bluuebunny/crossref_metadata_2025 huggingface dataset:
Short-Term Outcome of Isolated Kidney Transplantation in Children with Autosomal Recessive Polycystic Kidney Disease: A Case Series and Literature Review
Authors: Acharya Ratna , Upadhyay Kiran
Published: December 2023

Autosomal recessive polycystic kidney disease (ARPKD) is often associated with hepatobiliary disease in the form of hepatic fibrosis and/or Caroli disease. Combined liver–kidney transplantation (CLKT) is a transplant modality of choice in children with both end-stage renal disease (ESRD) and severe hepatic disease. However, there is no consensus on whether children with ARPKD-associated ESRD without severe hepatic disease can be treated with isolated kidney transplantation (KT) without the need for CLKT. We retrospectively studied the efficacy of isolated KT in children with ARPKD without severe hepatic disease, and followed the course of hepatic disease post KT. This is a single-center study of three children with ARPKD and ESRD who underwent isolated KT. None of them had severe hepatic disease at the time of KT. All children were clinically diagnosed with ARPKD in the immediate postnatal period. All had hepatic fibrosis of varying degrees and two had intrahepatic biliary duct (IHBD) dilatation. None had gastrointestinal (GI) bleed, portal hypertension or cholangitis. Two children had preemptive KT. Pre-transplant unilateral or bilateral native nephrectomy were performed for two children, and one underwent unilateral native nephrectomy at the time of KT. The median creatinine clearance at a median post-KT follow-up of 24 months was 60.3 mL/min/1.73 m2. The two-year graft and patient survival were both 100%. Post KT, all three patients continued to demonstrate evidence of hepatic fibrosis and IHBD on sonogram; however, none of them were either evaluated for or required liver transplantation given normal synthetic liver function and absence of portal hypertension or other severe hepatobiliary disease. There were no adverse events observed such as cholangitis, GI bleed, or multiorgan failure. Hence, an excellent short-term graft and patient survival was demonstrated in this study of children with ARPKD and mild to moderate hepatic disease who received isolated KT. Long-term follow-up and larger studies are important to assess the efficacy of isolated KT in this subset of children with ARPKD.
Microgravity Crystal Formation
Authors: Jackson Keegan , Brewer Frances , Wilkinson Ashley , Williams Amari , Whiteside Ben , Wright Hannah , Harper Lynn , Wilson Anne M.
Published: December 2023

The benefits of crystallization in a microgravity environment have been documented. Herein, we update the community on the results of a retrospective meta-analysis and data curation of 507 unique crystallization experiments that have been disseminated in the literature over a broad diversity of substrates. The analysis variables in the dataset that were evaluated include individual success metrics such as size, structural improvement, improved uniformity, increased resolution limit, and improved mosaicity. The overall databases were evaluated over time and by molecular complexity. Compared to ground experiments, crystals grown in a microgravity environment continue to show improvement across all metrics evaluated. The retrospective analysis demonstrates that success rates of crystallization experiments in microgravity improved over time. There also seems to be no correlation between complexity of molecule, using molecular weight as a surrogate for complexity, and successful crystallization under microgravity conditions. The microgravity environment provides improvement to crystal fabrication across metrics utilized for evaluation and molecular types, and the datasets utilized for this investigation are excellent tools for this evaluation.
Validation of a Digital Headache Calendar at a Tertiary Referral Center
Authors: Kjerrumgaard Amalie , Hvedstrup Jeppe , Carlsen Louise Ninett , Dyre Kristine , Schytz Henrik
Published: December 2023

Background: Headache calendars are essential tools in monitoring changes in headache frequency and type. They are used in clinical practice for long-term monitoring, but their validation remains limited. The aim of this study was to validate the use of a digital calendar in monitoring single migraine and tension-type headache attacks. Methods: From July 2022 to February 2023, patients diagnosed with migraine and tension-type headache were enrolled. The validation of the digital calendar involved the comparison of self-reported single headache attacks in the digital calendar with the diagnostic headache diary based on the ICHD-3 criteria for migraine and tension-type headache. Sensitivity and specificity were calculated to assess reliability, and the level of agreement was calculated using kappa statistics. Results: This study included 30 patients (87% women) diagnosed with migraine and tension-type headache. The level of agreement in the classification of a single migraine attack revealed a sensitivity of 82% and a specificity of 78%, representing a substantial level of agreement (κ = 0.60). The classification of a single tension-type headache attack revealed a sensitivity of 84% and a specificity of 72%, with a moderate level of agreement (κ = 0.54). Conclusions: The digital calendar proves effective in monitoring single headache attacks in patients with migraine and tension-type headache. In clinical practice, we recommend using the digital calendar as a monitoring tool for headache patients, as they can accurately identify true migraine and tension-type headache days.
Improving Dual-Population Differential Evolution Based on Hierarchical Mutation and Selection Strategy
Authors: Huang Yawei , Qian Xuezhong , Song Wei
Published: December 2023

The dual-population differential evolution (DDE) algorithm is an optimization technique that simultaneously maintains two populations to balance global and local search. It has been demonstrated to outperform single-population differential evolution algorithms. However, existing improvements to dual-population differential evolution algorithms often overlook the importance of selecting appropriate mutation and selection operators to enhance algorithm performance. In this paper, we propose a dual-population differential evolution (DPDE) algorithm based on a hierarchical mutation and selection strategy. We divided the population into elite and normal subpopulations based on fitness values. Information exchange between the two subpopulations was facilitated through a hierarchical mutation strategy, promoting a balanced exploration–exploitation trade-off in the algorithm. Additionally, this paper presents a new hierarchical selection strategy aimed at improving the population’s capacity to avoid local optima. It achieves this by accepting discarded trial vectors differently compared to previous methods. We expect that the newly introduced hierarchical selection and mutation strategies will work in synergy, effectively harnessing their potential to enhance the algorithm’s performance. Extensive experiments were conducted on the CEC 2017 and CEC 2011 test sets. The results showed that the DPDE algorithm offers competitive performance, comparable to six state-of-the-art differential evolution algorithms.
High-Resolution Mass Spectrometry-Based Metabolomics for Increased Grape Juice Metabolite Coverage
Authors: Nicolas Sébastien , Bois Benjamin , Billet Kevin , Romanet Rémy , Bahut Florian , Uhl Jenny , Schmitt-Kopplin Philippe , Gougeon Régis D.
Published: December 2023

The composition of the juice from grape berries is at the basis of the definition of technological ripeness before harvest, historically evaluated from global sugar and acid contents. If many studies have contributed to the identification of other primary and secondary metabolites in whole berries, deepening knowledge about the chemical composition of the sole flesh of grape berries (i.e., without considering skins and seeds) at harvest is of primary interest when studying the enological potential of widespread grape varieties producing high-added-value wines. Here, we used non-targeted DI-FT-ICR-MS and RP-UHPLC-Q-ToF-MS analyses to explore the extent of metabolite coverage of up to 290 grape juices from four Vitis vinifera grape varieties, namely Chardonnay, Pinot noir, Meunier, and Aligoté, sampled at harvest from 91 vineyards in Europe and Argentina, over three successive vintages. SPE pretreatment of samples led to the identification of more than 4500 detected C,H,O,N,S-containing elemental compositions, likely associated with tens of thousands of distinct metabolites. We further revealed that a major part of this chemical diversity appears to be common to the different juices, as exemplified by Pinot noir and Chardonnay samples. However, it was possible to build significant models for the discrimination of Chardonnay from Pinot noir grape juices, and of Chardonnay from Aligoté grape juices, regardless of the geographical origin or the vintage. Therefore, this metabolomic approach opens access to a remarkable holistic molecular description of the instantaneous composition of such a biological matrix, which is the result of complex interplays among environmental, biochemical, and vine growing practices.
Ultrashort Cationic Peptide Fmoc-FFK as Hydrogel Building Block for Potential Biomedical Applications
Authors: Gallo Enrico , Diaferia Carlo , Giordano Sabrina , Rosa Elisabetta , Carrese Barbara , Piccialli Gennaro , Borbone Nicola , Morelli Giancarlo , Oliviero Giorgia , Accardo Antonella
Published: December 2023

Fmoc-diphenylalanine (Fmoc-FF) is a low-molecular-weight peptide hydrogelator. This simple all-aromatic peptide can generate self-supporting hydrogel materials, which have been proposed as novel materials for diagnostic and pharmaceutical applications. Our knowledge of the molecular determinants of Fmoc-FF aggregation is used as a guide to design new peptide-based gelators, with features for the development of improved tools. Here, we enlarge the plethora of Fmoc-FF-based hydrogelated matrices by studying the properties of the Fmoc-FFK tripeptide, alone or in combination with Fmoc-FF. For multicomponent matrices, the relative weight ratios between Fmoc-FFK and Fmoc-FF (specifically, 1/1, 1/5, 1/10, and 1/20 w/w) are evaluated. All the systems and their multiscale organization are studied using different experimental techniques, including rheology, circular dichroism, Fourier transform infrared spectroscopy, and scanning electron microscopy (SEM). Preliminary profiles of biocompatibility for the studied systems are also described by testing them in vitro on HaCaT and 3T3-L1 cell lines. Additionally, the lysine (K) residue at the C-terminus of the Fmoc-FF moiety introduces into the supramolecular material chemical functions (amino groups) which may be useful for modification/derivatization with bioactive molecules of interest, including diagnostic probes, chelating agents, active pharmaceutical ingredients, or peptide nucleic acids.
Seismic Disturbances and Geodetic Effects: Unraveling the Impact of the Mw = 6.2 Petrinja Earthquake on the Croatian Positioning System CROPOS
Authors: Bjelotomić Oršulić Olga , Varga Matej , Yalvac Sefa
Published: December 2023

A destructive Mw = 6.2 earthquake struck NW Croatia on 29 December 2020, ranking among the most hazardous events in the country in the last century. This study assesses the impact of the earthquake on the permanent geodetic stations of the Croatian national positioning system. Using a novel approach, we combined positioning station data with satellite radar data for the first time in a geodynamic study across Croatia. The analysis involved collecting daily solutions data from 11 nearby network stations as well as multi-temporal satellite images before and after the earthquake. The results reveal a significant co-seismic shift, with the Sisak reference station experiencing the largest displacement of 5 cm to the southeast. Stations up to 100 km from the epicenter exhibited horizontal shifts between 1 and 2.5 cm and vertical shifts between 2 and 4 cm. Satellite images confirmed the co-seismic effects on the permanent stations. The study establishes a strong correlation between geodetic and geological findings, suggesting that vertical displacements result from superficial deposit consolidation in the river plains due to the earthquake shaking, while positional displacement reflects tectonic block movements along the activated strike-slip fault system. The late 2020 earthquake may have further relaxed the accumulated strain on the Mt. Medvednica thrust fault system, which had ruptured in early 2020 with a lower magnitude than expected.
Reconsidering Freud’s Uncanny: The Coppola Perspective
Authors: Weber Samuel
Published: December 2023

This essay reconsiders the Freudian notion of the Uncanny/Unheimlich by focusing on the attempt of the ego to project and maintain a coherent and consistent view of the world and of itself—an attempt that is intrinsically subverted by the very process of repetition that both conditions and disrupts all forms of identity and of identification.
A Cross-Sectional Study on Physical Activity and Burnout among Family Physicians in Slovenia during the First Year of the COVID-19 Pandemic: Are the Results Alarming Enough to Convince Decision-Makers to Support Family Medicine?
Authors: Tušek Bunc Ksenija , Uplaznik Janja , Selič-Zupančič Polona
Published: December 2023

Physical activity has a positive effect on general health, but its influence on burnout remains unclear. The aim of this study was to determine the association between physical activity and the incidence of burnout in Slovenian family physicians (FPs) and family medicine trainees (FMTs) during the COVID-19 pandemic, which exacerbated the already-existing problem of burnout. We conducted a cross-sectional observational study among Slovenian family physicians and FMTs in which sociodemographic variables, the type and duration of physical activity, and an assessment of burnout were collected using the Maslach Burnout Inventory. Comparisons between groups were made using the independent-samples t-test, Fisher’s exact test, and the Wilcoxon sign-rank test. A value of p < 0.05 determined the limit of statistical significance. Of 1230 FPs and FMTs invited to participate, 282 completed the survey (22.9% response rate); there were 243 (86.2%) FPs and 39 (13.8%) FMTs. The overall rating for burnout during the pandemic was high, at 48.6% of FPs and FMTs; 62.8% of respondents reported a high rating for emotional exhaustion and 40.1% for depersonalization. Compared to FMTs, emotional exhaustion and total burnout scores were higher for FPs (p < 0.001 and p = 0.010, respectively), but work status was not related to personal acomplishment, which 53.5% of all participants rated as low. Physical activity did not appear to be a statistically significant factor in the occurrence of burnout during the pandemic. Therefore, work status or occupational role (FP vs. FMT) should be thoroughly investigated in the future along with some other factors and a better response rate.
Multi-Session High-Definition Map-Monitoring System for Map Update
Authors: Wijaya Benny , Yang Mengmeng , Wen Tuopu , Jiang Kun , Wang Yunlong , Fu Zheng , Tang Xuewei , Sigomo Dennis Octovan , Miao Jinyu , Yang Diange
Published: December 2023

This research paper employed a multi-session framework to present an innovative approach to map monitoring within the domain of high-definition (HD) maps. The proposed methodology uses a machine learning algorithm to derive a confidence level for the detection of specific map elements in each frame and tracks the position of the element in subsequent frames. This creates a virtual belief system, which indicates the existence of the element on the HD map. To confirm the existence of the element and ensure the credibility of the map data, a reconstruction and matching technique was implemented. The notion of an expected observation area is also introduced by strategically limiting the vehicle’s observation range, thereby bolstering the detection confidence of the observed map elements. Furthermore, we leveraged data from multiple vehicles to determine the necessity for updates within specific areas, ensuring the accuracy and dependability of the map information. The validity and practicality of our approach were substantiated by real experimental data, and the monitoring accuracy exceeded 90%.
Ion Channels as a Therapeutic Target: Drug Design and Pharmacological Investigation
Authors: Guerrini Gabriella , Giovannoni Maria Paola
Published: December 2023

This Special Issue intends to illustrate the novelties in the field of ion channels [...]
The Cytoskeleton and Its Binding Proteins as Mechanosensors, Transducers, and Functional Regulators of Cells
Authors: Lee Wan
Published: December 2023

Due to its complement of diverse proteins, such as actin filaments, intermediate filaments, and microtubules, the cytoskeleton is essential not only for structural stability but also for regulating cellular signaling, intracellular transportation, and cell division [...]
Circular RNAs: Promising Treatment Targets and Biomarkers of Ischemic Stroke
Authors: Xu Guangchen , Liu Ge , Wang Ziyu , Li Yunman , Fang Weirong
Published: December 2023

Ischemic stroke is one of the most significant causes of morbidity and mortality worldwide. However, there is a dearth of effective drugs and treatment methods for ischemic stroke. Significant numbers of circular RNAs (circRNAs) exhibit abnormal expression following ischemic stroke and are considered potential therapeutic targets. CircRNAs have emerged as promising biomarkers due to their stable expression in peripheral blood and their potential significance in ischemic stroke diagnosis and prognosis. This review provides a summary of 31 circRNAs involved in the pathophysiological processes of apoptosis, autophagy, inflammation, oxidative stress, and angiogenesis following ischemic stroke. Furthermore, we discuss the mechanisms of action of said circRNAs and their potential clinical applications. Ultimately, circRNAs exhibit promise as both therapeutic targets and biomarkers for ischemic stroke.
The Molecular Basis of Male Infertility in Obesity: A Literature Review
Authors: George Biji Thomas , Jhancy Malay , Dube Rajani , Kar Subhranshu Sekhar , Annamma Lovely Muthiah
Published: December 2023

The rising incidence of obesity has coincided with rising levels of poor reproductive outcomes. The molecular basis for the association of infertility in obese males is now being explained through various mechanisms. Insulin resistance, hyperglycemia, and changes in serum and gonadal concentrations of adipokines, like leptin, adiponectin, resistin, and ghrelin have been implicated as causes of male infertility in obese males. The effects of obesity and hypogonadism form a vicious cycle whereby dysregulation of the hypothalamic–pituitary–testicular axis—due to the effect of the release of multiple mediators, thus decreasing GnRH release from the hypothalamus—causes decreases in LH and FSH levels. This leads to lower levels of testosterone, which further increases adiposity because of increased lipogenesis. Cytokines such as TNF-α and interleukins, sirtuins, and other inflammatory mediators like reactive oxygen species are known to affect fertility in obese male adults. There is evidence that parental obesity can be transferred through subsequent generations to offspring through epigenetic marks. Thus, negative expressions like obesity and infertility have been linked to epigenetic marks being altered in previous generations. The interesting aspect is that these epigenetic expressions can be reverted by removing the triggering factors. These positive modifications are also transmitted to subsequent generations.
Mass Spectrometry Study about In Vitro and In Vivo Reaction between Metformin and Glucose: A Preliminary Investigation on Alternative Biological Behavior
Authors: Bartolucci Gianluca , Pallecchi Marco , Braconi Laura , Dei Silvia , Teodori Elisabetta , Lapolla Annunziata , Sartore Giovanni , Traldi Pietro
Published: December 2023

Metformin is the most prescribed glucose-lowering drug worldwide; globally, over 100 million patients are prescribed this drug annually. Some different action mechanisms have been proposed for this drug, but, surprisingly, no metabolite of metformin has ever been described. It was considered interesting to investigate the possible reaction of metformin with glucose following the Maillard reaction pattern. The reaction was first performed in in vitro conditions, showing the formation of two adducts that originated by the condensation of the two molecular species with the losses of one or two water molecules. Their structures were investigated by liquid chromatography coupled with mass spectrometry (HPLC-MS), tandem mass spectrometry (MS/MS) and accurate mass measurements (HRMS). The species originated via the reaction of glucose and metformin and were called metformose and dehydrometformose, and some structural hypotheses were conducted. It is worth to emphasize that they were detected in urine samples from a diabetic patient treated with metformin and consequently they must be considered metabolites of the drug, which has never been identified before now. The glucose-related substructure of these compounds could reflect an improved transfer across cell membranes and, consequently, new hypotheses could be made about the biological targets of metformin.
Personalized Medicine in Severe Asthma: From Biomarkers to Biologics
Authors: Chen Chun-Yu , Wu Kang-Hsi , Guo Bei-Cyuan , Lin Wen-Ya , Chang Yu-Jun , Wei Chih-Wei , Lin Mao-Jen , Wu Han-Ping
Published: December 2023

Severe asthma is a complex and heterogeneous clinical condition presented as chronic inflammation of the airways. Conventional treatments are mainly focused on symptom control; however, there has been a shift towards personalized medicine. Identification of different phenotypes driven by complex pathobiological mechanisms (endotypes), especially those driven by type-2 (T2) inflammation, has led to improved treatment outcomes. Combining biomarkers with T2-targeting monoclonal antibodies is crucial for developing personalized treatment strategies. Several biological agents, including anti-immunoglobulin E, anti-interleukin-5, and anti-thymic stromal lymphopoietin/interleukin-4, have been approved for the treatment of severe asthma. These biological therapies have demonstrated efficacy in reducing asthma exacerbations, lowering eosinophil count, improving lung function, diminishing oral corticosteroid use, and improving the quality of life in selected patients. Severe asthma management is undergoing a profound transformation with the introduction of ongoing and future biological therapies. The availability of novel treatment options has facilitated the adoption of phenotype/endotype-specific approaches and disappearance of generic interventions. The transition towards precision medicine plays a crucial role in meticulously addressing the individual traits of asthma pathobiology. An era of tailored strategies has emerged, allowing for the successful targeting of immune-inflammatory responses that underlie uncontrolled T2-high asthma. These personalized approaches hold great promise for improving the overall efficacy and outcomes in the management of severe asthma. This article comprehensively reviews currently available biological agents and biomarkers for treating severe asthma. With the expanding repertoire of therapeutic options, it is becoming increasingly crucial to comprehend the influencing factors, understand the pathogenesis, and track treatment progress in severe asthma.
Characterization of Angraecum (Angraecinae, Orchidaceae) Plastomes and Utility of Sequence Variability Hotspots
Authors: Zhou Cheng-Yuan , Lin Wen-Jun , Li Ruyi , Wu Yuhan , Liu Zhong-Jian , Li Ming-He
Published: December 2023

Angraecum, commonly known as Darwin’s orchid, is the largest genus of Angraecinae (Orchidaceae). This genus exhibits a high morphological diversity, making it as a good candidate for macroevolutionary studies. In this study, four complete plastomes of Angraecum were firstly reported and the potential variability hotspots were explored. The plastomes possessed the typical quadripartite structure and ranged from 150,743 to 151,818 base pair (bp), with a guanine–cytosine (GC) content of 36.6–36.9%. The plastomes all contained 120 genes, consisting of 74 protein-coding genes (CDS), 38 transfer RNA (tRNA) genes and 8 ribosomal RNA (rRNA) genes; all ndh genes were pseudogenized or lost. A total of 30 to 46 long repeats and 55 to 63 SSRs were identified. Relative synonymous codon usage (RSCU) analysis indicated a high degree of conservation in codon usage bias. The Ka/Ks ratios of most genes were lower than 1, indicating that they have undergone purifying selection. Based on the ranking of Pi (nucleotide diversity) values, five regions (trnSGCU-trnGGCC, ycf1-trnNGGU, trnNGUU-rpl32, psaC-ndhE and trnSGCU-trnGGCC) and five protein-coding genes (rpl32, rps16, psbK, rps8, and ycf1) were identified. The consistent and robust phylogenetic relationships of Angraecum were established based on a total of 40 plastomes from the Epidendroideae subfamily. The genus Angraecum was strongly supported as a monophyletic group and sister to Aeridinae. Our study provides an ideal system for investigating molecular identification, plastome evolution and DNA barcoding for Angraecum.
The Discovery and Characterization of Conserved and Novel miRNAs in the Different Developmental Stages and Organs of Pikeperch (Sander lucioperca)
Authors: Verleih Marieke , Visnovska Tina , Nguinkal Julien A. , Rebl Alexander , Goldammer Tom , Andreassen Rune
Published: December 2023

Micro RNAs (miRNAs) are short non-coding RNAs that act as post-transcriptional gene expression regulators. Genes regulated in vertebrates include those affecting growth and development or stress and immune response. Pikeperch (Sander lucioperca) is a species that is increasingly being considered for farming in recirculation aquaculture systems. We characterized the pikeperch miRNA repertoire to increase the knowledge of the genomic mechanisms affecting performance and health traits by applying small RNA sequencing to different developmental stages and organs. There were 234 conserved and 8 novel miRNA genes belonging to 104 families. A total of 375 unique mature miRNAs were processed from these genes. Many mature miRNAs showed high relative abundances or were significantly more expressed at early developmental stages, like the miR-10 and miR-430 family, let-7, the miRNA clusters 106-25-93, and 17-19-92. Several miRNAs associated with immune responses (e.g., slu-mir-731-5p, slu-mir-2188-5p, and slu-mir-8159-5p) were enriched in the spleen. The mature miRNAs slu-mir-203a-3p and slu-mir-205-5p were enriched in gills. These miRNAs are similarly abundant in many vertebrates, indicating that they have shared regulatory functions. There was also a significantly increased expression of the disease-associated miR-462/miR-731 cluster in response to hypoxia stress. This first pikeperch miRNAome reference resource paves the way for future functional studies to identify miRNA-associated variations that can be utilized in marker-assisted breeding programs.
Molecular Characteristics, Functional Definitions, and Regulatory Mechanisms for Cross-Presentation Mediated by the Major Histocompatibility Complex: A Comprehensive Review
Authors: Liu Sen , Wei Shaoqiang , Sun Yan , Xu Guowei , Zhang Shidong , Li Jianxi
Published: December 2023

The major histocompatibility complexes of vertebrates play a key role in the immune response. Antigen-presenting cells are loaded on MHC I molecules, which mainly present endogenous antigens; when MHC I presents exogenous antigens, this is called cross-presentation. The discovery of cross-presentation provides an important theoretical basis for the study of exogenous antigens. Cross-presentation is a complex process in which MHC I molecules present antigens to the cell surface to activate CD8+ T lymphocytes. The process of cross-representation includes many components, and this article briefly outlines the origins and development of MHC molecules, gene structures, functions, and their classical presentation pathways. The cross-presentation pathways of MHC I molecules, the cell lines that support cross-presentation, and the mechanisms of MHC I molecular transporting are all reviewed. After more than 40 years of research, the specific mechanism of cross-presentation is still unclear. In this paper, we summarize cross-presentation and anticipate the research and development prospects for cross-presentation.
RNA-Seq Analysis of Trans-Differentiated ARPE-19 Cells Transduced by AAV9-AIPL1 Vectors
Authors: Galieva Alima , Egorov Alexander , Malogolovkin Alexander , Brovin Andrew , Karabelsky Alexander
Published: December 2023

Inherited retinal disorders (IRD) have become a primary focus of gene therapy research since the success of adeno-associated virus-based therapeutics (voretigene neparvovec-rzyl) for Leber congenital amaurosis type 2 (LCA2). Dozens of monogenic IRDs could be potentially treated with a similar approach using an adeno-associated virus (AAV) to transfer a functional gene into the retina. Here, we present the results of the design, production, and in vitro testing of the AAV serotype 9 (AAV9) vector carrying the codon-optimized (co) copy of aryl hydrocarbon receptor-interacting protein like-1 (AIPL1) as a possible treatment for LCA4. The pAAV-AIPL1co was able to successfully transduce retinal pigment epithelium cells (ARPE-19) and initiate the expression of human AIPL1. Intriguingly, cells transduced with AAV9-AIPL1co showed much less antiviral response than AAV9-AIPL1wt (wild-type AIPL1) transduced. RNA-sequencing (RNA-seq) analysis of trans-differentiated ARPE-19 cells transduced with AAV9-AIPL1co demonstrated significant differences in the expression of genes involved in the innate immune response. In contrast, AAV9-AIPL1wt induced the prominent activation of multiple interferon-stimulated genes. The key part of the possible regulatory molecular mechanism is the activation of dsRNA-responsive antiviral oligoadenylate synthetases, and a significant increase in the level of histone coding genes’ transcripts overrepresented in RNA-seq data (i.e., H1, H2A, H2B, H3, and H4). The RNA-seq data suggests that AAV9-AIPL1co exhibiting less immunogenicity than AAV9-AIPL1wt can be used for potency testing, using relevant animal models to develop future therapeutics for LCA4.
BRCA Mutations and Fertility Preservation
Authors: Dias Nunes Joana , Demeestere Isabelle , Devos Melody
Published: December 2023

Hereditary cancers mostly affect the adolescent and young adult population (AYA) at reproductive age. Mutations in BReast CAncer (BRCA) genes are responsible for the majority of cases of hereditary breast and ovarian cancer. BRCA1 and BRCA2 act as tumor suppressor genes as they are key regulators of DNA repair through homologous recombination. Evidence of the accumulation of DNA double-strand break has been reported in aging oocytes, while BRCA expression decreases, leading to the hypothesis that BRCA mutation may impact fertility. Moreover, patients exposed to anticancer treatments are at higher risk of fertility-related issues, and BRCA mutations could exacerbate the treatment-induced depletion of the ovarian reserve. In this review, we summarized the functions of both genes and reported the current knowledge on the impact of BRCA mutations on ovarian ageing, premature ovarian insufficiency, female fertility preservation strategies and insights about male infertility. Altogether, this review provides relevant up-to-date information on the impact of BRCA1/2 mutations on fertility. Notably, BRCA-mutated patients should be adequately counselled for fertility preservation strategies, considering their higher sensitivity to chemotherapy gonadotoxic effects.
N-Acetylcysteine Antagonizes NGF Activation of TrkA through Disulfide Bridge Interaction, an Effect Which May Contribute to Its Analgesic Activity
Authors: Govoni Stefano , Fantucci Piercarlo , Marchesi Nicoletta , Vertemara Jacopo , Pascale Alessia , Allegri Massimo , Calvillo Laura , Vanoli Emilio
Published: December 2023

N-acetylcysteine (NAC), a mucolytic agent and an antidote to acetaminophen intoxication, has been studied in experimental conditions and trials exploring its analgesic activity based on its antioxidant and anti-inflammatory properties. The purpose of this study is to investigate additional mechanisms, namely, the inhibition of nerve growth factor (NGF) and the activation of the Tropomyosin receptor kinase A (TrkA) receptor, which is responsible for nociception. In silico studies were conducted to evaluate dithiothreitol and NAC’s interaction with TrkA. We also measured the autophosphorylation of TrkA in SH-SY5Y cells via ELISA to assess NAC’s in vitro activity against NGF-induced TrkA activation. The in silico and in vitro tests show that NAC interferes with NGF-induced TrkA activation. In particular, NAC breaks the disulfide-bound Cys 300–345 of TrkA, perturbing the NGF-TrkA interaction and producing a rearrangement of the binding site, inducing a consequent loss of their molecular recognition and spatial reorganization, which are necessary for the induction of the autophosphorylation process. The latter was inhibited by 40% using 20 mM NAC. These findings suggest that NAC could have a role as a TrkA antagonist, an action that may contribute to the activity and use of NAC in various pain states (acute, chronic, nociplastic) sustained by NGF hyperactivity and/or accompanied by spinal cord sensitization.
Extracorporeal Membrane Oxygenation for Pulmonary Embolism: A Systematic Review and Meta-Analysis
Authors: Boey Jonathan Jia En , Dhundi Ujwal , Ling Ryan Ruiyang , Chiew John Keong , Fong Nicole Chui-Jiet , Chen Ying , Hobohm Lukas , Nair Priya , Lorusso Roberto , MacLaren Graeme , Ramanathan Kollengode
Published: December 2023

Background: The use of extracorporeal membrane oxygenation (ECMO) for high-risk pulmonary embolism (HRPE) with haemodynamic instability or profound cardiogenic shock has been reported. Guidelines currently support the use of ECMO only in patients with cardiac arrest or circulatory collapse and in conjunction with other curative therapies. We aimed to characterise the mortality of adults with HRPE treated with ECMO, identify factors associated with mortality, and compare different adjunct curative therapies. Methods: We conducted a systematic review and meta-analysis, searching four international databases from their inception until 25 June 2023 for studies reporting on more than five patients receiving ECMO for HRPE. Random-effects meta-analyses were conducted. The primary outcome was in-hospital mortality. A subgroup analysis investigating the outcomes with curative treatment for HRPE was also performed. The intra-study risk of bias and the certainty of evidence were also assessed. This study was registered with PROSPERO (CRD42022297518). Results: A total of 39 observational studies involving 6409 patients receiving ECMO for HRPE were included in the meta-analysis. The pooled mortality was 42.8% (95% confidence interval [CI]: 37.2% to 48.7%, moderate certainty). Patients treated with ECMO and catheter-directed therapy (28.6%) had significantly lower mortality (p < 0.0001) compared to those treated with ECMO and systemic thrombolysis (57.0%). Cardiac arrest prior to ECMO initiation (regression coefficient [B]: 1.77, 95%-CI: 0.29 to 3.25, p = 0.018) and pre-ECMO heart rate (B: −0.076, 95%-CI: −0.12 to 0.035, p = 0.0003) were significantly associated with mortality. The pooled risk ratio when comparing mortality between patients on ECMO and those not on ECMO was 1.51 (95%-CI: 1.07 to 2.14, p < 0.01) in favour of ECMO. The pooled mortality was 55.2% (95%-CI: 47.7% to 62.6%), using trim-and-fill analysis to account for the significant publication bias. Conclusions: More than 50% of patients receiving ECMO for HRPE survive. While outcomes may vary based on the curative therapy used, early ECMO should be considered as a stabilising measure when treating patients with HRPE. Patients treated concurrently with systemic thrombolysis have higher mortality than those receiving ECMO alone or with other curative therapies, particularly catheter-directed therapies. Further studies are required to explore ECMO vs. non-ECMO therapies in view of currently heterogenous datasets.
Prostate Artery Embolization in the Treatment of Massive Intractable Bleeding from Prostatic Neoplasms: A Case Report and Systematic Review
Authors: Moramarco Lorenzo , Grande Antonino M. , Vertemati Maurizio , Aseni Paolo
Published: December 2023

Lower urinary tract symptoms (LUTS) and hematuria are common symptoms in men with neoplasms, mainly affecting the elderly population. Prostatic arterial embolization (PAE) is a minimally invasive procedure that has shown promising results in managing LUTS and massive intractable prostatic hematuria in patients with benign prostatic hyperplasia (BPH) and prostate cancer (PCa). A few studies, however, have provided valuable insights into the durability and efficacy of PAE focusing on the long-term effectiveness, quality of life, and cancer-specific control of hemostasis and urinary symptoms. As a result of concomitant cardiovascular conditions, these patients often take anticoagulants or antithrombotics, which can worsen their hematuria and clinical status. Transurethral resection of the prostate (TURP) is considered a very high-risk procedure, even without massive bleeding, and requires discontinuation of vitamin K antagonists and antiplatelet therapies. Such patients usually have their surgery postponed, and PAE should be considered a safe alternative treatment. We aimed to report a narrative review from 1976 to June 2023 of the current state of PAE for massive and intractable hematuria, highlighting recent developments in this technique, including prospective cohort studies, and focusing on long-term outcome, safety, and complication management of patients with prostatic neoplasms who develop significant hemorrhagic symptoms. Additionally, we present a case report and a simple algorithm for treating intractable bleeding in a 92-year-old man with PCa and massive hematuria.
Illness Perception and the Severity of Depression and Anxiety Symptoms in Patients with Multimorbidity: Observational Cohort Studies
Authors: Jaltuszewska Sylwia , Chojnacka-Szawlowska Gabriela , Majkowicz Mikolaj , Zdonczyk Sebastian , Homenda Wojciech , Hebel Kazimiera
Published: December 2023

Introduction. Many studies have shown a correlation between the patient’s engagement in treatment and their perception of the illness. Aim: The aim of this study has been to explore the link between the patient’s perception of their illness with anxiety and depression, and to leverage this link to promote health education. Materials and methods: The study was carried out using the following tools: the Hospital Anxiety and Depression Scale and the Illness Perception Questionnaire–Revised. The study participants included N = 143 patients. Results: The participants’ age was statistically significantly associated with the expected duration of the illness (p < 0.01), the conviction that the treatment was effective (p < 0.01), and the perception of the severity of the disease symptoms (p < 0.05). The employment status was statistically significantly associated with the illness perception (p < 0.01). Anxiety and depression levels were statistically significantly associated with the perceived impact of the illness on life (p < 0.001) and emotional status (p < 0.001), the perceived control over the illness (p < 0.01), the potential for recovery (p < 0.001), the concern about the illness (p < 0.001), and the impact of the illness on emotional well-being (p < 0.001). Conclusions: Individuals who perceived a high severity of illness symptoms also assessed that the illness significantly impacted their life and emotional state. The authors demonstrate a strong link of a “negative” perception of the illness with depression and anxiety. A better understanding of the illness predicted a less severe depression and lower anxiety. Implications for practice: The results suggest that the study of illness perception holds significant potential to contribute effectively to educational and psychotherapeutic practices.
Path-Following and Obstacle-Avoidance Control of USV Based on Finite-Distance Convergence
Authors: Wei Junbao , Zhang Jianqiang , Liu Zhong , Qu Jianjing , Sui Bowen , Zhang Yuanyuan
Published: December 2023

The control problem of avoidance-path-following is a critical consideration in the research of unmanned surface vehicle (USV) navigation control, and it holds great significance for the navigation safety of USVs. A guidance and control scheme based on finite-distance convergence is proposed in this paper. First, the requirements for the USV to avoid obstacles from the perspective of path-following lateral error are analyzed. Then, a new performance function with finite-distance convergence is proposed to constrain the lateral error. Based on this, a heading guidance law and a backstepping controller are designed to ensure that the lateral error converges to a steady-state value within the prescribed navigation distance and that the stability is maintained, satisfying the requirements of obstacle avoidance for the USV. In addition, an adaptive velocity command is designed to adjust the velocity with the lateral error, which, to a certain extent, avoids the saturation of the heading actuator caused by the large lateral error. Finally, it is proven through theory and simulation that the control algorithm can guide the USV to achieve avoidance-path-following within a limited distance and to avoid obstacles effectively.
Clinical Efficacy of Preoperative and Intraoperative Intravitreal Ranibizumab as Adjuvant Therapy of Ahmed Glaucoma Valve Implantation Combined with Vitrectomy in the Management of Neovascular Glaucoma with Diabetic Vitreous Hemorrhage
Authors: Gao Shuang , Lin Zhongjing , Zhong Yisheng , Shen Xi
Published: December 2023

Neovascular glaucoma (NVG) secondary to proliferative diabetic retinopathy (PDR) is a devastating ocular disease with poor prognosis. Intravitreal ranibizumab injection (IVR) has been used as adjuvant therapy of surgical interventions preoperatively or intraoperatively. This study aimed to determine the efficacy and safety of combined IVR as adjuvant therapy in treating NVG with vitreous hemorrhage (VH) in PDR. A total of 39 NVG patients with VH (39 eyes) received IVR 3 to 5 days before surgery, and then they were assigned to either pars plana vitrectomy (PPV) + Ahmed glaucoma valve (AGV) implantation (Group 1, n = 22) or PPV + AGV implantation + intraoperative IVR (Group 2, n = 17). Patients were followed up for at least 9 months. Intraocular pressure (IOP), anti-glaucoma medications, best corrected visual acuity (BCVA), surgical success rates and postoperative complications were compared. Results showed that IOP decreased promptly after surgery and was notably maintained at a mid-term follow-up in both groups, and no significant differences were observed (all p > 0.05). Additional intraoperative IVR significantly reduced postoperative recurrent VH and iris neovascularization (p = 0.047, p = 0.025, respectively). There was no remarkable difference in postoperative anti-glaucoma medications, BCVA and complications between two groups (all p > 0.05). In conclusion, preoperative and intraoperative IVR as adjuvant therapy of AGV implantation combined with PPV could be a safe and effective treatment for NVG with VH in PDR. An additional intraoperative anti-VEGF injection could significantly reduce postoperative VH and iris neovascularization.
Expansionary Monetary Policy and Bank Loan Loss Provisioning
Authors: Guo Mengyang , Jia Xiaoran , Jin Justin Yiqiang , Kanagaretnam Kiridaran , Lobo Gerald J.
Published: December 2023

We explore how expansionary monetary policy (EMP) influences bank loan loss provisioning. We find that banks’ discretionary loan loss provisions (DLLPs) increase during periods of EMP. This effect is stronger for banks with greater risk-taking, a larger proportion of influential stakeholders, lower ex-ante transparency of loan loss provisions, and more stringent bank regulation, which is consistent with external stakeholders requiring more conservative and timelier loan loss provisioning. We also find that both the timeliness and the validity of banks’ loan loss provisions (LLPs) increase during EMP periods. Our results are robust to the use of instrumental variable estimation and exogenous variations in monetary policy. Lastly, we show that conservative (i.e., higher DLLPs) and timely loan loss provisioning discipline banks from excessive risk-taking during periods of EMP.
Analysis of the Impact of Land Use Change on Grain Production in Jiangsu Province, China
Authors: Cao Xufeng , Han Jiqin , Li Xueying
Published: December 2023

Located in the Yangtze River Delta region, Jiangsu Province has become the major grain production area of China and plays an important role in ensuring national food security. With rapid economic development and urbanization, the amount of cultivated land has decreased, which greatly affects food security. Based on the statistical data of grain production in Jiangsu Province since 2000 and the remote sensing data of 2000, 2010, and 2020, this paper used the stochastic frontier production function to calculate the output elasticity of various factors and the technical efficiency of grain production. The agglomeration effect of food production was investigated by using spatial correlation analysis. Finally, regression analysis was applied to examine the impact of land use change on grain yield and the technical efficiency of production. The results show that the grain-sown area is the decisive factor for the increase in grain output in Jiangsu Province. The technical efficiency of grain production in the province has been maintained at a relatively high level since 2000, showing a fluctuating upward trend, and the efficiency value in southern Jiangsu Province is greater than that in central and northern Jiangsu. The analysis of the spatial distribution characteristics of grain production technical efficiency shows that grain production has an agglomeration effect. The regression results showed that the complexity of land use and the density of the cultivated land patch were negatively correlated with grain yield and grain production technical efficiency, while the location of cultivated land was positively correlated with grain yield and grain production technical efficiency. The conclusion of this paper has important policy significance for promoting food production and ensuring food security.
Evaluation of Antioxidant Properties and Molecular Design of Lubricant Antioxidants Based on QSPR Model
Authors: Liu Jianfang , Zhang Yaoyun , Yi Chenglingzi , Zhang Rongrong , Yang Sicheng , Liu Ting , Jia Dan , Yang Qing , Peng Shuai
Published: December 2023

Two quantitative structure–property relationship (QSPR) models of hindered phenolic antioxidants in lubricating oils were established to help guide the molecular structure design of antioxidants. Firstly, stepwise regression (SWR) was used to filter out essential molecular descriptors without autocorrelation, including electronic, topological, spatial, and structural descriptors, and multiple linear regression (MLR) was used to construct QSPR models based on the screened variables. The two models are statistically sound, with R2 values of 0.942 and 0.941, respectively. The models’ reliability was verified by the frontier molecular orbital energy gaps of the antioxidants. A hindered phenolic additive was designed based on the models. Its antioxidant property is calculated to be 20.9% and 11.0% higher than that of typical commercial antioxidants methyl 3-(3,5-di-tert-butyl-4-hydroxyphenyl) propionate and 2,2′-methylenebis(6-tert-butyl-4-methylphenol), respectively. The structure–property relationship of hindered phenolic antioxidants in lubricating oil obtained by computer-assisted analysis can not only predict the antioxidant properties of existing hindered phenolic additives but also provide theoretical basis and data support for the design or modification of lubricating oil additives with higher antioxidant properties.