, 12 µM) and evaluated osteogenic differentiation using alkaline phosphatase staining (ALP) and alizarin red S staining (ARS) staining. The expression levels of osteocalcin (OCN), RUNT-related transcription factor 2 (RUNX2), osteoprotegerin (OPG), and receptor activator of the nuclear factor kappa ligand (RANKL) were detected by real-time quantitative PCR (RT-qPCR). The effects of ART on NF-κB p65 and Notch1 protein expression were analyzed by Western blot (WB) and immunofluorescence (IF). In the in vivo experiments, a postmenopausal osteoporosis rat model was established via ovariectomy. Bone tissue pathological injury was evaluated using hematoxylin eosin (HE) staining. Serum ALP levels were measured using a kit, bone density was determined by dual-energy X-ray absorptiometry, and serum levels of bone gla protein (BGP), OPG, RANKL, tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and IL-1β were measured by enzyme-linked immunosorbent assay (ELISA). Additionally, the expression of NF-κB p65 and Notch1 in tissues was assessed by immunohistochemistry. Results: In vitro experiments revealed that compared to the control group, ART dose-dependently promoted BMSCs proliferation and enhanced their osteogenic differentiation capability. The expression of OCN, RUNX2, and OPG significantly increased in the ART-treated group, while RANKL expression decreased significantly (p < 0.05). ART significantly inhibited the expression of NF-κB p65 and Notch1/Hes1 signaling pathway proteins (p < 0.05). Compared to ART treatment alone, combined treatment with ART and phorbol myristate acetate (PMA) or valproic acid (VPA) resulted in increased expression of NF-κB p65 and Notch1 proteins and decreased osteogenic differentiation capability (p < 0.05). In vivo experiments showed that in rats treated with ART, bone damage was significantly reduced, bone density and mineral content were restored considerably, and the expression of inflammatory factors (TNF-α, IL-6, IL-1β) decreased significantly (p < 0.05). Additionally, ART treatment significantly reduced the expression of NF-κB p65 and Notch1 proteins, increased OPG expression, and decreased BGP and RANKL levels (p < 0.05). Conclusion: In summary, ART facilitates the osteogenic differentiation of BMSCs by inhibiting the NF-κB and Notch1/Hes1 signaling pathways, thereby exerting significant protective effects against osteoporosis.
DHODH Alleviates Heart Failure via the Modulation of CoQ-Related Ferroptotic Inhibition
Authors: Wang Chen , Chen Chuchu , Zhou Jiabin , Shi Jiayu , Sun Hanrui , Li Jingyu , Gu Pengyang , Wang Xinglin , Lu Qi , Wang Shuai
Published: July 2024

Background: Heart failure (HF) is a clinical syndrome that seriously endangers human health and quality of life as the terminal stage of cardiovascular diseases. Ferroptosis as a new iron-dependent programmed cell death mode that is closely related to the occurrence and development of cardiovascular diseases. Dihydroorotate dehydrogenase (DHODH) has been found to play a crucial role in inhibiting ferroptosis and improving mitochondrial function, and its expression can be upregulated by estradiol (E2). Recent studies have found that DHODH can inhibit ferroptosis by reducing coenzyme Q (CoQ) to CoQH2. Therefore, this study aims to explore the effect of up-regulation of DHODH on the pathological hypertrophy and fibrosis of heart failure and its mechanisms. Methods: The mouse heart failure model was established by transverse aortic constriction (TAC), surgery in mice. Two days after the operation, a subcutaneous injection of E2 or the same volume of sesame oil was given for 8 weeks. Then, the left ventricular systolic function related indicators of mice were measured by echocardiography, and the degree of myocardial fibrosis of mice was detected by histological analysis; the expression levels of heart failure markers were detected by quantitative polymerase chain reaction (q-PCR) and western blot (WB) analysis; the morphological changes of mitochondria in cardiac cells of mice were observed by transmission electron microscopy. Cell model were established by stimulating with phenylephrine for 96 hours. Ferroptosis markers were detected by kits and WB analysis. Mitochondrial function was verified by a JC-1 fluorescent probe, and 2′,7′-Dichlorodihydrofluorescein diacetate (DCFH-DA) staining. The knockdown results were detected by WB analysis after transfection of small interfering RNA (siRNA) of CoQ. Fer-1 was added as a positive control to verify the ferroptosis-related changes of myocardial cells. Results: In the animal model, we found that E2 treatment alleviates TAC-induced cardiac hypertrophy and fibrosis and suppresses cardiomyocyte ferroptosis by promotes DHODH upregulation in murine cardiomyocytes. In the cell model, DHODH upregulation protects against phenylephrine-induced cardiomyocytes with failure. However, the effect on up-regulating DHODH was inhibited by transfection to down-regulate CoQ expression. Conclusions: The up-regulation of DHODH could effectively ameliorate the manifestations of heart failure such as myocardial hypertrophy and fibrosis in mice after TAC surgery, inhibit ferroptosis of cardiac myocytes, and ameliorate mitochondrial function. The mechanism involves CoQ-related biological processes.
Knockdown of TGF-β in Pancreatic Cancer Helps Ameliorate Gemcitabine Resistance
Authors: Wang Xinxing , Su Wei , Qin Chuan , Gao Ruxin , Shao Shuai , Xu Xianwen , Zhang Zhenhai , Gao Junlin
Published: July 2024

Background: The TGF-β gene is a gemcitabine (GEM) resistance gene; however, the mechanism by which it regulates GEM resistance in pancreatic cancer remains unclear. Methods: The PANC-1 cell line was treated with GEM and then stimulated with TGF-β. Subsequently, we constructed GEM-resistant pancreatic cancer cell lines, knocked down TGF-β in these cell lines, and detected changes in the proliferation and apoptosis of drug-resistant cancer cells. In addition, the protein expression levels of KLF-4, GFI-1, and ZEB-1 were determined. The xenograft tumor models of nude mice were constructed by subcutaneously injecting GEM-resistant PANC-1 cells into mouse axilla. The tumors were removed, dissected, and weighed after 6 weeks. The protein levels of KLF-4, GFI-1, and ZEB-1 in tumor tissues were quantified. In addition, the percentage of M2 macrophages in tumor tissues was determined using flow cytometry. Results: The protein levels of TGF-β in pancreatic cancer cells were significantly decreased after GEM treatment. The protein expression of KLF-4 was downregulated, whereas the expressions of GFI-1 and ZEB-1 were upregulated after TGF-β stimulation. Apoptosis increased and proliferation decreased after TGF-β knockdown in GEM-resistant pancreatic cancer cells, moreover, silencing TGF-β promoted the expression of Caspase 3 and Cleaved caspase 3. In addition, the protein expression of KLF-4 was upregulated, whereas the expressions of GFI-1 and ZEB-1 were downregulated. Further, the volume and weight of the transplanted tumor decreased after TGF-β knockdown. The protein expression of KLF-4 was upregulated, whereas the expressions of GFI-1 and ZEB-1 were downregulated in tumor tissues. In addition, the percentage of M2 macrophages decreased in tumor tissues after TGF-β knockdown. Conclusions: The knockdown of TGF-β inhibits epithelial-to-mesenchymal transition, suppresses the proliferation and promotes the apoptosis of drug-resistant cancer cells, and decreases the macrophage polarization to the M2 phenotype, consequently ameliorating GEM resistance in pancreatic cancer.
miRNA Signatures in Bronchopulmonary Dysplasia: Implications for Biomarkers, Pathogenesis, and Therapeutic Options
Authors: Maeda Hajime , Li Xiaoyun , Go Hayato , Dennery Phyllis A. , Yao Hongwei
Published: July 2024

Bronchopulmonary dysplasia (BPD) is a chronic lung disease in premature infants characterized by alveolar dysplasia, vascular simplification and dysmorphic vascular development. Supplemental oxygen and mechanical ventilation commonly used as life-saving measures in premature infants may cause BPD. microRNAs (miRNAs), a class of small, non-coding RNAs, regulate target gene expression mainly through post-transcriptional repression. miRNAs play important roles in modulating oxidative stress, proliferation, apoptosis, senescence, inflammatory responses, and angiogenesis. These cellular processes play pivotal roles in the pathogenesis of BPD. Accumulating evidence demonstrates that miRNAs are dysregulated in the lung of premature infants with BPD, and in animal models of this disease, suggesting contributing roles of dysregulated miRNAs in the development of BPD. Therefore, miRNAs are considered promising biomarker candidates and therapeutic agents for this disease. In this review, we discuss how dysregulated miRNAs and their modulation alter cellular processes involved in BPD. We then focus on therapeutic approaches targeting miRNAs for BPD. This review provides an overview of miRNAs as biomarkers, and highlights potential pathogenic roles, and therapeutic strategies for BPD using miRNAs.
Encephalomyocarditis Virus Structural Protein VP3 Interacts with MAVS and Promotes its Autophagic Degradation to Interfere with the Type I Interferon Signaling Pathway
Authors: Zhao Xu , Hou Zhengyang , Zhang Yaxin , Mao Daoqin , Yan Zhenfang , Yang Shunyu , Xie Jingying , Feng Ruofei
Published: July 2024

Background: Understanding the mechanisms through which interferon (IFN) signaling is negatively regulated is crucial for preserving the equilibrium of innate immune reactions, as the innate immune system functions, such as the original barrier, combat threats to the host. Although the function of the encephalomyocarditis virus (EMCV) viral proteins in antagonizing innate immunity has been related to earlier studies, the precise mechanism underlying the role of viral protein 3 (VP3) in type I IFN has yet to be fully illuminated. Methods: VP3 expression and many other adaptor molecules belonging to type I IFN pathway expression levels were evaluated using Western blotting. The IFN and other antiviral genes, such as interferon-stimulated genes (ISGs) 15 and 56, were assessed by real-time quantitative polymerase chain reaction (RT-qPCR). A 50% tissue culture infectious dose (TCID50) assay was utilized to explore the effect of VP3 on EMCV proliferation in human embryonic kidney (HEK293) cells. Co-immunoprecipitation (Co-IP) assays and confocal microscope analysis were used to investigate the underlying mechanisms mediated by VP3. Results: We discovered that the VP3 of EMCV acts as a suppressor of innate immune reactions. Increased levels of VP3 enhance viral reproduction through modulation of innate immune signaling pathways and suppression of antiviral responses. Additional information indicated that during viral infection, the VP3 of EMCV enhances autophagy and interacts specifically with mitochondrial antiviral signaling protein (MAVS), leading to its degradation in an autophagy pathway that relies on p62. Conclusions: Our findings showed that EMCV developed a tactic to combat host antiviral defenses by using autophagy to break down a protein that controls the innate immune response following a viral infection of the host. Notably, VP3 plays an important role in this process. Overall, these discoveries may provide a novel therapeutic target for EMCV.
Differently Distributed Iron Deposition in Mild and Moderate Stroke with Small Artery Occlusion: A Pilot Voxel-Based Susceptibility Mapping Study
Authors: Chen Jinan , Wang Yingfan , Zhu Yinjie , Lu Jing , Li Minghao , Wang Xiaoshan
Published: July 2024

Background: Small artery occlusion (SAO) is a common ischemic stroke subtype. However, its clinical outcome can be more severe than commonly understood. The severity of SAO can vary, ranging from mild to moderate. Iron deposition has been associated with the development and progression of stroke. However, its specific distribution and relationship with stroke severity in SAO remain unclear. The study’s purpose is to investigate the differences in iron deposition between mild stroke with SAO (SAO-MiS) and moderate stroke with SAO (SAO-MoS) through quantitative susceptibility mapping (QSM) and its association with neurological deficits. Methods: Sixty-eight SAO participants within 24 hours of first onset were enrolled and separated into SAO-MiS and SAO-MoS according to the National Institutes of Health Stroke Scale (NIHSS) scores. QSM helped calculate the susceptibility maps, reflecting the iron content within the brain. The susceptibility maps were analyzed using voxel-wise statistical analysis to compare the iron deposition between SAO-MiS and SAO-MoS. Then, differentially distributed iron deposition helped differentiate between mild and moderate stroke using support vector machine (SVM) methods. Results: Compared with SAO-MiS, SAO-MoS depicted elevated iron deposition in the left pallidum, parahippocampal gyrus, and superior frontal gyrus medial region, and is lower in the right superior/middle frontal gyrus and bilateral supplementary motor area. Based on iron deposition, the SVM classifier’s analysis revealed a high power to discriminate SAO-MoS from SAO-MiS. In addition, fibrinogen, triglyceride (TG), and total cholesterol (TC) were linked with QSM values in specific brain regions. Conclusions: Our study first revealed the brain iron distribution after SAO and differently distributed iron deposition in SAO-MiS and SAO-MoS. The results indicate that iron deposition could play a role in the pathophysiology of SAO and its correlation with stroke severity.
Global Epidemiologic Trends and Projections to 2030 in Non-Rheumatic Degenerative Mitral Valve Disease from 1990 to 2019: An Analysis of the Global Burden of Disease Study 2019
Authors: Wang Chengmei , Song Menglin , Chen Hao , Liang Pan , Luo Gang , Ren Wei , Yang Sijin
Published: July 2024

Background: No studies have updated the epidemiologic changes in non-rheumatic degenerative mitral valve disease (DMVD) since 2019, thus this study utilized data from the Global Study of Diseases, Injuries, and Risk Factors 2019 (GBD2019) to assess the burden of DMVD in 204 countries and territories over the period 1990–2019, as well as changes in the prevalence, incidence, deaths and changes in disability-adjusted life years (DALYs). Methods: Using the results from the GBD2019, analyzing the incidence, prevalence, deaths, and DALYs rates, as well as their age-standardized rates (ASR). Based on the human development index (HDI), the socio-demographic index (SDI), age, and sex. Results: In 2019, there were 24.229 million (95% uncertainty interval (UI) 23.081–25.419 million) existing cases of DMVD worldwide, with 1.064 million (95% UI 1.010–1.122 million) new cases and 0.034 million (95% UI 0.028–0.043 million) deaths, and 0.883 million (95% UI 0.754–1.092 million) disability-adjusted life years. The incidence, prevalence, deaths, and DALYs of DMVD and their ASR showed significant differences across sex, age groups, regions, and countries from 1990 to 2019. It is projected that by 2030, the incidence of DMVD in females will be 0.72 million with an ASR of 15.59 per 100,000 population, 0.51 million in males with an ASR of 11.75 per 100,000 population, and a total incidence of 1.23 million with an ASR of 14.03 per 100,000 population. Conclusions: DMVD remains a significant public health problem that cannot be ignored, despite a decreasing trend in the ASR of global incidence, prevalence, deaths and DALYs from 1990 to 2019. However, we note an adverse development trend in countries with low socio-demographic indexes and seriously aging societies, and sex inequality is particularly prominent. This indicates the need to reposition current prevention and treatment strategies, with some national health administrations developing corresponding strategies for preventing an increase in DMVD based on local health, education, economic conditions, sex differences, and age differences.
Distinct Profiles and New Pharmacological Targets for Heart Failure with Preserved Ejection Fraction
Authors: Palazzuoli Alberto , Severino Paolo , D’Amato Andrea , Myftari Vincenzo , Tricarico Lucia , Correale Michele , Dattilo Giuseppe , Fioretti Francesco , Nodari Savina
Published: July 2024

Background: Heart failure with preserved ejection fraction (HFpEF) is a multifactorial condition with a variety of pathophysiological causes and morphological manifestations. The inclusion criteria and patient classification have become overly simplistic due to the customary differentiation regarding the ejection fraction (EF) cutoff. EF is considered a measure of systolic function; nevertheless, it only represents a portion of the true contractile state and has been shown to have certain limits due to methodological and hemodynamic irregularities. Methods: As a result, broader randomized clinical trials have yet to incorporate the most recent criteria for HFpEF diagnosis, leading to a lack of data consistency and confusion in interpreting the results. The primary variations between the bigger clinical trials published in this context concerning patient selection and echocardiographic characteristics were analyzed. For all these reasons, we aim to clarify the main features and clinical impact of HFpEF in a study combining imaging, bio-humoral analysis, and clinical history to identify the specific subgroups that respond better to tailored treatment. Results: Disparate clinical characteristics and a lack of uniform diagnostic standards may cause suboptimal therapeutic feedback. To optimize treatment, we suggest shifting the paradigm from the straightforward EF measurement to a more comprehensive model that considers additional information, such as structural traits, related disorders, and biological and environmental data. Therefore, by evaluating certain echocardiographic and clinical factors, a stepwise diagnostic procedure may be useful in identifying patients at high risk, subjects with early HFpEF, and those with evident HFpEF. Conclusions: The present assessment underscores the significance of the precision medicine approach in guaranteeing optimal patient outcomes by providing the best care according to each distinct profile.
Cardiac Xenotransplantation: A Narrative Review
Authors: Thuan Phan Quang , Dinh Nguyen Hoang
Published: July 2024

Cardiac xenotransplantation (cXT) has emerged as a solution to heart donor scarcity, prompting an exploration of its scientific, ethical, and regulatory facets. The review begins with genetic modifications enhancing pig hearts for human transplantation, navigating through immunological challenges, rejection mechanisms, and immune responses. Key areas include preclinical milestones, complement cascade roles, and genetic engineering to address hyperacute rejection. Physiological counterbalance systems, like human thrombomodulin and endothelial protein C receptor upregulation in porcine xenografts, highlight efforts for graft survival enhancement. Evaluating pig and baboon donors and challenges with non-human primates illuminates complexities in donor species selection. Ethical considerations, encompassing animal rights, welfare, and zoonotic disease risks, are critically examined in the cXT context. The review delves into immune control mechanisms with aggressive immunosuppression and clustered regularly interspaced palindromic repeats associated protein 9 (CRISPR/Cas9) technology, elucidating hyperacute rejection, complement activation, and antibody-mediated rejection intricacies. CRISPR/Cas9’s role in creating pig endothelial cells expressing human inhibitor molecules is explored for rejection mitigation. Ethical and regulatory aspects emphasize the role of committees and international guidelines. A forward-looking perspective envisions precision medical genetics, artificial intelligence, and individualized heart cultivation within pigs as transformative elements in cXT’s future is also explored. This comprehensive analysis offers insights for researchers, clinicians, and policymakers, addressing the current state, and future prospects of cXT.
Poverty, Competition, and Mass Patronage: Evidence from Southern Italy
Authors: Troncone Massimo
Published: July 2024

This article argues that in a context of widespread clientelism and poverty, local public goods provision is a tool for mass patronage. Clientelistic incumbents under threat entice economically vulnerable voters into supporting the regime by creating jobs in the construction sector through infrastructural investments. The theory is tested using data on public works projects funded by the Cassa del Mezzogiorno, a massive place-based policy for the development of Southern Italy introduced after WWII. Empirically, I exploit within-politician shocks in competition induced by the electoral rule of the post-war Italian Senate. The results reveal that public works investments increase when Christian democratic senators are threatened in their own districts by the election of a communist senator, that this effect is particularly strong in areas characterized by low levels of employment, and that this distribution generates electoral returns.
Right-hemispheric white matter organization is associated with speech timing in autistic children
Authors: Davison Kelsey E. , Liu Talia , Belisle Rebecca , Perrachione Tyler , Qi Zhenghan , Gabrieli John , Tager-Flusberg Helen , Zuk Jennifer
Published: July 2024

Converging research evidence indicates that speech timing, including altered rate and pausing when speaking, is an important characteristic distinguishing autistic individuals from non-autistic peers. Although speech timing can impact effective social communication, it remains unclear what mechanisms underlie individual differences in speech timing in autism. Therefore, the present study examined the organization of key speech- and language-related neural pathways in relation to speech timing in autistic and non-autistic children. Secondary analysis of a multimodal dataset included 24 autistic children and 24 non-autistic children (ages: 5 – 17 years). Audio recordings from a naturalistic language sampling task (via narrative generation) were transcribed to extract speech timing features (i.e., speech rate, pause duration). White matter organization (as indicated by fractional anisotropy (FA)) was estimated for key tracts bilaterally (i.e., arcuate fasciculus (AF), superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF), and frontal aslant tract (FAT)). Results indicate associations between speech timing and right-hemispheric white matter organization (i.e., FA in right ILF and FAT) were specific to autistic children and not observed among non-autistic controls. Among non-autistic children, associations with speech timing were specific to the left hemisphere (i.e., FA in the left SLF). All effects are significant controlling for age, sex, and nonverbal IQ. Overall, these findings enhance understanding of the neural architecture influencing speech timing in autistic and non-autistic children and, thus, carry implications for understanding potential neural mechanisms underlying speech timing differences in autism.
More biomass burning aerosol is being advected westward over the southern tropical Atlantic since 2003
Authors: Tatro Tyler , Zuidema Paquita
Published: July 2024

Each year, agricultural fires in southern continental Africa emit approximately one third of the world’s biomass burning aerosol. This is advected westward by the prevailing circulation winds over a subtropical stratocumulus cloud deck. The radiative effects from the aerosol and aerosol-cloud interactions impact regional circulations and hydrology. Here we examine how changes in the coupled southern African earth system over the past 20 years impact the southeast Atlantic. We combine satellite-derived burned area datasets with ECMWF-reanalysis carbon monoxide, black carbon, and meteorology from the biomass burning season (May-October) in southern Africa. The burning season begins in May in woody savannas in the northwest and shifts to open savanna and grassland fires in the southeast, with small fires (less than 1 km2) contributing significantly to total burned area. More small fires are occurring in the middle of the biomass burning season and the overall season is shorter, corroborated by reanalysis carbon monoxide fields. Significantly increased free tropospheric winds, shifted southward, transport smoke aerosol further southwest over the southeast Atlantic. The increased aerosol advection is coupled with a southern shift in the south Atlantic subtropical high and an increase in the low cloud fraction on the southern edge of the stratocumulus cloud deck. While smoke emissions sources have not changed significantly, changes in the smoke transport pathway, attributed to increasing surface temperatures in southern Africa and tropical expansion, combined with an altered low cloud distribution, explain how the regional radiation balance has shifted to more top-of-atmosphere cooling in recent decades.
Who is willing to play skill-adapted exergames? Influences of sociodemographic factors and social comparison processes
Authors: König Laura M , Kanning Martina , Hauptmann Hanna , Feuchtner Tiare , Arigo Danielle
Published: July 2024

Physical inactivity bears risks for physical and mental health. Theoretically grounded, novel intervention approaches are needed that encourage a positive affective reaction. Exergames may provide this opportunity, especially if different skill levels of players are automatically adapted. Drawing from two pre-registered within-subjects online experiments (total N = 1931) where participants were presented with two scenarios (joining exergame as most versus least skilled player), we report on the willingness of adults to engage in (skill-adapted) exergames. We also describe individual differences in willingness based on sociodemographic characteristics and social comparison processes. Willingness was higher when joining as the most versus the least skilled player among younger (rs = -0.28) and more highly educated (rs 0.07 and 0.12) participants, and among those who owned gaming consoles (vs. not; ds 0.28 and 0.45) and had prior exergame experience (vs. not; ds -0.42 and -0.51). Men were more willing to join exergames as the least skilled player than women (d = -0.16). Social comparison orientation was positively associated with willingness (rs 0.08 to 0.22), as were tendencies to engage in upward identification (rs 0.18 and 0.21) and downward contrast (rs 0.12 and 0.17). Tailoring exergames to sociodemographic and psychological characteristics is likely to maximise their effectiveness for health promotion.