bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemical Composition, Antibacterial and Antibiotic-Modifying Activity of Croton grewioides Baill Essential Oil
Authors: Viturino José Jonas Ferreira , Camilo Cicera Janaine , de Carvalho Natália Kelly Gomes , Nascimento Joice Barbosa do , da Silva Maria Inacio , Pereira da Silva Mariana , Castro José Walber Gonçalves , Souza Geane Gabriele de Oliveira , Rodrigues Fabíola Fernandes Galvão , da Costa José Galberto Martins
Published: October 2024

Background: Croton grewioides Baill., a species native to the Caatinga, popularly known as canela de cunhã, is used in traditional medicine to treat gastrointestinal diseases such as diarrhea, gastritis and stomach ulcers. The combination of essential oils with antibiotics reveals several beneficial effects associated with the increased efficacy of these drugs against pathogenic agents. Through this perspective, this study aimed to identify the chemical composition of the essential oil of C. grewioides (OECG) and evaluate its antibacterial and antibiotic-modifying activities against standard and multiresistant bacteria. Methods: To analyze the compounds present in the oil, the techniques of gas chromatography coupled with mass spectrometry (GC/MS) and gas chromatography with a flame ionization detector (GC/FID) were used. In the bacteriological tests, the Minimum Inhibitory Concentration (MIC) was obtained by the broth microdilution technique. The modulating effect of the essential oil was determined by calculating the subinhibitory concentration, followed by a serial microdilution of the antibiotics. The MIC reduction factor (CRF) was calculated, and its data were expressed as a percentage. Results: The analysis of the chemical composition identified the presence of the major compound estragole with a relative abundance of 50.34%. The MIC values obtained demonstrated efficacy in K. pneumoniae isolated from urine with MIC values of 512 µg/mL. OECG potentiated the effects of all antibiotics tested on the strains S. aureus ATCC 29213, K. pneumoniae Carbapnemase, E. coli ATCC 25922 and S. aureus ATCC 29213 with their CRF of 97.65%, 99.80%, 99.85% and 99.88%, respectively. Conclusions: Thus, the essential oil of C. grewioides presents synergistic effects when combined with the antibiotics tested, in addition to acting in the fight against bacterial resistance to antibiotics.
Production of Lithium and Heavy Elements in AGB Stars Experiencing PIEs
Authors: Choplin Arthur , Siess Lionel , Goriely Stephane , Martinet Sebastien
Published: October 2024

Asymptotic giant branch (AGB) stars can experience proton ingestion events (PIEs), leading to a rich nucleosynthesis. During a PIE, the intermediate neutron capture process (i-process) develops, leading to the production of trans-iron elements. It is also suggested that lithium is produced during these events. We investigate the production of lithium and trans-iron elements in AGB stars experiencing a PIE with 1<Mini/M⊙<3 and −3<[Fe/H]<0. We find that lithium is produced in all PIE models with surface abundances 3< A(Li) <5. The surface enrichment and overall AGB lithium yield increases with decreasing stellar mass. The lithium enrichment is accompanied by a production of 13C with 3<12C/13C <9 at the surface just after the PIE. AGB stars experiencing PIE may be related to J-type carbon stars whose main features are excesses of lithium and13C. In addition to Li and 13C, heavy elements (e.g., Sr, Ba, Eu, Pb) are significantly produced in low-metallicity stars up to [Fe/H] ≃−1. The yields of our models are publicly available. Additionally, of interest to the Li nucleosynthesis, we provide an updated fitting formula for the 7Be(e−,νe)7Li electron capture rate.
Evaluation of Four Forensic Investigative Genetic Genealogy Analysis Approaches with Decreased Numbers of SNPs and Increased Genotyping Errors
Authors: Zang Yu , Wu Enlin , Li Tingjun , Liu Jiajun , Wu Riga , Li Ran , Sun Hongyu
Published: October 2024

Background: Forensic investigative genetic genealogy (FIGG) has developed rapidly in recent years and is considered a novel tool for crime investigation. However, crime scene samples are often of low quality and quantity and are challenging to analyze. Deciding which approach should be used for kinship inference in forensic practice remains a troubling problem for investigators. Methods: In this study, we selected four popular approaches—KING, IBS, TRUFFLE, and GERMLINE—comprising one method of moment (MoM) estimator and three identical by descent (IBD) segment-based tools and compared their performance at varying numbers of SNPs and levels of genotyping errors using both simulated and real family data. We also explored the possibility of making robust kinship inferences for samples with ultra-high genotyping errors by integrating MoM and the IBD segment-based methods. Results: The results showed that decreasing the number of SNPs had little effect on kinship inference when no fewer than 164 K SNPs were used for all four approaches. However, as the number decreased further, decreased efficiency was observed for the three IBD segment-based methods. Genotyping errors also had a significant effect on kinship inference, especially when they exceeded 1%. In contrast, MoM was much more robust to genotyping errors. Furthermore, the combination of the MoM and the IBD segment-based methods showed a higher overall accuracy, indicating its potential to improve the tolerance to genotyping errors. Conclusions: In conclusion, this study shows that different approaches have unique characteristics and should be selected for different scenarios. More importantly, the integration of the MoM and the IBD segment-based methods can improve the robustness of kinship inference and has great potential for applications in forensic practice.
Exploring Fish Parvalbumins through Allergen Names and Gene Identities
Authors: Dijkstra Johannes M. , Kuehn Annette , Sugihara Eiji , Kondo Yasuto
Published: October 2024

Parvalbumins are the main source of food allergies in fish meat, with each fish possessing multiple different parvalbumins. The naming convention of these allergens in terms of allergen codes (numbers) is species-specific. Allergen codes for parvalbumin isoallergens and allergen variants are based on sequence identities relative to the first parvalbumin allergen discovered in that particular species. This means that parvalbumins with similar allergen codes, such as catfish Pan h 1.0201 and redfish Seb m 1.0201, are not necessarily the most similar proteins, or encoded by the same gene. Here, we aim to elucidate the molecular basis of parvalbumins. We explain the complicated genetics of fish parvalbumins in an accessible manner for fish allergen researchers. Teleost or modern bony fish, which include most commercial fish species, have varying numbers of up to 22 parvalbumin genes. All have derived from ten parvalbumin genes in their common ancestor. We have named these ten genes “parvalbumin 1-to-10” (PVALB1-to-PVALB10), building on earlier nomenclature established for zebrafish. For duplicated genes, we use variant names such as, for example, “PVALB2A and PVALB2B”. As illustrative examples of our gene identification system, we systematically analyze all parvalbumin genes in two common allergy-inducing species in Japan: red seabream (Pagrus major) and chum salmon (Oncorhynchus keta). We also provide gene identifications for known parvalbumin allergens in various fish species.
Sleep Abnormalities in SLC13A5 Citrate Transporter Disorder
Authors: Adams Raegan M. , Ozlu Can , Bailey Lauren E. , Solidum Rayann M. , Cooper Sydney , Best Carrie R. , Elacio Jennifer , Kavanaugh Brian C. , Brown Tanya L. , Nye Kimberly , Liu Judy , Porter Brenda E. , Goodspeed Kimberly , Bailey Rachel M.
Published: October 2024

Background: SLC13A5 Citrate Transporter Disorder is a rare pediatric neurodevelopmental disorder. Patients have epilepsy, developmental disability, and impaired mobility. While sleep disorders are common in children with neurodevelopmental disorders, sleep abnormalities have not been reported in SLC13A5 patients. Methods: Here, we assessed sleep disturbances in patients through caregiver reported surveys and in a transgenic mouse model of SLC13A5 deficiency. A total of 26 patients were evaluated with the Sleep Disturbance Scale for Children three times over a one-year span. Sleep and wake activities were assessed in the SLC13A5 knock-out (KO) mice using wireless telemetry devices. Results: A high burden of clinically significant sleep disturbances were reported in the patients, with heterogeneous symptoms that remained stable across time. While sleep disturbances were common, less than 30% of patients were prescribed medications for sleep. Comparatively, in SLC13A5 KO mice using EEG recordings, significant alterations were found during light cycles, when rodents typically sleep. During the sleep period, SLC13A5 mice had increased activity, decreased paradoxical sleep, and changes in absolute power spectral density, indicating altered sleep architecture in the mouse model. Conclusions: Our results demonstrate a significant component of sleep disturbances in SLC13A5 patients and mice, highlighting a potential gap in patient care. Further investigation of sleep dysfunction and the underlying etiologies of sleep disturbances in SLC13A5 citrate transporter disorder is warranted.
Separating Risk Prediction: Myocardial Infarction vs. Ischemic Stroke in 6.2M Screenings
Authors: Jung Wonyoung , Park Sang Hyun , Han Kyungdo , Jeong Su-Min , Cho In Young , Kim Kihyung , Kim Yerim , Kim Sung Eun , Shin Dong Wook
Published: October 2024

Background: Traditional cardiovascular disease risk prediction models generate a combined risk assessment for myocardial infarction (MI) and ischemic stroke (IS), which may inadequately reflect the distinct etiologies and disparate risk factors of MI and IS. We aim to develop prediction models that separately estimate the risks of MI and IS. Methods: Our analysis included 6,242,404 individuals over 40 years old who participated in a cardiovascular health screening examination in 2009. Potential predictors were selected based on a literature review and the available data. Cox proportional hazards models were used to construct 5-year risk prediction models for MI, and IS. Model performance was assessed through discrimination and calibration. Results: During a follow-up of 39,322,434.39 person-years, 89,140 individuals were diagnosed with MI and 116,259 with IS. Both models included age, sex, body mass index, smoking, alcohol consumption, physical activity, diabetes, hypertension, dyslipidemia, chronic kidney disease, and family history. Statin use was factored into the classification of dyslipidemia. The c-indices for the prediction models were 0.709 (0.707–0.712) for MI, and 0.770 (0.768–0.772) for IS. Age and hypertension exhibited a more pronounced effect on IS risk prediction than MI, whereas smoking, body mass index, dyslipidemia, and chronic kidney disease showed the opposite effect. The models calibrated well for low-risk individuals. Conclusions: Our findings underscore the necessity of tailored risk assessments for MI and IS to facilitate the early detection and accurate identification of heterogeneous at-risk populations for atherosclerotic cardiovascular disease.
Psychometric Validation of the Purpose in Life Test-Short Form (PIL-SF) in Individuals Diagnosed with Severe Mental Illness
Authors: Rubio-Belmonte César , Mayordomo-Rodríguez Teresa , Marco-Ahullo Adrià , Aragonés-Barberá Inmaculada
Published: October 2024

Background: Meaning in Life (MiL) represents a key variable in mental health models of personal recovery. There is a need for straightforward and concise instruments to assess this construct quantitatively in individuals diagnosed with severe mental illness (SMI). Objective: The aim of the present study was to test the psychometric properties of the Purpose in Life Test-Short Form (PIL-SF), a brief self-report measuring the presence of MiL, in a sample of individuals with SMI. Methods: The participants were 41 adults (21 women, 51.8% and 20 men, 48.2%) aged 18 to 65 years (M = 50.05; SD = 10.73) with a diagnosis of SMI (schizophrenia, 61%; bipolar disorder, 26.8%; borderline personality disorder, 7.3%; and major depression, 4.9%) and clinically stable. The PIL-SF, Satisfaction with Life Scale (SWLS), Oxford Happiness Questionnaire—6 Item (OHQ-6), Engagement in Meaningful Activities Survey (EMAS), and Seeking of Noetic Goals—8 Item (SONG-8) were used. Descriptive analysis, estimation of the internal consistency, and Confirmatory Factor Analysis of the PIL-SF were conducted. Furthermore, correlations between the PIL-SF, SWLS, OHQ-6, EMAS, and SONG-8 were calculated. Results: The PIL-SF showed acceptable internal consistency (ω = 0.81) and an excellent fit as a unidimensional scale (CFI = 1.000, TLI = 1.070, RMSEA = 0.000, SRMR = 0.021), confirming its factorial structure. Regarding construct validity, correlations between the PIL-SF and the SWLS (ρ = 0.54, p < 0.001), the OHQ-6 (ρ = 0.52, p < 0.001), and EMAS (ρ = 0.44, p < 0.005) were positive and significant, whereas the correlations between the PIL-SF and the SONG-8NfM (ρ = −0.35, p < 0.025) were negative and significant. Conclusions: The Spanish version of the PIL-SF appears to be a reliable and valid instrument to measure the presence of MiL in adults with SMI.
Plant Growth Optimization Using Amber Light Supplemented with Different Blue Light Spectra
Authors: Trumpler Keli , Wu Bo-Sen , Addo Philip Wiredu , MacPherson Sarah , Lefsrud Mark
Published: October 2024

Blue (400–500 nm) and red (600–700 nm) light regions have been investigated for their effects on photosynthesis and plant growth, yet evidence for specific blue light wavelengths in plant research is lacking. Investigations into amber (595 nm) light are similarly limited. To ‘shed light’ on these two important wavelengths, this study investigated the combined effects of blue and amber light on plant growth and development in two model plants: tomato (Solanum lycopersicum cv. Beefsteak) and lettuce (Lactuca sativa cv. Breen). Plant growth responses were determined with four light treatments: B+BA (blue + broad amber, 455–602 nm), RB-NA (royal blue + narrow amber, 430–602 nm), RB-BA (royal blue + broad amber, 423–595 nm), and high-pressure sodium at a PPFD of 250 µmol m−2 s−1. After 21 days, the highest fresh and dry mass for both plant species was obtained under the RB-BA light treatment. Shifting the blue wavelength from 430 nm to 455 nm with broad amber lighting led to 40% less fresh mass for tomatoes, whereas only an approximate 5% reduction in fresh mass was observed for lettuce plants. Our findings demonstrate that an alternate and combined blue + amber light spectrum is effective for optimizing plant productivity.
Genome-Wide Identification and Expression Analysis of the PsTPS Gene Family in Pisum sativum
Authors: Yuan Hao , Liu Baoxia , Zhang Guwen , Feng Zhijuan , Wang Bin , Bu Yuanpeng , Xu Yu , Sun Zhihong , Liu Na , Gong Yaming
Published: October 2024

This study aimed to explore the role of the trehalose-6-phosphate synthase (TPS) gene family in the adaptation of peas to environmental stress. A comprehensive analysis of the PsTPS gene family identified 20 genes with conserved domains and specific chromosomal locations. Phylogenetic analysis delineated evolutionary relationships, while gene structure analysis revealed compositional insights, and motif analysis provided functional insights. Cis-regulatory element identification predicted gene regulation patterns. Tissue-specific and stress-induced expression profiling highlighted eight genes with ubiquitous expression, with PsTPS15 and PsTPS18 displaying elevated expression levels in roots, nodules, and young stems, and PsTPS13 and PsTPS19 expression downregulated in seeds. Transcriptome analysis identified a differential expression of 20 PsTPS genes, highlighting the significance of 14 genes in response to drought and salinity stress. Notably, under drought conditions, the expression of PsTPS4 and PsTPS6 was initially upregulated and then downregulated, whereas that of PsTPS15 and PsTPS19 was downregulated. Salinity stress notably altered the expression of PsTPS4, PsTPS6, and PsTPS19. Taken together, these findings elucidate the regulatory mechanisms of the PsTPS gene family and their potential as genetic targets for enhancing crop stress tolerance.
Docosahexaenoic Acid and Sleep Quality in Very and Extreme Preterm Infants
Authors: Barion Giovanna Rando , Marghetti Pietra Giovanna , Cagliari Patricia Zanotelli , Mastroeni Marco Fabio
Published: October 2024

The results regarding the association of plasma docosahexaenoic acid (DHA) levels with sleep duration conflict. This study aimed to investigate the effect of oral administration of DHA on the sleep quality of Brazilian extreme preterm infants. This cohort study is part of the Joinville Docosahexaenoic Acid Study (JoiDHA) conducted with 59 infants in Joinville, Brazil. Sleep quality was assessed using the Brief Infant Sleep Questionnaire, which consists of 12 questions about the quality of sleep the week prior to its application and was answered by the parents/guardians. Of the 59 children who participated in the study, 37 (62.7%) were supplemented with DHA and 22 (37.3%) did not receive DHA. The prevalence of poor sleep quality was higher among children with the weight status at birth <50th percentile (68.2%; p = 0.045) when compared to children ≥50th percentile. However, Poisson regression analysis showed that neither weight status at birth nor DHA use was associated with sleep quality, even after adjusting for the same variables. In summary, sleep quality 12–24 months after birth was not associated with DHA supplementation in very and extreme preterm infants. Additional studies that address the increase in DHA intake would be important for the understanding of the effect of this fatty acid on sleep quality.
Military Family-Centred Resilience-Building Programming Across the Deployment Cycle: A Scoping Review
Authors: Hébert Michèle L. , Tippe Joshua M. , Aquin Carley , Maximos Melody , Brémault-Phillips Suzette , Sevigny Phillip R.
Published: October 2024

Background: There is international agreement that military families (MFs)—active service members, reservists, veterans, and their families—must be resilient to overcome military life adversities. Resilience is defined either as skillsets or as processes implicating multi-systems in a socio-ecological context. While research on resilience-building specific to children and families who face adversity is growing, there is a paucity of evidence on MF-centred resilience-building. Objective: This review describes the evidence on such resilience-building programming and determines if adversity is considered a barrier or facilitator to resilience-building. Methods: This scoping review yielded 4050 peer-reviewed articles from database inception until December 2023, found in 12 databases. Articles were deduplicated, leaving 1317 that were independently screened for eligibility by two reviewers. Disagreements were resolved through discussion with a third reviewer. Findings: Of these articles, 27 were included; 5 additional articles were also included from other sources. The vast majority of included studies (91%) were conducted in the United States. These 32 articles were organised into categories, including demographics, research methodologies used, resilience program descriptors, and outcomes. Conclusions: Our results reveal that programs on building MF resilience vary widely, often measuring non-resilience health and social outcomes. We provide preliminary insights for MF health and policy. Our review findings will be invaluable for further evidence-based programming that builds resilience in MFs.
Profiling of Key Hub Genes Using a Two-State Weighted Gene Co-Expression Network of ‘Jao Khao’ Rice under Soil Salinity Stress Based on Time-Series Transcriptome Data
Authors: Khunsanit Prasit , Plaimas Kitiporn , Chadchawan Supachitra , Buaboocha Teerapong
Published: October 2024

RNA-sequencing enables the comprehensive detection of gene expression levels at specific time points and facilitates the identification of stress-related genes through co-expression network analysis. Understanding the molecular mechanisms and identifying key genes associated with salt tolerance is crucial for developing rice varieties that can thrive in saline environments, particularly in regions affected by soil salinization. In this study, we conducted an RNA-sequencing-based time-course transcriptome analysis of ‘Jao Khao’, a salt-tolerant Thai rice variety, grown under normal or saline (160 mM NaCl) soil conditions. Leaf samples were collected at 0, 3, 6, 12, 24, and 48 h. In total, 36 RNA libraries were sequenced. ‘Jao Khao’ was found to be highly salt-tolerant, as indicated by the non-significant differences in relative water content, cell membrane stability, leaf greenness, and chlorophyll fluorescence over a 9-day period under saline conditions. Plant growth was slightly retarded during days 3–6 but recovered by day 9. Based on time-series transcriptome data, we conducted differential gene expression and weighted gene co-expression network analyses. Through centrality change from normal to salinity network, 111 key hub genes were identified among 1,950 highly variable genes. Enriched genes were involved in ATP-driven transport, light reactions and response to light, ATP synthesis and carbon fixation, disease resistance and proteinase inhibitor activity. These genes were upregulated early during salt stress and RT-qPCR showed that ‘Jao Khao’ exhibited an early upregulation trend of two important genes in energy metabolism: RuBisCo (LOC_Os10g21268) and ATP synthase (LOC_Os10g21264). Our findings highlight the importance of managing energy requirements in the initial phase of the plant salt-stress response. Therefore, manipulation of the energy metabolism should be the focus in plant resistance breeding and the genes identified in this work can serve as potentially effective candidates.
Melatonin Mediates Cardiac Tissue Damage under Septic Conditions Induced by Lipopolysaccharide
Authors: Lazarević Milan , Kostić Miloš , Džopalić Tanja , Sokolović Danka , Lazarević Zorica , Milovanović Jelena , Ničković Vanja , Sokolović Dušan
Published: October 2024

Lipopolysaccharide (LPS) is known to induce oxidative stress and inflammation, leading to significant damage in cardiac tissues. This study investigates the protective effects of melatonin (MLT) against LPS-induced oxidative damage, inflammation, and apoptosis in rat heart tissue. Rats were divided into four groups (n = 6 per group): control, melatonin-treated, LPS-treated, and LPS + melatonin-treated. Oxidative stress markers, including thiobarbituric acid-reactive substances (TBARSs) and advanced oxidation protein products (AOPPs), were measured. Additionally, inflammatory markers, such as interleukin-6 (IL-6) levels, inducible nitric oxide synthase (iNOS) and nitric oxide (NO) content, and apoptotic markers, caspase-3, caspase-9, and acidic DNase activity, were evaluated. LPS treatment significantly increased TBARS, AOPP, and IL-6 levels, as well as the activity of caspase-3, acidic DNase and iNOS and NO content compared to the control group. Co-treatment with melatonin significantly reduced the levels of TBARS and AOPP levels, and caspase-3 and acidic DNase activities nearly matched those of the control group, while caspse-9 was still slightly increased. Interestingly, IL-6, iNOS and NO levels were significantly decreased but did not fully match the values in the control group. Melatonin mitigates LPS-induced oxidative stress, inflammation, and apoptosis in rat heart tissue by affecting all studied parameters, demonstrating its potential as a therapeutic agent for conditions characterized by oxidative stress and inflammation. Further research is warranted to explore the clinical applications of melatonin in cardiovascular diseases.
Small Molecules, α-Synuclein Pathology, and the Search for Effective Treatments in Parkinson’s Disease
Authors: Sechi Gian Pietro , Sechi M. Margherita
Published: October 2024

Parkinson’s disease (PD) is a progressive age-related neurodegenerative disorder affecting millions of people worldwide. Essentially, it is characterised by selective degeneration of dopamine neurons of the nigro-striatal pathway and intraneuronal aggregation of misfolded α-synuclein with formation of Lewy bodies and Lewy neurites. Moreover, specific small molecules of intermediary metabolism may have a definite pathophysiological role in PD. These include dopamine, levodopa, reduced glutathione, glutathione disulfide/oxidised glutathione, and the micronutrients thiamine and ß-Hydroxybutyrate. Recent research indicates that these small molecules can interact with α-synuclein and regulate its folding and potential aggregation. In this review, we discuss the current knowledge on interactions between α-synuclein and both the small molecules of intermediary metabolism in the brain relevant to PD, and many other natural and synthetic small molecules that regulate α-synuclein aggregation. Additionally, we analyse some of the relevant molecular mechanisms potentially involved. A better understanding of these interactions may have relevance for the development of rational future therapies. In particular, our observations suggest that the micronutrients ß-Hydroxybutyrate and thiamine might have a synergistic therapeutic role in halting or reversing the progression of PD and other neuronal α-synuclein disorders.
Antagonist of Growth Hormone-Releasing Hormone Receptor MIA-690 Suppresses the Growth of Androgen-Independent Prostate Cancers
Authors: Muñoz-Moreno Laura , Gómez-Calcerrada M. Isabel , Arenas M. Isabel , Carmena M. José , Prieto Juan C. , Schally Andrew V. , Bajo Ana M.
Published: October 2024

The development of resistance remains the primary challenge in treating castration-resistant prostate cancer (CRPC). GHRH receptors (GHRH-R), which are coupled to G-proteins (GPCRs), can mediate EGFR transactivation, offering an alternative pathway for tumour survival. This study aimed to evaluate the effects of the GHRH-R antagonist MIA-690, in combination with the EGFR inhibitor Gefitinib, on cell viability, adhesion, gelatinolytic activity, and the cell cycle in advanced prostate cancer PC-3 cells. The findings demonstrate a synergistic effect between MIA-690 and Gefitinib, leading to the inhibition of cell viability, adhesion, and metalloprotease activity. Cell cycle analysis suggests that both compounds induce cell cycle arrest, both individually and in combination. Furthermore, similar effects of the GHRH-R antagonist MIA-690 combined with Gefitinib were observed in PC-3 tumours developed by subcutaneous injection in athymic nude mice 36 days post-inoculation. These results indicate that combined therapy with a GHRH-R antagonist and an EGFR inhibitor exerts a stronger antitumor effect compared to monotherapy by preventing transactivation between EGFR and GHRH-R in CRPC.
An Inexpensive and Quick Method for Genotyping of HLA Variants Included in the Spanish Pharmacogenomic Portfolio of National Health System
Authors: Taladriz-Sender Irene , Hernández-Osio Gina , Zapata-Cobo Paula , Salvador-Martín Sara , García-González Xandra , Balas Antonio , Sanjurjo-Sáez María , López-Fernández Luis A.
Published: October 2024

The possibility of using the same genotyping technology (TaqMan) for all the genetic tests included in the new Spanish pharmacogenomics portfolio should enable the application of a multigenotyping platform to obtain a whole pharmacogenomics profile. However, HLA-typing is usually performed with other technologies and needs to be adapted to TaqMan assays. Our aim was to establish a set of TaqMan assays for correct typing of HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, and HLA-B*58:01. Therefore, we searched for and selected SNVs described in different populations as surrogate markers for these HLA alleles, designed TaqMan assays, and tested in a set of samples with known HLA-A and HLA-B. HLA-A*31:01 was correctly typed with a combination of rs1061235 and rs17179220 (PPV 100%, 95% CI 84.6–100-%; NPV 100%, 95% CI 96.5–100.0%), HLA-B*15:02 with rs10484555 (PPV 100%, 95% CI 69.2–100.0%; NPV 100%, 95% CI 96.8–100.0%) and rs144012689 (PPV 100%, 95% CI 69.2–100.0%; NPV 100%, 95% CI 96.8–100.0%), and HLA-B*57:01 with rs2395029 (PPV 99.5%, 95% CI 72.9–99.3%; NPV 99.5%, 95% CI 98.3–100.0%). HLA-B*58:01 was typed using two allele-specific TaqMan probes mixed with a ß-Globin reference and treated as a genotyping assay (PPV 100.0%, 95% CI 81.5–100.0%; NPV 100%, 95% CI 96.8–100.0%). In conclusion, we demonstrated a clinically useful way to type HLA-A and HLA-B alleles included in the Spanish pharmacogenomics portfolio using TaqMan assays.
Intestinal Epithelial Cell Brush Border Membrane Cl:HCO3 Exchanger Regulation by Mast Cells in Chronic Ileitis
Authors: Paulraj Raja Singh , Afroz Sheuli , Palaniappan Balasubramanian , Murughiyan Usha , Singh Soudamani , Arthur Subha , Sundaram Uma
Published: October 2024

Malabsorption of NaCl is the primary cause of diarrhea in inflammatory bowel disease (IBD). Coupled NaCl absorption occurs via the dual operation of Na:H and Cl:HCO3 exchange in the brush border membrane (BBM) of villus cells. Cl:HCO3 exchange is mediated by BBM transporters DRA (downregulated in adenoma) and PAT1 (putative anion transporter 1) in the mammalian small intestine. DRA/PAT1-mediated Cl:HCO3 exchange was significantly downregulated in the BBM of villus cells in a rabbit model of chronic ileitis, while Na:H exchange was unaffected. The inhibition of Cl:HCO3 exchange was restored in the rabbits when treated with a broad-spectrum immunomodulator, i.e. a glucocorticoid, indicating that the downregulation of DRA/PAT1 is likely to be immune-mediated during chronic enteritis. Mucosal mast cells are one type of key immune cells that are known to proliferate and release immune inflammatory mediators, thus playing a significant role in the pathogenesis of IBD. However, how mast cells may regulate DRA- and PAT1-mediated Cl:HCO3 exchange in a rabbit model of chronic ileitis is unknown. In this study, treatment of rabbits with chronic intestinal inflammation with the mast cell stabilizer ketotifen did not affect the mucosal architecture of the inflamed intestine. However, ketotifen treatment reversed the inhibition of Cl:HCO3 activity in the BBM of villus cells. This restoration of Cl:HCO3 activity to normal levels by ketotifen was found to be secondary to restoring the affinity of the exchangers for its substrate chloride. This observation was consistent with molecular studies, where the mRNA and BBM protein expressions of DRA and PAT1 remained unaffected in the villus cells under all experimental conditions. Thus, this study indicates that mast cells mediated the inhibition of coupled NaCl absorption by inhibiting Cl:HCO3 exchange in a rabbit model of chronic enteritis.
In Search of Spinal Muscular Atrophy Disease Modifiers
Authors: Chudakova Daria , Kuzenkova Ludmila , Fisenko Andrey , Savostyanov Kirill
Published: October 2024

The 5q Spinal Muscular Atrophy (SMA) is a hereditary autosomal recessive disease caused by defects in the survival motor neuron (SMN1) gene encoding survival motor neuron (SMN) protein. Currently, it is the leading cause of infantile mortality worldwide. SMA is a progressive neurodegenerative disease with “continuum of clinical severity”, which can be modulated by genetic and epigenetic factors known as disease modifiers (DMs). Individuals (even siblings) with the same defects in SMN1 gene might have strikingly different types of SMA, supposedly due to the impact of DMs. There are several therapeutic options for SMA, all of them focusing on the restoration of the SMN protein levels to normal. Determining DMs and the pathways in which they are involved might aid in enhancing existing curative approaches. Furthermore, DMs might become novel therapeutic targets or prognostic biomarkers of the disease. This narrative review provides a brief overview of the genetics and pathobiology of SMA, and its bona fide modifiers. We describe novel, emerging DMs, approaches and tools used to identify them, as well as their potential mechanisms of action and impact on disease severity. We also propose several disease-modifying molecular mechanisms which could provide a partial explanation of the staggering variability of SMA phenotypes.
Placental–Heart Axis: An Evolutionary Perspective
Authors: Matthews Jadyn , Rajakumar Brammy , Carreon Chrystalle Katte , Morton Sarah U.
Published: October 2024

To maintain its development, the growing fetus is directly dependent on the placenta, an organ that acts as both a modulator and mediator. As an essential component of pregnancy that is derived from both maternal and fetal tissues, the placenta facilitates the passage of all oxygen and nutrients from the expecting parent to their fetuses. Further, the placenta conveys multiple impacts of the maternal environment to the growing fetus. The timing of placental development parallels that of the fetal cardiovascular system, and placental anomalies are implicated as a potential cause of congenital heart disease. For example, congenital heart disease is more common in pregnancies complicated by maternal preeclampsia, a condition characterized by placental dysfunction. Given the placenta’s intermediary links to the maternal environment and fetal health outcomes, it is an emerging focus of evolutionary medicine, which seeks to understand how interactions between humans and the environment affect our biology and give rise to disease. The present review provides an overview of the evolutionary and developmental courses of the placenta as well as their implications on infant health.
Prospective Quantitative and Phenotypic Analysis of Platelet-Derived Extracellular Vesicles and Its Clinical Relevance in Ischemic Stroke Patients
Authors: Maciejewska-Renkowska Joanna , Wachowiak Justyna , Telec Magdalena , Kamieniarz-Mędrygał Maria , Michalak Sławomir , Kaźmierski Radosław , Kociemba Wojciech , Kozubski Wojciech P. , Łukasik Maria
Published: October 2024

The levels of platelet-derived extracellular vesicles (pEVs) have been reported as elevated in acute ischemic stroke (IS). However, the results of studies remain equivocal. This prospective, case-control study included 168 patients with IS, 63 matched disease controls (DC), and 21 healthy controls (HC). Total pEVs concentration, the concentration of phosphatidylserine-positive pEVs (PS+pEVs), the percentage of PS+pEVs (%PS+pEVs) and the concentration of pEVs with expression of CD62P+, CD40L+, CD31+, and active form of GPIIb/IIIa receptor (PAC-1+) were assessed on days 1, 3, 10, and 90 with the Apogee A50-Micro flow cytometer. The concentrations of pEVs, PS+pEVs, and %PS+pEVs were significantly higher after IS vs. HC (p < 0.001). PS+pEVs were higher after stroke vs. controls (p < 0.01). The concentrations of pEVs with expression of studied molecules were higher on D1 and D3 after stroke vs. controls. The concentration of pEVs after platelet stimulation with ADP was significantly diminished on D3. IS most notably affects the phenotype of pEVs with a limited effect on the number of pEVs. Ischemic stroke moderately disturbs platelet microvesiculation, most notably in the acute phase, affecting the phenotype of pEVs, with a limited impact on the number of pEVs.
Engineered M13-Derived Bacteriophages Capable of Gold Nanoparticle Synthesis and Nanogold Manipulations
Authors: Karczewska-Golec Joanna , Sadowska Kamila , Golec Piotr , Karczewski Jakub , Węgrzyn Grzegorz
Published: October 2024

For years, gold nanoparticles (AuNPs) have been widely used in medicine and industry. Although various experimental procedures have been reported for their preparation and manipulation, none of them is optimal for all purposes. In this work, we engineered the N-terminus of the pIII minor coat protein of bacteriophage (phage) M13 to expose a novel HLYLNTASTHLG peptide that effectively and specifically binds gold. In addition to binding gold, this engineered phage could synthesize spherical AuNPs of 20 nm and other sizes depending on the reaction conditions, aggregate them, and precipitate gold from a colloid, as revealed by transmission electron microscopy (TEM), atomic force microscopy (AFM), and scanning electron microscopy (SEM), as well as ultraviolet–visible (UV–vis) and Fourier-transform infrared (FTIR) spectroscopic methods. We demonstrated that the engineered phage exposing a foreign peptide selected from a phage-displayed library may serve as a sustainable molecular factory for both the synthesis of the peptide and the subsequent overnight preparation of AuNPs from gold ions at room temperature and neutral pH in the absence of strong reducing agents, such as commonly used NaBH4. Taken together, the results suggest the potential applicability of the engineered phage and the new, in vitro-identified gold-binding peptide in diverse biomimetic manipulations.
Special Issue: MAPK Signaling Cascades in Human Health and Diseases
Authors: Seger Rony
Published: October 2024

In order to survive and fulfil their functions, cells of any organism need to be able to respond to a large number of extracellular factors, also termed extracellular stimuli [...]
Different Patterns of Pd-Promoted C-H Bond Activation in (Z)-4-Hetarylidene-5(4H)-oxazolones and Consequences in Photophysical Properties
Authors: Martínez Miguel , Dalmau David , Crespo Olga , García-Orduña Pilar , Lahoz Fernando , Martín Antonio , Urriolabeitia Esteban P.
Published: October 2024

This work aims to amplify the fluorescence of (Z)-4-hetarylidene-5(4H)-oxazolones 1 by suppression of the hula-twist non-radiative deactivation pathway by C^N-orthopalladation of the 4-hetarylidene ring. Different (Z)-4-hetarylidene-2-phenyl-5(4H)-oxazolones, 1a–1c, prepared by the Erlenmeyer–Plöchl method, have been studied. The orthopalladation of (Z)-2-phenyl-4-(5-thiazolylmethylene)-5(4H)-oxazolone (1a) takes place by C-H bond activation of the H4 of the heterocycle and C^N-chelation, giving the dinuclear trifluoroacetate derivative 2a. By further metathesis of bridging ligands in 2a, complexes containing the orthometalated oxazolone and a variety of ligands 3a–5a, were prepared. The study of the photophysical properties of 1a–5a shows that the bonding of the Pd metal to the 4-hetaryliden-5(4H)-oxazolone does not promote, in these cases, an increase in fluorescence. Interestingly, the orthopalladation of (Z)-2-phenyl-4-(4-thiazolylmethylene)-5(4H)-oxazolone (1b) gives orthopalladated 2b, where the incorporation of the Pd to the oxazolone takes place by C-H bond activation of the ortho-H2 of the 2-phenyl group, ring opening of the oxazolone heterocycle and simultaneous N,N-bonding of the N atoms of the thiazole ring and the generated benzamide fragment. This N^N^C-tridentate dianionic bonding mode is obtained for the first time in oxazolones. Despite a similar lock of the hula-twist deactivation, 2b does not show fluorescence.
The Association Between Rheumatic Disease Therapies and Cardiovascular Outcomes in People with HIV—A Retrospective Cohort Study
Authors: Titanji Boghuma K. , Nagatomi Shumpei , Gallini Julia W. , Cui Xiangqin , Hanberg Jennifer S. , Hsieh Evelyn , Marconi Vincent C.
Published: October 2024

Introduction: Inflammation is a significant contributor to cardiovascular disease (CVD) in people with HIV (PWH), who face twice the risk of CVD compared to the general population. The presence of co-existing rheumatic disease (RD) may further exacerbate inflammation and increase the incidence of CVD events in this population. Methods: We conducted a retrospective cohort study using electronic health record (EHR) data from the Veterans Affairs Medical Center in Atlanta, covering the period from 2000 to 2019. A total of 5000 patients aged 20–87 years who were diagnosed with HIV and receiving care at the Atlanta VAMC between 2000 and 2019 were eligible for this analysis. This study included 3930 veterans with HIV and assessed the impact of rheumatic disease therapies (RDTs) on CVD outcomes. The primary outcome was the first occurrence of a CVD event. Results: Rheumatic disease was significantly associated with an increased risk of CVD events (OR = 2.67; p < 0.001). Additionally, exposure to multiple RDTs (aHR = 2.121, p = 0.047), NSAIDs (aHR = 1.694, p = 0.003), glucocorticoids (aHR = 2.332, p < 0.0001), and hypouricemic agents and colchicine (aHR = 3.445, p < 0.0001) were all significantly associated with increased CVD events. Conclusions: The co-existence of HIV infection and rheumatic disease, along with the use of RDTs, may amplify the risk of CVD events in PWH. These findings underscore the need for further investigation into the relationship between RD, RDTs, and CVD risk in larger, controlled studies, given the potential implications for treatment decisions in this patient population. A limitation of our study is that due to its retrospective design, we could not examine the impact of the sequential use of RDT groups and RD severity on CVD events.
Phenotypic Evaluation of Rare Cystic Fibrosis Transmembrane Conductance Regulator Mutation Combinations in People with Cystic Fibrosis in Queensland, Australia
Authors: Evans Ieuan Edward Shepherd , Wood Michelle , Moore Vanessa , Reid David William
Published: October 2024

Background: Cystic fibrosis (CF) is a multisystem disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. We describe the distribution of CFTR mutation profiles in sub-tropical Queensland, Australia, and characterise the phenotypes associated with ‘rare’ CFTR mutation combinations. Methods: We conducted a retrospective observational study to analyse the CFTR mutation profiles of 322 people with CF (pwCF) under the care of a large adult CF centre in Queensland, Australia. Molecular pathology results were available for all identifiable CFTR mutations. The CFTR2 database was utilised to characterise the less common CFTR mutations to define mutation classes and explore associated phenotypic sequelae. Results: In total, eighty-seven different genotypes were identified within our CF cohort, with the most abundant mutation being the F508del mutation, 298/322 (92.5%). Thirty-six pwCF with CFTR mutations are considered to have ‘rare’ CFTR mutations, and eleven with previously undefined phenotypes. For these eleven pwCF, late diagnosis in adulthood was confirmed in 5/11 pwCF (45.5%) with CFTR modulator therapy only initiated in 5/11 (45.5%). Conclusions: The profile of more common CFTR genotypes within our cohort of adult pwCF living in Queensland, Australia, generally reflects the global predominance of F508del, G542X, G551D, N1303K, and R117H. The phenotypic heterogeneity of disease seen within the eleven pwCF in our cohort with previously undefined CFTR genotypes highlights that rare mutations can also be associated with severe disease and continue to be at risk of delayed diagnosis. Access to CFTR modulator therapies for this group of pwCF remains limited and should remain a research priority.
Targeting Human Pancreatic Cancer with a Fluorophore-Conjugated Mucin 4 (MUC4) Antibody: Initial Characterization in Orthotopic Cell Line Mouse Models
Authors: Jaiswal Sunidhi , Cox Kristin E. , Amirfakhri Siamak , Din Parast Saleh Aylin , Kobayashi Keita , Lwin Thinzar M. , Talib Sumbal , Aithal Abhijit , Mallya Kavita , Jain Maneesh , Mohs Aaron M. , Hoffman Robert M. , Batra Surinder K. , Bouvet Michael
Published: October 2024

Background/Objectives: Pancreatic cancer is the third leading cause of death related to cancer. The only possible cure presently is complete surgical resection; however, this is limited by difficulty in clearly defining tumor margins. Enhancement of the visualization of pancreatic ductal adenocarcinoma (PDAC) tumor margins using near-infrared dye-conjugated tumor-specific antibodies was pioneered by using anti-CEA, anti-CA19.9, and anti-MUC5AC in orthotopic mouse models of pancreatic cancer. Recently, an antibody to Mucin 4 (MUC4) conjugated to a fluorescent probe has shown promise in targeting colon tumors in orthotopic mouse models. Methods: In the present study, we targeted pancreatic cancer using an anti-MUC4 antibody conjugated to IRDye800 (anti-MUC4-IR800) in orthotopic mouse models. Two pancreatic cancer human cell lines were used, SW1990 and CD18/HPAF. Results: Anti-MUC4-IR800 targeted the two pancreatic cancer cell line tumors in orthotopic mouse models with high tumor-to-pancreas ratios and high tumor-to-liver ratios, with greater targeting seen in SW1990. Conclusions: The present results suggest anti-MUC4-IR800’s potential to be used in fluorescence-guided surgical resection of pancreatic cancer.
Paper-and-Pencil vs. Electronic Patient Records: Analyzing Time Efficiency, Personnel Requirements, and Usability Impacts on Healthcare Administration
Authors: Berger Matthias Fabian , Petritsch Johanna , Hecker Andrzej , Pustak Sabrina , Michelitsch Birgit , Banfi Chiara , Kamolz Lars-Peter , Lumenta David Benjamin
Published: October 2024

Background: This study investigates the impact of transitioning from paper and pencil (P&P) methods to electronic patient records (EPR) on workflow and usability in surgical ward rounds. Methods: Surgical ward rounds were audited by two independent observers to evaluate the effects of transitioning from P&P to EPR. Key observations included the number of medical personnel and five critical workflow aspects before and after EPR implementation. Additionally, usability was assessed using the System Usability Scale (SUS) and the Post-Study System Usability Questionnaire (PSSUQ). Results: A total of 192 P&P and 160 EPR observations were analyzed. Physicians experienced increased administrative workload with EPR, while nurses adapted more easily. Ward teams typically consisted of two physicians and three or four nurses. Usability scores rated the system as “Not Acceptable” across all professional groups. Conclusions: The EPR system introduced usability challenges, particularly for physicians, despite potential benefits like improved data access. Usability flaws hindered system acceptance, highlighting the need for better workflow integration. Addressing these issues could improve efficiency and reduce administrative strain. As artificial intelligence becomes more integrated into clinical practice, healthcare professionals must critically assess AI-driven tools to ensure safe and effective patient care.
How the Oocyte Nucleolus Is Turned into a Karyosphere: The Role of Heterochromatin and Structural Proteins
Authors: Nikolova Venera , Markova Maya , Zhivkova Ralitsa , Chakarova Irina , Hadzhinesheva Valentina , Delimitreva Stefka
Published: October 2024

Oocyte meiotic maturation includes large-scale chromatin remodeling as well as cytoskeleton and nuclear envelope rearrangements. This review addresses the dynamics of key cytoskeletal proteins (tubulin, actin, vimentin, and cytokeratins) and nuclear envelope proteins (lamin A/C, lamin B, and the nucleoporin Nup160) in parallel with chromatin reorganization in maturing mouse oocytes. A major feature of this reorganization is the concentration of heterochromatin into a spherical perinucleolar rim called surrounded nucleolus or karyosphere. In early germinal vesicle (GV) oocytes with non-surrounded nucleolus (without karyosphere), lamins and Nup160 are at the nuclear envelope while cytoplasmic cytoskeletal proteins are outside the nucleus. At the beginning of karyosphere formation, lamins and Nup160 follow the heterochromatin relocation assembling a new spherical structure in the GV. In late GV oocytes with surrounded nucleolus (fully formed karyosphere), the nuclear envelope gradually loses its integrity and cytoplasmic cytoskeletal proteins enter the nucleus. At germinal vesicle breakdown, lamin B occupies the karyosphere interior while all the other proteins stay at the karyosphere border or connect to chromatin. In metaphase oocytes, lamin A/C surrounds the spindle, Nup160 localizes to its poles, actin and lamin B are attached to the spindle fibers, and cytoplasmic intermediate filaments associate with both the spindle fibers and the metaphase chromosomes.