bluuebunny/crossref_metadata_2025 huggingface dataset:
TRNT-1 Deficiency Is Associated with Loss of tRNA Integrity and Imbalance of Distinct Proteins
Authors: Fatica Thet , Naas Turaya , Liwak Urszula , Slaa Hannah , Souaid Maryam , Frangione Brianna , Kattini Ribal , Gaudreau-Lapierre Antoine , Trinkle-Mulcahy Laura , Chakraborty Pranesh , Holcik Martin
Published: May 2023

Mitochondrial diseases are a group of heterogeneous disorders caused by dysfunctional mitochondria. Interestingly, a large proportion of mitochondrial diseases are caused by defects in genes associated with tRNA metabolism. We recently discovered that partial loss-of-function mutations in tRNA Nucleotidyl Transferase 1 (TRNT1), the nuclear gene encoding the CCA-adding enzyme essential for modifying both nuclear and mitochondrial tRNAs, causes a multisystemic and clinically heterogenous disease termed SIFD (sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay; SIFD). However, it is not clear how mutations in a general and essential protein like TRNT1 cause disease with such clinically broad but unique symptomatology and tissue involvement. Using biochemical, cell, and mass spectrometry approaches, we demonstrate that TRNT1 deficiency is associated with sensitivity to oxidative stress, which is due to exacerbated, angiogenin-dependent cleavage of tRNAs. Furthermore, reduced levels of TRNT1 lead to phosphorylation of Eukaryotic Translation Initiation Factor 2 Subunit Alpha (eIF2α), increased reactive oxygen species (ROS) production, and changes in the abundance of distinct proteins. Our data suggest that the observed variable SIFD phenotypes are likely due to dysregulation of tRNA maturation and abundance, which in turn negatively affects the translation of distinct proteins.
Machine-Learning-Based Hybrid Modeling for Geological Hazard Susceptibility Assessment in Wudou District, Bailong River Basin, China
Authors: Wang Zhijun , Chen Zhuofan , Ma Ke , Zhang Zuoxiong
Published: May 2023

In the mapping and assessment of mountain hazard susceptibility using machine learning models, the selection of model parameters plays a critical role in the accuracy of predicting models. In this study, we present a novel approach for developing a prediction model based on random forest (RF) by incorporating ensembles of hyperparameter optimization. The performance of the RF model is enhanced by employing a Bayesian optimization (Bayes) method and a genetic algorithm (GA) and verified in the Wudu section of the Bailong River basin, China, which is a typical hazard-prone, mountainous area. We identified fourteen influential factors based on field measurements to describe the “avalanche–landslide–debris flow” hazard chains in the study area. We constructed training (80%) and validation (20%) datasets for 378 hazard sites. The performance of the models was assessed using standard statistical metrics, including recall, confusion matrix, accuracy, F1, precision, and area under the operating characteristic curve (AUC), based on a multicollinearity analysis and Relief-F two-step evaluation. The results indicate that all three models, i.e., RF, GA-RF, and Bayes-RF, achieved good performance (AUC: 0.89~0.92). The Bayes-RF model outperformed the other two models (AUC = 0.92). Therefore, this model is highly accurate and robust for mountain hazard susceptibility assessment and is useful for the study area as well as other regions. Additionally, stakeholders can use the susceptibility map produced to guide mountain hazard prevention and control measures in the region.
Seeking Flood Risk-Minimization: How to Benefit from the Use/Availability of Heavy Rainfall-Risk Maps
Authors: Bone Christian , Rubinato Matteo , Bosseler Bert , Schlüter Marco
Published: May 2023

The 2021 flooding events in The Netherlands, Belgium and Germany have sensitized many municipalities across Europe and especially in Germany, the federal states of North Rhine-Westphalia (NRW) and Rhineland-Palatinate, having been particularly affected, have formulated more extensive requirements for the municipalities to be able to manage these drastic situations. Flood risks and heavy rainfall maps are crucial instruments in this context because they serve as a basis for identifying risks and also for selecting suitable measures to minimize them and, in 2021, in Germany, the Federal Agency for Cartography and Geodesy (BKG) made available for the first time a state-wide, cross-municipal heavy rainfall information map for the state of North Rhine-Westphalia, in which heavy rainfall and flooding risks are recognizable for every citizen. Therefore, municipalities that already had their own heavy rainfall maps had a comparative possibility of plausibility checks, while those that did not yet have their own heavy rainfall map, had the possibility to benefit from these resources. Especially in this second scenario, the municipalities and the wastewater utilities need reliable practical advice on how to classify the information from the maps regarding drainage consequences, and this paper aims to fill this void, summarizing the experience of the 80 municipalities represented in the KomNetAbwasser in dealing with heavy rainfall maps and discussing requirements for their informative value. Furthermore, measures for risk minimization and their prioritization are also proposed, focusing on risk identification, organizational tasks, action planning and implementation, analysis of the hazard maps, risk assessment and the selection of emergency measures.
Adaptation and Validation of the Spanish Version of Kogan’s Attitude toward Older People Scale (KAOP)
Authors: Fernández-Muñoz Juan José , Parra-Fernández Maria Laura , Onieva-Zafra Maria Dolores , Expósito-González Raúl , Marquinez-Rengifo José Manuel , Fernández-Martínez Elia
Published: May 2023

It is essential to understand the behavior and attitudes of nurses towards older people to improve clinical practice and quality of care in the gerontological sector. A clearer understanding of the attitudes that drive nurses toward the desire to work with older people would be a good starting point to encourage the development of positive and nurturing attitudes. A cross-sectional study with non-probabilistic sampling and a self-administered questionnaire was conducted among 381 nursing students of the Faculty of Nursing at the University of Castilla La-Mancha to evaluate the psychometric properties of the Spanish Version of the Kogan’s Attitudes Towards Older People Scale (KAOP-S). Construct validity, internal consistency, and reliability were assessed. In total, 298 females and 83 males completed the questionnaires. Their mean age was 20.42 years. The results revealed a Cronbach’s alpha coefficient of 0.75 for the scale, which is comparable with other published versions of the KAOP Scale. The results of the exploratory factor analysis established that the scale has a two-factor solution and an explained variance of 25% in the sample. The KAOP-S was found to be a reliable and valid tool with good content and construct validity for assessing nursing students’ attitudes towards older people.
The Role of Subjective Wellbeing in Mediating Social Trust to the Mental Health of Health Workers
Authors: Xiong Change , Yao Yanqiu , Hu Tong , Cheng Jing , Xu Shandan , Liu Chaojie
Published: May 2023

Mental health problems of health workers are attracting increasing concerns in China and the world. A trustful relationship between health workers and patients is the foundation of quality patient care, which is currently under serious threat. This study aimed to determine the associations of social trust on subjective wellbeing and mental health of health workers. Using the survey data of 262 health workers extracted from the 2018 Chinese Family Panel Studies, a structural equation model with partial least square approach was established. The results showed that social trust was linked to both subjective wellbeing (β = 0.251, p < 0.01) and mental health (β = −0.210, p < 0.01). The effect of social trust on mental health was partially mediated by subjective wellbeing (51.87%). The association between social trust and subjective wellbeing was moderated by socioeconomic status: social trust has a stronger effect on subjective wellbeing in those with higher socioeconomic status. Erosion of social trust may present a serious risk to mental health and subjective wellbeing of health workers. High socioeconomic status can amplify the effect of social trust.
A Report of a Symptomatic Progressive Myeloma during Pregnancy and Postpartum Period from Asymptomatic State
Authors: Elgabry Gehad , Spencer Lydia , Siddiqi Hisam , Ojha Soumya , Wandroo Farooq
Published: May 2023

Multiple myeloma is a plasma cell malignancy that is most commonly observed in males in the sixth and seventh decade of life. The clinical scenario of multiple myeloma with concurrent pregnancy is considered to be very rare. We detail here the case of a young female with known IgG kappa multiple myeloma who was found to have a steady elevation of her IgG kappa paraprotein during pregnancy and symptomatic progression in the postpartum period. She delivered a healthy baby at 40 weeks gestation. We present a review of all reported cases of known multiple myeloma progressing during pregnancy and in the postpartum period, the treatments given, and their outcomes. The report also provides suggestions for diagnosis and management of myeloma during pregnancy in order to have an outcome of successful uncomplicated pregnancy with healthy offspring.
Molecular Diagnostics in Tomato: Chip Digital PCR Assays Targeted to Identify and Quantify Clavibacter michiganensis subsp. michiganensis and Ralstonia solanacearum in planta
Authors: Morcia Caterina , Piazza Isabella , Ghizzoni Roberta , Terzi Valeria , Carrara Ilaria , Bolli Giovanni , Chiusa Giorgio
Published: May 2023

Clavibacter michiganensis subsp. michiganensis (Cmm) and Ralstonia solanacearum (Rs) are important bacterial pathogens of tomatoes (Solanum lycopersicum), are included in A2 list in the EPPO (European and Mediterranean Plant Protection Organization) region and are recommended for regulation as quarantine pests. The control of quarantine pathogens requires accurate and rapid detection tools. In this study, a method based on chip digital PCR (cdPCR) was developed to identify and quantify Cmm and Rs. The assays were tested on pure bacteria samples and on tomato samples naturally contaminated or spiked with bacteria DNA. For a better estimation of infection level in host plants, duplex assays that are able to simultaneously amplify plant and bacteria DNA were developed. The two cdPCR assays proposed can be used for the rapid and timely detection of this group of high-risk quarantine bacteria to prevent the spread of pathogens and the occurrence of disease in other areas.
Associations of Content and Context of Communication with Prostate-Specific Antigen Testing
Authors: Alford Nicholas A. , Wongpaiboon Manasicha , Luque John S. , Harris Cynthia M. , Tawk Rima H.
Published: May 2023

There is limited research about the content and context of communication on prostate-specific antigen (PSA) testing among men in the state of Florida. The purpose of this study is to understand how the content communication (discussion of advantages and disadvantages of PSA testing between provider and patient; provider recommendations of PSA testing) and the context of communication (continuity of care denoted by the presence of a personal doctor) influence PSA testing. Data were drawn from the Florida Behavioral Risk Factor Surveillance System. Receipt of PSA testing was the primary outcome. Multiple logistic regression analyses were used to adjust for sociodemographic, clinical, healthcare access, and lifestyle characteristics when associating the content and context of communication with PSA testing. Discussions were classified into four mutually exclusive categories: discussions of advantages and disadvantages, only advantages, only disadvantages, and no discussion. The most significant predictors for PSA testing included physician recommendation, discussions including advantages, older age, non-smoking, and having a personal doctor. Individualized PSA screening may be a pathway to reducing racial disparities in screening for prostate cancer (PCa) and, by extension, lower incidence and mortality rates. Developing a bill to create an Office of Men’s Health at Health & Human Services is recommended.
Distinguishing Prevention from Treatment in Suicide Prevention. Comment on Turner et al. The Paradox of Suicide Prevention. Int. J. Environ. Res. Public Health 2022, 19, 14983
Authors: Obegi Joseph H.
Published: May 2023

In “The Paradox of Suicide Prevention”, Turner and colleagues made an important contribution: they applied Rose’s prevention paradox to suicide prevention efforts in healthcare systems. However, in doing so, they conflated prevention and treatment and did not distinguish suicide from suicidality. Their views may confuse efforts to design and implement clinical pathways for preventing suicide.
Spatiotemporal Distribution and Influencing Factors of Theft during the Pre-COVID-19 and COVID-19 Periods: A Case Study of Haining City, Zhejiang, China
Authors: Jiang Xiaomin , Zheng Ziwan , Zheng Ye , Mao Zhewei
Published: May 2023

Theft is an inevitable problem in the context of urbanization and poses a challenge to people’s lives and social stability. The study of theft and criminal behavior using spatiotemporal, big, demographic, and neighborhood data is important for guiding security prevention and control. In this study, we analyzed the theft frequency and location characteristics of the study area through mathematical statistics and hot spot analysis methods to discover the spatiotemporal divergence characteristics of theft in the study area during the pre-COVID-19 and COVID-19 periods. We detected the spatial variation pattern of the regression coefficients of the local areas of thefts in Haining City by modeling the influencing factors using the geographically weighted regression (GWR) analysis method. The results explained the relationship between theft and the influencing factors and showed that the regression coefficients had both positive and negative values in the pre-COVID-19 and COVID-19 periods, indicating that the spatial distribution of theft in urban areas of Haining City was not smooth. Factors related to life and work indicated densely populated areas had increased theft, and theft was negatively correlated with factors related to COVID-19. The other influencing factors were different in terms of their spatial distributions. Therefore, in terms of police prevention and control, video surveillance and police patrols need to be deployed in a focused manner to increase their inhibiting effect on theft according to the different effects of influencing factors during the pre-COVID-19 and COVID-19 periods.
Comprehensive Genetic Study of Malignant Cervical Paraganglioma
Authors: Snezhkina Anastasiya , Pavlov Vladislav , Fedorova Maria , Kalinin Dmitry , Pudova Elena , Kobelyatskaya Anastasiya , Bakhtogarimov Ildar , Krasnov George , Kudryavtseva Anna
Published: May 2023

Malignant middle ear paraganglioma (MEPGL) is an exceedingly rare tumor of the neuroendocrine system. In general, MEPGLs represent as slow growing and hypervascularized benign neoplasms. The genetic basis of MEPGL tumorigenesis has been poorly investigated. We report a case of malignant MEPGL accompanied by the comprehensive genetic analysis of the primary tumor and metastasis. Based on whole-exome sequencing data, the germline pathogenic mutation p.R230H in the SDHB gene, encoding for subunit B of mitochondrial complex II, was found in a patient. Analysis of somatic mutation spectra revealed five novel variants in different genes, including a potentially deleterious variant in UNC13C that was common for the tumor and metastasis. Identified somatic variants clustered into SBS1 and SBS5 mutational signatures. Of note, the primary tumor was characterized by Ki-67 4% and had an elevated mutational load (1.4/Mb); the metastasis’ mutational load was about 4.5 times higher (6.4/Mb). In addition, we revealed somatic loss of the wild-type SDHB allele, as well as loss of heterozygosity (LOH) at the 11p locus. Thus, germline mutation in SDHB combined with somatic LOH seem to be drivers that lead to the tumor’s initiation and progression. Other somatic changes identified can be additional disease-causing factors. Obtained results expand our understanding of molecular genetic mechanisms associated with the development of this rare tumor.
New Evidence on BPA’s Role in Adipose Tissue Development of Proinflammatory Processes and Its Relationship with Obesity
Authors: González-Casanova Jorge Enrique , Bermúdez Valmore , Caro Fuentes Nelson Javier , Angarita Lissé Chiquinquirá , Caicedo Nelson Hernando , Rivas Muñoz Jocelyn , Rojas-Gómez Diana Marcela
Published: May 2023

Bisphenol A (BPA) is a xenobiotic with endocrine disruptor properties which interacts with various receptors, eliciting a cellular response. In the plastic industry, BPA is widely used in the production of polycarbonate and epoxy-phenolic resins to provide elastic properties. It can be found in the lining of canned foods, certain plastic containers, thermal printing papers, composite dental fillings, and medical devices, among other things. Therefore, it is a compound that, directly or indirectly, is in daily contact with the human organism. BPA is postulated to be a factor responsible for the global epidemic of obesity and non-communicable chronic diseases, belonging to the obesogenic and diabetogenic group of compounds. Hence, this endocrine disruptor may be responsible for the development of metabolic disorders, promoting in fat cells an increase in proinflammatory pathways and upregulating the expression and release of certain cytokines, such as IL6, IL1β, and TNFα. These, in turn, at a systemic and local level, are associated with a chronic low-grade inflammatory state, which allows the perpetuation of the typical physiological complications of obesity.
Endotheliopathy in Acute COVID-19 and Long COVID
Authors: Vassiliou Alice G. , Vrettou Charikleia S. , Keskinidou Chrysi , Dimopoulou Ioanna , Kotanidou Anastasia , Orfanos Stylianos E.
Published: May 2023

The pulmonary endothelium is a highly regulated organ that performs a wide range of functions under physiological and pathological conditions. Since endothelial dysfunction has been demonstrated to play a direct role in sepsis and acute respiratory distress syndrome, its role in COVID-19 has also been extensively investigated. Indeed, apart from the COVID-19-associated coagulopathy biomarkers, new biomarkers were recognised early during the pandemic, including markers of endothelial cell activation or injury. We systematically searched the literature up to 10 March 2023 for studies examining the association between acute and long COVID-19 severity and outcomes and endothelial biomarkers.
Editorial for the Special Issue—“Recent Advances of Novel Pharmaceutical Designs for Anti-Cancer Therapies”
Authors: Biersack Bernhard
Published: May 2023

Cancer is one of the leading causes of death worldwide, despite the promising developments in terms of the curing and management of certain cancer types that have occurred over the last decades saving and prolonging the lives of numerous patients [...]
1,5-Anhydro-D-Fructose Exhibits Satiety Effects via the Activation of Oxytocin Neurons in the Paraventricular Nucleus
Authors: Nakata Masanori , Yamaguchi Yuto , Monnkawa Hikaru , Takahashi Midori , Zhang Boyang , Santoso Putra , Yada Toshihiko , Maruyama Ikuro
Published: May 2023

1,5-Anhydro-D-fructose (1,5-AF) is a bioactive monosaccharide that is produced by the glycogenolysis in mammalians and is metabolized to 1,5-anhydro-D-glucitol (1,5-AG). 1,5-AG is used as a marker of glycemic control in diabetes patients. 1,5-AF has a variety of physiological activities, but its effects on energy metabolism, including feeding behavior, are unclarified. The present study examined whether 1,5-AF possesses the effect of satiety. Peroral administration of 1,5-AF, and not of 1,5-AG, suppressed daily food intake. Intracerebroventricular (ICV) administration of 1,5-AF also suppressed feeding. To investigate the neurons targeted by 1,5-AF, we investigated c-Fos expression in the hypothalamus and brain stem. ICV injection of 1,5-AF significantly increased c-Fos positive oxytocin neurons and mRNA expression of oxytocin in the paraventricular nucleus (PVN). Moreover, 1,5-AF increased cytosolic Ca2+ concentration of oxytocin neurons in the PVN. Furthermore, the satiety effect of 1,5-AF was abolished in oxytocin knockout mice. These findings reveal that 1,5-AF activates PVN oxytocin neurons to suppress feeding, indicating its potential as the energy storage monitoring messenger to the hypothalamus for integrative regulation of energy metabolism.
Pharmacological Modulation of Excitotoxicity through the Combined Use of NMDA Receptor Inhibition and Group III mGlu Activation Reduces TMT-Induced Neurodegeneration in the Rat Hippocampus
Authors: Pershina Ekaterina V. , Chernomorets Irina Yu. , Fedorov Dmitry A. , Arkhipov Vladimir I.
Published: May 2023

We studied the neuroprotective properties of the non-competitive NMDA receptor antagonist memantine, in combination with a positive allosteric modulator of metabotropic glutamate receptors of Group III, VU 0422288. The treatment was started 48 h after the injection of neurotoxic agent trimethyltin (TMT) at 7.5 mg/kg. Three weeks after TMT injection, functional and morphological changes in a rat hippocampus were evaluated, including the expression level of genes characterizing glutamate transmission and neuroinflammation, animal behavior, and hippocampal cell morphology. Significant neuronal cell death occurred in the CA3 and CA4 regions, and to a lesser extent, in the CA1 and CA2 regions. The death of neurons in the CA1 field was significantly reduced in animals with a combined use of memantine and VU 0422288. In the hippocampus of these animals, the level of expression of genes characterizing glutamatergic synaptic transmission (Grin2b, Gria1, EAAT2) did not differ from the level in control animals, as well as the expression of genes characterizing neuroinflammation (IL1b, TGF beta 1, Aif1, and GFAP). However, the expression of genes characterizing neuroinflammation was markedly increased in the hippocampus of animals treated with memantine or VU 0422288 alone after TMT. The results of immunohistochemical studies confirmed a significant activation of microglia in the hippocampus three weeks after TMT injection. In contrast to the hilus, microglia in the CA1 region had an increase in rod-like cells. Moreover, in the CA1 field of the hippocampus of the animals of the MEM + VU group, the amount of such microglia was close to the control. Thus, the short-term modulation of glutamatergic synaptic transmission by memantine and subsequent activation of Group III mGluR significantly affected the dynamics of neurodegeneration in the hippocampus.
The State of the Art of Pediatric Multiple Sclerosis
Authors: Teleanu Raluca Ioana , Niculescu Adelina-Gabriela , Vladacenco Oana Aurelia , Roza Eugenia , Perjoc Radu-Stefan , Teleanu Daniel Mihai
Published: May 2023

Multiple sclerosis (MS) represents a chronic immune-mediated neurodegenerative disease of the central nervous system that generally debuts around the age of 20–30 years. Still, in recent years, MS has been increasingly recognized among the pediatric population, being characterized by several peculiar features compared to adult-onset disease. Unfortunately, the etiology and disease mechanisms are poorly understood, rendering the already limited MS treatment options with uncertain efficacy and safety in pediatric patients. Thus, this review aims to shed some light on the progress in MS therapeutic strategies specifically addressed to children and adolescents. In this regard, the present paper briefly discusses the etiology, risk factors, comorbidities, and diagnosis possibilities for pediatric-onset MS (POMS), further moving to a detailed presentation of current treatment strategies, recent clinical trials, and emerging alternatives. Particularly, promising care solutions are indicated, including new treatment formulations, stem cell therapies, and cognitive training methods.
Multiple Shades of Gray—Macrophages in Acute Allograft Rejection
Authors: Lackner Katharina , Ebner Susanne , Watschinger Katrin , Maglione Manuel
Published: May 2023

Long-term results following solid organ transplantation do not mirror the excellent short-term results achieved in recent decades. It is therefore clear that current immunosuppressive maintenance protocols primarily addressing the adaptive immune system no longer meet the required clinical need. Identification of novel targets addressing this shortcoming is urgently needed. There is a growing interest in better understanding the role of the innate immune system in this context. In this review, we focus on macrophages, which are known to prominently infiltrate allografts and, during allograft rejection, to be involved in the surge of the adaptive immune response by expression of pro-inflammatory cytokines and direct cytotoxicity. However, this active participation is janus-faced and unspecific targeting of macrophages may not consider the different subtypes involved. Under this premise, we give an overview on macrophages, including their origins, plasticity, and important markers. We then briefly describe their role in acute allograft rejection, which ranges from sustaining injury to promoting tolerance, as well as the impact of maintenance immunosuppressants on macrophages. Finally, we discuss the observed immunosuppressive role of the vitamin-like compound tetrahydrobiopterin and the recent findings that suggest the innate immune system, particularly macrophages, as its target.
Genome-Wide Characteristics of GH9B Family Members in Melon and Their Expression Profiles under Exogenous Hormone and Far-Red Light Treatment during the Grafting Healing Process
Authors: Zhu Yulei , Guo Jieying , Wu Fang , Yu Hanqi , Min Jiahuan , Zhao Yingtong , Xu Chuanqiang
Published: May 2023

β-1,4-glucanase can not only promote the wound healing of grafted seedlings but can also have a positive effect on a plant’s cell wall construction. As a critical gene of β-1,4-glucanase, GH9B is involved in cell wall remodeling and intercellular adhesion and plays a vital role in grafting healing. However, the GH9B family members have not yet been characterized for melons. In this study, 18 CmGH9Bs were identified from the melon genome, and these CmGH9Bs were located on 15 chromosomes. Our phylogenetic analysis of these CmGH9B genes and GH9B genes from other species divided them into three clusters. The gene structure and conserved functional domains of CmGH9Bs in different populations differed significantly. However, CmGH9Bs responded to cis elements such as low temperature, exogenous hormones, drought, and injury induction. The expression profiles of CmGH9Bs were different. During the graft healing process of the melon scion grafted onto the squash rootstock, both exogenous naphthyl acetic acid (NAA) and far-red light treatment significantly induced the upregulated expression of CmGH9B14 related to the graft healing process. The results provided a technical possibility for managing the graft healing of melon grafted onto squash by regulating CmGH9B14 expression.
Profiling the Urobiota in a Pediatric Population with Neurogenic Bladder Secondary to Spinal Dysraphism
Authors: De Maio Flavio , Grotti Giacomo , Mariani Francesco , Buonsenso Danilo , Santarelli Giulia , Bianco Delia Mercedes , Posteraro Brunella , Sanguinetti Maurizio , Rendeli Claudia
Published: May 2023

The human bladder has been long thought to be sterile until that, only in the last decade, advances in molecular biology have shown that the human urinary tract is populated with microorganisms. The relationship between the urobiota and the development of urinary tract disorders is now of great interest. Patients with spina bifida (SB) can be born with (or develop over time) neurological deficits due to damaged nerves that originate in the lower part of the spinal cord, including the neurogenic bladder. This condition represents a predisposing factor for urinary tract infections so that the most frequently used approach to treat patients with neurogenic bladder is based on clean intermittent catheterization (CIC). In this study, we analyzed the urobiota composition in a pediatric cohort of patients with SB compared to healthy controls, as well as the urobiota characteristics based on whether patients received CIC or not.
Combined Supplementation of Clostridium butyricum and Bifidobacterium infantis Diminishes Chronic Unpredictable Mild Stress-Induced Intestinal Alterations via Activation of Nrf-2 Signaling Pathway in Rats
Authors: Fatima Sabiha , Altwaijry Haifa , Abulmeaty Mahmoud M. A. , Abudawood Manal , Siddiqi Nikhat J. , Alrashoudi Reem Hamoud , Alsobaie Sarah
Published: May 2023

Exposure to long-term chronic unpredictable mild stress (CUMS) can cause redox imbalance and inflammation, which may affect the integrity of the gut barrier. The present study was conducted to investigate the effects of a probiotics bacterium mixture, including Clostridium butyricum (C. butyricum) and Bifidobacterium infantis (B. infantis), on the intestinal homeostasis in rats exposed to multiple low-intensity stressors for 28 days. The mechanism of CUMS-induced altered intestinal homeostasis was evaluated by focusing on the nuclear factor-E2-related factor-2 (Nrf-2) pathway. In contrast to the CUMS group, probiotic mixture supplementation significantly (p < 0.01) reversed the stress-induced elevated corticosterone level, protein and lipid oxidation, and increased enzymatic and non-enzymatic antioxidant levels, as well as upregulated Nrf-2/HO-1 pathway. Probiotics supplementation further significantly (p < 0.01) decreased the CUMS-induced inflammation, altered T-lymphocyte levels, and suppressed the protein expression of nuclear factor kappa B (NF-κB) in rat intestines. Improvement in histological changes and intestinal barrier integrity further validate the beneficial effects of probiotic mixtures on CUMS-induced altered intestinal morphology. In conclusion, our results suggest that the combination of C. butyricum and B. infantis significantly attenuated CUMS-induced oxidative stress, inflammation, and T-lymphocyte modulation by upregulating Nrf-2/HO-1 signaling and inhibiting NF-κB expression in rat intestine.
The Air–Liquid Interface Reorganizes Membrane Lipids and Enhances the Recruitment of Slc26a3 to Lipid-Rich Domains in Human Colonoid Monolayers
Authors: Tse C. Ming , Zhang Zixin , Lin Ruxian , Sarker Rafiquel , Donowitz Mark , Singh Varsha
Published: May 2023

Cholesterol-rich membrane domains, also called lipid rafts (LRs), are specialized membrane domains that provide a platform for intracellular signal transduction. Membrane proteins often cluster in LRs that further aggregate into larger platform-like structures that are enriched in ceramides and are called ceramide-rich platforms (CRPs). The role of CRPs in the regulation of intestinal epithelial functions remains unknown. Down-regulated in adenoma (DRA) is an intestinal Cl−/HCO3− antiporter that is enriched in LRs. However, little is known regarding the mechanisms involved in the regulation of DRA activity. The air–liquid interface (ALI) was created by removing apical media for a specified number of days; from 12–14 days post-confluency, Caco-2/BBe cells or a colonoid monolayer were grown as submerged cultures. Confocal imaging was used to examine the dimensions of membrane microdomains that contained DRA. DRA expression and activity were enhanced in Caco-2/BBe cells and human colonoids using an ALI culture method. ALI causes an increase in acid sphingomyelinase (ASMase) activity, an enzyme responsible for enhancing ceramide content in the plasma membrane. ALI cultures expressed a larger number of DRA-containing platforms with dimensions >2 µm compared to cells grown as submerged cultures. ASMase inhibitor, desipramine, disrupted CRPs and reduced the ALI-induced increase in DRA expression in the apical membrane. Exposing normal human colonoid monolayers to ALI increased the ASMase activity and enhanced the differentiation of colonoids along with basal and forskolin-stimulated DRA activities. ALI increases DRA activity and expression by increasing ASMase activity and platform formation in Caco-2/BBe cells and by enhancing the differentiation of colonoids.
From Pathogenesis to Intervention: The Importance of the Microbiome in Oral Mucositis
Authors: Bruno Julia S. , Al-Qadami Ghanyah H. , Laheij Alexa M. G. A. , Bossi Paolo , Fregnani Eduardo R. , Wardill Hannah R.
Published: May 2023

Oral mucositis (OM) is a common and impactful toxicity of standard cancer therapy, affecting up to 80% of patients. Its aetiology centres on the initial destruction of epithelial cells and the increase in inflammatory signals. These changes in the oral mucosa create a hostile environment for resident microbes, with oral infections co-occurring with OM, especially at sites of ulceration. Increasing evidence suggests that oral microbiome changes occur beyond opportunistic infection, with a growing appreciation for the potential role of the microbiome in OM development and severity. This review collects the latest articles indexed in the PubMed electronic database which analyse the bacterial shift through 16S rRNA gene sequencing methodology in cancer patients under treatment with oral mucositis. The aims are to assess whether changes in the oral and gut microbiome causally contribute to oral mucositis or if they are simply a consequence of the mucosal injury. Further, we explore the emerging role of a patient’s microbial fingerprint in OM development and prediction. The maintenance of resident bacteria via microbial target therapy is under constant improvement and should be considered in the OM treatment.
Pax4 in Health and Diabetes
Authors: Ko Jenna , Fonseca Vivian A. , Wu Hongju
Published: May 2023

Paired box 4 (Pax4) is a key transcription factor involved in the embryonic development of the pancreatic islets of Langerhans. Consisting of a conserved paired box domain and a homeodomain, this transcription factor plays an essential role in early endocrine progenitor cells, where it is necessary for cell-fate commitment towards the insulin-secreting β cell lineage. Knockout of Pax4 in animal models leads to the absence of β cells, which is accompanied by a significant increase in glucagon-producing α cells, and typically results in lethality within days after birth. Mutations in Pax4 that cause an impaired Pax4 function are associated with diabetes pathogenesis in humans. In adulthood, Pax4 expression is limited to a distinct subset of β cells that possess the ability to proliferate in response to heightened metabolic needs. Upregulation of Pax4 expression is known to promote β cell survival and proliferation. Additionally, ectopic expression of Pax4 in pancreatic islet α cells or δ cells has been found to generate functional β-like cells that can improve blood glucose regulation in experimental diabetes models. Therefore, Pax4 represents a promising therapeutic target for the protection and regeneration of β cells in the treatment of diabetes. The purpose of this review is to provide a thorough and up-to-date overview of the role of Pax4 in pancreatic β cells and its potential as a therapeutic target for diabetes.
Distinct Signaling Pathways for Autophagy-Driven Cell Death and Survival in Adult Hippocampal Neural Stem Cells
Authors: Jeong Seol-Hwa , An Hyun-Kyu , Ha Shinwon , Yu Seong-Woon
Published: May 2023

Autophagy is a cellular catabolic process that degrades and recycles cellular materials. Autophagy is considered to be beneficial to the cell and organism by preventing the accumulation of toxic protein aggregates, removing damaged organelles, and providing bioenergetic substrates that are necessary for survival. However, autophagy can also cause cell death depending on cellular contexts. Yet, little is known about the signaling pathways that differentially regulate the opposite outcomes of autophagy. We have previously reported that insulin withdrawal (IW) or corticosterone (CORT) induces autophagic cell death (ACD) in adult hippocampal neural stem (HCN) cells. On the other hand, metabolic stresses caused by 2-deoxy-D-glucose (2DG) and glucose-low (GL) induce autophagy without death in HCN cells. Rather, we found that 2DG-induced autophagy was cytoprotective. By comparing IW and CORT conditions with 2DG treatment, we revealed that ERK and JNK are involved with 2DG-induced protective autophagy, whereas GSK-3β regulates death-inducing autophagy. These data suggest that cell death and survival-promoting autophagy undergo differential regulation with distinct signaling pathways in HCN cells.
The Role of the Residue at Position 2 in the Catalytic Activity of AA9 Lytic Polysaccharide Monooxygenases
Authors: Liu Yucui , Ma Wei , Fang Xu
Published: May 2023

AA9 lytic polysaccharide monooxygenases (LPMOs) are copper-dependent metalloenzymes that play a major role in cellulose degradation and plant infection. Understanding the AA9 LPMO mechanism would facilitate the improvement of plant pathogen control and the industrial application of LPMOs. Herein, via point mutation, we investigated the role of glycine 2 residue in cellulose degradation by Thermoascus aurantiacus AA9 LPMOs (TaAA9). A computational simulation showed that increasing the steric properties of this residue by replacing glycine with threonine or tyrosine altered the H-bonding network of the copper center and copper coordination geometry, decreased the surface charge of the catalytic center, weakened the TaAA9-substrate interaction, and enhanced TaAA9-product binding. Compared with wild-type TaAA9, G2T-TaAA9 and G2Y-TaAA9 variants showed attenuated copper affinity, reduced oxidative product diversity and decreased substrate Avicel binding, as determined using ITC, MALDI-TOF/TOF MS and cellulose binding analyses, respectively. Consistently, the enzymatic activity and synergy with cellulase of the G2T-TaAA9 and G2Y-TaAA9 variants were lower than those of TaAA9. Hence, the investigated residue crucially affects the catalytic activity of AA9 LPMOs, and we propose that the electropositivity of copper may correlate with AA9 LPMO activity. Thus, the relationship among the amino acid at position 2, surface charge and catalytic activity may facilitate an understanding of the proteins in AA9 LPMOs.
In Vivo and In Vitro Characterization of Close Analogs of Compound KA-11, a New Antiseizure Drug Candidate
Authors: Andres-Mach Marta , Zagaja Mirosław , Szala-Rycaj Joanna , Szewczyk Aleksandra , Abram Michał , Jakubiec Marcin , Ciepiela Katarzyna , Socała Katarzyna , Wlaź Piotr , Latacz Gniewomir , Khan Nadia , Kaminski Krzysztof
Published: May 2023

Epilepsy is a neurological disorder involving a number of disease syndromes with a complex etiology. A properly matched antiseizure drug (ASD) gives remission in up to 70% of patients. Nevertheless, there is still a group of about 30% of patients suffering from drug-resistant epilepsy. Consequently, the development of new more effective and/or safer ASDs is still an unmet clinical need. Thus, our current studies were focused on the structural optimization/modifications of one of the leading compounds, KA-11, aiming at the improvement of its antiseizure activity. As a result, we designed and synthesized two close analogs with highly pronounced drug-like physicochemical properties according to in silico predictions, namely KA-228 and KA-232, which were subsequently tested in a panel of animal seizure models, i.e., MES, 6 Hz (32 mA), scPTZ and ivPTZ. Among these compounds, KA-232, which was designed as a water-soluble salt, was distinctly more effective than KA-228 and assured similar antiseizure protection as its chemical prototype KA-11. With the aim of a more detailed characterization of both new molecules, in vitro binding tests were performed to evaluate the potential mechanisms of action. Furthermore, KA-232 was also evaluated in several ADME-Tox studies, and the results obtained strongly supported its drug-like potential. The proposed chemical modification of KA-11 enabled the identification of new pharmacologically active chemotypes, particularly water-soluble KA-232, which, despite the lack of better efficacy than the leading compound, may be used as a chemical prototype for the development of new ASDs, as well as substances potentially active in other neurological or neurodegenerative conditions.
The Two Substrate Reduction Therapies for Type 1 Gaucher Disease Are Not Equivalent. Comment on Hughes et al. Switching between Enzyme Replacement Therapies and Substrate Reduction Therapies in Patients with Gaucher Disease: Data from the Gaucher Outcome Survey (GOS). J. Clin. Med. 2022, 11, 5158
Authors: Mistry Pramod K. , Kishnani Priya S. , Balwani Manisha , Charrow Joel M. , Hull Judy , Weinreb Neal J. , Cox Timothy M.
Published: May 2023

In their paper, Hughes et al. [...]
Anti-Drug Antibodies in the Biological Therapy of Autoimmune Rheumatic Diseases
Authors: Pizano-Martinez Oscar , Mendieta-Condado Edgar , Vázquez-Del Mercado Mónica , Martínez-García Erika Aurora , Chavarria-Avila Efrain , Ortuño-Sahagún Daniel , Márquez-Aguirre Ana Laura
Published: May 2023

Autoimmune rheumatic diseases are a cluster of heterogeneous disorders that share some clinical symptoms such as pain, tissue damage, immune deregulation, and the presence of inflammatory mediators. Biologic disease-modifying antirheumatic drugs are some of the most effective treatments for rheumatic diseases. However, their molecular and pharmacological complexity makes them potentially immunogenic and capable of inducing the development of anti-drug antibodies. TNF inhibitors appear to be the main contributors to immunogenicity because they are widely used, especially in rheumatoid arthritis. Immunogenicity response on these treatments is crucial since the appearance of ADAs has consequences in terms of safety and efficacy. Therefore, this review proposes an overview of the immunogenicity of biological agents used in autoimmune rheumatic diseases highlighting the prevalence of anti-drug antibodies.
Does Tobacco Smoking Affect the Postoperative Outcome of MIS Lumbar Decompression Surgery?
Authors: Khashan Morsi , Ofir Dror , Hochberg Uri , Schermann Haggai , Regev Gilad J. , Lidar Zvi , Salame Khalil
Published: May 2023

Background: Tobacco smoking is a major cause of morbidity and mortality worldwide. Several authors reported a significant negative impact of smoking on the outcome of spinal surgeries. However, comparative studies on the effect of smoking on the outcome of minimally invasive (MIS) spinal decompression are rare with conflicting results. In this study, we aimed to evaluate clinical outcomes and postoperative complications following MIS decompression in current and former smoking patients compared to those of non-smoking patients. Methods: We used our prospectively collected database to retrospectively analyse the records of 188 consecutive patients treated with MIS lumbar decompression at our institution between November 2013 and July 2017. Patients were divided into groups of smokers (S), previous smokers (PS) and non-smokers (N). The S group and the PS group comprised 31 and 40 patients, respectively. The N group included 117 patients. The outcome measures included perioperative complications, revision surgery and length of stay. Patient-reported outcome measures included a visual analogue scale (VAS) for back pain and leg pain, as well as the Oswestry disability index (ODI) for evaluating functional outcomes. Results: Demographic variables, comorbidity and other preoperative variables were comparable between the three groups. A comparison of perioperative complications and revision surgery rates showed no significant difference between the groups. All groups showed significant improvement in their ODI and VAS scores at 12 and 24 months following surgery. As shown by a multivariate analysis, current smokers had lower chances of improvement, exceeding the minimal clinical important difference (MCID) in ODI and VAS for leg pain at 12 months but not 24 months postoperatively. Conclusions: Our findings show that except for a possible delay in improvement in leg pain and disability, tobacco smoking has no substantial adverse impact on complications and revision rates following MIS spinal decompressions.
Gender Differences in Neuromuscular Control during the Preparation Phase of Single-Leg Landing Task in Badminton
Authors: Hu Zhe , Zhang Yanan , Dong Tengfei , Dong Maolin , Kim Sukwon , Kim Youngsuk
Published: May 2023

Background: Studies on the biomechanical mechanisms of an anterior cruciate ligament (ACL) injury have been extensively studied, but studies on the neuromuscular control-related risk factors for an ACL injury in specific maneuvers have not been reported for badminton players. Study design: Controlled laboratory study. Methods: Sixteen badminton players (8 male, 8 female) performed a single-leg badminton ball landing task, and lower limb muscle activity, kinematic data, and ground reaction force were measured during this procedure using marker-based movement analysis, force plates, and electromyography (EMG). Gender differences in the lower limb kinematic data, mean values of normalized lower limb muscle activation (MVC%), and co-contraction values during the landing preparation phase (100 ms before initial contact) were analyzed using MANOVA. Results: In the badminton landing task, the knee valgus angle was greater in females than in males (6.27 ± 2.75 vs. 1.72 ± 3.20) in the pre-landing preparation position. Compared to male badminton players, females exhibited greater gluteus maximus (44.92 ± 18.00 vs. 20.34 ± 11.64), rectus femoris (41.56 ± 9.84 vs. 26.14 ± 10.46), and medial gastrocnemius (37.39 ± 17.31 vs. 19.11 ± 11.17) lateral gastrocnemius (36.86 ± 17.82 vs. 13.59 ± 2.71) muscle activity (MVC%). Conclusion: Female badminton players exhibit neuromuscular control strategies that may be inadequate for ACL protection and may be a potential risk factor for a high incidence of ACL injury In the future, when devising injury prevention plans for female badminton players, optimizing neuromuscular control during the pre-landing phase can be targeted.
Structure and Oxidation Resistance of Mo-Y-Zr-Si-B Coatings Deposited by DCMS and HIPIMS Methods Using Mosaic Targets
Authors: Sytchenko Alina D. , Loginov Pavel A. , Nozhkina Alla V. , Levashov Evgeny A. , Kiryukhantsev-Korneev Philipp V.
Published: May 2023

In this study, Mo-(Y,Zr)-Si-B coatings were obtained by direct current magnetron sputtering (DCMS) and high-power impulse magnetron sputtering (HIPIMS) using mosaic targets. The results showed that the addition of Y and Zr into the composition of Mo-Si-B coatings led to the suppression of columnar grain growth, a decrease in the crystallite size of h-MoSi2 phase from ~50 to ~5 nm, and an increase in the amorphous to crystalline phases ratio Doping of the Mo-Si-B coating with Y and Zr promoted an increase in oxidation resistance at a temperature of 1000 °C. The introduction of yttrium into the composition of Mo-Si-B contributed to an increase in their crack resistance when heated to 1300 °C. High oxidation resistance of the coatings was provided by a defect-free SiO2 + MoO3 + Y2O3 surface layer. The transition from the DCMS mode to HIPIMS decreased the texture of the Mo-Si-B coatings. The use of an HIPIMS mode led to a decrease in the oxidation rate of Mo-(Y)-Si-B coatings at T = 1000 °C by 1.6–4.5 times compared to DCMS. In the case of Mo-Y-Si-B coatings, the use of HIPIMS led to a decrease of more than 50% in the thickness of the oxide layer at a temperature of 1300 °C.