bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimating the Vertical Distribution of Biomass in Subtropical Tree Species Using an Integrated Random Forest and Least Squares Machine Learning Mode
Authors: Li Guo , Li Can , Jia Guanyu , Han Zhenying , Huang Yu , Hu Wenmin
Published: June 2024

Accurate quantification of forest biomass (FB) is the key to assessing the carbon budget of terrestrial ecosystems. Using remote sensing to apply inversion techniques to the estimation of FBs has recently become a research trend. However, the limitations of vertical scale analysis methods and the nonlinear distribution of forest biomass stratification have led to significant uncertainties in FB estimation. In this study, the biomass characteristics of forest vertical stratification were considered, and based on the integration of random forest and least squares (RF-LS) models, the FB prediction potential improved. The results indicated that compared with traditional biomass estimation methods, the overall R2 of FB retrieval increased by 12.01%, and the root mean square error (RMSE) decreased by 7.50 Mg·hm−2. The RF-LS model we established exhibited better performance in FB inversion and simulation assessments. The indicators of forest canopy height, soil organic matter content, and red-edge chlorophyll vegetation index had greater impacts on FB estimation. These indexes could be the focus of consideration in FB estimation using the integrated RF-LS model. Overall, this study provided an optimization method to map and evaluate FB by fine stratification of above-ground forest and reveals important indicators for FB inversion and the applicability of the RF-LS model. The results could be used as a reference for the accurate inversion of subtropical forest biomass parameters and estimation of carbon storage.
Tree Rings Elucidate Differential Drought Responses in Stands of Three Mexican Pines
Authors: Vivar-Vivar Eduardo Daniel , Pompa-García Marín , Camarero Jesús Julio
Published: June 2024

Knowledge regarding the growth of trees is essential to understanding their response to predicted warmer and drier climate scenarios. We used the annual rings of three Mexican pines (Pinus montezumae Lamb., Pinus oocarpa Schiede ex Schltdl., and Pinus monophylla Torr. & Frém) to explore their drought responses. Correlation analyses showed that hydroclimatic factors differentially impact tree species in terms of the intensity and temporality. The negative influence of the maximum temperature and positive effect of the precipitation on the growth indices were notable, with P. montezumae being the most responsive species, followed by P. oocarpa and P. monophylla. The climate–growth relationships were specific and driven by the differential hydrothermal conditions across the study areas. SPEI analyses indicated that P. monophylla is better able to tolerate drought than P. montezumae or P. oocarpa, especially in recent years. The lower resilience of P. montezumae and P. oocarpa could predispose them to a higher mortality risk if warming and drying rates increase. Our findings strengthen the understanding of the responses of tree growth to seasonal drought, which is critical considering the biogeographic shifts that will potentially be experienced by these forests in the future. This knowledge improves the understanding of young Mexican stands and could contribute to the design of management strategies in the face of predicted climatic variations.
Mapping Forest Stock Volume Using Phenological Features Derived from Time-Serial Sentinel-2 Imagery in Planted Larch
Authors: Li Qianyang , Lin Hui , Long Jiangping , Liu Zhaohua , Ye Zilin , Zheng Huanna , Yang Peisong
Published: June 2024

As one of the important types of forest resources, mapping forest stock volume (FSV) in larch (Larix decidua) forests holds significant importance for forest resource management, carbon cycle research, and climate change monitoring. However, the accuracy of FSV mapping using common spectral and texture features is often limited due to their failure in fully capturing seasonal changes and growth cycle characteristics of vegetation. Phenological features can effectively provide essential information regarding the growth status of forests. In this study, multi-temporal Sentinel-2 satellite imagery were initially acquired in the Wangyedian Forest Farm in Chifeng City, Inner Mongolia. Subsequently, various phenological features were extracted from time series variables constructed by Gaussian Process Regression (GPR) using Savitzky–Golay filters, stepwise differentiation, and Fourier transform techniques. The alternative features were further refined through Pearson’s correlation coefficient analysis and the forward selection algorithm, resulting in six groups of optimal subsets. Finally, four models including the Random Forest (RF), K-Nearest Neighbors (KNN), Support Vector Machine (SVM), and Multiple Linear Regression (MLR) algorithms were developed to estimate FSV. The results demonstrated that incorporating phenological features significantly enhanced model performance, with the SVM model exhibiting the best performance—achieving an R2 value of 0.77 along with an RMSE value of 46.36 m3/hm2 and rRMSE value of 22.78%. Compared to models without phenological features, inclusion of these features led to a 0.25 increase in R2 value while reducing RMSE by 10.40 m3/hm2 and rRMSE by 5%. Overall, integration of phenological feature variables not only improves the accuracy of larch forest FSV mapping but also has potential implications for delaying saturation phenomena.
Metric Space Indices for Dynamic Optimization in a Peer to Peer-Based Image Classification Crowdsourcing Platform
Authors: Loor Fernando , Gil-Costa Veronica , Marin Mauricio
Published: June 2024

Large-scale computer platforms that process users’ online requests must be capable of handling unexpected spikes in arrival rates. These platforms, which are composed of distributed components, can be configured with parameters to ensure both the quality of the results obtained for each request and low response times. In this work, we propose a dynamic optimization engine based on metric space indexing to address this problem. The engine is integrated into the platform and periodically monitors performance metrics to determine whether new configuration parameter values need to be computed. Our case study focuses on a P2P platform designed for classifying crowdsourced images related to natural disasters. We evaluate our approach under scenarios with high and low workloads, comparing it against alternative methods based on deep reinforcement learning. The results show that our approach reduces processing time by an average of 40%.
Poststocking Behavior and Survival of Large Yearling Muskellunge (Esox masquinongy) in Two Northern Iowa Natural Lakes
Authors: Meerbeek Jonathan R.
Published: June 2024

Muskellunge are commonly stocked to maintain populations throughout much of North America. Poststocking survival is variable, and many jurisdictions are experimenting with stocking Muskellunge at advanced life stages (e.g., yearlings) or sizes to promote more consistent recruitment within populations. Yet, little is known about short-term poststocking behavior or survival of Muskellunge in natural lakes or if stocking larger fish results in improved poststocking survival. Radiotelemetry was used to evaluate the behavior and survival of large (mean of 418 mm; standard error of 3.4) spring-stocked yearling Muskellunge in two northern Iowa natural lakes of varying biotic and abiotic complexity. Hatchery-reared Muskellunge were fitted with radio transmitters (n = 10–15 fish/lake), stocked in each lake with conspecifics, and tracked either daily or weekly up to 112 days poststocking. Telemetry data were used to evaluate dispersal and movement, depth and vegetation use, proximity to shore, and survival. In both lakes, fish dispersed rapidly from each stocking site. Movement among lakes was similar and peaked during the first week poststocking and declined thereafter. Muskellunge were frequently located in offshore habitats in both lakes, but both depth and vegetation use varied among lakes and weeks poststocking, with Muskellunge found in deeper, more vegetated habitats in the larger, more complex natural lake. Muskellunge in both systems had high poststocking survival (86.7–90.0%). The results of this study provide managers with more information regarding yearling Muskellunge poststocking behavior and survival and indicate that larger fish may be a suitable alternative for fisheries where high poststocking mortality may be acting as a bottleneck for maintaining quality Muskellunge fisheries.
Environmentally Relevant Concentrations of Tetracycline Promote Horizontal Transfer of Antimicrobial Resistance Genes via Plasmid-Mediated Conjugation
Authors: Zhou Haibo , Lu Zhaoxin , Liu Xinmei , Bie Xiaomei , Xue Feng , Tang Sijie , Feng Qiushi , Cheng Yiyu , Yang Jun
Published: June 2024

The ubiquitous presence of antimicrobial-resistant organisms and antimicrobial resistance genes (ARGs) constitutes a major threat to global public safety. Tetracycline (TET) is a common antimicrobial agent that inhibits bacterial growth and is frequently detected in aquatic environments. Although TET may display coselection for resistance, limited knowledge is available on whether and how it might influence plasmid-mediated conjugation. Subinhibitory concentrations (3.9–250 ng/mL) of TET promoted horizontal gene transfer (HGT) via the mobilizable plasmid pVP52-1 from the donor Vibrio parahaemolyticus NJIFDCVp52 to the recipient Escherichia coli EC600 by 1.47- to 3.19-fold. The transcription levels of tetracycline resistance genes [tetA, tetR(A)], conjugation-related genes (traA, traD), outer membrane protein genes (ompA, ompK, ompV), reactive oxygen species (ROS)-related genes (oxyR, rpoS), autoinducer-2 (AI-2) synthesis gene (luxS), and SOS-related genes (lexA, recA) in the donor and recipient were significantly increased. Furthermore, the overproduced intracellular ROS generation and increased cell membrane permeability under TET exposure stimulated the conjugative transfer of ARGs. Overall, this study provides important insights into the contributions of TET to the spread of antimicrobial resistance.
Quantized Nonfragile State Estimation of Memristor-Based Fractional-Order Neural Networks with Hybrid Time Delays Subject to Sensor Saturations
Authors: Shao Xiaoguang , Lu Yanjuan , Zhang Jie , Lyu Ming , Yang Yu
Published: June 2024

This study addresses the issue of nonfragile state estimation for memristor-based fractional-order neural networks with hybrid randomly occurring delays. Considering the finite bandwidth of the signal transmission channel, quantitative processing is introduced to reduce network burden and prevent signal blocking and packet loss. In a real-world setting, the designed estimator may experience potential gain variations. To address this issue, a fractional-order nonfragile estimator is developed by incorporating a logarithmic quantizer, which ultimately improves the reliability of the state estimator. In addition, by combining the generalized fractional-order Lyapunov direct method with novel Caputo–Wirtinger integral inequalities, a lower conservative criterion is derived to guarantee the asymptotic stability of the augmented system. At last, the accuracy and practicality of the desired estimation scheme are demonstrated through two simulation examples.
Unraveling the Genetic Foundations of Broiler Meat Quality: Advancements in Research and Their Impact
Authors: Lu Tian , Abdalla Gibril Bahareldin Ali , Xu Jiguo , Xiong Xinwei
Published: June 2024

As societal progress elevates living standards, the focus on meat consumption has shifted from quantity to quality. In broiler production, optimizing meat quality has become paramount, prompting efforts to refine various meat attributes. Recent advancements in sequencing technologies have revealed the genome’s complexity, surpassing previous conceptions. Through experimentation, numerous genetic elements have been linked to crucial meat quality traits in broiler chickens. This review synthesizes the current understanding of genetic determinants associated with meat quality attributes in broilers. Researchers have unveiled the pivotal insights detailed herein by employing diverse genomic methodologies such as QTL-based investigations, candidate gene studies, single-nucleotide polymorphism screening, genome-wide association studies, and RNA sequencing. These studies have identified numerous genes involved in broiler meat quality traits, including meat lightness (COL1A2 and ACAA2), meat yellowness (BCMO1 and GDPD5), fiber diameter (myostatin and LncIRS1), meat pH (PRDX4), tenderness (CAPN1), and intramuscular fat content (miR-24-3p and ANXA6). Consequently, a comprehensive exploration of these genetic elements is imperative to devise novel molecular markers and potential targets, promising to revolutionize strategies for enhancing broiler meat quality.
Prediction of Soil Liquefaction Triggering Using Rule-Based Interpretable Machine Learning
Authors: Torres Emerzon , Dungca Jonathan
Published: June 2024

Seismic events remain a significant threat, causing loss of life and extensive damage in vulnerable regions. Soil liquefaction, a complex phenomenon where soil particles lose confinement, poses a substantial risk. The existing conventional simplified procedures, and some current machine learning techniques, for liquefaction assessment reveal limitations and disadvantages. Utilizing the publicly available liquefaction case history database, this study aimed to produce a rule-based liquefaction triggering classification model using rough set-based machine learning, which is an interpretable machine learning tool. Following a series of procedures, a set of 32 rules in the form of IF-THEN statements were chosen as the best rule set. While some rules showed the expected outputs, there are several rules that presented attribute threshold values for triggering liquefaction. Rules that govern fine-grained soils emerged and challenged some of the common understandings of soil liquefaction. Additionally, this study also offered a clear flowchart for utilizing the rule-based model, demonstrated through practical examples using a borehole log. Results from the state-of-practice simplified procedures for liquefaction triggering align well with the proposed rule-based model. Recommendations for further evaluations of some rules and the expansion of the liquefaction database are warranted.
An Exuberant Case of Ulceronodular-Rupioid (Malignant) Syphilis in an HIV Patient: A Proposal for New Diagnostic Criteria
Authors: Jimenez Dennys , Rabe Marian Santillan , Agarwal Apeksha N. , Dalton Scott R. , Anstead Gregory M.
Published: June 2024

We report the case of a 28-year-old male with uncontrolled human immunodeficiency virus (HIV) infection who presented with extensive ulcerated lesions with dark lamellated crusting on his face, torso, and limbs. The patient had a rapid plasma reagin (RPR) titer of 1:512, indicative of syphilis. A skin biopsy revealed granulomata surrounded by lymphocytes, histiocytes, and plasma cells, with spirochetes visible on immunohistochemical staining. The patient’s rash resolved with hyperpigmented scarring after penicillin and doxycycline treatment. This severe form of secondary syphilis has been termed malignant syphilis, lues maligna, ulceronodular syphilis, or rupioid syphilis. We propose a single descriptive name for this entity, ulceronodular-rupioid syphilis. In 1969, Fisher proposed criteria for malignant syphilis based on lesion appearance, histopathologic findings, high RPR values, and rapid response to treatment. We found that the Fisher criteria were imprecise with respect to specific histopathologic findings, the quantitation of RPR values, and what constitutes rapid response to treatment. Thus, we examined an additional 74 cases from the literature and propose new diagnostic criteria based on rash appearance, histopathologic characteristics, non-treponemal and treponemal test positivity, and response to therapy. We also found that uncontrolled viremia, and not a low CD4 count, is a major risk factor for ulceronodular-rupioid syphilis in HIV patients.
Evaluation of Whole Genome Sequencing-Based Predictions of Antimicrobial Resistance to TB First Line Agents: A Lesson from 5 Years of Data
Authors: Sharma Meenu Kaushal , Stobart Michael , Akochy Pierre-Marie , Adam Heather , Janella Debra , Rabb Melissa , Alawa Mohey , Sekirov Inna , Tyrrell Gregory J. , Soualhine Hafid
Published: June 2024

Phenotypic susceptibility testing of the Mycobacterium tuberculosis complex (MTBC) isolate requires culture growth, which can delay rapid detection of resistant cases. Whole genome sequencing (WGS) and data analysis pipelines can assist in predicting resistance to antimicrobials used in the treatment of tuberculosis (TB). This study compared phenotypic susceptibility testing results and WGS-based predictions of antimicrobial resistance (AMR) to four first-line antimicrobials—isoniazid, rifampin, ethambutol, and pyrazinamide—for MTBC isolates tested between the years 2018–2022. For this 5-year retrospective analysis, the WGS sensitivity for predicting resistance for isoniazid, rifampin, ethambutol, and pyrazinamide using Mykrobe was 86.7%, 100.0%, 100.0%, and 47.8%, respectively, and the specificity was 99.4%, 99.5%, 98.7%, and 99.9%, respectively. The predictive values improved slightly using Mykrobe corrections applied using TB Profiler, i.e., the WGS sensitivity for isoniazid, rifampin, ethambutol, and pyrazinamide was 92.31%, 100%, 100%, and 57.78%, respectively, and the specificity was 99.63%. 99.45%, 98.93%, and 99.93%, respectively. The utilization of WGS-based testing addresses concerns regarding test turnaround time and enables analysis for MTBC member identification, antimicrobial resistance prediction, detection of mixed cultures, and strain genotyping, all through a single laboratory test. WGS enables rapid resistance detection compared to traditional phenotypic susceptibility testing methods using the WHO TB mutation catalog, providing an insight into lesser-known mutations, which should be added to prediction databases as high-confidence mutations are recognized. The WGS-based methods can support TB elimination efforts in Canada and globally by ensuring the early start of appropriate treatment, rapidly limiting the spread of TB outbreaks.
Novel Lipid Nanocomplex Co-Carrying Bcl2 siRNA and Quantum Dots for EGF Receptor-Targeted Anti-Cancer Theranosis
Authors: Choi Moon Jung , Kang Seong Jae , Lee Yeon Kyung , Choi Kang Chan , Lee Do Hyun , Jeong Hwa Yeon , Kim Min Woo , Kim Keun Sik , Park Yong Serk
Published: June 2024

Many different types of nanoparticles have been suggested for tumor-targeted theranosis. However, most systems were prepared through a series of complicated processes and could not even overcome the blood–immune barriers. For the accurate diagnosis and effective treatment of cancers, herein we suggested the lipid micellar structure capturing quantum dot (QD) for cancer theranosis. The QD/lipid micelles (QDMs) were prepared using a simple self-assembly procedure and then conjugated with anti-epidermal growth factor receptor (EGFR) antibodies for tumor targeting. As a therapeutic agent, Bcl2 siRNA-cholesterol conjugates were loaded on the surface of QDMs. The EGFR-directed QDMs containing Bcl2 siRNA, so-called immuno-QDM/siBcl2 (iQDM/siBcl2), exhibited the more effective delivery of QDs and siBcl2 to target human colorectal cancer cells in cultures as well as in mouse xenografts. The effective in vivo targeting of iQDM/siBcl2 resulted in a more enhanced therapeutic efficacy of siBcl2 to the target cancer in mice. Based on the results, anti-EGFR QDM capturing therapeutic siRNA could be suggested as an alternative modality for tumor-targeted theranosis.
NOTCH3 and Pulmonary Arterial Hypertension
Authors: Winicki Nolan M. , Puerta Cristian , Besse Casandra E. , Zhang Yu , Thistlethwaite Patricia A.
Published: June 2024

NOTCH3 receptor signaling has been linked to the regulation of smooth muscle cell proliferation and the maintenance of smooth muscle cells in an undifferentiated state. Pulmonary arterial hypertension (World Health Organization Group 1 idiopathic disease: PAH) is a fatal disease characterized clinically by elevated pulmonary vascular resistance caused by extensive vascular smooth muscle cell proliferation, perivascular inflammation, and asymmetric neointimal hyperplasia in precapillary pulmonary arteries. In this review, a detailed overview of the specific role of NOTCH3 signaling in PAH, including its mechanisms of activation by a select ligand, downstream signaling effectors, and physiologic effects within the pulmonary vascular tree, is provided. Animal models showing the importance of the NOTCH3 pathway in clinical PAH will be discussed. New drugs and biologics that inhibit NOTCH3 signaling and reverse this deadly disease are highlighted.
EGG: Accuracy Estimation of Individual Multimeric Protein Models Using Deep Energy-Based Models and Graph Neural Networks
Authors: Siciliano Andrew Jordan , Zhao Chenguang , Liu Tong , Wang Zheng
Published: June 2024

Reliable and accurate methods of estimating the accuracy of predicted protein models are vital to understanding their respective utility. Discerning how the quaternary structure conforms can significantly improve our collective understanding of cell biology, systems biology, disease formation, and disease treatment. Accurately determining the quality of multimeric protein models is still computationally challenging, as the space of possible conformations is significantly larger when proteins form in complex with one another. Here, we present EGG (energy and graph-based architectures) to assess the accuracy of predicted multimeric protein models. We implemented message-passing and transformer layers to infer the overall fold and interface accuracy scores of predicted multimeric protein models. When evaluated with CASP15 targets, our methods achieved promising results against single model predictors: fourth and third place for determining the highest-quality model when estimating overall fold accuracy and overall interface accuracy, respectively, and first place for determining the top three highest quality models when estimating both overall fold accuracy and overall interface accuracy.
Enhancing Machine-Learning Prediction of Enzyme Catalytic Temperature Optima through Amino Acid Conservation Analysis
Authors: Cao Yinyin , Qiu Boyu , Ning Xiao , Fan Lin , Qin Yanmei , Yu Dong , Yang Chunhe , Ma Hongwu , Liao Xiaoping , You Chun
Published: June 2024

Enzymes play a crucial role in various industrial production and pharmaceutical developments, serving as catalysts for numerous biochemical reactions. Determining the optimal catalytic temperature (Topt) of enzymes is crucial for optimizing reaction conditions, enhancing catalytic efficiency, and accelerating the industrial processes. However, due to the limited availability of experimentally determined Topt data and the insufficient accuracy of existing computational methods in predicting Topt, there is an urgent need for a computational approach to predict the Topt values of enzymes accurately. In this study, using phosphatase (EC 3.1.3.X) as an example, we constructed a machine learning model utilizing amino acid frequency and protein molecular weight information as features and employing the K-nearest neighbors regression algorithm to predict the Topt of enzymes. Usually, when conducting engineering for enzyme thermostability, researchers tend not to modify conserved amino acids. Therefore, we utilized this machine learning model to predict the Topt of phosphatase sequences after removing conserved amino acids. We found that the predictive model’s mean coefficient of determination (R2) value increased from 0.599 to 0.755 compared to the model based on the complete sequences. Subsequently, experimental validation on 10 phosphatase enzymes with undetermined optimal catalytic temperatures shows that the predicted values of most phosphatase enzymes based on the sequence without conservative amino acids are closer to the experimental optimal catalytic temperature values. This study lays the foundation for the rapid selection of enzymes suitable for industrial conditions.
Regulation of Neuronal Chloride Homeostasis by Pro- and Mature Brain-Derived Neurotrophic Factor (BDNF) via KCC2 Cation–Chloride Cotransporters in Rat Cortical Neurons
Authors: Hamze Mira , Brier Cathy , Buhler Emmanuelle , Zhang Jinwei , Medina Igor , Porcher Christophe
Published: June 2024

The strength of inhibitory neurotransmission depends on intracellular neuronal chloride concentration, primarily regulated by the activity of cation–chloride cotransporters NKCC1 (Sodium–Potassium–Chloride Cotransporter 1) and KCC2 (Potassium–Chloride Cotransporter 2). Brain-derived neurotrophic factor (BDNF) influences the functioning of these co-transporters. BDNF is synthesized from precursor proteins (proBDNF), which undergo proteolytic cleavage to yield mature BDNF (mBDNF). While previous studies have indicated the involvement of BDNF signaling in the activity of KCC2, its specific mechanisms are unclear. We investigated the interplay between both forms of BDNF and chloride homeostasis in rat hippocampal neurons and in utero electroporated cortices of rat pups, spanning the behavioral, cellular, and molecular levels. We found that both pro- and mBDNF play a comparable role in immature neurons by inhibiting the capacity of neurons to extrude chloride. Additionally, proBDNF increases the endocytosis of KCC2 while maintaining a depolarizing shift of EGABA in maturing neurons. Behaviorally, proBDNF-electroporated rat pups in the somatosensory cortex exhibit sensory deficits, delayed huddling, and cliff avoidance. These findings emphasize the role of BDNF signaling in regulating chloride transport through the modulation of KCC2. In summary, this study provides valuable insights into the intricate interplay between BDNF, chloride homeostasis, and inhibitory synaptic transmission, shedding light on the underlying cellular mechanisms involved.
Optimizing Messenger RNA Analysis Using Ultra-Wide Pore Size Exclusion Chromatography Columns
Authors: D’Atri Valentina , Lardeux Honorine , Goyon Alexandre , Imiołek Mateusz , Fekete Szabolcs , Lauber Matthew , Zhang Kelly , Guillarme Davy
Published: June 2024

Biopharmaceutical products, in particular messenger ribonucleic acid (mRNA), have the potential to dramatically improve the quality of life for patients suffering from respiratory and infectious diseases, rare genetic disorders, and cancer. However, the quality and safety of such products are particularly critical for patients and require close scrutiny. Key product-related impurities, such as fragments and aggregates, among others, can significantly reduce the efficacy of mRNA therapies. In the present work, the possibilities offered by size exclusion chromatography (SEC) for the characterization of mRNA samples were explored using state-of-the-art ultra-wide pore columns with average pore diameters of 1000 and 2500 Å. Our investigation shows that a column with 1000 Å pores proved to be optimal for the analysis of mRNA products, whatever the size between 500 and 5000 nucleotides (nt). We also studied the influence of mobile phase composition and found that the addition of 10 mM magnesium chloride (MgCl2) can be beneficial in improving the resolution and recovery of large size variants for some mRNA samples. We demonstrate that caution should be exercised when increasing column length or decreasing the flow rate. While these adjustments slightly improve resolution, they also lead to an apparent increase in the amount of low-molecular-weight species (LMWS) and monomer peak tailing, which can be attributed to the prolonged residence time inside the column. Finally, our optimal SEC method has been successfully applied to a wide range of mRNA products, ranging from 1000 to 4500 nt in length, as well as mRNA from different suppliers and stressed/unstressed samples.
Exploring the Ocular Surface Microbiome and Tear Proteome in Glaucoma
Authors: Spörri Livia , Uldry Anne-Christine , Kreuzer Marco , Herzog Elio L. , Zinkernagel Martin S. , Unterlauft Jan D. , Zysset-Burri Denise C.
Published: June 2024

Although glaucoma is a leading cause of irreversible blindness worldwide, its pathogenesis is incompletely understood, and intraocular pressure (IOP) is the only modifiable risk factor to target the disease. Several associations between the gut microbiome and glaucoma, including the IOP, have been suggested. There is growing evidence that interactions between microbes on the ocular surface, termed the ocular surface microbiome (OSM), and tear proteins, collectively called the tear proteome, may also play a role in ocular diseases such as glaucoma. This study aimed to find characteristic features of the OSM and tear proteins in patients with glaucoma. The whole-metagenome shotgun sequencing of 32 conjunctival swabs identified Actinobacteria, Firmicutes, and Proteobacteria as the dominant phyla in the cohort. The species Corynebacterium mastitidis was only found in healthy controls, and their conjunctival microbiomes may be enriched in genes of the phospholipase pathway compared to glaucoma patients. Despite these minor differences in the OSM, patients showed an enrichment of many tear proteins associated with the immune system compared to controls. In contrast to the OSM, this emphasizes the role of the proteome, with a potential involvement of immunological processes in glaucoma. These findings may contribute to the design of new therapeutic approaches targeting glaucoma and other associated diseases.
Expression of Wild-Type and Mutant Human TDP-43 in Yeast Inhibits TOROID (TORC1 Organized in Inhibited Domain) Formation and Autophagy Proportionally to the Levels of TDP-43 Toxicity
Authors: Park Sangeun , Park Sei-Kyoung , Liebman Susan W.
Published: June 2024

TDP-43 forms aggregates in the neurons of patients with several neurodegenerative diseases. Human TDP-43 also aggregates and is toxic in yeast. Here, we used a yeast model to investigate (1) the nature of TDP-43 aggregates and (2) the mechanism of TDP-43 toxicity. Thioflavin T, which stains amyloid but not wild-type TDP-43 aggregates, also did not stain mutant TDP-43 aggregates made from TDP-43 with intragenic mutations that increase or decrease its toxicity. However, 1,6-hexanediol, which dissolves liquid droplets, dissolved wild-type or mutant TDP-43 aggregates. To investigate the mechanism of TDP-43 toxicity, the effects of TDP-43 mutations on the autophagy of the GFP-ATG8 reporter were examined. Mutations in TDP-43 that enhance its toxicity, but not mutations that reduce its toxicity, caused a larger reduction in autophagy. TOROID formation, which enhances autophagy, was scored as GFP-TOR1 aggregation. TDP-43 inhibited TOROID formation. TORC1 bound to both toxic and non-toxic TDP-43, and to TDP-43, with reduced toxicity due to pbp1Δ. However, extragenic modifiers and TDP-43 mutants that reduced TDP-43 toxicity, but not TDP-43 mutants that enhanced toxicity, restored TOROID formation. This is consistent with the hypothesis that TDP-43 is toxic in yeast because it reduces TOROID formation, causing the inhibition of autophagy. Whether TDP-43 exerts a similar effect in higher cells remains to be determined.
Investigating Contributions of Canonical Transient Receptor Potential Channel 3 to Hippocampal Hyperexcitability and Seizure-Induced Neuronal Cell Death
Authors: Phelan Kevin D. , Shwe U Thaung , Wu Hong , Zheng Fang
Published: June 2024

Canonical transient receptor potential channel 3 (TRPC3) is the most abundant TRPC channel in the brain and is highly expressed in all subfields of the hippocampus. Previous studies have suggested that TRPC3 channels may be involved in the hyperexcitability of hippocampal pyramidal neurons and seizures. Genetic ablation of TRPC3 channel expression reduced the intensity of pilocarpine-induced status epilepticus (SE). However, the underlying cellular mechanisms remain unexplored and the contribution of TRPC3 channels to SE-induced neurodegeneration is not determined. In this study, we investigated the contribution of TRPC3 channels to the electrophysiological properties of hippocampal pyramidal neurons and hippocampal synaptic plasticity, and the contribution of TRPC3 channels to seizure-induced neuronal cell death. We found that genetic ablation of TRPC3 expression did not alter basic electrophysiological properties of hippocampal pyramidal neurons and had a complex impact on epileptiform bursting in CA3. However, TRPC3 channels contribute significantly to long-term potentiation in CA1 and SE-induced neurodegeneration. Our results provided further support for therapeutic potential of TRPC3 inhibitors and raised new questions that need to be answered by future studies.
Modified mRNA-Mediated CCN5 Gene Transfer Ameliorates Cardiac Dysfunction and Fibrosis without Adverse Structural Remodeling
Authors: Song Min Ho , Yoo Jimeen , Kwon Do-A , Chepurko Elena , Cho Sunghye , Fargnoli Anthony , Hajjar Roger J. , Park Woo Jin , Zangi Lior , Jeong Dongtak
Published: June 2024

Modified mRNAs (modRNAs) are an emerging delivery method for gene therapy. The success of modRNA-based COVID-19 vaccines has demonstrated that modRNA is a safe and effective therapeutic tool. Moreover, modRNA has the potential to treat various human diseases, including cardiac dysfunction. Acute myocardial infarction (MI) is a major cardiac disorder that currently lacks curative treatment options, and MI is commonly accompanied by fibrosis and impaired cardiac function. Our group previously demonstrated that the matricellular protein CCN5 inhibits cardiac fibrosis (CF) and mitigates cardiac dysfunction. However, it remains unclear whether early intervention of CF under stress conditions is beneficial or more detrimental due to potential adverse effects such as left ventricular (LV) rupture. We hypothesized that CCN5 would alleviate the adverse effects of myocardial infarction (MI) through its anti-fibrotic properties under stress conditions. To induce the rapid expression of CCN5, ModRNA-CCN5 was synthesized and administrated directly into the myocardium in a mouse MI model. To evaluate CCN5 activity, we established two independent experimental schemes: (1) preventive intervention and (2) therapeutic intervention. Functional analyses, including echocardiography and magnetic resonance imaging (MRI), along with molecular assays, demonstrated that modRNA-mediated CCN5 gene transfer significantly attenuated cardiac fibrosis and improved cardiac function in both preventive and therapeutic models, without causing left ventricular rupture or any adverse cardiac remodeling. In conclusion, early intervention in CF by ModRNA-CCN5 gene transfer is an efficient and safe therapeutic modality for treating MI-induced heart failure.
Characterization and Hydrolysis Studies of a Prodrug Obtained as Ester Conjugate of Geraniol and Ferulic Acid by Enzymatic Way
Authors: Lerin Lindomar Alberto , Botti Giada , Dalpiaz Alessandro , Bianchi Anna , Ferraro Luca , Chaibi Chaimae , Zappaterra Federico , Meola Domenico , Giovannini Pier Paolo , Pavan Barbara
Published: June 2024

Ferulic acid (Fer) and geraniol (Ger) are natural compounds whose antioxidant and anti-inflammatory activity confer beneficial properties, such as antibacterial, anticancer, and neuroprotective effects. However, the short half-lives of these compounds impair their therapeutic activities after conventional administration. We propose, therefore, a new prodrug (Fer-Ger) obtained by a bio-catalyzed ester conjugation of Fer and Ger to enhance the loading of solid lipid microparticles (SLMs) designed as Fer-Ger delivery and targeting systems. SLMs were obtained by hot emulsion techniques without organic solvents. HPLC-UV analysis evidenced that Fer-Ger is hydrolyzed in human or rat whole blood and rat liver homogenates, with half-lives of 193.64 ± 20.93, 20.15 ± 0.75, and 3.94 ± 0.33 min, respectively, but not in rat brain homogenates. Studies on neuronal-differentiated mouse neuroblastoma N2a cells incubated with the reactive oxygen species (ROS) inductor H2O2 evidenced the Fer-Ger ability to prevent oxidative injury, despite the fact that it appears ROS-promoting. The amounts of Fer-Ger encapsulated in tristearin SLMs, obtained in the absence or presence of glucose, were 1.5 ± 0.1%, allowing the control of the prodrug release (glucose absence) or to sensibly enhance its water dissolution rate (glucose presence). These new “green” carriers can potentially prolong the beneficial effects of Fer and Ger or induce neuroprotection as nasal formulations.
Immune Checkpoints in Endometriosis—A New Insight in the Pathogenesis
Authors: Suszczyk Dorota , Skiba Wiktoria , Pawłowska-Łachut Anna , Dymanowska-Dyjak Izabela , Włodarczyk Karolina , Paduch Roman , Wertel Iwona
Published: June 2024

Endometriosis (EMS) is an oestrogen-dependent, chronic disease affecting women of a reproductive age. One of the important factors involved in the development of this disease is the complex disorders associated with the functioning of the immune system. Recent evidence has shown that EMS development is associated with changes in systemic and local immunity, including functional disturbances of effector and antigen-presenting cells. One of the reasons for immune imbalance can be the improper expression of immune checkpoints (ICPs). ICPs and their ligands are responsible for maintaining self-tolerance and the modulation of the initiation, duration, and magnitude of the immune response of effector cells in normal tissues to avoid tissue damage. Considering the complex nature of co-stimulatory or co-inhibitory ICPs and the signalling between effector cells and APCs, we hypothesise that changes in cells’ activity caused by ICPs may lead to serious immune system disturbances in patients with endometriosis. Moreover, both upregulation and downregulation in the expression of ICPs may be implicated in this process, including the reduced activity of effector cells against endometrial implants and disturbances in the antigen-presenting process. In this narrative review, we discuss, for the first time, key findings from the emerging literature, describing the associations between ICPs and their possible implication in the pathogenesis of endometriosis.
Cannabinoid Analgesia in Postoperative Pain Management: From Molecular Mechanisms to Clinical Reality
Authors: Carrascosa Antonio J. , Navarrete Francisco , Saldaña Raquel , García-Gutiérrez María S. , Montalbán Belinda , Navarro Daniela , Gómez-Guijarro Fernando M. , Gasparyan Ani , Murcia-Sánchez Elena , Torregrosa Abraham B. , Pérez-Doblado Paloma , Gutiérrez Luisa , Manzanares Jorge
Published: June 2024

Postoperative pain (POP) is a challenging clinical phenomenon that affects the majority of surgical patients and demands effective management to mitigate adverse outcomes such as persistent pain. The primary goal of POP management is to alleviate suffering and facilitate a seamless return to normal function for the patient. Despite compelling evidence of its drawbacks, opioid analgesia remains the basis of POP treatment. Novel therapeutic approaches rely on multimodal analgesia, integrating different pharmacological strategies to optimize efficacy while minimizing adverse effects. The recognition of the imperative role of the endocannabinoid system in pain regulation has prompted the investigation of cannabinoid compounds as a new therapeutic avenue. Cannabinoids may serve as adjuvants, enhancing the analgesic effects of other drugs and potentially replacing or at least reducing the dependence on other long-term analgesics in pain management. This narrative review succinctly summarizes pertinent information on the molecular mechanisms, clinical therapeutic benefits, and considerations associated with the plausible use of various cannabinoid compounds in treating POP. According to the available evidence, cannabinoid compounds modulate specific molecular mechanisms intimately involved in POP. However, only two of the eleven clinical trials that evaluated the efficacy of different cannabinoid interventions showed positive results.
Self-Assembly of Molecular Landers Equipped with Functional Moieties on the Surface: A Mini Review
Authors: El Hasnaoui Nadia , Fatimi Ahmed , Benjalal Youness
Published: June 2024

The bottom-up fabrication of supramolecular and self-assembly on various substrates has become an extremely relevant goal to achieve prospects in the development of nanodevices for electronic circuitry or sensors. One of the branches of this field is the self-assembly of functional molecular components driven through non-covalent interactions on the surfaces, such as van der Waals (vdW) interactions, hydrogen bonding (HB), electrostatic interactions, etc., allowing the controlled design of nanostructures that can satisfy the requirements of nanoengineering concepts. In this context, non-covalent interactions present opportunities that have been previously explored in several molecular systems adsorbed on surfaces, primarily due to their highly directional nature which facilitates the formation of well-ordered structures. Herein, we review a series of research works by combining STM (scanning tunneling microscopy) with theoretical calculations, to reveal the processes used in the area of self-assembly driven by molecule Landers equipped with functional groups on the metallic surfaces. Combining these processes is necessary for researchers to advance the self-assembly of supramolecular architectures driven by multiple non-covalent interactions on solid surfaces.
Cilostazol Attenuates Hepatic Steatosis and Intestinal Disorders in Nonalcoholic Fatty Liver Disease
Authors: Min Tianqi , Qiu Shuting , Bai Yan , Cao Hua , Guo Jiao , Su Zhengquan
Published: June 2024

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases in the world, which begins with liver lipid accumulation and is associated with metabolic syndrome. Also, the name chosen to replace NAFLD was metabolic dysfunction-associated steatotic liver disease (MASLD). We performed focused drug screening and found that Cilostazol effectively ameliorated hepatic steatosis and might offer potential for NAFLD treatment. Our aim was to investigate the therapeutic effects of Cilostazol on the glycolipid metabolism and intestinal flora in NAFLD mice and explore the specific mechanism. In this study, 7-week-old male C57BL/6J mice were fed a high-fat diet (HFD) for 8 weeks to induce NAFLD, and then treated with intragastric administration for 12 weeks. The results showed that Cilostazol inhibited liver lipid de novo synthesis by regulating the AMPK-ACC1/SCD1 pathway and inhibited liver gluconeogenesis by the AMPK-PGC1α-G6P/PEPCK pathway. Cilostazol improved the intestinal flora diversity and intestinal microbial composition in the NAFLD mice, and specifically regulated Desulfovibrio and Akkermansia. In addition, Cilostazol increased the level of short-chain fatty acids in the NAFLD mice to a level similar to that in the blank Control group. Cilostazol reduces liver lipid accumulation in NAFLD mice by improving glucose and lipid metabolism disorders and intestinal dysfunction, thereby achieving the purpose of treating NAFLD.
SCGB1C1 Plays a Critical Role in Suppression of Allergic Airway Inflammation through the Induction of Regulatory T Cell Expansion
Authors: Kim Sung-Dong , Kang Shin-Ae , Mun Sue-Jean , Yu Hak-Sun , Roh Hwan-Jung , Cho Kyu-Sup
Published: June 2024

The nanosized vesicles secreted from various cell types into the surrounding extracellular space are called extracellular vesicles (EVs). Although mesenchymal stem cell-derived EVs are known to have immunomodulatory effects in asthmatic mice, the role of identified pulmonary genes in the suppression of allergic airway inflammation remains to be elucidated. Moreover, the major genes responsible for immune regulation in allergic airway diseases have not been well documented. This study aims to evaluate the immunomodulatory effects of secretoglobin family 1C member 1 (SCGB1C1) on asthmatic mouse models. C57BL/6 mice were sensitized to ovalbumin (OVA) using intraperitoneal injection and were intranasally challenged with OVA. To evaluate the effect of SCGB1C1 on allergic airway inflammation, 5 μg/50 μL of SCGB1C1 was administrated intranasally before an OVA challenge. We evaluated airway hyperresponsiveness (AHR), total inflammatory cells, eosinophils in the bronchoalveolar lavage fluid (BALF), lung histology, serum immunoglobulin (Ig), the cytokine profiles of BALF and lung-draining lymph nodes (LLN), and the T cell populations in LLNs. The intranasal administration of SCGB1C1 significantly inhibited AHR, the presence of eosinophils in BALF, eosinophilic inflammation, goblet cell hyperplasia in the lung, and serum total and allergen-specific IgE. SCGB1C1 treatment significantly decreased the expression of interleukin (IL)-5 in the BALF and IL-4 in the LLN, but significantly increased the expression of IL-10 and transforming growth factor (TGF)-β in the BALF. Furthermore, SCGB1C1 treatment notably increased the populations of CD4+CD25+Foxp3+ regulatory T cells (Tregs) in asthmatic mice. The intranasal administration of SCGB1C1 provides a significant reduction in allergic airway inflammation and improvement of lung function through the induction of Treg expansion. Therefore, SCGB1C1 may be the major regulator responsible for suppressing allergic airway inflammation.
Angiogenesis and Ovarian Cancer: What Potential Do Different Subtypes of Circulating Endothelial Cells Have for Clinical Application?
Authors: Asante Du-Bois , Tierno Domenico , Woode Michael , Scaggiante Bruna
Published: June 2024

Ovarian cancer (OC) remains the most fatal disease of gynaecologic malignant tumours. The neovasculature in the tumour microenvironment principally comprises endothelial cells. Haematogenous cancer metastases are significantly impacted by tumour neovascularisation, which predominantly depends on the tumour-derived endothelial vasculogenesis. There is an urgent need for biomarkers for the diagnosis, prognosis and prediction of drug response. Endothelial cells play a key role in angiogenesis and other forms of tumour vascularisation. Subtypes of circulating endothelial cells may provide interesting non-invasive biomarkers of advanced OC that might have the potential to be included in clinical analysis for patients’ stratification and therapeutic management. In this review, we summarise the reported studies on circulating endothelial subtypes in OC, detailing their isolation methods as well as their potential diagnostic, prognostic, predictive and therapeutic utility for clinical application. We highlight key biomarkers for the identification of circulating endothelial cell subtypes and their targets for therapies and critically point out future challenges.