bluuebunny/crossref_metadata_2025 huggingface dataset:
The Characteristics and Expression Analysis of the Tomato SlRBOH Gene Family under Exogenous Phytohormone Treatments and Abiotic Stresses
Authors: Wang Yuanhui , Liu Zesheng , Li Long , Pan Xuejuan , Yao Kangding , Wei Wenying , Liao Weibiao , Wang Chunlei
Published: May 2024

Respiratory burst oxidase homologs (RBOHs), also known as NADPH oxidases, contribute significantly to the production of ROS in plants, alongside other major sources such as photosynthesis and electron transport in chloroplasts. It has been shown that plant RBOHs play an active role in plant adversity response and electron transport. However, the phylogenetic analysis and characterization of the SlRBOH gene family in tomatoes have not been systematically studied. This study identified 11 SlRBOH genes in the tomato genome using a genome-wide search approach. The physicochemical properties, chromosomal localization, subcellular localization, secondary structure, conserved motifs, gene structure, phylogenetics, collinear relationships, cis-acting elements, evolutionary selection pressures, tissue expressions, and expression patterns under exogenous phytohormones (ABA and MeJA) and different abiotic stresses were also analyzed. We found that the SlRBOHs are distributed across seven chromosomes, collinearity reflecting their evolutionary relationships with corresponding genes in Arabidopsis thaliana and rice. Additionally, all the SlRBOH members have five conserved domains and 10 conserved motifs and have similar gene structures. In addition, the results of an evolutionary selection pressure analysis showed that SlRBOH family members evolved mainly by purifying selection, making them more structurally stable. Cis-acting element analyses showed that SlRBOHs were responsive to light, hormone, and abiotic stresses. Tissue expression analysis showed that SlRBOH family members were expressed in all tissues of tomato to varying degrees, and most of the SlRBOHs with the strongest expression were found in the roots. In addition, the expressions of tomato SlRBOH genes were changed by ABA, MeJA, dark period extension, NaCl, PEG, UV, cold, heat, and H2O2 treatments. Specifically, SlRBOH4 was highly expressed under NaCl, PEG, heat, and UV treatments, while SlRBOH2 was highly expressed under cold stress. These results provide a basis for further studies on the function of SlRBOHs in tomato.
Estimating Binding Energies of π-Stacked Aromatic Dimers Using Force Field-Driven Molecular Dynamics
Authors: Doveiko Daniel , Kubiak-Ossowska Karina , Chen Yu
Published: May 2024

π–π stacking are omnipresent interactions, crucial in many areas of chemistry, and often studied using quantum chemical methods. Here, we report a simple and computationally efficient method of estimating the binding energies of stacked polycyclic aromatic hydrocarbons based on steered molecular dynamics. This method leverages the force field parameters for accurate calculation. The presented results show good agreement with those obtained through DFT at the ωB97X-D3/cc-pVQZ level of theory. It is demonstrated that this force field-driven SMD method can be applied to other aromatic molecules, allowing insight into the complexity of the stacking interactions and, more importantly, reporting π–π stacking energy values with reasonable precision.
Bacillus altitudinis AD13−4 Enhances Saline–Alkali Stress Tolerance of Alfalfa and Affects Composition of Rhizosphere Soil Microbial Community
Authors: Khoso Muneer Ahmed , Wang Mingyu , Zhou Zhenzhen , Huang Yongxue , Li Shenglin , Zhang Yiming , Qian Guangtao , Ko Song Nam , Pang Qiuying , Liu Changli , Li Lixin
Published: May 2024

Saline and alkaline stresses limit plant growth and reduce crop yield. Soil salinization and alkalization seriously threaten the sustainable development of agriculture and the virtuous cycle of ecology. Biofertilizers made from plant growth−promoting rhizobacteria (PGPR) not only enhance plant growth and stress tolerance, but also are environmentally friendly and cost-effective. There have been many studies on the mechanisms underlying PGPRs enhancing plant salt resistance. However, there is limited knowledge about the interaction between PGPR and plants under alkaline–sodic stress. To clarify the mechanisms underlying PGPR’s improvement of plants’ tolerance to alkaline–sodic stress, we screened PGPR from the rhizosphere microorganisms of local plants growing in alkaline–sodic land and selected an efficient strain, Bacillus altitudinis AD13−4, as the research object. Our results indicate that the strain AD13−4 can produce various growth-promoting substances to regulate plant endogenous hormone levels, cell division and differentiation, photosynthesis, antioxidant capacity, etc. Transcriptome analysis revealed that the strain AD13−4 significantly affected metabolism and secondary metabolism, signal transduction, photosynthesis, redox processes, and plant–pathogen interactions. Under alkaline–sodic conditions, inoculation of the strain AD13−4 significantly improved plant biomass and the contents of metabolites (e.g., soluble proteins and sugars) as well as secondary metabolites (e.g., phenols, flavonoids, and terpenoids). The 16S rRNA gene sequencing results indicated that the strain AD13−4 significantly affected the abundance and composition of the rhizospheric microbiota and improved soil activities and physiochemical properties. Our study provides theoretical support for the optimization of saline–alkali-tolerant PGPR and valuable information for elucidating the mechanism of plant alkaline–sodic tolerance.
Alteration of Gut Microbiota Composition and Diversity in Acute and/or Chronic Graft-versus-Host Disease Following Hematopoietic Stem Cell Transplantation: A Prospective Cohort Study
Authors: Gavriilaki Eleni , Christoforidi Maria , Ouranos Konstantinos , Minti Fani , Mallouri Despina , Varelas Christos , Lazaridou Andriana , Baldoumi Eirini , Panteliadou Alkistis , Bousiou Zoi , Batsis Ioannis , Sakellari Ioanna , Gioula Georgia
Published: May 2024

Changes in gut microbiome composition have been implicated in the pathogenesis of graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Our objective was to explore the microbial abundance in patients with GvHD after allo-HSCT. We conducted a single-center, prospective study in patients who underwent allo-HSCT and developed grade II or higher acute GvHD and/or moderate or severe chronic GvHD, to explore the microbial abundance of taxa at the phylum, family, genus, and species level, and we utilized alpha and beta diversity indices to further describe our findings. We collected fecal specimens at −2 to +2 (T1), +11 to +17 (T2), +25 to +30 (T3), +90 (T4), and +180 (T5) days to assess changes in gut microbiota, with day 0 being the day of allo-HSCT. We included 20 allo-HSCT recipients in the study. Compared with timepoint T1, at timepoint T4 we found a significant decrease in the abundance of Proteobacteria phylum (14.22% at T1 vs. 4.07% at T4, p = 0.01) and Enterobacteriaceae family (13.3% at T1 vs. <0.05% at T4, p < 0.05), as well as a significant increase in Enterococcus species (0.1% at T1 vs. 12.8% at T4, p < 0.05) in patients who developed acute GvHD. Regarding patients who developed chronic GvHD after allo-HSCT, there was a significant reduction in the abundance of Eurobactereaceae family (1.32% at T1 vs. 0.53% at T4, p < 0.05) and Roseruria genus (3.97% at T1 vs. 0.09% at T4, p < 0.05) at T4 compared with T1. Alpha and beta diversity analyses did not reveal a difference in the abundance of bacteria at the genus level in GvHD patients at T4 compared with T1. Our study reinforces results from previous studies regarding changes in gut microbiota in patients with acute GvHD and provides new data regarding the gut microbiome changes in chronic GvHD. Future studies will need to incorporate clinical parameters in their analyses to establish their association with specific changes in gut microbiota in patients with GvHD after allo-HSCT.
Melanoma Management: Exploring Staging, Prognosis, and Treatment Innovations
Authors: Shalata Walid , Attal Zoe Gabrielle , Solomon Adam , Shalata Sondos , Abu Saleh Omar , Tourkey Lena , Abu Salamah Fahed , Alatawneh Ibrahim , Yakobson Alexander
Published: May 2024

Melanoma, a malignant neoplasm originating from melanocytes, stands as one of the most prevalent cancers globally, ranking fifth in terms of estimated new cases in recent years. Its aggressive nature and propensity for metastasis pose significant challenges in oncology. Recent advancements have led to a notable shift towards targeted therapies, driven by a deeper understanding of cutaneous tumor pathogenesis. Immunotherapy and tyrosine kinase inhibitors have emerged as promising strategies, demonstrating the potential to improve clinical outcomes across all disease stages, including neoadjuvant, adjuvant, and metastatic settings. Notably, there has been a groundbreaking development in the treatment of brain metastasis, historically associated with poor prognosis in oncology but showcasing impressive results in melanoma patients. This review article provides a comprehensive synthesis of the most recent knowledge on staging and prognostic factors while highlighting emerging therapeutic modalities, with a particular focus on neoadjuvant and adjuvant strategies, notably immunotherapy and targeted therapies, including the ongoing trials.
An In Silico Analysis of Genetic Variants and Structural Modeling of the Human Frataxin Protein in Friedreich’s Ataxia
Authors: Da Conceição Loiane Mendonça Abrantes , Cabral Lucio Mendes , Pereira Gabriel Rodrigues Coutinho , De Mesquita Joelma Freire
Published: May 2024

Friedreich’s Ataxia (FRDA) stands out as the most prevalent form of hereditary ataxias, marked by progressive movement ataxia, loss of vibratory sensitivity, and skeletal deformities, severely affecting daily functioning. To date, the only medication available for treating FRDA is Omaveloxolone (Skyclarys®), recently approved by the FDA. Missense mutations within the human frataxin (FXN) gene, responsible for intracellular iron homeostasis regulation, are linked to FRDA development. These mutations induce FXN dysfunction, fostering mitochondrial iron accumulation and heightened oxidative stress, ultimately triggering neuronal cell death pathways. This study amalgamated 226 FXN genetic variants from the literature and database searches, with only 18 previously characterized. Predictive analyses revealed a notable prevalence of detrimental and destabilizing predictions for FXN mutations, predominantly impacting conserved residues crucial for protein function. Additionally, an accurate, comprehensive three-dimensional model of human FXN was constructed, serving as the basis for generating genetic variants I154F and W155R. These variants, selected for their severe clinical implications, underwent molecular dynamics (MD) simulations, unveiling flexibility and essential dynamic alterations in their N-terminal segments, encompassing FXN42, FXN56, and FXN78 domains pivotal for protein maturation. Thus, our findings indicate potential interaction profile disturbances in the FXN42, FXN56, and FXN78 domains induced by I154F and W155R mutations, aligning with the existing literature.
A “Pro-Asp-Thr” Amino Acid Repeat from Vibrio sp. QY108 Alginate Lyase Exhibits Alginate-Binding Capacity and Enhanced Soluble Expression and Thermostability
Authors: Fu Zheng , Zhang Fengchao , Wang Hainan , Tang Luyao , Yu Wengong , Han Feng
Published: May 2024

Alginate lyases cleave the 1,4-glycosidic bond of alginate by eliminating sugar molecules from its bond. While earlier reported alginate lyases were primarily single catalytic domains, research on multi-module alginate lyases has been lfiguimited. This study identified VsAly7A, a multi-module alginate lyase present in Vibrio sp. QY108, comprising a “Pro-Asp-Thr(PDT)” fragment and two PL-7 catalytic domains (CD I and CD II). The “PDT” fragment enhances the soluble expression level and increases the thermostability and binding affinity to the substrate. Moreover, CD I exhibited greater catalytic efficiency than CD II. The incorporation of PDT-CD I resulted in an increase in the optimal temperature of VsAly7A, whereas CD II displayed a preference for polyG degradation. The multi-domain structure of VsAly7A provides a new idea for the rational design of alginate lyase, whilst the “PDT” fragment may serve as a fusion tag in the soluble expression of recombinant proteins.
Hormone Regulation in Testicular Development and Function
Authors: Li Lu , Lin Wanqing , Wang Zhaoyang , Huang Rufei , Xia Huan , Li Ziyi , Deng Jingxian , Ye Tao , Huang Yadong , Yang Yan
Published: May 2024

The testes serve as the primary source of androgens and the site of spermatogenesis, with their development and function governed by hormonal actions via endocrine and paracrine pathways. Male fertility hinges on the availability of testosterone, a cornerstone of spermatogenesis, while follicle-stimulating hormone (FSH) signaling is indispensable for the proliferation, differentiation, and proper functioning of Sertoli and germ cells. This review covers the research on how androgens, FSH, and other hormones support processes crucial for male fertility in the testis and reproductive tract. These hormones are regulated by the hypothalamic–pituitary–gonad (HPG) axis, which is either quiescent or activated at different stages of the life course, and the regulation of the axis is crucial for the development and normal function of the male reproductive system. Hormonal imbalances, whether due to genetic predispositions or environmental influences, leading to hypogonadism or hypergonadism, can precipitate reproductive disorders. Investigating the regulatory network and molecular mechanisms involved in testicular development and spermatogenesis is instrumental in developing new therapeutic methods, drugs, and male hormonal contraceptives.
The Protective Role of KANK1 in Podocyte Injury
Authors: Oda Keiko , Katayama Kan , Zang Liqing , Toda Masaaki , Tanoue Akiko , Saiki Ryosuke , Yasuma Taro , D’Alessandro-Gabazza Corina N. , Shimada Yasuhito , Mori Mutsuki , Suzuki Yasuo , Murata Tomohiro , Hirai Toshinori , Tryggvason Karl , Gabazza Esteban C. , Dohi Kaoru
Published: May 2024

Approximately 30% of steroid-resistant nephrotic syndromes are attributed to monogenic disorders that involve 27 genes. Mutations in KANK family members have also been linked to nephrotic syndrome; however, the precise mechanism remains elusive. To investigate this, podocyte-specific Kank1 knockout mice were generated to examine phenotypic changes. In the initial assessment under normal conditions, Kank1 knockout mice showed no significant differences in the urinary albumin-creatinine ratio, blood urea nitrogen, serum creatinine levels, or histological features compared to controls. However, following kidney injury with adriamycin, podocyte-specific Kank1 knockout mice exhibited a significantly higher albumin-creatinine ratio and a significantly greater sclerotic index than control mice. Electron microscopy revealed more extensive foot process effacement in the knockout mice than in control mice. In addition, KANK1-deficient human podocytes showed increased detachment and apoptosis following adriamycin exposure. These findings suggest that KANK1 may play a protective role in mitigating podocyte damage under pathological conditions.
Pharmacological Inhibition of MMP-12 Exerts Protective Effects on Angiotensin II-Induced Abdominal Aortic Aneurysms in Apolipoprotein E-Deficient Mice
Authors: Di Gregoli Karina , Atkinson Georgia , Williams Helen , George Sarah J. , Johnson Jason L.
Published: May 2024

Human abdominal aortic aneurysms (AAAs) are characterized by increased activity of matrix metalloproteinases (MMP), including MMP-12, alongside macrophage accumulation and elastin degradation, in conjunction with superimposed atherosclerosis. Previous genetic ablation studies have proposed contradictory roles for MMP-12 in AAA development. In this study, we aimed to elucidate if pharmacological inhibition of MMP-12 activity with a phosphinic peptide inhibitor protects from AAA formation and progression in angiotensin (Ang) II-infused Apoe−/− mice. Complimentary studies were conducted in a human ex vivo model of early aneurysm development. Administration of an MMP-12 inhibitor (RXP470.1) protected hypercholesterolemia Apoe−/− mice from Ang II-induced AAA formation and rupture-related death, associated with diminished medial thinning and elastin fragmentation alongside increased collagen deposition. Proteomic analyses confirmed a beneficial effect of MMP-12 inhibition on extracellular matrix remodeling proteins combined with inflammatory pathways. Furthermore, RXP470.1 treatment of mice with pre-existing AAAs exerted beneficial effects as observed through suppressed aortic dilation and rupture, medial thinning, and elastin destruction. Our findings indicate that pharmacological inhibition of MMP-12 activity retards AAA progression and improves survival in mice providing proof-of-concept evidence to motivate translational work for MMP-12 inhibitor therapy in humans.
The Known, the Unknown and the Future of the Pathophysiology of Endometriosis
Authors: Ochoa Bernal Maria Ariadna , Fazleabas Asgerally T.
Published: May 2024

Endometriosis is one of the most common causes of chronic pelvic pain and infertility, affecting 10% of women of reproductive age. A delay of up to 9 years is estimated between the onset of symptoms and the diagnosis of endometriosis. Endometriosis is currently defined as the presence of endometrial epithelial and stromal cells at ectopic sites; however, advances in research on endometriosis have some authors believing that endometriosis should be re-defined as “a fibrotic condition in which endometrial stroma and epithelium can be identified”. There are several theories on the etiology of the disease, but the origin of endometriosis remains unclear. This review addresses the role of microRNAs (miRNAs), which are naturally occurring post-transcriptional regulatory molecules, in endometriotic lesion development, the inflammatory environment within the peritoneal cavity, including the role that cytokines play during the development of the disease, and how animal models have helped in our understanding of the pathology of this enigmatic disease.
Colonic Epithelial Permeability to Ions Is Restored after Vedolizumab Treatment and May Predict Clinical Response in Inflammatory Bowel Disease Patients
Authors: Cicala Michele , Gori Manuele , Balestrieri Paola , Altomare Annamaria , Tullio Alessandro , Di Cola Simone , Dejongh Sander , Graziani Maria Giovanna , Pagnini Cristiano , Carotti Simone , Perrone Giuseppe , Ribolsi Mentore , Fiorani Marcello , Guarino Michele P. L. , Farré Ricard
Published: May 2024

Vedolizumab (VDZ) is used for treating inflammatory bowel disease (IBD) patients. A study investigating colonic epithelial barrier function ex vivo following VDZ is lacking. This work aims to evaluate ex vivo the colonic epithelial barrier function in IBD patients at baseline and during VDZ treatment, and to investigate the relationships between barrier function and clinical parameters. Colonic specimens were obtained from 23 IBD patients before, and at 24 and 52 weeks after VDZ treatment, and from 26 healthy volunteers (HV). Transepithelial electrical resistance (TEER, permeability to ions) and paracellular permeability were measured in Ussing chambers. IBD patients showed increased epithelial permeability to ions (TEER, 13.80 ± 1.04 Ω × cm2 vs. HV 20.70 ± 1.52 Ω × cm2, p < 0.001) without changes in paracellular permeability of a 4 kDa probe. VDZ increased TEER (18.09 ± 1.44 Ω × cm2, p < 0.001) after 52 weeks. A clinical response was observed in 58% and 25% of patients at week 24, and in 62% and 50% at week 52, in ulcerative colitis and Crohn’s disease, respectively. Clinical and endoscopic scores were strongly associated with TEER. TEER < 14.65 Ω × cm2 predicted response to VDZ (OR 11; CI 2–59). VDZ reduces the increased permeability to ions observed in the colonic epithelium of IBD patients before treatment, in parallel to a clinical, histological (inflammatory infiltrate), and endoscopic improvement. A low TEER predicts clinical response to VDZ therapy.
Pin1 Exacerbates Non-Alcoholic Fatty Liver Disease by Enhancing Its Activity through Binding to ACC1
Authors: Jin Yiyi , Shangguan Zhaoshui , Pang Jiao , Chen Yuwen , Lin Suijin , Liu Hekun
Published: May 2024

Non-alcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterized by diffuse hepatocellular steatosis due to fatty deposits in hepatocytes, excluding alcohol and other known liver injury factors. However, there are no specific drugs for the clinical treatment of NAFLD. Therefore, research on the pathogenesis of NAFLD at the cellular and molecular levels is a promising approach to finding therapeutic targets and developing targeted drugs for NAFLD. Pin1 is highly expressed during adipogenesis and contributes to adipose differentiation, but its specific mechanism of action in NAFLD is unclear. In this study, we investigated the role of Pin1 in promoting the development of NAFLD and its potential mechanisms in vitro and in vivo. First, Pin1 was verified in the NAFLD model in vitro using MCD diet-fed mice by Western Blot, RT-qPCR and immunohistochemistry (IHC) assays. In the in vitro study, we used the oleic acid (OA) stimulation-induced lipid accumulation model and examined the lipid accumulation in each group of cells by oil red O staining as well as BODIPY staining. The results showed that knockdown of Pin1 inhibited lipid accumulation in hepatocytes in an in vitro lipid accumulation model and improved lipid indices and liver injury levels. Moreover, in vivo, WT and Pin1-KO mice were fed a methionine-choline deficient (MCD) diet for 4 weeks to induce the NAFLD model. The effects of Pin1 on lipid accumulation, hepatic fibrosis, and oxidative stress were evaluated by biochemical analysis, glucose and insulin tolerance tests, histological analysis, IHC, RT-qPCR and Western blot assays. The results indicate that Pin1 knockdown significantly alleviated hepatic steatosis, fibrosis and inflammation in MCD-induced NAFLD mice, improved glucose tolerance and alleviated insulin resistance in mice. Further studies showed that the AMPK/ACC1 signalling pathway might take part in the process by which Pin1 regulates NAFLD, as evidenced by the inhibition of the AMPK/ACC1 pathway. In addition, immunofluorescence (IF), coimmunoprecipitation (Co-IP) and GST pull-down experiments also showed that Pin1 interacts directly with ACC1 and inhibits ACC1 phosphorylation levels. Our study suggests that Pin1 promotes NAFLD progression by inhibiting the activation of the AMPK/ACC1 signalling pathway, and it is possible that this effect is achieved by Pin1 interacting with ACC1 and inhibiting the phosphorylation of ACC1.
Development of a Normal Porcine Cell Line Growing in a Heme-Supplemented, Serum-Free Condition for Cultured Meat
Authors: Seo Yeon Ah , Cha Min Jeong , Park Sehyeon , Lee Seungki , Lim Ye Jin , Son Dong Woo , Lee Eun Ji , Kim Pil , Chang Suhwan
Published: May 2024

A key element for the cost-effective development of cultured meat is a cell line culturable in serum-free conditions to reduce production costs. Heme supplementation in cultured meat mimics the original meat flavor and color. This study introduced a bacterial extract generated from Corynebacterium that was selected for high-heme expression by directed evolution. A normal porcine cell line, PK15, was used to apply the bacterial heme extract as a supplement. Consistent with prior research, we observed the cytotoxicity of PK15 to the heme extract at 10 mM or higher. However, after long-term exposure, PK15 adapted to tolerate up to 40 mM of heme. An RNA-seq analysis of these heme-adapted PK15 cells (PK15H) revealed a set of altered genes, mainly involved in cell proliferation, metabolism, and inflammation. We found that cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1), lactoperoxidase (LPO), and glutathione peroxidase 5 (GPX5) were upregulated in the PK15H heme dose dependently. When we reduced serum serially from 2% to serum free, we derived the PK15H subpopulation that was transiently maintained with 5–10 mM heme extract. Altogether, our study reports a porcine cell culturable in high-heme media that can be maintained in serum-free conditions and proposes a marker gene that plays a critical role in this adaptation process.
Differential Gene Expression Involved in Bone Turnover of Mice Expressing Constitutively Active TGFβ Receptor Type I
Authors: Myint Ohnmar , Sakunrangsit Nithidol , Pholtaisong Jatuphol , Toejing Parichart , Pho-on Pinyada , Leelahavanichkul Asada , Sridurongrit Somyoth , Aporntewan Chatchawit , Greenblatt Matthew B. , Lotinun Sutada
Published: May 2024

Transforming growth factor beta (TGF-β) is ubiquitously found in bone and plays a key role in bone turnover. Mice expressing constitutively active TGF-β receptor type I (Mx1;TβRICA mice) are osteopenic. Here, we identified the candidate genes involved in bone turnover in Mx1;TβRICA mice using RNA sequencing analysis. A total of 285 genes, including 87 upregulated and 198 downregulated genes, were differentially expressed. According to the KEGG analysis, some genes were involved in osteoclast differentiation (Fcgr4, Lilrb4a), B cell receptor signaling (Cd72, Lilrb4a), and neutrophil extracellular trap formation (Hdac7, Padi4). Lilrb4 is related to osteoclast inhibition protein, whereas Hdac7 is a Runx2 corepressor that regulates osteoblast differentiation. Silencing Lilrb4 increased the number of osteoclasts and osteoclast marker genes. The knocking down of Hdac7 increased alkaline phosphatase activity, mineralization, and osteoblast marker genes. Therefore, our present study may provide an innovative idea for potential therapeutic targets and pathways in TβRI-associated bone loss.
Assessment of Gamma Knife Stereotactic Radiosurgery as an Adjuvant Therapy in First-Line Management of Newly Diagnosed Glioblastoma: Insights from Ten Years at a Neuroscience Center
Authors: Valerio Jose E. , Wolf Aizik , Wu Xiaodong , Santiago Rea Noe , Fernandez Gomez Maria , Borro Matteo , Alvarez-Pinzon Andres M.
Published: May 2024

Gamma knife radiosurgery (GKRS), a form of stereotactic radiosurgery (SRS), has gained importance in treating glioblastoma alongside conventional chemotherapy. This study aims to assess the efficacy of combining GKRS with surgery and chemotherapy to enhance treatment outcomes for glioblastoma patients. This prospective clinical study, adhering to STROBE guidelines, assessed 121 glioblastoma patients from June 2008 to December 2022. All patients who had not undergone prior radiotherapy underwent open surgical tumor resection, GKRS, and adjuvant chemotherapy. In the analyzed cohort, the median survival post-diagnosis was 21.2 months (95% CI: 11.4–26.7) and the median progression-free survival was 13.6 months (95% CI: 12.5–28.3). The median time to first recurrence post-treatment was 14.5 months (range: 4–33 months). The median prescribed dose for GKRS was 12 Gy (range: 10–17 Gy), with a median target volume of 6.0 cm3 (range: 1.6–68 cm3). Post GKRS, 92 patients experienced local recurrence, 21 experienced distant recurrence, and 87 received additional treatment, indicating diverse responses and treatment engagement. This study evaluates the use of GKRS for glioblastomas, emphasizing its efficacy and complications in a single-center trial. It suggests integrating GKRS into initial treatment and for recurrences, highlighting the comparable survival rates but underscoring the need for further research.
Physics of the Unsteady Response of Turbine Cascade to Pulsed Flow Conditions
Authors: Bertojo Pierre , Binder Nicolas , Gressier Jeremie
Published: May 2024

The present contribution is in direct continuation of previous work which aimed at demonstrating the possible benefit of the unsteady feeding of turbines. Some numerical analyses of the flow inside a skeletal cascade revealed that instantaneous overloading occurs on the blades. However, such an academic case is far from a realistic configuration. The present paper investigates the influence of a simplified thickness distribution to check whether the instantaneous benefit is still observed. Based on numerical simulations, an analysis of the physical origin of the overloading is proposed on a single blade. It results in the choice of a triangular thickness distribution, which should promote the physical phenomena responsible for the overloading. A parametric study of such a distribution demonstrates that it is possible to obtain instantaneous performance very close to the optimum of the flat plate. Conclusions drawn from the single-blade analysis are extended to cascades and stator–rotor configurations and show an increase in the complexity of physical phenomena. Ultimately, the aim is to optimize the geometric shape to obtain maximum overloading. Consequently, the same type of study was carried out for the expansion phase, and similar results were obtained.
In-Browser Implementation of a Gamification Rule Definition Language Interpreter
Authors: Swacha Jakub , Przetacznik Wiktor
Published: May 2024

One of the practical obstacles limiting the use of cloud-based gamification applications is the lack of an Internet connection of adequate quality. In this paper, we describe a practical solution to this problem by the implementation of client-side gamification rule processing so that most events generated by players can be processed without the need to involve server-side functions; therefore, only a handful of data have to be transmitted to the server for global state synchronization, and only when an Internet connection is available. For this purpose, we adopt a simple textual gamification rule definition format, implement the rule parser and event processor, and evaluate the solution in terms of performance in experimental conditions. The obtained results are optimistic, showing that the developed solution can easily handle rule sets and event streams of realistic sizes. The solution is planned to be integrated into the next version of the FGPE gamified programming education platform.
Age and Density of Mated Females Affect Dispersal Strategies in Spider Mite Tetranychus ludeni Zacher
Authors: Zhou Peng , He Xiong Z. , Chen Chen , Wang Qiao
Published: May 2024

The dispersal strategies of a species can affect its invasion success. Investigations into the dispersal strategies of invasive species in relation to different factors help improve our understanding of invasion mechanisms and provide knowledge for population management and invasion evaluation. Tetranychus ludeni Zacher (Acari: Tetranychidae) is an invasive species which is native to Europe but is now cosmopolitan. Here, we examined the effects of age and density on dispersal in mated females. Our results show that older females that are capable of producing more eggs within 24 h were more likely to disperse and moved longer distances than younger ones with fewer eggs. Older females spread most of their eggs out of their natal habitats and over longer distances, which reduced competition and increased offspring fitness. Females exhibited significantly increased dispersal probability and distances with an increase in population density to avoid crowding. The synchronization of dispersal and reproduction, along with the positive density-dependent dispersal strategy, may facilitate the habitat colonization and invasion speed of T. ludeni.
Prognostic Significance of Serum Uric Acid and Exercise Capacity in Older Adults Hospitalized for Worsening Cardiovascular Disease
Authors: Hirashiki Akihiro , Shimizu Atsuya , Kamihara Takahiro , Kokubo Manabu , Hashimoto Kakeru , Ueda Ikue , Murohara Toyoaki
Published: May 2024

Elevated serum uric acid (sUA) is associated with the risk of developing cardiovascular disease (CVD). Here, we examined the prognostic significance of sUA and exercise capacity in 411 Japanese adults (age, ≥65; mean, 81 years) hospitalized for worsening CVD. When the patients were stratified by sUA into three groups (<5.3, 5.4–6.9, >7.0 mg/dL), the high-sUA group had a significantly worse peak VO2 and composite endpoint (rehospitalization due to worsening CVD and all-cause mortality) compared with low- and moderate-sUA groups (p < 0.001). When the patients were stratified by sUA into five groups (sUA < 3.9, 4.0–5.9, 6.0–7.9, 8.0–8.9, and >10.0 mg/dL), the incidence of the composite endpoint was significantly higher in the highest sUA group compared with that in the reference group, but only in women. Univariate Cox regression analysis, but not a multivariate analysis, indicated that sUA was significantly associated with the composite endpoint. Although sUA and exercise capacity may have some degree of prognostic significance in older patients with CVD, this significance may differ between men and women.
Therapeutic Potential of Targeting the JAK/STAT Pathway in Psoriasis: Focus on TYK2 Inhibition
Authors: Dragotto Martina , D’Onghia Martina , Trovato Emanuele , Tognetti Linda , Rubegni Pietro , Calabrese Laura
Published: May 2024

Psoriasis is an inflammatory skin disease with a chronic relapsing course and an often-detrimental impact on patients’ quality of life. Thanks to incredible advances in research over the past few decades, the therapeutic armamentarium of psoriasis is now reasonably broad and structured, with several therapeutic agents that have demonstrated successful long-term control of this condition. However, there are still unfulfilled gaps resulting from the inherent limitations of existing therapies, which have paved the way for the identification of new therapeutic strategies or the improvement of existing ones. A great deal of attention has recently been paid to the JAK/STAT pathway, playing a crucial role in chronic inflammatory skin diseases, including psoriasis. Indeed, in a disease with such a complex pathogenesis, the possibility to antagonize multiple molecular pathways via JAK/STAT inhibition offers an undeniable therapeutic advantage. However, data from clinical trials evaluating the use of oral JAK inhibitors in immune-mediated disorders, such as RA, have arisen safety concerns, suggesting a potentially increased risk of class-specific AEs such as infections, venous thromboembolism, and malignancies. New molecules are currently under investigation for the treatment of psoriasis, such as deucravacitinib, an oral selective inhibitor that binds to the regulatory domain of TYK2, brepocitinib (PF-06700841) and PF-06826647 that bind to the active site in the catalytic domain. Due to the selective TYK2 blockade allowing the inhibition of key cytokine-mediated signals, such as those induced by IL-12 and IL-23, anti-TYK2 agents appear to be very promising as the safety profile seems to be superior compared with pan-JAK inhibitors. The aim of our review is to thoroughly explore the rationale behind the usage of JAK inhibitors in PsO, their efficacy and safety profiles, with a special focus on oral TYK2 inhibitors, as well as to provide a forward-looking update on novel therapeutic strategies targeting the TYK2 pathway in psoriasis.
Impact of a Novel Antiseptic Lavage Solution on Acute Periprosthetic Joint Infection in Hip and Knee Arthroplasty
Authors: Andriollo Luca , Sangaletti Rudy , Velluto Calogero , Perticarini Loris , Benazzo Francesco , Rossi Stefano Marco Paolo
Published: May 2024

Background: Periprosthetic joint infection (PJI) represents a challenge following hip or knee arthroplasty, demanding immediate intervention to prevent implant failure and systemic issues. Bacterial biofilm development on orthopedic devices worsens PJI severity, resulting in recurrent hospitalizations and significant economic burdens. The objective of this retrospective cohort study is to evaluate the efficacy of this novel antiseptic solution, never previously evaluated in vivo, in managing early post-operative or acute hematogenous PJI following primary hip and knee joint replacements. Methods: The inclusion criteria consist of patients with total hip arthroplasty (THA) or knee arthroplasty diagnosed with acute PJI through preoperative and intraoperative investigations, in accordance with the MSIS ICM 2018 criteria. The minimum required follow-up was 12 months from the cessation of antibiotic therapy. This novel antiseptic lavage solution is composed of ethanol, acetic acid, sodium acetate, benzalkonium chloride and water. Data included demographic characteristics, diagnostic criteria, surgical techniques, post-operative treatment and follow-up outcomes. Results: A total of 39 patients treated with Debridement, Antibiotics Pearls and Retention of the Implant (DAPRI) procedures using this solution between May 2021 and April 2023 were analyzed. At a mean follow-up of 24.6 ± 6.4 months, infection recurrence-free survival rates were 87.2%, with no local allergic reactions or relevant systemic adverse effects detected. Persistent PJI necessitated two-stage revision surgery. Conclusions: This novel antiseptic lavage solution shows promise as an adjunctive tool in the treatment of PJI, demonstrating support in infection control while maintaining a favorable safety profile.
Anomaly Detection and Biomarkers Localization in Retinal Images
Authors: Tiosano Liran , Abutbul Ron , Lender Rivkah , Shwartz Yahel , Chowers Itay , Hoshen Yedid , Levy Jaime
Published: May 2024

Background: To design a novel anomaly detection and localization approach using artificial intelligence methods using optical coherence tomography (OCT) scans for retinal diseases. Methods: High-resolution OCT scans from the publicly available Kaggle dataset and a local dataset were used by four state-of-the-art self-supervised frameworks. The backbone model of all the frameworks was a pre-trained convolutional neural network (CNN), which enabled the extraction of meaningful features from OCT images. Anomalous images included choroidal neovascularization (CNV), diabetic macular edema (DME), and the presence of drusen. Anomaly detectors were evaluated by commonly accepted performance metrics, including area under the receiver operating characteristic curve, F1 score, and accuracy. Results: A total of 25,315 high-resolution retinal OCT slabs were used for training. Test and validation sets consisted of 968 and 4000 slabs, respectively. The best performing across all anomaly detectors had an area under the receiver operating characteristic of 0.99. All frameworks were shown to achieve high performance and generalize well for the different retinal diseases. Heat maps were generated to visualize the quality of the frameworks’ ability to localize anomalous areas of the image. Conclusions: This study shows that with the use of pre-trained feature extractors, the frameworks tested can generalize to the domain of retinal OCT scans and achieve high image-level ROC-AUC scores. The localization results of these frameworks are promising and successfully capture areas that indicate the presence of retinal pathology. Moreover, such frameworks have the potential to uncover new biomarkers that are difficult for the human eye to detect. Frameworks for anomaly detection and localization can potentially be integrated into clinical decision support and automatic screening systems that will aid ophthalmologists in patient diagnosis, follow-up, and treatment design. This work establishes a solid basis for further development of automated anomaly detection frameworks for clinical use.
Refractive Errors of School Children from Economically Disadvantaged Areas in Northwest México
Authors: Teran Emiliano , Romo-García Efrain , Santiago Hector C.
Published: May 2024

Background: Refractive errors, including myopia, hyperopia, and astigmatism, are the leading causes of visual impairment in school-aged children and can significantly impact their academic performance and quality of life. This study aimed to assess the prevalence of refractive errors among school children from economically disadvantaged areas in Northwest México, using a consistent methodology to facilitate comparison with global data. Methods: We adopted the Refractive Error Study in Children (RESC) protocol by the World Health Organization to examine the prevalence of myopia, hyperopia, and astigmatism. The study comprised a systematic sampling of children aged 6 to 18 years from diverse schools in Northwest México. Trained optometrists conducted visual acuity testing and autorefraction, while ophthalmologists performed cycloplegic refraction to ensure accuracy. Results: The study found a myopia (SE ≤−1.50 D at least one eye) prevalence of 14.55% (95% CI: 13.27–15.91), with a higher incidence in females (6.92%) compared to males (6.00%) in at least one eye. Hyperopia (SE ≥ +1.00 D at least one eye) was less common, at 3.23% (95% CI: 2.61–3.95), with a slightly higher occurrence in males in at least one eye. Astigmatism (Cylinder ≥ 0.75 D at least one eye) was present in 18.63% (95% CI: 17.21–20.12) of the students in at least one eye, with no significant difference between genders. These findings are consistent with other studies in regions such as Puerto Rico and Iran, indicating widespread refractive error issues among schoolchildren. Conclusions: The high prevalence of refractive errors, particularly myopia and astigmatism, highlights the critical need for regular vision screenings in schools and the implementation of public health interventions to provide corrective eyewear. Our study confirms the importance of utilizing standardized methodologies like the RESC protocol to compare refractive error prevalence across different geographical and socio-economic contexts, thereby informing global public health strategies.
Using Participatory Action Research to Redirect Tinnitus Treatment and Research—An Interview Study
Authors: Kajüter Julia , Schaap Gerko , Sools Anneke , Simões Jorge Piano
Published: May 2024

Background: Chronic bothersome tinnitus is a prevalent tinnitus subtype placing a high burden on affected individuals, economies, and healthcare systems. Patient and professional perspectives seem to be partly misaligned on how to improve tinnitus research and treatments in the future. This qualitative interview study was aimed at exploring, comparing, and stipulating the perspectives of different tinnitus stakeholder groups on ways of redirecting research and treatments to reduce patients’ suffering while accounting for challenges within these practices. Methods: This study used the participatory action research approach to facilitate the stakeholder involvement. Semi-structured online interviews including five participants (two tinnitus patients, two tinnitus researchers and medical specialists, one general practitioner) were conducted. Inductive grounded theory and the constant comparative method were used for data analysis. Results: Four categories for suggested research adaptations ((I) ethical patient involvement; (II) prioritising cure versus coping research; (III) funding; (IV) ethical publication) and six categories for suggested treatment adaptations ((I) ethical professional support; (II) patient involvement; (III) interdisciplinarity; (IV) professional tinnitus education; (V) clinical treatment guidelines; (VI) psychological treatment) were identified. Participants held partly similar priorities such as increasing pathophysiological and cure research. Differences between participants included, for instance, patients aiming for increasing patient involvement in tinnitus research and treatments compared to professionals arguing that the excessive focus on patients’ conditions might reduce the patients’ chances of habituating to their symptoms. Conclusions: Four action redirections for improving tinnitus research and treatment practices were defined: (I) facilitating communication between and within stakeholder groups, (II) increasing the reflective use of patient involvement, (III) increasing interdisciplinarity, and (IV) reducing barriers to receiving psychological treatment.
COVID-19 Posttraumatic Stress Disorder and Mental Health among Spanish Adolescents: SESSAMO Project
Authors: Yárnoz-Goñi Nora , Goñi-Sarriés Adriana , Díez-Suárez Azucena , Pírez Guillermo , Morata-Sampaio Leticia , Sánchez-Villegas Almudena
Published: May 2024

Background: Child and adolescent mental health problems have increased after the COVID-19 pandemic. The objective of this study was to establish the association of the presence and intensity of posttraumatic stress due to COVID-19 with the presence of (1) self-harm and suicide risk, (2) depressive and anxious symptoms, (3) eating disorders and (4) problematic Internet and video game use. Methods: A cross-sectional analysis was performed on a sample of second–fourth grade secondary school students (14 to 16 years old) from Navarra and the Canary Islands recruited at the SESSAMO project. Validated questionnaires were used to assess the intensity of posttraumatic stress due to COVID-19, risk of suicide and presence of self-harm, symptoms of mental disorder and problematic use of the Internet and video games. Results: Out of 1423 participants analyzed, those with the highest level of posttraumatic stress showed a significant increase in the risk of suicide (OR = 5.18; 95% CI = 2.96–9.05) and in the presence of eating disorder symptoms (OR = 3.93; 95% CI = 2.21–7.00), and higher anxiety and depression scores (b coefficient for anxiety = 11.1; CI = 9.7–12.5; for depression = 13.0; CI = 11.5–14.5) as compared to those with the lowest level. Participants with a high level of posttraumatic stress were almost 10 times more likely to present problematic video game use (OR = 9.49; 95% CI = 3.13–28.82). Conclusions: Years after the pandemic, posttraumatic stress derived from it continues to impact the mental health of adolescents. Further long-term research is needed, as well as close follow-up and intervention in this population.
Comparison of The Results of Sponsored Genetic Testing Panels for Inherited Retinal Diseases
Authors: Bao Yicheng K. , Situ Betty A. , Runner Margaret , Moshfeghi Andrew , Ameri Hossein
Published: May 2024

Background/Objectives: Gene therapy’s emergence has made molecular diagnosis for inherited retinal diseases clinically significant. Free genetic testing panels have improved testing access in clinical practice, yet the interpretation of results, especially variants of unknown significance (VUS), remains challenging and requires expertise. This study shares our experience in utilizing sponsored IRD panel tests by Invitae and Blueprint Genetics (BG), reporting their positivity rates, and comparing their reclassification of variants through amendments. Methods: This retrospective study analyzed genetic test reports from patients who underwent testing via Invitae or BG panels. A positive test was determined if there was a pathogenic mutation in an autosomal dominant gene, two pathogenic mutations in an autosomal recessive gene, or a pathogenic mutation in an X-linked gene in a male patient. Results: The testing positivity rates were 34.9% for Invitae (n = 109) and 42.1% for BG (n = 107). Invitae had more pathogenic variants per report (0.87 vs. 0.58 variants, p = 0.0038) and issued more amendments than BG (0.54 vs. 0.03 amendments; p < 0.01). Of the Invitae variant classification changes, 66.2% switched a VUS to benign. In the BG group, 75% of variant reclassifications changed a VUS to pathogenic. As a result of the Invitae amendments, 88% did not change the overall report result. Conclusions: While free-of-charge genetic testing panels offer valuable insights for diagnosing IRD, limitations such as low diagnostic yield and variant classification discrepancies persist between Invitae and BG. VUS should not be considered pathogenic in the clinical decision-making process. Careful interpretation of genetic testing is required.