bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk Factors Analysis for 90-Day Mortality of Adult Patients with Mild Traumatic Brain Injury in an Italian Emergency Department
Authors: Orso Daniele , Furlanis Giulia , Romanelli Alice , Gheller Federica , Tecchiolli Marzia , Cominotto Franco
Published: February 2024

Purpose: The most prominent risk factors for mortality after mild traumatic brain injury (TBI) have not been established. This study aimed to establish risk factors related to 90-day mortality after a traumatic event. Methods: A retrospective cohort study on adult patients entering the Emergency Department of the University Hospital of Trieste for mild TBI from 1 January 2020 to 31 December 2020 was conducted. Results: The final population was 1221 patients (median age of 78 years). The 90-day mortality rate was 7% (90 patients). In the Cox regression model (likelihood ratio 110.9; p < 2 × 10−16), the variables that significantly correlated to 90-day mortality were age (less than 75 years old is a protective factor, HR 0.29 [95%CI 0.16–0.54]; p < 0.001); chronic liver disease (HR 4.59 [95%CI 2.56–8.24], p < 0.001); cognitive impairment (HR 2.76 [95%CI 1.78–4.27], p < 0.001); intracerebral haemorrhage (HR 15.38 [95%CI 6.13–38.63], p < 0.001); and hospitalization (HR 2.56 [95%CI 1.67–3.92], p < 0.001). Cardiovascular disease (47% vs. 11%; p < 0.001) and cognitive impairment (36% vs. 10%; p < 0.001) were more prevalent in patients over 75 years of age than the rest of the population. Conclusions: In our cohort of patients with mild TBI, 90-day mortality was low but not negligible. The risk factors associated with 90-day mortality included age, history of chronic liver disease, and cognitive impairment, as well as evidence of intracerebral hemorrhage and hospitalization. The mortality of the sub-population of older patients was likely to be linked to cardiovascular comorbidities and neurodegenerative diseases.
Philip Huynh’s The Forbidden Purple City: New Canadian Refugee Narratives and the Borders of the Socio-Political Community
Authors: Carmona-Rodríguez Pedro Miguel
Published: February 2024

This paper examines Philip Huynh’s short story collection The Forbidden Purple City in relation to its engagement with the nativity–territory–citizenship triad on which Western socio-political communities found the principles of affiliation of their members. First, the Canadian reaffirmation of a discourse of national benevolence is contextualised to later draw on how the collection is nurtured by boundary-crossing ethics that interrogates any sequential relation between past and present, Vietnam and Canada, which usually structures refugee narratives. It is argued then that disruptive and productive time/space interconnections delegitimate any simplistic representations of easily assimilated grateful refugees, fracturing the convenient narration of Canada as a benefactor concerned with old and new international humanitarian causes. The newness of Huynh’s stories relies on their mobilisation of the discourse of state citizenship through exceptional migrancy and its disruptive border nature. In contrast to premises of birth and geographical territory, which lose ground as backbones of any affiliation, citizenship appears incomplete and processual. The stories use the precarious performativity of collective homogeneity expected of a former settler colony, like Canada, to launch agency and resistance to state homogenisation, and de-institutionalise the refugee subject to critically intervene sovereignty and political subjectivity. Finally, the stories evince that Canada’s social spectrum is ideal to explore the threshold opened by the adjacency of sameness and otherness embodied by Huynh’s protagonists. Their condition as diasporic refugee subjects augments the transformative potential of new refugee narratives, in which literal and metaphorical polymorphous borders unveil the bases of the contemporary Canadian socio-political community.
Person-Centred Care: A Support Strategy for Managing Non-Communicable Diseases
Authors: Lorber Mateja , Reljić Nataša Mlinar , Kegl Barbara , Fekonja Zvonka , Štiglic Gregor , Davey Adam , Kmetec Sergej
Published: February 2024

Background: Over the last decade, the inadequacy and unsustainability of current healthcare services for managing long-term co-morbid and multi-morbid diseases have become evident. Methods: This study, involving 426 adults with at least one non-communicable disease in Slovenia, aimed to explore the link between quality of life, life satisfaction, person-centred care, and non-communicable disease management. Results: Results indicated generally positive perceptions of quality of life, general health, and life satisfaction of individuals with non-communicable diseases. Participants assessed their physical health as the highest of the four quality of life domains, followed by the environment, social relations, and psychological health. Significant differences occurred in life satisfaction, general health, quality of life, and person-centred care for managing non-communicable diseases. But, there were no significant differences in person-centred care according to the living environment. The study revealed a positive association between person-centred care and effective non-communicable disease management, which is also positively associated with quality of life, general health, and life satisfaction. Conclusions: Person-centred care is currently the most compassionate and scientific practice conceived, representing a high ethical standard. However, implementing this approach in healthcare systems requires a cohesive national strategy led by capable individuals to foster stakeholder collaboration. Such an approach is crucial to address the deficiencies of existing healthcare services and ensure person-centred care sustainability in non-communicable disease management.
The Babyccino: The Role of Caffeine in the Prevention of Acute Kidney Injury in Neonates—A Literature Review
Authors: Aithal Nimisha , Kandasamy Yogavijayan
Published: February 2024

Acute kidney injury (AKI) in neonates is associated with increased morbidity and mortality. Theophylline (a methylxanthine) has been shown to prevent neonatal AKI but is seldom used due to its unfavorable profile. Caffeine, another methylxanthine, is utilized ubiquitously to treat apnea of prematurity, but there are no randomized trials evaluating its efficacy in preventing neonatal AKI. This literature review aims to summarize the existing research pertaining to the relationship between caffeine and neonatal AKI. The review was conducted using Pubmed, Embase, Google Scholar, and Cochrane. Inclusion criteria incorporated empirical studies, being published in English, and being available electronically. All eight studies identified were included. Seven studies found caffeine-exposed premature neonates had lower rates of AKI than caffeine-unexposed neonates. Four found reduced AKI severity with caffeine exposure. One study included term neonates and did not find a difference in the AKI rate between caffeine-exposed and non-exposed babies. Limitations include exclusively observational studies, short study periods, heterogenous definitions of prematurity, and a lack of assessment of dose–effect relationships. In conclusion, premature neonates exposed to caffeine appear to have lower rates and potentially less severe AKI. Further research is needed before caffeine can be considered for use in the primary prevention of neonatal AKI.
Capacity Planning of Virtual Wards for Frail and Elderly Patients
Authors: Grange Harriet , Johns Gemma , Ahuja Alka , Harper Paul , Williams Elizabeth , Gartner Daniel
Published: February 2024

This paper investigates the planning of virtual ward (VW) capacity including the remote monitoring of frail and elderly patients. The main objective is to optimize VW hub locations across a region in the United Kingdom. Furthermore, assigning the optimal number of clinicians to different regions needs to be considered. We develop a mathematical model that minimizes the setup and travel costs of VW hubs and staff. Our experimental analysis evaluates different levels of demand considering postcode areas within different Trusts, also known as Health Boards, in the National Health Service (NHS). Furthermore, our experiments provide insights into how many hub locations should be deployed and staffed. This can be used to individually find the number of remote monitors and clinicians for each facility as well as the system overall.
The Effects of Artificial Intelligence Chatbots on Women’s Health: A Systematic Review and Meta-Analysis
Authors: Kim Hyun-Kyoung
Published: February 2024

Purpose: This systematic review and meta-analysis aimed to investigate the effects of artificial intelligence chatbot interventions on health outcomes in women. Methods: Ten relevant studies published between 2019 and 2023 were extracted from the PubMed, Cochrane Library, EMBASE, CINAHL, and RISS databases in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. This review focused on experimental studies concerning chatbot interventions in women’s health. The literature was assessed using the ROB 2 quality appraisal checklist, and the results were visualized with a risk-of-bias visualization program. Results: This review encompassed seven randomized controlled trials and three single-group experimental studies. Chatbots were effective in addressing anxiety, depression, distress, healthy relationships, cancer self-care behavior, preconception intentions, risk perception in eating disorders, and gender attitudes. Chatbot users experienced benefits in terms of internalization, acceptability, feasibility, and interaction. A meta-analysis of three studies revealed significant effects in reducing anxiety (I2 = 0%, Q = 8.10, p < 0.017), with an effect size of −0.30 (95% CI, −0.42 to −0.18). Conclusions: Artificial intelligence chatbot interventions had positive effects on physical, physiological, and cognitive health outcomes. Using chatbots may represent pivotal nursing interventions for female populations to improve health status and support women socially as a form of digital therapy.
Bioactive Compounds in the Residue Obtained from Fruits of Some Cultivars of Lonicera caerulea
Authors: Cosmulescu Sina , Vijan Loredana , Mazilu Ivona Cristina , Badea Georgiana
Published: February 2024

This paper aimed to investigate the bioactive compounds in the dry powder residue of honeysuckle cultivars after extracting the juice. Based on the analyses performed on the total content of phenolic compounds, flavonoids, anthocyanins, tannins, carotenoids and vitamin C, the results indicated that dried Lonicera caerulea residue represented a rich source of phenolic compounds (8041.36 mg GAE 100 g−1), of which about 80% were tannins (6432.10 mg GAE 100 g−1). The flavonoid content varied around 2436.95 mg CE 100 g−1. Vitamin C (185 mg 100 g−1), lycopene and β-carotene (over 2.5 and 2.8 mg 100 g−1, respectively) were also quantified. Among the phenolic acids, chlorogenic acid predominated (316 mg 100 g−1), followed by cryptochlorogenic acid (135 mg 100 g−1) and neochlorogenic acid (32 mg 100 g−1). Flavonoids were mainly represented by catechin (2594 mg 100 g−1) and anthocyanins (1442 mg 100 g−1). Similar amounts of epicatechin and rutin were measured (156 mg 100 g−1 and 148 mg 100 g−1), while the isoquercetin concentration was below 15 mg 100 g−1. In conclusion, the high level of phytocompounds and the diverse composition of dry Lonicera caerulea residue support its high nutraceutical value and high health-promoting potential.
Pathogenic Factors and Mechanisms of the Alternaria Leaf Spot Pathogen in Apple
Authors: Cao Chen , Gong Shun , Li Yan , Tang Jinqi , Li Tianzhong , Zhang Qiulei
Published: February 2024

Alternaria leaf spot seriously threatens the sustainable development of the global apple industry, causing significant losses and reducing fruit quality and yield. The causal agent Alternaria alternata f. sp. mali (Alternaria mali, ALT) produces various molecules to modulate infection, such as cell wall-degrading enzymes, toxins, and elicitor-like molecules. ALT produces the host-specific AM-toxin, an important pathogenicity factor. ALT also releases effectors into apple cells that modify host defense, but these proteins have not yet been described. Here, we identified the pathogenic fungal types responsible for early defoliation from diseased leaves of Fuji (Malus domestica cv. ‘Fuji’) apple collected from five districts in Shandong Province, China. The ALT isolates ALT2 to ALT7 were pathogenic to four apple cultivars, with ALT7 being the most aggressive. We extracted mycotoxins (AM-toxin-2 to AM-toxin-7) from each isolate and used them to treat different apple varieties, which led to leaf-spot symptoms and damaged chloroplasts and nuclear membranes, followed by cell death. AM-toxin-7 produced the most severe symptoms, but chloroplasts remained intact when the mycotoxin was inactivated. Mass spectrometry identified 134 secretory proteins in ALT7 exosomes, and three secreted proteins (AltABC, AltAO, and AltPDE) were confirmed to be involved in apple pathogenesis. Therefore, ALT secretes AM-toxin and secretory proteins as an infection strategy to promote fungal invasion and overcome the host defense system.
Active Packaging Systems to Extend the Shelf Life of ‘Italia’ Table Grapes
Authors: Higuchi Maíra Tiaki , Aguiar Aline Cristina de , Leles Nathalia Rodrigues , Ribeiro Luana Tainá Machado , Bosso Bruna Evelise Caetano , Yamashita Fábio , Youssef Khamis , Roberto Sergio Ruffo
Published: February 2024

Sulfur dioxide (SO2)-generating pads associated with perforated plastic liners are often used to control gray mold in table grapes during cold storage; however, SO2 may cause bleaching, shattered berries, and an unwanted taste. To overcome this difficulty, a field ultrafast SO2-generating pad was designed to be used for a few hours before packaging grape bunches as an alternative for eradicating spores of fungi from berry skin. This study aimed to assess the postharvest conservation and shelf life of ‘Italia’ table grapes packaged in plastic clamshells and perforated plastic liners using the field ultra-fast SO2-generating pads before packaging, associated with or without slow- or dual-phase SO2-generating pads during cold storage. The packaged grapes were cold stored (1.0 ± 1.0 °C; 95% relative humidity), and after 45 d, grapes were placed at room temperature (22.0 ± 1.0 °C) without plastic liners and SO2-generating pads for 3 d. Before and after the grapes had been subjected to the field ultra-fast SO2-generating pads, the quantification of filamentous fungi on the surface of the berries was assessed. The use of field ultra-fast SO2-generating pads before packaging, associated with slow- or dual-phase SO2-generating pads during cold storage, resulted in a lower incidence of gray mold after 45 d of storage, with low weight loss and shattered berries, good preservation of stem freshness, and no impairment in the color and firmness of the berries. Additionally, a significant decrease in disease incidence was observed when using only the dual-phase SO2-generating pads in cold storage, with good maintenance of bunch quality.
The Prevalence, Risk Factors, and Antimicrobial Resistance Determinants of Helicobacter pylori Detected in Dyspeptic Patients in North–Central Bangladesh
Authors: Ferdaus Syeda Jannatul , Paul Shyamal Kumar , Nasreen Syeda Anjuman , Haque Nazia , Sadekuzzaman Mohammad , Karim Mohammad Reazul , Islam Syed Mahmudul , Al Mamun Abdullah , Sathi Fardousi Akter , Basak Proma , Nahid Rifat Binte , Aktar Suraiya , Kobayashi Nobumichi
Published: February 2024

Chronic infection of Helicobacter pylori represents a key factor in the etiology of gastrointestinal diseases, with high endemicity in South Asia. The present study aimed to determine the prevalence of H. pylori among dyspeptic patients in north–central Bangladesh (Mymensingh) and analyze risk factors of infection and antimicrobial resistance (AMR) determinants in the pathogen. Endoscopic gastrointestinal biopsy samples were collected from dyspeptic patients for a one-year period from March 2022 and were checked for the presence of H. pylori via the rapid urease test and PCR and further analyzed for the status of virulence factors vacA/cagA and genetic determinants related to AMR via PCR with direct sequencing or RFLP. Among a total of 221 samples collected, 80 (36%) were positive for H. pylori, with the vacA+/cagA+ genotype being detected in almost half of them. H. pylori was most prevalent in the age group of 41–50-year-olds, with it being more common in males and rural residents with a lower economic status and using nonfiltered water, though the rates of these factors were not significantly different from those of the H. pylori-negative group. Relatively higher frequency was noted for the A2147G mutation in 23S rRNA, related to clarithromycin resistance (18%, 7/39). Amino acid substitutions in PBP-1A (T556S) and GyrA (N87K and D91N) and a 200 bp deletion in rdxA were detected in samples from some patients with recurrence after treatment with amoxicillin, levofloxacin, and metronidazole, respectively. The present study describes the epidemiological features of H. pylori infection in the area outside the capital in Bangladesh, revealing the spread of AMR-associated mutations.
Dynamic Cytoophidia during Late-Stage Drosophila Oogenesis
Authors: Zhang Shi-Qi , Liu Ji-Long
Published: February 2024

CTP synthase (CTPS) catalyzes the final step of de novo synthesis of CTP. CTPS was first discovered to form filamentous structures termed cytoophidia in Drosophila ovarian cells. Subsequent studies have shown that cytoophidia are widely present in cells of three life domains. In the Drosophila ovary model, our previous studies mainly focused on the early and middle stages, with less involvement in the later stages. In this work, we focus on the later stages of female germline cells in Drosophila. We use live-cell imaging to capture the continuous dynamics of cytoophidia in Stages 10–12. We notice the heterogeneity of cytoophidia in the two types of germline cells (nurse cells and oocytes), manifested in significant differences in morphology, distribution, and dynamics. Surprisingly, we also find that neighboring nurse cells in the same egg chamber exhibit multiple dynamic patterns of cytoophidia over time. Although the described dynamics may be influenced by the in vitro incubation conditions, our observation provides an initial understanding of the dynamics of cytoophidia during late-stage Drosophila oogenesis.
First-in-Class Humanized Antibody against Alternatively Spliced Tissue Factor Augments Anti-Metastatic Efficacy of Chemotherapy in a Preclinical Model of Pancreatic Ductal Adenocarcinoma
Authors: Lewis Clayton S. , Backman Charles , Ahsan Sabahat , Cliff Ashley , Hariharan Arthi , Yeh Jen Jen , Zhang Xiang , Xie Changchun , Sohal Davendra P. S. , Bogdanov Vladimir Y.
Published: February 2024

Alternatively spliced tissue factor (asTF) promotes the progression of pancreatic ductal adenocarcinoma (PDAC) by activating β1-integrins on PDAC cell surfaces. hRabMab1, a first-in-class humanized inhibitory anti-asTF antibody we recently developed, can suppress PDAC primary tumor growth as a single agent. Whether hRabMab1 has the potential to suppress metastases in PDAC is unknown. Following in vivo screening of three asTF-proficient human PDAC cell lines, we chose to make use of KRAS G12V-mutant human PDAC cell line PaCa-44, which yields aggressive primary orthotopic tumors with spontaneous spread to PDAC-relevant anatomical sites, along with concomitant severe leukocytosis. The experimental design featured orthotopic tumors formed by luciferase labeled PaCa-44 cells; administration of hRabMab1 alone or in combination with gemcitabine/paclitaxel (gem/PTX); and the assessment of the treatment outcomes on the primary tumor tissue as well as systemic spread. When administered alone, hRabMab1 exhibited poor penetration of tumor tissue; however, hRabMab1 was abundant in tumor tissue when co-administered with gem/PTX, which resulted in a significant decrease in tumor cell proliferation; leukocyte infiltration; and neovascularization. Gem/PTX alone reduced primary tumor volume, but not metastatic spread; only the combination of hRabMab1 and gem/PTX significantly reduced metastatic spread. RNA-seq analysis of primary tumors showed that the addition of hRabMab1 to gem/PTX enhanced the downregulation of tubulin binding and microtubule motor activity. In the liver, hRabMab1 reduced liver metastasis as a single agent. Only the combination of hRabMab1 and gem/PTX eliminated tumor cell-induced leukocytosis. We here demonstrate for the first time that hRabMab1 may help suppress metastasis in PDAC. hRabMab1’s ability to improve the efficacy of chemotherapy is significant and warrants further investigation.
Changes in the Concentrations of Proangiogenic Cytokines in Human Brain Glioma and Acute Lymphoblastic Leukemia
Authors: Oldak Lukasz , Zielinska Zuzanna , Milewska Patrycja , Chludzinska-Kasperuk Sylwia , Latoch Eryk , Konończuk Katarzyna , Krawczuk-Rybak Maryna , Starosz Aleksandra , Grubczak Kamil , Reszeć Joanna , Gorodkiewicz Ewa
Published: February 2024

Acute lymphoblastic leukemia (ALL) and glioma are some of the most common malignancies, with ALL most often affecting children and glioma affecting adult men. Proangiogenic cytokines and growth factors play an important role in the development of both of these tumors. Glioma is characterized by an extremely extensive network of blood vessels, which continues to expand mainly in the process of neoangiogenesis, the direct inducers of which are cytokines from the family of vascular endothelial growth factors, i.e., vascular endothelial growth factor (VEGF-A) and its receptor vascular endothelial growth factor receptor 2 (VEGF-R2), as well as a cytokine from the fibroblast growth factor family, fibroblast growth factor 2 (FGF-2 or bFGF). Growth factors are known primarily for their involvement in the progression and development of solid tumors, but there is evidence that local bone marrow angiogenesis and increased blood vessel density are also present in hematological malignancies, including leukemias. The aim of this study was to examine changes in the concentrations of VEGF-A, VEGF-R2, and FGF-2 (with a molecular weight of 17 kDa) in a group of patients divided into specific grades of malignancy (glioma) and a control group; changes of VEGF-A and FGF-2 concentrations in childhood acute lymphoblastic leukemia and a control group; and to determine correlations between the individual proteins as well as the influence of the patient’s age, diet, and other conditions that may place the patient in the risk group. During the statistical analysis, significant differences in concentrations were found between the patient and control groups in samples from people with diagnosed glioma and from children with acute lymphoblastic leukemia, but in general, there are no significant differences in the concentrations of VEGF-A, VEGF-R2, and FGF-2 between different grades of glioma malignancy. Among individuals treated for glioma, there was no significant impact from the patient’s gender and age, consumption of food from plastic packaging, frequency of eating vegetables and fruit, smoking of tobacco products, the intensity of physical exercise, or the general condition of the body (Karnofsky score) on the concentrations of the determined cytokines and receptor. The listed factors do not bring about an actual increase in the risk of developing brain glioma.
The Role of Cilostazol, a Phosphodiesterase-3 Inhibitor, in the Development of Atherosclerosis and Vascular Biology: A Review with Meta-Analysis
Authors: Sohn Minji , Lim Soo
Published: February 2024

Atherosclerotic cardiovascular disease (ASCVD) stands as the leading global cause of mortality. Addressing this vital and pervasive condition requires a multifaceted approach, in which antiplatelet intervention plays a pivotal role, together with antihypertensive, antidiabetic, and lipid-lowering therapies. Among the antiplatelet agents available currently, cilostazol, a phosphodiesterase-3 inhibitor, offers a spectrum of pharmacological effects. These encompass vasodilation, the impediment of platelet activation and aggregation, thrombosis inhibition, limb blood flow augmentation, lipid profile enhancement through triglyceride reduction and high-density lipoprotein cholesterol elevation, and the suppression of vascular smooth muscle cell proliferation. However, the role of cilostazol has not been clearly documented in many guidelines for ASCVD. We comprehensively reviewed the cardiovascular effects of cilostazol within randomized clinical trials that compared it to control or active agents and involved individuals with previous coronary artery disease or stroke, as well as those with no previous history of such conditions. Our approach demonstrated that the administration of cilostazol effectively reduced adverse cardiovascular events, although there was less evidence regarding its impact on myocardial infarction. Most studies have consistently reported its favorable effects in reducing intermittent claudication and enhancing ambulatory capacity in patients with peripheral arterial disease. Furthermore, cilostazol has shown promise in mitigating restenosis following coronary stent implantation in patients with acute coronary syndrome. While research from more diverse regions is still needed, our findings shed light on the broader implications of cilostazol in the context of atherosclerosis and vascular biology, particularly for individuals at high risk of ASCVD.
Nicotinamide Mononucleotide (NMN) Works in Type 2 Diabetes through Unexpected Effects in Adipose Tissue, Not by Mitochondrial Biogenesis
Authors: Popescu Roua Gabriela , Dinischiotu Anca , Soare Teodoru , Vlase Ene , Marinescu George Cătălin
Published: February 2024

Nicotinamide mononucleotide (NMN) has emerged as a promising therapeutic intervention for age-related disorders, including type 2 diabetes. In this study, we confirmed the previously observed effects of NMN treatment on glucose uptake and investigated its underlying mechanisms in various tissues and cell lines. Through the most comprehensive proteomic analysis to date, we discovered a series of novel organ-specific effects responsible for glucose uptake as measured by the IPGTT: adipose tissue growing (suggested by increased protein synthesis and degradation and mTOR proliferation signaling upregulation). Notably, we observed the upregulation of thermogenic UCP1, promoting enhanced glucose conversion to heat in intermuscular adipose tissue while showing a surprising repressive effect on mitochondrial biogenesis in muscle and the brain. Additionally, liver and muscle cells displayed a unique response, characterized by spliceosome downregulation and concurrent upregulation of chaperones, proteasomes, and ribosomes, leading to mildly impaired and energy-inefficient protein synthesis machinery. Furthermore, our findings revealed remarkable metabolic rewiring in the brain. This involved increased production of ketone bodies, downregulation of mitochondrial OXPHOS and TCA cycle components, as well as the induction of well-known fasting-associated effects. Collectively, our data elucidate the multifaceted nature of NMN action, highlighting its organ-specific effects and their role in improving glucose uptake. These findings deepen our understanding of NMN’s therapeutic potential and pave the way for novel strategies in managing metabolic disorders.
RNA N6-Methyladenosine Modification in DNA Damage Response and Cancer Radiotherapy
Authors: Wang Cui , Yao Shibo , Zhang Tinghui , Sun Xiaoya , Bai Chenjun , Zhou Pingkun
Published: February 2024

The N6-methyladenosine (M6A) modification is the most common internal chemical modification of RNA molecules in eukaryotes. This modification can affect mRNA metabolism, regulate RNA transcription, nuclear export, splicing, degradation, and translation, and significantly impact various aspects of physiology and pathobiology. Radiotherapy is the most common method of tumor treatment. Different intrinsic cellular mechanisms affect the response of cells to ionizing radiation (IR) and the effectiveness of cancer radiotherapy. In this review, we summarize and discuss recent advances in understanding the roles and mechanisms of RNA M6A methylation in cellular responses to radiation-induced DNA damage and in determining the outcomes of cancer radiotherapy. Insights into RNA M6A methylation in radiation biology may facilitate the improvement of therapeutic strategies for cancer radiotherapy and radioprotection of normal tissues.
Role of CARD9 in Cell- and Organ-Specific Immune Responses in Various Infections
Authors: Lee Ji Seok , Kim Chaekyun
Published: February 2024

The caspase recruitment domain-containing protein 9 (CARD9) is an intracellular adaptor protein that is abundantly expressed in cells of the myeloid lineage, such as neutrophils, macrophages, and dendritic cells. CARD9 plays a critical role in host immunity against infections caused by fungi, bacteria, and viruses. A CARD9 deficiency impairs the production of inflammatory cytokines and chemokines as well as migration and infiltration, thereby increasing susceptibility to infections. However, CARD9 signaling varies depending on the pathogen causing the infection. Furthermore, different studies have reported altered CARD9-mediated signaling even with the same pathogen. Therefore, this review focuses on and elucidates the current literature on varied CARD9 signaling in response to various infectious stimuli in humans and experimental mice models.
Pluripotent Stem Cells as a Preclinical Cellular Model for Studying Hereditary Spastic Paraplegias
Authors: Damiani Devid , Baggiani Matteo , Della Vecchia Stefania , Naef Valentina , Santorelli Filippo Maria
Published: February 2024

Hereditary spastic paraplegias (HSPs) comprise a family of degenerative diseases mostly hitting descending axons of corticospinal neurons. Depending on the gene and mutation involved, the disease could present as a pure form with limb spasticity, or a complex form associated with cerebellar and/or cortical signs such as ataxia, dysarthria, epilepsy, and intellectual disability. The progressive nature of HSPs invariably leads patients to require walking canes or wheelchairs over time. Despite several attempts to ameliorate the life quality of patients that have been tested, current therapeutical approaches are just symptomatic, as no cure is available. Progress in research in the last two decades has identified a vast number of genes involved in HSP etiology, using cellular and animal models generated on purpose. Although unanimously considered invaluable tools for basic research, those systems are rarely predictive for the establishment of a therapeutic approach. The advent of induced pluripotent stem (iPS) cells allowed instead the direct study of morphological and molecular properties of the patient’s affected neurons generated upon in vitro differentiation. In this review, we revisited all the present literature recently published regarding the use of iPS cells to differentiate HSP patient-specific neurons. Most studies have defined patient-derived neurons as a reliable model to faithfully mimic HSP in vitro, discovering original findings through immunological and –omics approaches, and providing a platform to screen novel or repurposed drugs. Thereby, one of the biggest hopes of current HSP research regards the use of patient-derived iPS cells to expand basic knowledge on the disease, while simultaneously establishing new therapeutic treatments for both generalized and personalized approaches in daily medical practice.
HIV Reservoirs and Treatment Strategies toward Curing HIV Infection
Authors: Matsuda Kouki , Maeda Kenji
Published: February 2024

Combination antiretroviral therapy (cART) has significantly improved the prognosis of individuals living with human immunodeficiency virus (HIV). Acquired immunodeficiency syndrome has transformed from a fatal disease to a treatable chronic infection. Currently, effective and safe anti-HIV drugs are available. Although cART can reduce viral production in the body of the patient to below the detection limit, it cannot eliminate the HIV provirus integrated into the host cell genome; hence, the virus will be produced again after cART discontinuation. Therefore, research into a cure (or remission) for HIV has been widely conducted. In this review, we focus on drug development targeting cells latently infected with HIV and assess the progress including our current studies, particularly in terms of the “Shock and Kill”, and “Block and Lock” strategies.
Genomic Alterations Affecting Competitive Endogenous RNAs (ceRNAs) and Regulatory Networks (ceRNETs) with Clinical Implications in Triple-Negative Breast Cancer (TNBC)
Authors: Qattan Amal
Published: February 2024

The concept of competitive endogenous RNA regulation has brought on a change in the way we think about transcriptional regulation by miRNA–mRNA interactions. Rather than the relatively simple idea of miRNAs negatively regulating mRNA transcripts, mRNAs and other non-coding RNAs can regulate miRNAs and, therefore, broad networks of gene products through competitive interactions. While this concept is not new, its significant roles in and implications on cancer have just recently come to light. The field is now ripe for the extrapolation of technologies with a substantial clinical impact on cancer. With the majority of the genome consisting of non-coding regions encoding regulatory RNAs, genomic alterations in cancer have considerable effects on these networks that have been previously unappreciated. Triple-negative breast cancer (TNBC) is characterized by high mutational burden, genomic instability and heterogeneity, making this aggressive breast cancer subtype particularly relevant to these changes. In the past few years, much has been learned about the roles of competitive endogenous RNA network regulation in tumorigenesis, disease progression and drug response in triple-negative breast cancer. In this review, we present a comprehensive view of the new knowledge and future perspectives on competitive endogenous RNA networks affected by genomic alterations in triple-negative breast cancer. An overview of the competitive endogenous RNA (ceRNA) hypothesis and its bearing on cellular function and disease is provided, followed by a thorough review of the literature surrounding key competitive endogenous RNAs in triple-negative breast cancer, the genomic alterations affecting them, key disease-relevant molecular and functional pathways regulated by them and the clinical implications and significance of their dysregulation. New knowledge of the roles of these regulatory mechanisms and the current acceleration of research in the field promises to generate insights into the diagnosis, classification and treatment of triple-negative breast cancer through the elucidation of new molecular mechanisms, therapeutic targets and biomarkers.
Clinical Relevance of Tumour-Infiltrating Immune Cells in HER2-Negative Breast Cancer Treated with Neoadjuvant Therapy
Authors: Arqueros Cristina , Gallardo Alberto , Vidal Silvia , Osuna-Gómez Rubén , Tibau Ariadna , Lidia Bell Olga , Ramón y Cajal Teresa , Lerma Enrique , Lobato-Delgado Bárbara , Salazar Juliana , Barnadas Agustí
Published: February 2024

Currently, therapy response cannot be accurately predicted in HER2-negative breast cancer (BC). Measuring stromal tumour-infiltrating lymphocytes (sTILs) and mediators of the tumour microenvironment and characterizing tumour-infiltrating immune cells (TIICs) may improve treatment response in the neoadjuvant setting. Tumour tissue and peripheral blood samples were retrospectively collected from 118 patients, and sTILs were evaluated. Circulating exosomes and myeloid-derived suppressor cells were determined by flow cytometry. TIICs markers (CD4, CD8, CD20, CD1a, and CD68) were assessed immunohistochemically. High sTILs were significantly associated with pathological complete response (pCR; p = 0.048) and event-free survival (EFS; p = 0.027). High-CD68 cells were significantly associated with pCR in triple-negative (TN, p = 0.027) and high-CD1a cells with EFS in luminal-B (p = 0.012) BC. Cluster analyses of TIICs revealed two groups of tumours (C1 and C2) that had different immune patterns and clinical outcomes. An immunoscore based on clinicopathological variables was developed to identify high risk (C1) or low-risk (C2) patients. Additionally, cluster analyses revealed two groups of tumours for both luminal-B and TNBC. Our findings support the association of sTILs with pCR and show an immunological component in a subset of patients with HER2-negative BC. Our immunoscore may be useful for future escalation or de-escalation treatments.
Chimeric Antigen Receptor T Cell Therapy for Hepatocellular Carcinoma: Where Do We Stand?
Authors: Aggeletopoulou Ioanna , Kalafateli Maria , Triantos Christos
Published: February 2024

Hepatocellular carcinoma (HCC) remains a global health challenge that urgently calls for innovative therapeutic strategies. Chimeric antigen receptor T cell (CAR T) therapy has emerged as a promising avenue for HCC treatment. However, the therapeutic efficacy of CAR T immunotherapy in HCC patients is significantly compromised by some major issues including the immunosuppressive environment within the tumor, antigen heterogeneity, CAR T cell exhaustion, and the advanced risk for on-target/off-tumor toxicity. To overcome these challenges, many ongoing preclinical and clinical trials are underway focusing on the identification of optimal target antigens and the decryption of the immunosuppressive milieu of HCC. Moreover, limited tumor infiltration constitutes a significant obstacle of CAR T cell therapy that should be addressed. The continuous effort to design molecular targets for CAR cells highlights the importance for a more practical approach for CAR-modified cell manufacturing. This review critically examines the current landscape of CAR T cell therapy for HCC, shedding light on the changes in innate and adaptive immune responses in the context of HCC, identifying potential CAR T cell targets, and exploring approaches to overcome inherent challenges. Ongoing advancements in scientific research and convergence of diverse treatment modalities offer the potential to greatly enhance HCC patients’ care in the future.
Identification of Molecular Mechanisms in Radiation Cystitis: Insights from RNA Sequencing
Authors: Mota Sabrina , Ward Elijah P. , Bartolone Sarah N. , Chancellor Michael B. , Zwaans Bernadette M. M.
Published: February 2024

Pelvic cancer survivors who were treated with radiation therapy are at risk for developing (hemorrhagic) radiation cystitis (RC) many years after completion of radiation therapy. Patients with RC suffer from lower urinary tract symptoms, including frequency, nocturia, pelvic pain, and incontinence. In advanced stages, hematuria can occur, potentially escalating to life-threatening levels. Current therapeutic options for RC are limited, partly due to ethical concerns regarding bladder biopsy in patients with fragile bladder tissue. This study aimed to leverage our established preclinical model to elucidate the molecular pathways implicated in radiation-induced tissue changes in the bladder. Female C57Bl/6 mice received a single dose of 40 Gy using CT-guided imaging and a two-beam irradiation approach using the SARRP irradiator. Bladders from irradiated and age-matched littermate controls were harvested at 1 week [n = 5/group] or 6 months [n = 5/group] after irradiation, RNA was harvested, and mRNA sequencing was performed at paired-end 150bp on the Illumina NovaSeq6000 with a target of 30 million reads per sample. Following RNA sequencing, thorough bioinformatics analysis was performed using iPathwayGuide v2012 (ADVAITA Bioinformatics). Findings of the RNA sequencing were validated using qPCR analysis. At 1 week post-irradiation, altered gene expression was detected in genes involved in DNA damage response, apoptosis, and transcriptional regulation. By 6 months post-irradiation, significant changes in gene expression were observed in inflammation, collagen catabolism, and vascular health. Affected pathways included the p53, JAK-STAT, and PI3K-Akt pathways. These findings were validated in vivo in bladder tissues from our preclinical model. This is the first study to determine the molecular changes in the bladder in response to radiation treatment. We have successfully pinpointed several pathways and specific genes that undergo modification, thereby contributing to the progression of radiation cystitis. These insights enhance our understanding of the pathophysiology of radiation cystitis and may ultimately pave the way to the identification of potential new therapeutic targets.
IL-12p40 Monomer: A Potential Player in Macrophage Regulation
Authors: Jeong Brian , Pahan Kalipada
Published: February 2024

Macrophages are myeloid phagocytic leukocytes whose functions are to protect against infections, mediate T-cell responses, and maintain tissue homeostasis. IL-12p40 monomer is a cytokine that is largely produced by macrophages, and it has, for the longest time, been considered a largely non-functional cytokine of the IL-12 family. However, new research has emerged that demonstrates that this p40 monomer may play a bigger role in shaping immune environments. To shed light on the specific effects of p40 monomer on macrophages and their surrounding environment, we showed, through cell culture studies, qPCR, ELISA, and immunofluorescence analyses, that the direct administration of recombinant p40 monomer to RAW 264.7 cells and primary lung macrophages stimulated the production of both pro-inflammatory (TNFα) and anti-inflammatory (IL-10) signals. Accordingly, p40 monomer prevented the full pro-inflammatory effects of LPS, and the neutralization of p40 monomer by mAb a3-3a stimulated the pro-inflammatory effects of LPS. Furthermore, we demonstrated that the intranasal administration of p40 monomer upregulated TNFα+IL-10+ macrophages in vivo in the lungs of mice. Collectively, these results indicate an important immunoregulatory function of p40 monomer in the upregulation of both pro- and anti-inflammatory molecules in macrophages.
Analyzing Biomedical Datasets with Symbolic Tree Adaptive Resonance Theory
Authors: Petrenko Sasha , Hier Daniel B. , Bone Mary A. , Obafemi-Ajayi Tayo , Timpson Erik J. , Marsh William E. , Speight Michael , Wunsch Donald C.
Published: February 2024

Biomedical datasets distill many mechanisms of human diseases, linking diseases to genes and phenotypes (signs and symptoms of disease), genetic mutations to altered protein structures, and altered proteins to changes in molecular functions and biological processes. It is desirable to gain new insights from these data, especially with regard to the uncovering of hierarchical structures relating disease variants. However, analysis to this end has proven difficult due to the complexity of the connections between multi-categorical symbolic data. This article proposes symbolic tree adaptive resonance theory (START), with additional supervised, dual-vigilance (DV-START), and distributed dual-vigilance (DDV-START) formulations, for the clustering of multi-categorical symbolic data from biomedical datasets by demonstrating its utility in clustering variants of Charcot–Marie–Tooth disease using genomic, phenotypic, and proteomic data.
Genealogical Data-Driven Visits of Historical Cemeteries
Authors: Lo Duca Angelica , Abrate Matteo , Marchetti Andrea , Moretti Manuela
Published: February 2024

This paper describes the Integration of Archives and Cultural Places (IaCuP) project, which aims to integrate information about a historical cemetery, including its map and grave inventory, with genealogical and documentary knowledge extracted from relevant historical archives. The integrated data are accessible to cemetery visitors through an interactive mobile application, enabling them to navigate a graphical representation of the cemetery while exploring comprehensive visualizations of genealogical data. The basic idea stems from the desire to provide people with access to the rich context of cultural sites, which have often lost their original references over the centuries, making it challenging for individuals today to interpret the meanings embedded within them. The proposed approach leverages large language models (LLMs) to extract information from relevant documents and Web technologies to represent such information as interactive visualizations. As a practical case study, this paper focuses on the Jewish Cemetery in Pisa and the Historical Archives of the Jewish Community in Pisa, working on the genealogical tree of one of the most representative families resting in the cemetery.
E. coli MnmA Is an Fe-S Cluster-Independent 2-Thiouridylase
Authors: Ogunkola Moses , Wolff Lennart , Fenteng Eric Asare , Duffus Benjamin R. , Leimkühler Silke
Published: February 2024

All kingdoms of life have more than 150 different forms of RNA alterations, with tRNA accounting for around 80% of them. These chemical alterations include, among others, methylation, sulfuration, hydroxylation, and acetylation. These changes are necessary for the proper codon recognition and stability of tRNA. In Escherichia coli, sulfur modification at the wobble uridine (34) of lysine, glutamic acid, and glutamine is essential for codon and anticodon binding and prevents frameshifting during translation. Two important proteins that are involved in this thiolation modification are the L-cysteine desulfurase IscS, the initial sulfur donor, and tRNA-specific 2-thiouridylase MnmA, which adenylates and finally transfers the sulfur from IscS to the tRNA. tRNA-specific 2-thiouridylases are iron–sulfur clusters (Fe-S), either dependent or independent depending on the organism. Here, we dissect the controversy of whether the E. coli MnmA protein is an Fe-S cluster-dependent or independent protein. We show that when Fe-S clusters are bound to MnmA, tRNA thiolation is inhibited, making MnmA an Fe-S cluster-independent protein. We further show that 2-thiouridylase only binds to tRNA from its own organism.
Endometallofullerenes in the Gas Phase: Progress and Prospect
Authors: Hou Yameng , Kong Xianglei
Published: February 2024

This review describes the progress of the gas-phase study of endometallofullerenes (EMFs) by mass spectrometry and theoretical calculation over the past 15 years. The attention herein focuses on the gas-phase syntheses, reactions, and generation mechanisms of some novel EMF ions, along with their structures and properties. The highlighted new species include EMFs with small-size carbon cages of C2n (n < 60), multiple metal atoms (Mx@C2n, x ≥ 3), late transition metals, and encaged ionic bonds. Furthermore, the gas-phase experimental and calculational supports for top-down or bottom-up models are summarized and discussed. These gas-phase results not only provide experimental evidence for the existence of related novel EMF species and possible synthesis methods for them, but they also provide new insights about chemical bonds in restricted space. In addition, the opportunities and further development directions faced by gas-phase EMF study are anticipated.