bluuebunny/crossref_metadata_2025 huggingface dataset:
Dual Targeting of DNA Damage Response Proteins Implicated in Cancer Radioresistance
Authors: Vasilopoulos Spyridon N. , Güner Hüseyin , Uça Apaydın Merve , Pavlopoulou Athanasia , Georgakilas Alexandros G.
Published: December 2023

Ionizing radiation can induce different types of DNA lesions, leading to genomic instability and ultimately cell death. Radiation therapy or radiotherapy, a major modality in cancer treatment, harnesses the genotoxic potential of radiation to target and destroy cancer cells. Nevertheless, cancer cells have the capacity to develop resistance to radiation treatment (radioresistance), which poses a major obstacle in the effective management of cancer. It has been shown that administration of platinum-based drugs to cancer patients can increase tumor radiosensitivity, but despite this, it is associated with severe adverse effects. Several lines of evidence support that activation of the DNA damage response and repair machinery in the irradiated cancer cells enhances radioresistance and cellular survival through the efficient repair of DNA lesions. Therefore, targeting of key DNA damage repair factors would render cancer cells vulnerable to the irradiation effects, increase cancer cell killing, and reduce the risk of side effects on healthy tissue. Herein, we have employed a computer-aided drug design approach for generating ab initio a chemical compound with drug-like properties potentially targeting two proteins implicated in multiple DNA repair pathways. The findings of this study could be taken into consideration in clinical decision-making in terms of co-administering radiation with DNA damage repair factor-based drugs.
Effects of Platelet Count on Blood Pressure: Evidence from Observational and Genetic Investigations
Authors: He Zhen , Chen Zekai , de Borst Martin H. , Zhang Qingying , Snieder Harold , Thio Chris H. L. ,   on behalf of the International Consortium of Blood Pressure
Published: December 2023

Platelet count has been associated with blood pressure, but whether this association reflects causality remains unclear. To strengthen the evidence, we conducted a traditional observational analysis in the Lifelines Cohort Study (n = 167,785), and performed bi-directional Mendelian randomization (MR) with summary GWAS data from the UK Biobank (n = 350,475) and the International Consortium of Blood Pressure (ICBP) (n = 299,024). Observational analyses showed positive associations between platelet count and blood pressure (OR = 1.12 per SD, 95% CI: 1.10 to 1.14 for hypertension; B = 0.07, 95% CI: 0.07 to 0.08 for SBP; B = 0.07 per SD, 95% CI: 0.06 to 0.07 for DBP). In MR, a genetically predicted higher platelet count was associated with higher SBP (B = 0.02 per SD, 95% CI = 0.00 to 0.04) and DBP (B = 0.03 per SD, 95% CI = 0.01 to 0.05). IVW models and sensitivity analyses of the association between platelet count and DBP were consistent, but not all sensitivity analyses were statistically significant for the platelet count-SBP relation. Our findings indicate that platelet count has modest but significant effects on SBP and DBP, suggesting causality and providing further insight into the pathophysiology of hypertension.
Marginal Distribution Fitting Method for Modelling Flood Extremes on a River Network
Authors: Skahill Brian , Smith Cole Haden , Russell Brook T.
Published: December 2023

This study utilized a max-stable process (MSP) model with a dependence structure defined via a non-Euclidean distance metric, with the goal of modelling extreme flood data on a river network. The dataset was composed of mean daily discharge observations from 22 United States Geological Survey streamflow gaging stations for river basins in Missouri and Arkansas. The analysis included the application of the elastic-net penalty to automatically build spatially varying trend surfaces to model the marginal distributions. The dependence model accounted for the river distance between hydrologically connected gaging sites and the hydrologic distance, defined as the Euclidean distance between the centers of site’s associated drainage areas, for all stations. Modelling the marginal distributions and spatial dependence among the extremes are two key components for spatially modelling extremes. Among the 16 covariates evaluated for marginal fitting, 7 were selected to spatially model the generalized extreme value (GEV) location parameter (for each gaging station’s contributing drainage basin, its outlet elevation, centroid x coordinate, centroid elevation, area, average basin width, elevation range, and median land surface slope). The three covariates selected for the GEV scale parameter included the area, average basin width, and median land surface slope. The GEV shape parameter was assumed to be constant throughout the entire study area. Comparisons of estimates obtained from the spatial covariate model with their corresponding “at-site” estimates resulted in computed values of 0.95, 0.95, 0.94 and 0.85, 0.84, 0.90 for the coefficient of determination, Nash–Sutcliffe efficiency, and Kling–Gupta efficiency for the GEV location and scale parameters, respectively. Brown–Resnick MSP models were fit to independent multivariate events extracted from a set of common discharge data, transformed to unit Fréchet margins while considering different permutations of the non-Euclidean dependence model. Each of the fitted model’s log-likelihood values indicated improved fits when using hydrologic distance rather than Euclidean distance. They also demonstrated that accounting for flow-connected dependence and anisotropy further improved model fit. In this study, the results from both parts were illustrative; however, further research with larger datasets and more heterogeneous systems is recommended.
Translation and Psychometric Properties of the Portuguese Version of the Timed Instrumental Activities of Daily Living (TIADL)
Authors: Galhardas Luis , Raimundo Armando , Marmeleira José
Published: December 2023

(1) Background: to examine the psychometric properties of the Portuguese version of the Timed Instrumental Activities of Daily Living (TIADL) in nursing home residents. (2) Methods: Fifty-two participants (85.8 ± 4.2 years) were assessed on two occasions, 10–14 days apart. The same rater administered all assessments. Internal consistency was analysed through Cronbach’s α. The reliability was estimated using the intraclass correlation coefficients (ICCs), and the standard error of the mean (SEM) was used to estimate the minimal detectable change (MDC). Construct validity was determined by Spearman’s correlation coefficients. (3) Results: For internal consistency, Cronbach’s α (0.81) revealed high internal reliability. All of the subtests demonstrated good or excellent reliability and also presented acceptable measurement precision, considering the criterion SEM < SD/2. According to Spearman’s rho, correlations with the Portuguese version of the TIADL, the Useful Field of View test, and semantic and phonemic fluency tests were significant, with moderate positive and negative correlations (0.4 < rs < 0.69). (4) Conclusions: The Portuguese version of the TIADL had good to excellent test–retest reliability (ICC > 0.90) and acceptable measurement precision. This test could be a valuable clinical tool for assessing actual performance in instrumental activities of daily living in nursing home residents.
The Role of Resilience in the Relationship between Sociodemographic, Clinical Characteristics, and Social Support among Breast Cancer Patients in Serbia
Authors: Tomić Sanja D , Malenković Goran , Šljivo Armin , Mujičić Ermina , Tomić Slobodan
Published: December 2023

Background. The management of breast cancer treatments within the limitations of family, social, and professional life is emotionally burdening and negatively affects physical, psychological, and social well-being, reducing the overall quality of life of patients and their families. Methods: This cross-sectional descriptive–analytical study was conducted from March to August 2023 at the “Dr. Radivoj Simonović” General Hospital in Sombor. A total of 236 breast cancer patients participated in this study. The research was conducted using the following instruments: a questionnaire on sociodemographic and clinical characteristics of patients, the Berlin Social-Support Scales—for assessing social support—and the Connor–Davidson Resilience Scale—for assessing resilience. This study aimed to determine the predictors and levels of social support and resilience of breast cancer patients. We also wanted to examine whether resilience is a mediator between patients’ sociodemographic and clinical characteristics and levels of social support. Results: The total average value of social support was 3.51 ± 0.63, while on the resilience scale, the respondents achieved a total average score of 52.2 ± 9.63. Perceived and actually received social support of breast cancer patients were positively correlated with resilience [p < 0.01], while no statistically significant correlations were found for the need for support and satisfaction. The sets of predictors can significantly predict their effects on all types of perceived social support (emotional social support: 9%; perceived instrumental social support: 9%) and all types of received social support (actually received emotional social support: 8%; actually received instrumental social support: 7%; actually received informational social support: 8%). There is a potential mediating role of resilience in relation to sociodemographic factors, clinical characteristics, and the need for support. Conclusion: This study confirms that a strong connection exists between social support and resilience. However, the analysis did not confirm the mediating role of resilience between the sociodemographic and clinical characteristics on the one hand and social support on the other.
Instruments of Child-to-Parent Violence: Systematic Review and Meta-Analysis
Authors: Burgos-Benavides Luis , Cano-Lozano M. Carmen , Ramírez Andrés , Rodríguez-Díaz Francisco Javier
Published: December 2023

This systematic review and reliability generalization meta-analysis synthesized psychometric literature on instrumentation assessing child-to-parent violence published through September 2023 across four databases. In the screening, we identified studies reporting Cronbach’s alpha internal consistency estimates for the child-to-parent violence scales. The eligible reliability coefficients ranged from 0.610 to 0.930, mostly exceeding the minimum threshold of 0.700. Random-effects models calculated pooled Cronbach’s alphas separately for global, father-specific, and mother-specific subscales. The results demonstrated cumulative values of 0.83 (global: standard error = 0.0129), 0.800 (fathers: standard error = 0.0203), and 0.81 (mothers: standard error = 0.0179), denoting largely adequate reliability. However, significant between-study heterogeneity was observed. While the mean alpha levels seem acceptable for most tools, substantial variability coupled with the possibility of some studies violating reliability assumptions indicates that a conservative interpretation is warranted. Ongoing scale refinement and additional psychometric evaluations will strengthen the rigor methodology in this developing research domain. However, these results should be interpreted with caution, as there is a high level of heterogeneity, and it is possible that some studies have not verified the assumptions underlying Cronbach’s alpha.
Is a Maximal Strength-Training Program Effective on Physical Fitness, Injury Incidence, and Injury Burden in Semi-Professional Soccer Players? A Randomized Controlled Trial
Authors: Durán-Custodio Roberto , Castillo Daniel , Raya-González Javier , Yanci Javier
Published: December 2023

The aims of the study were to analyze the effects of a 12-week maximal strength- training program on injury incidence, injury burden, and physical fitness in semi-professional soccer players and to compare the perceived exertion load and well-being state between injured and non-injured soccer players. Twenty semi-professional male soccer players participated in this study. Participants were randomly allocated to an experimental group (EG, n = 10 players), who performed a maximal strength-training program, or to a control group (CG, n = 10 players), who only performed their regular soccer training. Physical fitness was measured at baseline and after the training program. In addition, the injury incidence, burden, training/match load, and the state of well-being of the players were recorded. The EG showed significant improvements in vertical jumps, change in direction ability, linear sprints, repeated sprint ability, isometric strength (p < 0.003; effect size = 1.78–11.86), and quadriceps–hamstring imbalance in both legs (p < 0.001; effect size = 2.37–3.71) in comparison to the CG. In addition, the EG players showed a significantly (p < 0.05) lower injury burden (p < 0.001, relative risk = 5.05, 95% confidence interval = 3.27–7.79). This study demonstrated the beneficial effects of a 12-week maximal strength-training program on physical fitness attributes and injury burden in semi-professional soccer players.
Dual-Specificity Phosphatases in Regulation of Tumor-Associated Macrophage Activity
Authors: Patysheva Marina R. , Prostakishina Elizaveta A. , Budnitskaya Arina A. , Bragina Olga D. , Kzhyshkowska Julia G.
Published: December 2023

The regulation of protein kinases by dephosphorylation is a key mechanism that defines the activity of immune cells. A balanced process of the phosphorylation/dephosphorylation of key protein kinases by dual-specificity phosphatases is required for the realization of the antitumor immune response. The family of dual-specificity phosphatases is represented by several isoforms found in both resting and activated macrophages. The main substrate of dual-specificity phosphatases are three components of mitogen-activated kinase signaling cascades: the extracellular signal-regulated kinase ERK1/2, p38, and Janus kinase family. The results of the study of model tumor-associated macrophages supported the assumption of the crucial role of dual-specificity phosphatases in the formation and determination of the outcome of the immune response against tumor cells through the selective suppression of mitogen-activated kinase signaling cascades. Since mitogen-activated kinases mostly activate the production of pro-inflammatory mediators and the antitumor function of macrophages, the excess activity of dual-specificity phosphatases suppresses the ability of tumor-associated macrophages to activate the antitumor immune response. Nowadays, the fundamental research in tumor immunology is focused on the search for novel molecular targets to activate the antitumor immune response. However, to date, dual-specificity phosphatases received limited discussion as key targets of the immune system to activate the antitumor immune response. This review discusses the importance of dual-specificity phosphatases as key regulators of the tumor-associated macrophage function.
Biological Diagnosis of Alzheimer’s Disease Based on Amyloid Status: An Illustration of Confirmation Bias in Medical Research?
Authors: Souchet Benoît , Michaïl Alkéos , Billoir Baptiste , Braudeau Jérôme
Published: December 2023

Alzheimer’s disease (AD) was first characterized by Dr. Alois Alzheimer in 1906 by studying a demented patient and discovering cerebral amyloid plaques and neurofibrillary tangles. Subsequent research highlighted the roles of Aβ peptides and tau proteins, which are the primary constituents of these lesions, which led to the amyloid cascade hypothesis. Technological advances, such as PET scans using Florbetapir, have made it possible to visualize amyloid plaques in living patients, thus improving AD’s risk assessment. The National Institute on Aging and the Alzheimer’s Association introduced biological diagnostic criteria in 2011, which underlined the amyloid deposits diagnostic value. However, potential confirmation bias may have led researchers to over-rely on amyloid markers independent of AD’s symptoms, despite evidence of their limited specificity. This review provides a critical examination of the current research paradigm in AD, including, in particular, the predominant focus on amyloid and tau species in diagnostics. We discuss the potential multifaceted consequences of this approach and propose strategies to mitigate its overemphasis in the development of new biomarkers. Furthermore, our study presents comprehensive guidelines aimed at enhancing the creation of biomarkers for accurately predicting AD dementia onset. These innovations are crucial for refining patient selection processes in clinical trial enrollment and for the optimization of therapeutic strategies. Overcoming confirmation bias is essential to advance the diagnosis and treatment of AD and to move towards precision medicine by incorporating a more nuanced understanding of amyloid biomarkers.
Inflammation in Hypervolemic Hemodialysis Patients: The Roles of RelB and Caspase-4
Authors: Ulrich Christof , Canim Zeynep , Herberger Eva , Girndt Matthias , Fiedler Roman
Published: December 2023

Hypervolemia is associated with inflammation in hemodialysis (HD) patients. How hypervolemia triggers inflammation is not entirely known. We initiated a cross-sectional study enrolling 40 hemodialysis patients who were categorized into normovolemic (N; 23) and hypervolemic (H; 17) groups by bioimpedance measurement. A caspase activity assay in combination with a specific caspase-4 inhibitor was used to detect caspase-4 activity in isolated peripheral blood mononuclear cells (PBMCs). Transcription factors RelA (pS529) and RelB (pS552) were analyzed by phospho-flow cytometry. Serum endotoxins were detected by an amebocyte lysate-based assay, and IL-6 (interleukin-6) and TNF-α (Tumor necrosis factor-α) gene expression were detected using the ELISA technique. Hypervolemic patients were older, more frequently had diabetes and showed increased CRP and IL-6 levels. Caspase-4 activity, which is linked to intracellular endotoxin detection, was significantly elevated in H patients. While the frequency of RelA-expressing immune cells and the expression density in these cells did not differ, the monocytic frequency of cells positively stained for RelB (pS552) was significantly decreased in H patients. Increased caspase-4 activity in H patients may indicate a cause of inflammation in H patients. The post-translational modification of RelB (pS552) is linked to downregulation of NF-kB activity and may indicate the resolution of inflammation, which is more distinct in N patients compared to H patients. Therefore, both higher inflammatory loads and lower inflammatory resolution capacities are characteristics of H patients.
Clonality and Diversity in the Soft Rot Dickeya solani Phytopathogen
Authors: Van Gijsegem Frédérique , Portier Perrine , Taghouti Géraldine , Pédron Jacques
Published: December 2023

Bacterial diversity analyses often suffer from a bias due to sampling only from a limited number of hosts or narrow geographic locations. This was the case for the phytopathogenic species Dickeya solani, whose members were mainly isolated from a few hosts–potato and ornamentals–and from the same geographical area–Europe and Israel, which are connected by seed trade. Most D. solani members were clonal with the notable exception of the potato isolate RNS05.1.2A and two related strains that are clearly distinct from other D. solani genomes. To investigate if D. solani genomic diversity might be broadened by analysis of strains isolated from other environments, we analysed new strains isolated from ornamentals and from river water as well as strain CFBP 5647 isolated from tomato in the Caribbean island Guadeloupe. While water strains were clonal to RNS05.1.2A, the Caribbean tomato strain formed a third clade. The genomes of the three clades are highly syntenic; they shared almost 3900 protein families, and clade-specific genes were mainly included in genomic islands of extrachromosomal origin. Our study thus revealed both broader D. solani diversity with the characterisation of a third clade isolated in Latin America and a very high genomic conservation between clade members.
Impact of Conventional and Potential New Metal-Based Drugs on Lipid Metabolism in Osteosarcoma MG-63 Cells
Authors: Bispo Daniela S. C. , Correia Marlene , Carneiro Tatiana J. , Martins Ana S. , Reis Aliana A. N. , Carvalho Ana L. M. Batista de , Marques Maria P. M. , Gil Ana M.
Published: December 2023

This work investigated the mechanisms of action of conventional drugs, cisplatin and oxaliplatin, and the potentially less deleterious drug Pd2Spermine (Spm) and its Pt(II) analog, against osteosarcoma MG-63 cells, using nuclear-magnetic-resonance metabolomics of the cellular lipidome. The Pt(II) chelates induced different responses, namely regarding polyunsaturated-fatty-acids (increased upon cisplatin), suggesting that cisplatin-treated cells have higher membrane fluidity/permeability, thus facilitating cell entry and justifying higher cytotoxicity. Both conventional drugs significantly increased triglyceride levels, while Pt2Spm maintained control levels; this may reflect enhanced apoptotic behavior for conventional drugs, but not for Pt2Spm. Compared to Pt2Spm, the more cytotoxic Pd2Spm (IC50 comparable to cisplatin) induced a distinct phospholipids profile, possibly reflecting enhanced de novo biosynthesis to modulate membrane fluidity and drug-accessibility to cells, similarly to cisplatin. However, Pd2Spm differed from cisplatin in that cells had equivalent (low) levels of triglycerides as Pt2Spm, suggesting the absence/low extent of apoptosis. Our results suggest that Pd2Spm acts on MG-63 cells mainly through adaptation of cell membrane fluidity, whereas cisplatin seems to couple a similar effect with typical signs of apoptosis. These results were discussed in articulation with reported polar metabolome adaptations, building on the insight of these drugs’ mechanisms, and particularly of Pd2Spm as a possible cisplatin substitute.
Trimethylamine N-Oxide as a Mediator Linking Peripheral to Central Inflammation: An In Vitro Study
Authors: Janeiro Manuel H. , Solas Maite , Orbe Josune , Rodríguez Jose A. , Sanchez de Muniain Leyre , Escalada Paula , Yip Ping K. , Ramirez Maria J.
Published: December 2023

In this study, the plausible role of trimethylamine N-oxide (TMAO), a microbiota metabolite, was investigated as a link between peripheral inflammation and the inflammation of the central nervous system using different cell lines. TMAO treatment favored the differentiation of adipocytes from preadipocytes (3T3-L1 cell line). In macrophages (RAW 264.7 cell line), which infiltrate adipose tissue in obesity, TMAO increased the expression of pro-inflammatory cytokines. The treatment with 200 μM of TMAO seemed to disrupt the blood–brain barrier as it induced a significant decrease in the expression of occludin in hCMECs. TMAO also increased the expression of pro-inflammatory cytokines in primary neuronal cultures, induced a pro-inflammatory state in primary microglial cultures, and promoted phagocytosis. Data obtained from this project suggest that microbial dysbiosis and increased TMAO secretion could be a key link between peripheral and central inflammation. Thus, TMAO-decreasing compounds may be a promising therapeutic strategy for neurodegenerative diseases.
Identification of Differential Circular RNA Expression Profiles and Functional Networks in Human Macrophages Induced by Virulent and Avirulent Mycobacterium tuberculosis Strains
Authors: Zhu Yifan , Kong Delai , Wang Zijian , Li Ting , Tang Tian , Peng Yongchong , Hu Changmin , Chao Jin , Chen Huanchun , Chen Yingyu , Guo Aizhen
Published: December 2023

Circular RNAs (circRNAs) are noncoding RNAs with diverse functions. However, most Mycobacterium tuberculosis (M.tb)-related circRNAs remain undiscovered. In this study, we infected THP-1 cells with virulent and avirulent M.tb strains and then sequenced the cellular circRNAs. Bioinformatic analysis predicted 58,009 circRNAs in all the cells. In total, 2035 differentially expressed circRNAs were identified between the M.tb-infected and uninfected THP-1 cells and 1258 circRNAs were identified in the virulent and avirulent M.tb strains. Further, the top 10 circRNAs were confirmed by Sanger sequencing, among which four circRNAs, namely circSOD2, circCHSY1, circTNFRSF21, and circDHTKD1, which were highly differentially expressed in infected cells compared with those in uninfected cells, were further confirmed by ring formation, specific primers, and RNase R digestion. Next, circRNA-miRNA-mRNA subnetworks were constructed, such as circDHTKD1/miR-660-3p/IL-12B axis. Some of the individual downstream genes, such as miR-660-3p and IL-12B, were previously reported to be associated with cellular defense against pathological processes induced by M.tb infection. Because macrophages are important immune cells and the major host cells of M.tb, these findings provide novel ideas for exploring the M.tb pathogenesis and host defense by focusing on the regulation of circRNAs during M.tb infection.
The Role of Transcription Factors in the Loss of Inter-Chromosomal Co-Expression for Breast Cancer Subtypes
Authors: Trujillo-Ortíz Rodrigo , Espinal-Enríquez Jesús , Hernández-Lemus Enrique
Published: December 2023

Breast cancer encompasses a diverse array of subtypes, each exhibiting distinct clinical characteristics and treatment responses. Unraveling the underlying regulatory mechanisms that govern gene expression patterns in these subtypes is essential for advancing our understanding of breast cancer biology. Gene co-expression networks (GCNs) help us identify groups of genes that work in coordination. Previous research has revealed a marked reduction in the interaction of genes located on different chromosomes within GCNs for breast cancer, as well as for lung, kidney, and hematopoietic cancers. However, the reasons behind why genes on the same chromosome often co-express remain unclear. In this study, we investigate the role of transcription factors in shaping gene co-expression networks within the four main breast cancer subtypes: Luminal A, Luminal B, HER2+, and Basal, along with normal breast tissue. We identify communities within each GCN and calculate the transcription factors that may regulate these communities, comparing the results across different phenotypes. Our findings indicate that, in general, regulatory behavior is to a large extent similar among breast cancer molecular subtypes and even in healthy networks. This suggests that transcription factor motif usage does not fully determine long-range co-expression patterns. Specific transcription factor motifs, such as CCGGAAG, appear frequently across all phenotypes, even involving multiple highly connected transcription factors. Additionally, certain transcription factors exhibit unique actions in specific subtypes but with limited influence. Our research demonstrates that the loss of inter-chromosomal co-expression is not solely attributable to transcription factor regulation. Although the exact mechanism responsible for this phenomenon remains elusive, this work contributes to a better understanding of gene expression regulatory programs in breast cancer.
Altering Calcium Sensitivity in Heart Failure: A Crossroads of Disease Etiology and Therapeutic Innovation
Authors: Saad Nancy S. , Mashali Mohammed A. , Repas Steven J. , Janssen Paul M. L.
Published: December 2023

Heart failure (HF) presents a significant clinical challenge, with current treatments mainly easing symptoms without stopping disease progression. The targeting of calcium (Ca2+) regulation is emerging as a key area for innovative HF treatments that could significantly alter disease outcomes and enhance cardiac function. In this review, we aim to explore the implications of altered Ca2+ sensitivity, a key determinant of cardiac muscle force, in HF, including its roles during systole and diastole and its association with different HF types—HF with preserved and reduced ejection fraction (HFpEF and HFrEF, respectively). We further highlight the role of the two rate constants kon (Ca2+ binding to Troponin C) and koff (its dissociation) to fully comprehend how changes in Ca2+ sensitivity impact heart function. Additionally, we examine how increased Ca2+ sensitivity, while boosting systolic function, also presents diastolic risks, potentially leading to arrhythmias and sudden cardiac death. This suggests that strategies aimed at moderating myofilament Ca2+ sensitivity could revolutionize anti-arrhythmic approaches, reshaping the HF treatment landscape. In conclusion, we emphasize the need for precision in therapeutic approaches targeting Ca2+ sensitivity and call for comprehensive research into the complex interactions between Ca2+ regulation, myofilament sensitivity, and their clinical manifestations in HF.
Copper in Gynecological Diseases
Authors: Conforti Rocío A. , Delsouc María B. , Zorychta Edith , Telleria Carlos M. , Casais Marilina
Published: December 2023

Copper (Cu) is an essential micronutrient for the correct development of eukaryotic organisms. This metal plays a key role in many cellular and physiological activities, including enzymatic activity, oxygen transport, and cell signaling. Although the redox activity of Cu is crucial for enzymatic reactions, this property also makes it potentially toxic when found at high levels. Due to this dual action of Cu, highly regulated mechanisms are necessary to prevent both the deficiency and the accumulation of this metal since its dyshomeostasis may favor the development of multiple diseases, such as Menkes’ and Wilson’s diseases, neurodegenerative diseases, diabetes mellitus, and cancer. As the relationship between Cu and cancer has been the most studied, we analyze how this metal can affect three fundamental processes for tumor progression: cell proliferation, angiogenesis, and metastasis. Gynecological diseases are characterized by high prevalence, morbidity, and mortality, depending on the case, and mainly include benign and malignant tumors. The cellular processes that promote their progression are affected by Cu, and the mechanisms that occur may be similar. We analyze the crosstalk between Cu deregulation and gynecological diseases, focusing on therapeutic strategies derived from this metal.
The Utility of Noninvasive Urinary Biomarkers for the Evaluation of Vesicoureteral Reflux in Children
Authors: Colceriu Marius-Cosmin , Aldea Paul Luchian , Boț (Răchişan) Andreea-Liana , Bulată Bogdan , Delean Dan , Grama Alina , Mititelu Alexandra , Decea Roxana Maria , Sevastre-Berghian Alexandra , Clichici Simona , Pop Tudor Lucian , Mocan Teodora
Published: December 2023

Vesicoureteral reflux (VUR) is one of the most important disorders encountered in pediatric nephrology due to its frequency and potential evolution to chronic kidney disease (CKD). The aim of our study was to identify noninvasive and easy-to-determine urinary markers to facilitate the diagnosis and staging of VUR. We performed a cross-section study including 39 patients with VUR followed over three years (August 2021–September 2023) and 39 children without urinary disorder (the control group). We measured the urinary concentration of interleukin-6 (IL-6), cathelicidin (LL-37), and neutrophil gelatinase-associated lipocalin (NGAL) in VUR and healthy controls. Moreover, we analyzed the correlation between these biomarkers and the presence of renal scars (RS), reflux nephropathy (RN), and CKD. The NGAL concentrations were significantly higher in patients with VUR than in the controls (p = 0.02). Regarding the severity of the reflux, NGAL/creatinine and LL-37/creatinine were positively correlated with severe reflux (p = 0.04, respectively, p = 0.02). In patients with VUR and RS, LL-37/creatinine was significantly lower (p = 0.01). LL-37/creatinine with an AUC of 0.71 and NGAL/creatinine with an AUC of 0.72 could be acceptable diagnostic tests for severe VUR. In conclusion, urinary IL-6, NGAL, and LL-37 could serve as valuable markers for diagnosing and predicting outcomes in patients with VUR and RN.
Mesenchymal–Epithelial Transition Kinase Inhibitor Therapy in Patients with Advanced Papillary Renal-Cell Carcinoma: A Systematic Review and Meta-Analysis
Authors: Moraes Francisco Cezar Aquino de , Vilbert Maysa , Alves Vinícius Freire Costa , de Oliveira Almeida Gustavo , Priantti Jonathan N. , Madeira Thiago , Stecca Carlos , Fernandes Marianne Rodrigues , dos Santos Ney Pereira Carneiro
Published: December 2023

Papillary subtypes of renal-cell carcinoma (pRCC) represent 10–15% of the cases and commonly have MET alterations. This systematic review and single-arm meta-analysis evaluated MET inhibitor therapy (METi) efficacy and safety in adults with confirmed advanced pRCC. The search strategy included PubMed, Web-of-science, Cochrane, and Scopus. We used the DerSimonian/Laird random effect model for all analyses; p-value < 5% was considered significant, and heterogeneity was assessed with I2. Three clinical trials and six cohort studies were included with 504 patients; 31% were MET-driven. Our pooled analysis demonstrated an objective response rate (ORR) in MET-driven, MET-independent, and overall patients of: 36% (95%CI: 10–62), 0% (95%CI: 0–3), and 21% (95%CI: 1–41), respectively. One-year disease control and progression-free survival rates were, respectively, 70% (95%CI: 52–88) and 15% (95%CI: 10–20). Twelve- and twenty-four-month survival rates were, respectively, 43% (95%CI: 23–64) and 10% (95%CI: 0–30). The prevalence of adverse events of any grade and grades 3–5 were 96% (95%CI: 91–100) and 44% (95%CI: 37–50), respectively. We suggest METi has anti-tumor activity and is tolerable in patients with advanced pRCC.
How Neutrophils Shape the Immune Response: Reassessing Their Multifaceted Role in Health and Disease
Authors: Shafqat Areez , Khan Jibran Ahmad , Alkachem Aghiad Yahya , Sabur Homaira , Alkattan Khaled , Yaqinuddin Ahmed , Sing Garwin Kim
Published: December 2023

Neutrophils are the most abundant of the circulating immune cells and are the first to be recruited to sites of inflammation. Neutrophils are a heterogeneous group of immune cells from which are derived extracellular traps (NETs), reactive oxygen species, cytokines, chemokines, immunomodulatory factors, and alarmins that regulate the recruitment and phenotypes of neutrophils, macrophages, dendritic cells, T cells, and B cells. In addition, cytokine-stimulated neutrophils can express class II major histocompatibility complex and the internal machinery necessary for successful antigen presentation to memory CD4+ T cells. This may be relevant in the context of vaccine memory. Neutrophils thus emerge as orchestrators of immune responses that play a key role in determining the outcome of infections, vaccine efficacy, and chronic diseases like autoimmunity and cancer. This review aims to provide a synthesis of current evidence as regards the role of these functions of neutrophils in homeostasis and disease.
Joint QTL Mapping and Transcriptome Sequencing Analysis Reveal Candidate Genes for Salinity Tolerance in Oryza sativa L. ssp. Japonica Seedlings
Authors: Li Shuangshuang , Xu Shanbin , Zheng Jie , Du Haoqiang , Li Chong , Shen Shen , Liang Shaoming , Wang Jingguo , Liu Hualong , Yang Luomiao , Xin Wei , Jia Yan , Zou Detang , Zheng Hongliang
Published: December 2023

Salinity stress is one of the major abiotic stresses affecting crop growth and production. Rice is an important food crop in the world, but also a salt-sensitive crop, and the rice seedling stage is the most sensitive to salt stress, which directly affects the final yield formation. In this study, two RIL populations derived from the crosses of CD (salt-sensitive)/WD (salt-tolerant) and KY131 (salt-sensitive)/XBJZ (salt-tolerant) were used as experimental materials, and the score of salinity toxicity (SST), the relative shoot length (RSL), the relative shoot fresh weight (RSFW), and the relative shoot dry weight (RSDW) were used for evaluating the degree of tolerance under salt stress in different lines. The genetic linkage map containing 978 and 527 bin markers were constructed in two RIL populations. A total of 14 QTLs were detected on chromosomes 1, 2, 3, 4, 7, 9, 10, 11, and 12. Among them, qSST12-1, qSST12-2, and qRSL12 were co-localized in a 140-kb overlap interval on chromosome 12, which containing 16 candidate genes. Furthermore, transcriptome sequencing and qRT-PCR were analyzed in CD and WD under normal and 120 mM NaCl stress. LOC_Os12g29330, LOC_Os12g29350, LOC_Os12g29390, and LOC_Os12g29400 were significantly induced by salt stress in both CD and WD. Sequence analysis showed that LOC_Os12g29400 in the salt-sensitive parents CD and KY131 was consistent with the reference sequence (Nipponbare), whereas the salt-tolerant parents WD and XBJZ differed significantly from the reference sequence both in the promoter and exon regions. The salt-tolerant phenotype was identified by using two T3 homozygous mutant plants of LOC_Os12g29400; the results showed that the score of salinity toxicity (SST) of the mutant plants (CR-3 and CR-5) was significantly lower than that of the wild type, and the seedling survival rate (SSR) was significantly higher than that of the wild type, which indicated that LOC_Os12g29400 could negatively regulate the salinity tolerance of rice at the seedling stage. The results lay a foundation for the analysis of the molecular mechanism of rice salinity tolerance and the cultivation of new rice varieties.
Severity of Peripheral Infection Differentially Affects Brain Functions in Mice via Microglia-Dependent and -Independent Mechanisms
Authors: Le Yen-Phung , Saito Kozo , Parajuli Bijay , Sakai Kent , Kubota Yuto , Miyakawa Miho , Shinozaki Youichi , Shigetomi Eiji , Koizumi Schuichi
Published: December 2023

Peripheral infection induces inflammation in peripheral tissues and the brain, impacting brain function. Glial cells are key players in this process. However, the effects of peripheral infection on glial activation and brain function remain unknown. Here, we showed that varying degrees of peripheral infection had different effects on the regulation of brain functions by microglia-dependent and -independent mechanisms. Acute mild infection (one-day LPS challenge: 1LPS) exacerbated middle cerebral artery occlusion (MCAO) injury, and severe infection (four-day LPS challenge: 4LPS) for one week suppressed it. MCAO injury was assessed by triphenyltetrazolium chloride staining. We observed early activation of microglia in the 1LPS and 4LPS groups. Depleting microglia with a colony-stimulating factor-1 receptor (CSF1R) antagonist had no effect on 1LPS-induced brain injury exacerbation but abolished 4LPS-induced protection, indicating microglial independence and dependence, respectively. Microglia-independent exacerbation caused by 1LPS involved peripheral immune cells including macrophages. RNA sequencing analysis of 4LPS-treated microglia revealed increased factors related to anti-inflammatory and neuronal tissue repair, suggesting their association with the protective effect. In conclusion, varying degrees of peripheral inflammation had contradictory effects (exacerbation vs. protection) on MCAO, which may be attributed to microglial dependence. Our findings highlight the significant impact of peripheral infection on brain function, particularly in relation to glial cells.
Effects of Radioactive 56MnO2 Particle Inhalation on Mouse Lungs: A Comparison between C57BL and BALB/c
Authors: Abishev Zhaslan , Ruslanova Bakhyt , Apbassova Saulesh , Shabdarbayeva Dariya , Chaizhunussova Nailya , Dyusupov Altai , Azhimkhanov Almas , Zhumadilov Kassym , Stepanenko Valeriy , Ivanov Sergey , Shegay Peter , Kaprin Andrey , Hoshi Masaharu , Fujimoto Nariaki
Published: December 2023

The effects of residual radiation from atomic bombs have been considered to be minimal because of its low levels of external radioactivity. However, studies involving atomic bomb survivors exposed to only residual radiation in Hiroshima and Nagasaki have indicated possible adverse health effects. Thus, we investigated the biological effects of radioactive dust of manganese dioxide 56 (56MnO2), a major radioisotope formed in soil by neutron beams from a bomb. Previously, we investigated C57BL mice exposed to 56MnO2 and found pulmonary gene expression changes despite low radiation doses. In this study, we examined the effects in a radiation-sensitive strain of mice, BALB/c, and compared them with those in C57BL mice. The animals were exposed to 56MnO2 particles at two radioactivity levels and examined 3 and 65 days after exposure. The mRNA expression of pulmonary pathophysiology markers, including Aqp1, Aqp5, and Smad7, and radiation-sensitive genes, including Bax, Phlda3, and Faim3, was determined in the lungs. The radiation doses absorbed in the lungs ranged from 110 to 380 mGy; no significant difference was observed between the two strains. No exposure-related pathological changes were observed in the lungs of any group. However, the mRNA expression of Aqp1 was significantly elevated in C57BL mice but not in BALB/c mice 65 days after exposure, whereas no changes were observed in external γ-rays (2 Gy) in either strain. In contrast, Faim3, a radiation-dependently downregulated gene, was reduced by 56MnO2 exposure in BALB/c mice but not in C57BL mice. These data demonstrate that inhalation exposure to 56MnO2 affected the expression of pulmonary genes at doses <380 mGy, which is comparable to 2 Gy of external γ-irradiation, whereas the responses differed between the two mouse strains.
Cardiogenic Shock Integrated PHenotyping for Event Reduction: A Pilot Metabolomics Analysis
Authors: Morici Nuccia , Frigerio Gianfranco , Campolo Jonica , Fustinoni Silvia , Sacco Alice , Garatti Laura , Villanova Luca , Tavazzi Guido , Kapur Navin , Pappalardo Federico
Published: December 2023

Cardiogenic shock (CS) portends a dismal prognosis if hypoperfusion triggers uncontrolled inflammatory and metabolic derangements. We sought to investigate metabolomic profiles and temporal changes in IL6, Ang-2, and markers of glycocalyx perturbation from admission to discharge in eighteen patients with heart failure complicated by CS (HF-CS). Biological samples were collected from 18 consecutive HF-CS patients at admission (T0), 48 h after admission (T1), and at discharge (T2). ELISA analytical techniques and targeted metabolomics were performed Seven patients (44%) died at in-hospital follow-up. Among the survivors, IL-6 and kynurenine were significantly reduced at discharge compared to baseline. Conversely, the amino acids arginine, threonine, glycine, lysine, and asparagine; the biogenic amine putrescine; multiple sphingolipids; and glycerophospholipids were significantly increased. Patients with HF-CS have a metabolomic fingerprint that might allow for tailored treatment strategies for the patients’ recovery or stabilization.
Pathogenic Variants in USH1G/SANS Alter Protein Interaction with Pre-RNA Processing Factors PRPF6 and PRPF31 of the Spliceosome
Authors: Fritze Jacques S. , Stiehler Felizitas F. , Wolfrum Uwe
Published: December 2023

Pre-mRNA splicing is an essential process orchestrated by the spliceosome, a dynamic complex assembled stepwise on pre-mRNA. We have previously identified that USH1G protein SANS regulates pre-mRNA splicing by mediating the intranuclear transfer of the spliceosomal U4/U6.U5 tri-snRNP complex. During this process, SANS interacts with the U4/U6 and U5 snRNP-specific proteins PRPF31 and PRPF6 and regulates splicing, which is disturbed by variants of USH1G/SANS causative for human Usher syndrome (USH), the most common form of hereditary deaf–blindness. Here, we aim to gain further insights into the molecular interaction of the splicing molecules PRPF31 and PRPF6 to the CENTn domain of SANS using fluorescence resonance energy transfer assays in cells and in silico deep learning-based protein structure predictions. This demonstrates that SANS directly binds via two distinct conserved regions of its CENTn to the two PRPFs. In addition, we provide evidence that these interactions occur sequentially and a conformational change of an intrinsically disordered region to a short α-helix of SANS CENTn2 is triggered by the binding of PRPF6. Furthermore, we find that pathogenic variants of USH1G/SANS perturb the binding of SANS to both PRPFs, implying a significance for the USH1G pathophysiology.
The Potential Role of Gossypetin in the Treatment of Diabetes Mellitus and Its Associated Complications: A Review
Authors: Naidoo Karishma , Khathi Andile
Published: December 2023

Type 2 diabetes mellitus (T2DM) is a metabolic disorder caused by insulin resistance and dysfunctional beta (β)-cells in the pancreas. Hyperglycaemia is a characteristic of uncontrolled diabetes which eventually leads to fatal organ system damage. In T2DM, free radicals are continuously produced, causing extensive tissue damage and subsequent macro-and microvascular complications. The standard approach to managing T2DM is pharmacological treatment with anti-diabetic medications. However, patients’ adherence to treatment is frequently decreased by the side effects and expense of medications, which has a detrimental impact on their health outcomes. Quercetin, a flavonoid, is a one of the most potent anti-oxidants which ameliorates T2DM. Thus, there is an increased demand to investigate quercetin and its derivatives, as it is hypothesised that similar structured compounds may exhibit similar biological activity. Gossypetin is a hexahydroxylated flavonoid found in the calyx of Hibiscus sabdariffa. Gossypetin has a similar chemical structure to quercetin with an extra hydroxyl group. Furthermore, previous literature has elucidated that gossypetin exhibits neuroprotective, hepatoprotective, reproprotective and nephroprotective properties. The mechanisms underlying gossypetin’s therapeutic potential have been linked to its anti-oxidant, anti-inflammatory and immunomodulatory properties. Hence, this review highlights the potential role of gossypetin in the treatment of diabetes and its associated complications.