bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Detection of Alternaria alternata Haplotypes Isolated from Carya illinoinensis Using PCR-RFLP Analysis of Alt a1 Gene Region
Authors: Achilonu Conrad Chibunna , Gryzenhout Marieka , Marais Gert Johannes , Ghosh Soumya
Published: May 2023

Alternaria black spot disease on pecan is caused by the opportunistic pathogen Alternaria alternata and poses a serious threat to the local South African and global pecan industry. Several diagnostic molecular marker applications have been established and used in the screening of various fungal diseases worldwide. The present study investigated the potential for polymorphism within samples of A. alternata isolates obtained from eight different geographical locations in South Africa. Pecan (Carya illinoinensis) leaves, shoots, and nuts-in-shuck with Alternaria black spot disease were sampled, and 222 A. alternata isolates were retrieved. For rapid screening to identify Alternaria black spot pathogens, polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP) analysis of the Alternaria major allergen (Alt a1) gene region was used, followed by the digestion of the amplicons with HaeIII and HinfI endonucleases. The assay resulted in five (HaeIII) and two (HinfI) band patterns. Unique banding patterns from the two endonucleases showed the best profile and isolates were grouped into six clusters using a UPGMA (unweighted pair group method with arithmetic averages) distance matrix (Euclidean) dendrogram method on R-Studio. The analysis confirmed that the genetic diversity of A. alternata does not depend on host tissues or the pecan cultivation region. The grouping of selected isolates was confirmed by DNA sequence analysis. The Alt a1 phylogeny corroborated no speciation within the dendrogram groups and showed 98–100% bootstrap similarity. This study reports the first documented rapid and reliable technique for routine screening identification of pathogens causing Alternaria black spot in South Africa.
New Insights in 9q21.13 Microdeletion Syndrome: Genotype–Phenotype Correlation of 28 Patients
Authors: De Falco Alessandro , Iolascon Achille , Ascione Flora , Piscopo Carmelo
Published: May 2023

The implementation of array comparative genomic hybridisation (array-CGH) allows us to describe new microdeletion/microduplication syndromes which were previously not identified. 9q21.13 microdeletion syndrome is a genetic condition due to the loss of a critical genomic region of approximately 750kb and includes several genes, such as RORB and TRPM6. Here, we report a case of a 7-year-old boy affected by 9q21.13 microdeletion syndrome. He presents with global developmental delay, intellectual disability, autistic behaviour, seizures and facial dysmorphism. Moreover, he has severe myopia, which was previously reported in only another patient with 9q21.13 deletion, and brain anomalies which were never described before in 9q21.13 microdeletion syndrome. We also collect 17 patients from a literature search and 10 cases from DECIPHER database with a total number of 28 patients (including our case). In order to better investigate the four candidate genes RORB, TRPM6, PCSK5, and PRUNE2 for neurological phenotype, we make, for the first time, a classification in four groups of all the collected 28 patients. This classification is based both on the genomic position of the deletions included in the 9q21.3 locus deleted in our patient and on the different involvement of the four-candidate gene. In this way, we compare the clinical problems, the radiological findings, and the dysmorphic features of each group and of all the 28 patients in our article. Moreover, we perform the genotype–phenotype correlation of the 28 patients to better define the syndromic spectrum of 9q21.13 microdeletion syndrome. Finally, we propose a baseline ophthalmological and neurological monitoring of this syndrome.
Association of Surfactant Protein D Single Nucleotide Polymorphisms rs721917, rs2243639, rs3088308 with Recurrent Aphthous Stomatitis in Pakistani Population
Authors: Rizvi Zainab , Choudhry Nakhshab , Gondal Aamir Jamal , Yasmin Nighat
Published: May 2023

Recurrent aphthous stomatitis (RAS) is a benign ulcerative condition, defined by the recurrent formation of non-contagious mucosal ulcers. Surfactant protein D (SP-D) is secreted frequently at surfaces exposed directly to body fluids. This study aims to investigate the association of SP-D single nucleotide polymorphisms (SNPs) with the onset of RAS. Blood samples from 212 subjects (106 cases/controls each) were collected during 2019 and genotyped for SP-D SNPs (rs721917, rs2243639, rs3088308) by polymerase chain reaction and restriction fragment length polymorphism followed by 12% polyacrylamide gel electrophoresis. Minor aphthous (75.5%) was the commonly observed ulcer type as compared to herpetiform (21.7%) and major aphthous ulcers (2.8%). A family history of RAS was reported in 70% of cases. RAS was found significantly associated with rs3088308 genotypes T/A (95% (Cl): 1.57–5.03, p = 0.0005), A/A (95% (Cl): 1.8–6.7, p = 0.0002), T-allele (95% (Cl): 1.09–2.36, p = 0.01), A-allele (95% (Cl): 1.42–3.91, p = 0.01), rs721917 genotype T/T (95% (Cl): 1.15–25.35, p = 0.03), and T-allele (95% (Cl): 1.28–3.10, p = 0.002). Female gender and obese body mass index (BMI) were significantly associated with rs3088308 genotypes T/A (95% (CI): 1.89–15.7, p = 0.001), T/T (95% (Cl): 1.52–11.9, p = 0.005), A-allele (95% (Cl): 1.65–7.58, p < 0.001), and T-allele (95% (Cl): 1.4–10.1, p <0.001) and rs721917 genotype T/T (95% (CI) = 1.3–33, p = 0.02), respectively. This study describes the association of SP-D SNPs (rs721917, rs3088308) with RAS in the Pakistani population.
The Influence of Whey Protein on Muscle Strength, Glycemic Control and Functional Tasks in Older Adults with Type 2 Diabetes Mellitus in a Resistance Exercise Program: Randomized and Triple Blind Clinical Trial
Authors: Soares André Luiz de Seixas , Machado-Lima Adriana , Brech Guilherme Carlos , Greve Júlia Maria D’Andréa , dos Santos Joselma Rodrigues , Inojossa Thiago Resende , Rogero Marcelo Macedo , Salles João Eduardo Nunes , Santarem-Sobrinho José Maria , Davis Catherine L. , Alonso Angelica Castilho
Published: May 2023

Objectives: To evaluate the effect of whey protein (WP) supplementation associated with resistance training (RT) on glycemic control, functional tasks, muscle strength, and body composition in older adults living with type 2 diabetes mellitus (T2DM). Secondly, to evaluate the safety of the protocol for renal function. Methods: The population comprised twenty-six older men living with T2DM (68.5 ± 11.5 years old). The participants were randomly assigned to the Protein Group (PG) and the Control Group (CG). The handgrip test and evolution of exercise loads, according to the Omni Resistance Exercise Scale, evaluated muscle strength. Functional tasks were assessed by force platform in three different protocols: Sit-to-Stand, Step/Quick Turn, and Step Up/Over. Body composition was evaluated by bioimpedance and glycemic control and renal function were assessed by biochemical analyses. Both groups performed RT for 12 weeks, twice a week, prioritizing large muscle groups. Protein supplementation was 20 g of whey protein isolate and the CG was supplemented with an isocaloric drink, containing 20 g of maltodextrin. Results: There was a significant difference in muscle strength, according to the evolution of the exercise loads, but it was not confirmed in the handgrip test. However, there was no significant difference between the groups, regarding performance in functional tasks, glycemic control, or body composition. Renal function showed no alteration. Conclusion: The intake of 20 g of WP in older male adults living with T2DM did not increase the effect of RT on muscle strength, functional tasks, and glycemic control. The intervention was proven safe regarding renal function.
Hematological Changes in Gas Station Workers
Authors: Giardini Isabela , da Poça Katia Soares , da Silva Paula Vieira Baptista , Andrade Silva Valnice Jane Caetano , Cintra Deborah Santos , Friedrich Karen , Geraldino Barbara Rodrigues , Otero Ubirani Barros , Sarpa Marcia
Published: May 2023

(1) Background: Benzene, toluene, and xylene isomers (BTX) are present in gasoline. Exposure to benzene may lead to the appearance of a series of signs, symptoms, and complications, which are characterized by benzene poisoning, which is an occupational disease. This study evaluated the presence of signs and symptoms related to occupational exposure and whether occupational exposure to BTX is associated with the development of hematological changes. (2) Material and Methods: This cross-sectional epidemiological study included 542 participants, in which 324 were gas station workers (GSWs) and 218 were office workers (OWs) with no occupational exposure to benzene. To characterize the type of exposure (exposed and not exposed), trans,trans-Muconic acid (tt-MA), Hippuric acid (HA), and Methylhippuric acid (MHA) were used as exposure biomarkers. The tt-MA analysis revealed that the GSWs had 0.29 mg/g of urinary creatinine and the OWs had 0.13 mg/g of urinary creatinine. For HA, the GSWs presented 0.49 g/g of creatinine while the OWs presented 0.07. MHA analysis revealed that the GSWs had 1.57 g/g creatinine and the OWs had 0.01 g/g creatinine. Occupation habits and clinical symptoms were collected by questionnaire and blood samples were analyzed for hematological parameters. The persistence of hematological changes was evaluated with three serial blood collections every 15 days followed by laboratory hematological analysis. A descriptive analysis by the Chi-square test method was performed to evaluate the association between occupational exposure to fuels and the occurrence of changes in hematological parameters. (3) Results: In the GSWs, the most described signs and symptoms were somnolence (45.1%), headache (38.3%), dizziness (27.5%), tingling (25.4%), and involuntary movement (25%). Twenty GSWs that presented hematological alterations performed serial collections fifteen days apart. In addition, these workers presented total leukocyte counts above the upper limit and lymphocyte counts close to the lower limit. Leukocytosis and lymphopenia are hematological alterations present in chronic benzene poisoning. (4) Conclusions: The results found an initial change in different hematological parameters routinely used in clinics to evaluate health conditions. These findings reveal the importance of valuing clinical changes, even in the absence of disease, during the health monitoring of gas station workers and other groups that share the same space.
The Feasibility and Acceptability of the Adverse Childhood Experiences Questionnaire in Danish Antenatal Care—A Qualitative Study of Midwives’ Implementation Experiences
Authors: Johnsen Helle , Lichtenberg Vibeke de , Rydahl Eva , Karentius Sara Mbaye , Dueholm Signe Camilla Hjuler , Friis-Alstrup Majbritt , Backhausen Mette Grønbæk , Røhder Katrine , Schiøtz Michaela Louise , Broberg Lotte , Juhl Mette
Published: May 2023

Adverse childhood experiences have a potential lifelong impact on health. A traumatic upbringing may increase antenatal health risks in mothers-to-be and impact child development in their offspring. Yet, little is known about the identification of adverse childhood experiences in antenatal care. The objective of this study was to explore the feasibility and acceptability of the adverse childhood experiences questionnaire among midwives and factors affecting its implementation. Three Danish maternity wards participated in the study. The data consisted of observations of midwifery visits and informal conversations with midwives, as well as mini group interviews and dialogue meetings with midwives. The data were analysed using systematic text condensation. Analysis of the data revealed three main categories; “Relevance of the adverse childhood experiences questionnaire”, “Challenges related to use of the adverse childhood experiences questionnaire” and “Apprehensions, emotional strain, and professional support”. The findings showed that the adverse childhood experiences questionnaire was feasible to implement in Danish antenatal care. Midwives’ acceptability of the questionnaire was high. Training courses and dialogue meetings motivated the midwives to work with the questionnaire in practice. The main factors affecting the implementation process were time restrictions, worries of overstepping women’s boundaries, and a lack of a specific intervention for women affected by their traumatic upbringing circumstances.
Association between the Nursing Practice Environment and Safety Perception with Patient Safety Culture during COVID-19
Authors: Membrillo-Pillpe Nataly Julissa , Zeladita-Huaman Jhon Alex , Jauregui-Soriano Kimberlym , Zegarra-Chapoñan Roberto , Franco-Chalco Eduardo , Samillan-Yncio Gabriela
Published: May 2023

Aims: In this study, we aimed to identify the relationship between nursing practice environments (NPEs) and safety perceptions with patient safety culture (PSC) during COVID-19. Design: We conducted a quantitative, non-experimental, correlational, and cross-sectional study. We interviewed 211 nurses from Peru using two scales: PES–NWI and HSOPSC. We used the Shapiro–Wilk test and Spearman’s coefficient and estimated two regression models. Results: NPE was reported as favorable by 45.5% of the participants, and PSC was reported as neutral by 61.1%. Safety perception, the workplace, and NPE predict PSC. All NPE factors were correlated with PSC. However, safety perception, support of nurses subscale, the nurse manager’s ability, and leadership were predictors of PSC. Conclusion: To promote a safe work culture, health institutions should foster leadership that prioritizes safety, strengthens managers’ abilities, encourages interprofessional collaboration, and considers nurses’ feedback for constant improvement.
The Scorching Truth: Investigating the Impact of Heatwaves on Selangor’s Elderly Hospitalisations
Authors: Yong Kun Hing , Teo Yen Nee , Azadbakht Mohsen , Phung Hai , Chu Cordia
Published: May 2023

Global climate change has contributed to the intensity, frequency, and duration of heatwave events. The association between heatwaves and elderly mortality is highly researched in developed countries. In contrast, heatwave impact on hospital admissions has been insufficiently studied worldwide due to data availability and sensitivity. In our opinion, the relationship between heatwaves and hospital admissions is worthwhile to explore as it could have a profound impact on healthcare systems. Therefore, we aimed to investigate the associations between heatwaves and hospitalisations for the elderly by age group in Selangor, Malaysia, from 2010 to 2020. We further explored the impact of heatwaves on the risks of cause-specific hospital admissions across age groups within the elderly. This study applied generalized additive models (GAMs) with the Poisson family and distributed lag models (DLMs) to estimate the effect of heatwaves on hospitalisations. According to the findings, there was no significant increase in hospitalisations for those aged 60 and older during heatwaves; however, a rise in mean apparent temperature (ATmean) by 1 °C significantly increased the risk of hospital admission by 12.9%. Heatwaves had no immediate effects on hospital admissions among elderly patients, but significant delay effects were identified for ATmean with a lag of 0–3 days. The hospital admission rates of the elderly groups started declining after a 5-day average following the heatwave event. Females were found to be relatively more vulnerable than males during heatwave periods. Consequently, these results can provide a reference to improve public health strategies to target elderly people who are at the greatest risk of hospitalisations due to heatwaves. Development of early heatwave and health warning systems for the elderly would assist with preventing and reducing health risks while also minimising the burden on the whole hospital system in Selangor, Malaysia.
Early Alterations in Structural and Functional Properties in the Neuromuscular Junctions of Mutant FUS Mice
Authors: Mukhamedyarov Marat A. , Khabibrakhmanov Aydar N. , Khuzakhmetova Venera F. , Giniatullin Arthur R. , Zakirjanova Guzalia F. , Zhilyakov Nikita V. , Mukhutdinova Kamilla A. , Samigullin Dmitry V. , Grigoryev Pavel N. , Zakharov Andrey V. , Zefirov Andrey L. , Petrov Alexey M.
Published: May 2023

Amyotrophic lateral sclerosis (ALS) is manifested as skeletal muscle denervation, loss of motor neurons and finally severe respiratory failure. Mutations of RNA-binding protein FUS are one of the common genetic reasons of ALS accompanied by a ‘dying back’ type of degeneration. Using fluorescent approaches and microelectrode recordings, the early structural and functional alterations in diaphragm neuromuscular junctions (NMJs) were studied in mutant FUS mice at the pre-onset stage. Lipid peroxidation and decreased staining with a lipid raft marker were found in the mutant mice. Despite the preservation of the end-plate structure, immunolabeling revealed an increase in levels of presynaptic proteins, SNAP-25 and synapsin 1. The latter can restrain Ca2+-dependent synaptic vesicle mobilization. Indeed, neurotransmitter release upon intense nerve stimulation and its recovery after tetanus and compensatory synaptic vesicle endocytosis were markedly depressed in FUS mice. There was a trend to attenuation of axonal [Ca2+]in increase upon nerve stimulation at 20 Hz. However, no changes in neurotransmitter release and the intraterminal Ca2+ transient in response to low frequency stimulation or in quantal content and the synchrony of neurotransmitter release at low levels of external Ca2+ were detected. At a later stage, shrinking and fragmentation of end plates together with a decrease in presynaptic protein expression and disturbance of the neurotransmitter release timing occurred. Overall, suppression of synaptic vesicle exo–endocytosis upon intense activity probably due to alterations in membrane properties, synapsin 1 levels and Ca2+ kinetics could be an early sign of nascent NMJ pathology, which leads to neuromuscular contact disorganization.
Exploring FeLV-Gag-Based VLPs as a New Vaccine Platform—Analysis of Production and Immunogenicity
Authors: Ortiz Raquel , Barajas Ana , Pons-Grífols Anna , Trinité Benjamin , Tarrés-Freixas Ferran , Rovirosa Carla , Urrea Victor , Barreiro Antonio , Gonzalez-Tendero Anna , Cardona Maria , Ferrer Laura , Clotet Bonaventura , Carrillo Jorge , Aguilar-Gurrieri Carmen , Blanco Julià
Published: May 2023

Feline leukemia virus (FeLV) is one of the most prevalent infectious diseases in domestic cats. Although different commercial vaccines are available, none of them provides full protection. Thus, efforts to design a more efficient vaccine are needed. Our group has successfully engineered HIV-1 Gag-based VLPs that induce a potent and functional immune response against the HIV-1 transmembrane protein gp41. Here, we propose to use this concept to generate FeLV-Gag-based VLPs as a novel vaccine strategy against this retrovirus. By analogy to our HIV-1 platform, a fragment of the FeLV transmembrane p15E protein was exposed on FeLV-Gag-based VLPs. After optimization of Gag sequences, the immunogenicity of the selected candidates was evaluated in C57BL/6 and BALB/c mice, showing strong cellular and humoral responses to Gag but failing to generate anti-p15E antibodies. Altogether, this study not only tests the versatility of the enveloped VLP-based vaccine platform but also sheds light on FeLV vaccine research.
Involvement of Lipid Rafts in the Invasion of Opportunistic Bacteria Serratia into Eukaryotic Cells
Authors: Berson Yuliya , Khaitlina Sofia , Tsaplina Olga
Published: May 2023

Cell membrane rafts form signaling platforms on the cell surface, controlling numerous protein–protein and lipid–protein interactions. Bacteria invading eukaryotic cells trigger cell signaling to induce their own uptake by non-phagocytic cells. The aim of this work was to reveal the involvement of membrane rafts in the penetration of the bacteria Serratia grimesii and Serratia proteamaculans into eukaryotic cells. Our results show that the disruption of membrane rafts by MβCD in the three cell lines tested, M-HeLa, MCF-7 and Caco-2, resulted in a time-dependent decrease in the intensity of Serratia invasion. MβCD treatment produced a more rapid effect on the bacterial susceptibility of M-HeLa cells compared to other cell lines. This effect correlated with a faster assembly of the actin cytoskeleton upon treatment with MβCD in M-HeLa cells in contrast to that in Caco-2 cells. Moreover, the 30 min treatment of Caco-2 cells with MβCD produced an increase in the intensity of S. proteamaculans invasion. This effect correlated with an increase in EGFR expression. Together with the evidence that EGFR is involved in S. proteamaculans invasion but not in S. grimesii invasion, these results led to the conclusion that an increase in EGFR amount on the plasma membrane with the undisassembled rafts of Caco-2 cells after 30 min of treatment with MβCD may increase the intensity of S. proteamaculans but not of S. grimesii invasion. Thus, the MβCD-dependent degradation of lipid rafts, which enhances actin polymerization and disrupts signaling pathways from receptors on the host cell’s surface, reduces Serratia invasion.
Next Generation CD44v6-Specific CAR-NK Cells Effective against Triple Negative Breast Cancer
Authors: Raftery Martin J. , Franzén Alexander Sebastian , Radecke Clarissa , Boulifa Abdelhadi , Schönrich Günther , Stintzing Sebastian , Blohmer Jens-Uwe , Pecher Gabriele
Published: May 2023

There is a medical need to develop new and effective therapies against triple-negative breast cancer (TNBC). Chimeric antigen receptor (CAR) natural killer (NK) cells are a promising alternative to CAR-T cell therapy for cancer. A search for a suitable target in TNBC identified CD44v6, an adhesion molecule expressed in lymphomas, leukemias and solid tumors that is implicated in tumorigenesis and metastases. We have developed a next-generation CAR targeting CD44v6 that incorporates IL-15 superagonist and checkpoint inhibitor molecules. We could show that CD44v6 CAR-NK cells demonstrated effective cytotoxicity against TNBC in 3D spheroid models. The IL-15 superagonist was specifically released upon recognition of CD44v6 on TNBC and contributed to the cytotoxic attack. PD1 ligands are upregulated in TNBC and contribute to the immunosuppressive tumor microenvironment (TME). Competitive inhibition of PD1 neutralized inhibition by PD1 ligands expressed on TNBC. In total, CD44v6 CAR-NK cells are resistant to TME immunosuppression and offer a new therapeutic option for the treatment of BC, including TNBC.
Biosynthesis of Novel Ascorbic Acid Esters and Their Encapsulation in Lignin Nanoparticles as Carriers and Stabilizing Systems
Authors: Capecchi Eliana , Piccinino Davide , Nascimben Chiara , Tomaino Elisabetta , Ceccotti Vlas Natalia , Gabellone Sofia , Saladino Raffaele
Published: May 2023

A dual-target strategy was designed for the application of lignin nanoparticles in the lipase mediated biosynthesis of novel 3-O-ethyl-L-ascorbyl-6-ferulate and 3-O-ethyl-L-ascorbyl-6-palmitate and in their successive solvent-shift encapsulation in order to improve stability and antioxidant activity against temperature and pH-dependent degradation. The loaded lignin nanoparticles were fully characterized in terms of kinetic release, radical scavenging activity and stability under pH 3 and thermal stress (60 °C), showing improved antioxidant activity and high efficacy in the protection of ascorbic acid esters from degradation.
Chronic Kidney Disease Induced by Cadmium and Diabetes: A Quantitative Case-Control Study
Authors: Yimthiang Supabhorn , Vesey David A. , Pouyfung Phisit , Khamphaya Tanaporn , Gobe Glenda C. , Satarug Soisungwan
Published: May 2023

Kidney disease associated with chronic cadmium (Cd) exposure is primarily due to proximal tubule cell damage. This results in a sustained decline in glomerular filtration rate (GFR) and tubular proteinuria. Similarly, diabetic kidney disease (DKD) is marked by albuminuria and a declining GFR and both may eventually lead to kidney failure. The progression to kidney disease in diabetics exposed to Cd has rarely been reported. Herein, we assessed Cd exposure and the severity of tubular proteinuria and albuminuria in 88 diabetics and 88 controls, matched by age, gender and locality. The overall mean blood and Cd excretion normalized to creatinine clearance (Ccr) as ECd/Ccr were 0.59 µg/L and 0.0084 µg/L filtrate (0.96 µg/g creatinine), respectively. Tubular dysfunction, assessed by β2-microglobulin excretion rate normalized to Ccr(Eβ2M/Ccr) was associated with both diabetes and Cd exposure. Doubling of Cd body burden, hypertension and a reduced estimated GFR (eGFR) increased the risks for a severe tubular dysfunction by 1.3-fold, 2.6-fold, and 84-fold, respectively. Albuminuria did not show a significant association with ECd/Ccr, but hypertension and eGFR did. Hypertension and a reduced eGFR were associated with a 3-fold and 4-fold increases in risk of albuminuria. These findings suggest that even low levels of Cd exposure exacerbate progression of kidney disease in diabetics.
The Prognostic Value of Anti-PLA2R Antibodies Levels in Primary Membranous Nephropathy
Authors: Kukuy Olga Lesya , Cohen Ron , Gilburd Boris , Zeruya Eleanor , Weinstein Talia , Agur Timna , Dinour Dganit , Beckerman Pazit , Volkov Alexander , Nissan Johnatan , Davidson Tima , Amital Howard , Shoenfeld Yehuda , Shovman Ora
Published: May 2023

Anti-PLA2R antibodies (Ab) are a diagnostic and prognostic biomarker in primary membranous nephropathy (PMN). We assessed the relationship between the levels of anti-PLA2R Ab at diagnosis and different variables related to disease activity and prognosis in a western population of PMN patients. Forty-one patients with positive anti-PLA2R Ab from three nephrology departments in Israel were enrolled. Clinical and laboratory data were collected at diagnosis and after one year of follow-up, including serum anti-PLA2R Ab levels (ELISA) and glomerular PLA2R deposits on biopsy. Univariable statistical analysis and permutation-based ANOVA and ANCOVA tests were performed. The median [(interquartile range (IQR)) age of the patients was 63 [50–71], with 28 (68%) males. At the time of diagnosis, 38 (93%) of the patients had nephrotic range proteinuria, and 19 (46%) had heavy proteinuria (≥8 gr/24 h). The median [IQR] level of anti-PLA2R at diagnosis was 78 [35–183] RU/mL. Anti-PLA2R levels at diagnosis were correlated with 24 h proteinuria, hypoalbuminemia and remission after one year (p = 0.017, p = 0.003 and p = 0.034, respectively). The correlations for 24 h proteinuria and hypoalbuminemia remained significant after adjustment for immunosuppressive treatment (p = 0.003 and p = 0.034, respectively). Higher levels of anti-PLA2R Ab at diagnosis in patients with active PMN from a western population are associated with higher proteinuria, lower serum albumin and remission one year after the diagnosis. This finding supports the prognostic value of anti-PLA2R Ab levels and their possible use in stratifying PMN patients.
Deciphering the Molecular Mechanisms of Autonomic Nervous System Neuron Induction through Integrative Bioinformatics Analysis
Authors: Takayama Yuzo , Akagi Yuka , Kida Yasuyuki S.
Published: May 2023

In vitro derivation of human neurons in the autonomic nervous system (ANS) is an important technology, given its regulatory roles in maintaining homeostasis in the human body. Although several induction protocols for autonomic lineages have been reported, the regulatory machinery remains largely undefined, primarily due to the absence of a comprehensive understanding of the molecular mechanism regulating human autonomic induction in vitro. In this study, our objective was to pinpoint key regulatory components using integrated bioinformatics analysis. A protein–protein interaction network construction for the proteins encoded by the differentially expressed genes from our RNA sequencing data, and conducting subsequent module analysis, we identified distinct gene clusters and hub genes involved in the induction of autonomic lineages. Moreover, we analyzed the impact of transcription factor (TF) activity on target gene expression, revealing enhanced autonomic TF activity that could lead to the induction of autonomic lineages. The accuracy of this bioinformatics analysis was corroborated by employing calcium imaging to observe specific responses to certain ANS agonists. This investigation offers novel insights into the regulatory machinery in the generation of neurons in the ANS, which would be valuable for further understanding and precise regulation of autonomic induction and differentiation.
Near-Infrared Light-Activated Mesoporous Polydopamine for Temporomandibular Joint Osteoarthritis Combined Photothermal-Chemo Therapy
Authors: Li Qianli , Hou Yi , Cao Pinyin , Bi Ruiye , Zhu Songsong
Published: May 2023

The treatments generally employed for temporomandibular joint osteoarthritis (TMJOA) involve physical therapy and chemotherapy, etc., whose therapeutic efficacies are impaired by the side effects and suboptimal stimulus responsiveness. Although the intra-articular drug delivery system (DDS) has shown effectiveness in addressing osteoarthritis, there is currently little reported research regarding the use of stimuli-responsive DDS in managing TMJOA. Herein, we prepared a novel near-infrared (NIR) light-sensitive DDS (DS-TD/MPDA) by using mesoporous polydopamine nanospheres (MPDA) as NIR responders and drug carriers; diclofenac sodium (DS) as the anti-inflammatory medication; and 1-tetradecanol (TD) with a phase-inversion temperature of 39 °C as the drug administrator. Upon exposure to 808 nm NIR laser, DS-TD/MPDA could raise the temperature up to the melting point of TD through photothermal conversion, and intelligently trigger DS release. The resultant nanospheres exhibited an excellent photothermal effect and effectively controlled the release of DS through laser irradiation to accommodate the multifunctional therapeutic effect. More importantly, the biological evaluation of DS-TD/MPDA for TMJOA treatment was also performed for the first time. The experiments’ results demonstrated that DS-TD/MPDA displayed a good biocompatibility in vitro and in vivo during metabolism. After injection into the TMJ of rats afflicted with TMJOA induced by unilateral anterior crossbite for 14 days, DS-TD/MPDA could alleviate the deterioration of TMJ cartilage, thus ameliorating osteoarthritis. Therefore, DS-TD/MPDA could be a promising candidate for photothermal-chemotherapy for TMJOA.
Neurosteroids Mediate Neuroprotection in an In Vitro Model of Hypoxic/Hypoglycaemic Excitotoxicity via δ-GABAA Receptors without Affecting Synaptic Plasticity
Authors: Puig-Bosch Xènia , Ballmann Markus , Bieletzki Stefan , Antkowiak Bernd , Rudolph Uwe , Zeilhofer Hanns Ulrich , Rammes Gerhard
Published: May 2023

Neurosteroids and benzodiazepines are modulators of the GABAA receptors, thereby causing anxiolysis. Furthermore, benzodiazepines such as midazolam are known to cause adverse side-effects on cognition upon administration. We previously found that midazolam at nanomolar concentrations (10 nM) blocked long-term potentiation (LTP). Here, we aim to study the effect of neurosteroids and their synthesis using XBD173, which is a synthetic compound that promotes neurosteroidogenesis by binding to the translocator protein 18 kDa (TSPO), since they might provide anxiolytic activity with a favourable side-effect profile. By means of electrophysiological measurements and the use of mice with targeted genetic mutations, we revealed that XBD173, a selective ligand of the translocator protein 18 kDa (TSPO), induced neurosteroidogenesis. In addition, the exogenous application of potentially synthesised neurosteroids (THDOC and allopregnanolone) did not depress hippocampal CA1-LTP, the cellular correlate of learning and memory. This phenomenon was observed at the same concentrations that neurosteroids conferred neuroprotection in a model of ischaemia-induced hippocampal excitotoxicity. In conclusion, our results indicate that TSPO ligands are promising candidates for post-ischaemic recovery exerting neuroprotection, in contrast to midazolam, without detrimental effects on synaptic plasticity.
Halogen Bond to Experimentally Significant N-Heterocyclic Carbenes (I, IMe2, IiPr2, ItBu2, IPh2, IMes2, IDipp2, IAd2; I = Imidazol-2-ylidene)
Authors: Jabłoński Mirosław
Published: May 2023

The subjects of the article are halogen bonds between either XCN or XCCH (X = Cl, Br, I) and the carbene carbon atom in imidazol-2-ylidene (I) or its derivatives (IR2) with experimentally significant and systematically increased R substituents at both nitrogen atoms: methyl = Me, iso-propyl = iPr, tert-butyl = tBu, phenyl = Ph, mesityl = Mes, 2,6-diisopropylphenyl = Dipp, 1-adamantyl = Ad. It is shown that the halogen bond strength increases in the order Cl < Br < I and the XCN molecule forms stronger complexes than XCCH. Of all the carbenes considered, IMes2 forms the strongest and also the shortest halogen bonds with an apogee for complex IMes2⋯ICN for which D0 = 18.71 kcal/mol and dC⋯I = 2.541 Å. In many cases, IDipp2 forms as strong halogen bonds as IMes2. Quite the opposite, although characterized by the greatest nucleophilicity, ItBu2 forms the weakest complexes (and the longest halogen bonds) if X ≠ Cl. While this finding can easily be attributed to the steric hindrance exerted by the highly branched tert-butyl groups, it appears that the presence of the four C-H⋯X hydrogen bonds may also be of importance here. Similar situation occurs in the case of complexes with IAd2.
Nanoparticles and Other Nanostructures and the Control of Pathogens: From Bench to Vaccines
Authors: Boudier Ariane , Le Faou Alain
Published: May 2023

Parasites and microorganisms (protozoa, bacteria, and viruses) are still a concern despite progress in hygiene and anti-infectious therapy [...]
Rare Diseases: Implementation of Molecular Diagnosis, Pathogenesis Insights and Precision Medicine Treatment
Authors: Larizza Lidia , Cubellis Maria Vittoria
Published: May 2023

Rare Diseases (RD) do not have an exact definition since local authorities define the criteria in different ways, from fewer than 5 people in 10,000, according to the European Union, to the standard world average of 40 cases per 100,000 people [...]
Role of Calcium Modulation in the Pathophysiology and Treatment of Alzheimer’s Disease
Authors: Baracaldo-Santamaría Daniela , Avendaño-Lopez Sara Sofia , Ariza-Salamanca Daniel Felipe , Rodriguez-Giraldo Mateo , Calderon-Ospina Carlos A. , González-Reyes Rodrigo E. , Nava-Mesa Mauricio O.
Published: May 2023

Alzheimer’s disease (AD) is a chronic neurodegenerative disease and the most frequent cause of progressive dementia in senior adults. It is characterized by memory loss and cognitive impairment secondary to cholinergic dysfunction and N-methyl-D-aspartate (NMDA)-mediated neurotoxicity. Intracellular neurofibrillary tangles, extracellular plaques composed of amyloid-β (Aβ), and selective neurodegeneration are the anatomopathological hallmarks of this disease. The dysregulation of calcium may be present in all the stages of AD, and it is associated with other pathophysiological mechanisms, such as mitochondrial failure, oxidative stress, and chronic neuroinflammation. Although the cytosolic calcium alterations in AD are not completely elucidated, some calcium-permeable channels, transporters, pumps, and receptors have been shown to be involved at the neuronal and glial levels. In particular, the relationship between glutamatergic NMDA receptor (NMDAR) activity and amyloidosis has been widely documented. Other pathophysiological mechanisms involved in calcium dyshomeostasis include the activation of L-type voltage-dependent calcium channels, transient receptor potential channels, and ryanodine receptors, among many others. This review aims to update the calcium-dysregulation mechanisms in AD and discuss targets and molecules with therapeutic potential based on their modulation.
Revolutionizing Radiotoxicity Management with Mesenchymal Stem Cells and Their Derivatives: A Focus on Radiation-Induced Cystitis
Authors: Helissey Carole , Cavallero Sophie , Guitard Nathalie , Théry Hélène , Chargari Cyrus , François Sabine
Published: May 2023

Although radiation therapy plays a crucial role in cancer treatment, and techniques have improved continuously, irradiation induces side effects in healthy tissue. Radiation cystitis is a potential complication following the therapeutic irradiation of pelvic cancers and negatively impacts patients’ quality of life (QoL). To date, no effective treatment is available, and this toxicity remains a therapeutic challenge. In recent times, stem cell-based therapy, particularly the use of mesenchymal stem cells (MSC), has gained attention in tissue repair and regeneration due to their easy accessibility and their ability to differentiate into several tissue types, modulate the immune system and secrete substances that help nearby cells grow and heal. In this review, we will summarize the pathophysiological mechanisms of radiation-induced injury to normal tissues, including radiation cystitis (RC). We will then discuss the therapeutic potential and limitations of MSCs and their derivatives, including packaged conditioned media and extracellular vesicles, in the management of radiotoxicity and RC.
Proton Pumps: Molecular Mechanisms, Inhibitors and Activators of Proton Pumping
Authors: Siletsky Sergey A.
Published: May 2023

Protein molecular machines, also known as proton pumps, are the most important element of biological membranes [...]
Individualized or Uniform De-Escalation Strategies for Antiplatelet Therapy in Acute Coronary Syndrome: A Review of Clinical Trials with Platelet Function Testing and Genetic Testing-Based Protocols
Authors: El Abdallaoui Oumaima El Alaoui , Tornyos Dániel , Lukács Réka , Szabó Dóra , Komócsi András
Published: May 2023

This comprehensive literature review assessed the effectiveness of precision medicine approaches in individualizing P2Y12 de-escalation strategies, such as platelet function testing guidance, genetic testing guidance, and uniform de-escalation, for acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). Analyzing six trials with a total of 13,729 patients, the cumulative analyses demonstrated a significant reduction in major adverse cardiac events (MACE), net adverse clinical events (NACE), and major and minor bleeding events with P2Y12 de-escalation. Specifically, the analysis found a 24% reduction of MACE and a 22% reduction of adverse event risk (relative risk (RR) 0.76, 95% confidence interval (CI): 0.71–0.82, and RR: 0.78, 95% CI 0.67–0.92, respectively). Reductions in bleeding events were highest with uniform unguided de-escalation, followed by guided de-escalations, while ischemic event rates were similarly lower across all three strategies. Although the review highlights the potential of individualized P2Y12 de-escalation strategies to offer a safer alternative to the long-term potent P2Y12 inhibitor-based dual antiplatelet therapy, it also indicates that laboratory-guided precision medicine approaches may not yet offer the expected benefits, necessitating further research to optimize individualized strategies and evaluate the potential of precision medicine approaches in this context.
The Mutational Landscape of SARS-CoV-2
Authors: Saldivar-Espinoza Bryan , Garcia-Segura Pol , Novau-Ferré Nil , Macip Guillem , Martínez Ruben , Puigbò Pere , Cereto-Massagué Adrià , Pujadas Gerard , Garcia-Vallve Santiago
Published: May 2023

Mutation research is crucial for detecting and treating SARS-CoV-2 and developing vaccines. Using over 5,300,000 sequences from SARS-CoV-2 genomes and custom Python programs, we analyzed the mutational landscape of SARS-CoV-2. Although almost every nucleotide in the SARS-CoV-2 genome has mutated at some time, the substantial differences in the frequency and regularity of mutations warrant further examination. C>U mutations are the most common. They are found in the largest number of variants, pangolin lineages, and countries, which indicates that they are a driving force behind the evolution of SARS-CoV-2. Not all SARS-CoV-2 genes have mutated in the same way. Fewer non-synonymous single nucleotide variations are found in genes that encode proteins with a critical role in virus replication than in genes with ancillary roles. Some genes, such as spike (S) and nucleocapsid (N), show more non-synonymous mutations than others. Although the prevalence of mutations in the target regions of COVID-19 diagnostic RT-qPCR tests is generally low, in some cases, such as for some primers that bind to the N gene, it is significant. Therefore, ongoing monitoring of SARS-CoV-2 mutations is crucial. The SARS-CoV-2 Mutation Portal provides access to a database of SARS-CoV-2 mutations.
Fisetin, an Anti-Inflammatory Agent, Overcomes Radioresistance by Activating the PERK-ATF4-CHOP Axis in Liver Cancer
Authors: Kim Tae Woo
Published: May 2023

Fisetin, a well-known plant flavonol from the natural flavonoid group, is found in traditional medicines, plants, vegetables, and fruits. Fisetin also has anti-oxidant, anti-inflammatory, and anti-tumor effects. This study investigated the anti-inflammatory effects of fisetin in LPS-induced Raw264.7 cells and found that fisetin reduced the LPS-induced production of pro-inflammation markers, such as TNF-α, IL-1β, and IL-6, demonstrating the anti-inflammatory effects of fisetin. Furthermore, this study investigated the anti-cancer effects of fisetin and found that fisetin induced apoptotic cell death and ER stress through intracellular calcium (Ca2+) release, the PERK-ATF4-CHOP signaling pathway, and induction of GRP78 exosomes. However, the suppression of PERK and CHOP inhibited the fisetin-induced cell death and ER stress. Interestingly, fisetin induced apoptotic cell death and ER stress and inhibited the epithelial-mesenchymal transition phenomenon under radiation in radiation-resistant liver cancer cells. These findings indicate that the fisetin-induced ER stress can overcome radioresistance and induce cell death in liver cancer cells following radiation. Therefore, the anti-inflammatory agent fisetin, in combination with radiation, may be a powerful immunotherapy strategy to overcome resistance in an inflammatory tumor microenvironment.
Revisiting Fur Regulon Leads to a Comprehensive Understanding of Iron and Fur Regulation
Authors: Hou Chaofan , Liu Lin , Ju Xian , Xiao Yunzhu , Li Bingyu , You Conghui
Published: May 2023

Iron is an essential element because it functions as a cofactor of many enzymes, but excess iron causes cell damage. Iron hemostasis in Escherichia coli was transcriptionally maintained by the ferric uptake regulator (Fur). Despite having been studied extensively, the comprehensive physiological roles and mechanisms of Fur-coordinated iron metabolism still remain obscure. In this work, by integrating a high-resolution transcriptomic study of the Fur wild-type and knockout Escherichia coli K-12 strains in the presence or absence of iron with high-throughput ChIP-seq assay and physiological studies, we revisited the regulatory roles of iron and Fur systematically and discovered several intriguing features of Fur regulation. The size of the Fur regulon was expanded greatly, and significant discrepancies were observed to exist between the regulations of Fur on the genes under its direct repression and activation. Fur showed stronger binding strength to the genes under its repression, and genes that were repressed by Fur were more sensitive to Fur and iron regulation as compared to the genes that were activated by Fur. Finally, we found that Fur linked iron metabolism to many essential processes, and the systemic regulations of Fur on carbon metabolism, respiration, and motility were further validated or discussed. These results highlight how Fur and Fur-controlled iron metabolism affect many cellular processes in a systematic way.
Modulation of Membrane Trafficking of AQP5 in the Lens in Response to Changes in Zonular Tension Is Mediated by the Mechanosensitive Channel TRPV1
Authors: Petrova Rosica S. , Nair Nikhil , Bavana Nandini , Chen Yadi , Schey Kevin L. , Donaldson Paul J.
Published: May 2023

In mice, the contraction of the ciliary muscle via the administration of pilocarpine reduces the zonular tension applied to the lens and activates the TRPV1-mediated arm of a dual feedback system that regulates the lens’ hydrostatic pressure gradient. In the rat lens, this pilocarpine-induced reduction in zonular tension also causes the water channel AQP5 to be removed from the membranes of fiber cells located in the anterior influx and equatorial efflux zones. Here, we determined whether this pilocarpine-induced membrane trafficking of AQP5 is also regulated by the activation of TRPV1. Using microelectrode-based methods to measure surface pressure, we found that pilocarpine also increased pressure in the rat lenses via the activation of TRPV1, while pilocarpine-induced removal of AQP5 from the membrane observed using immunolabelling was abolished by pre-incubation of the lenses with a TRPV1 inhibitor. In contrast, mimicking the actions of pilocarpine by blocking TRPV4 and then activating TRPV1 resulted in sustained increase in pressure and the removal of AQP5 from the anterior influx and equatorial efflux zones. These results show that the removal of AQP5 in response to a decrease in zonular tension is mediated by TRPV1 and suggest that regional changes to PH2O contribute to lens hydrostatic pressure gradient regulation.
Bioefficacy of an Oil-Emulsion Formulation of Entomopathogenic Fungus, Metarhizium anisopliae against Adult Red Palm Weevil, Rhynchophorus ferrugineus
Authors: Lei Cheong Jia , Ahmad Raja Hasya Ilyana Raja , Halim Najihah Abdul , Asib Norhayu , Zakaria Azlina , Azmi Wahizatul Afzan
Published: May 2023

The red palm weevil (RPW), Rhynchophorus ferrugineus, poses a severe threat to agro-industrial crops, particularly major cultivated palm species. Infestations result in economic losses due to reduced fruit quality and yield. The entomopathogenic fungus, Metarhizium anisopliae, has shown promise as a potential biocontrol agent against the RPW. However, the use of an emulsion formulation of M. anisopliae for managing this serious insect pest has yet to be fully explored. The oil-emulsion formulation containing this entomopathogen may enhance the conidia’s stability, prolong its lifetime, and reduce the impact of heat stress or UV irradiation on the fungus. Therefore, this study aimed to investigate the bioefficacy of a new oil-in-glycerol emulsion formulation on mycoinsecticidal activity against RPW adults by direct and indirect bioassays. Results showed that conidia concentration was directly proportional to the RPW mortality percentage. The LT50 of 8.183 days was achieved by the conidial formulation against RPW, with a significantly lower LC50 (1.910 × 105 conidia mL−1) compared to the aqueous conidia suspension (LT50 = 8.716 days; LC50 = 7.671 × 105 conidia mL−1). Indirect bioassays revealed that the oil-in-glycerol emulsion had a disease-spreading ability that resulted in up to 56.67% RPW mortality. A zero E-value reading indicates that the DNA sequence being studied is highly similar to that of the fungal species M. anisopliae, which has been identified in the NCBI database. Although the new emulsion formulation has improved the efficacy and pathogenicity of M. anisopliae in vitro, it is important to also consider the fungal pathogen’s compatibility with other agricultural practices to prevent any loss of control efficiency in the actual usage environment.