bluuebunny/crossref_metadata_2025 huggingface dataset:
Covalent Adaptable Networks from Polyacrylates Based on Oxime–Urethane Bond Exchange Reaction
Authors: Sotoyama Yu , Iwata Naoto , Furumi Seiichi
Published: December 2024

Covalent adaptable networks (CANs) are polymer networks cross-linked via dynamic covalent bonds that can proceed with bond exchange reactions upon applying external stimuli. In this report, a series of cross-linked polyacrylate films were fabricated by changing the combination of acrylate monomer and the amount of diacrylate cross-linker possessing oxime–urethane bonds as a kind of dynamic covalent bond to evaluate their rheological relaxation properties. Model analysis of the experimental relaxation curves of cross-linked polyacrylate films was conducted by assuming that they consist of two types of relaxation, one of which is related to the oxime–urethane bond exchange reaction, and another of which is associated with the melting of the aggregated cross-linker. It was found that the contribution from the relaxation due to the bond exchange reaction becomes dominant only when the normal-alkyl acrylates are used as a monomer. The relaxation time was almost constant even when the amount of the cross-linker was adjusted. Moreover, it was also indicated that the miscibility of the cross-linker is very important for the fabrication of CANs with good self-healing ability and reprocessability.
Mining Translation Inhibitors by a Unique Peptidyl-Aminonucleoside Synthetase Reveals Cystocin Biosynthesis and Self-Resistance
Authors: Alferova Vera A. , Zotova Polina A. , Baranova Anna A. , Guglya Elena B. , Belozerova Olga A. , Pipiya Sofiya O. , Kudzhaev Arsen M. , Logunov Stepan E. , Prokopenko Yuri A. , Marenkova Elisaveta A. , Marina Valeriya I. , Novikova Evgenia A. , Komarova Ekaterina S. , Starodumova Irina P. , Bueva Olga V. , Evtushenko Lyudmila I. , Ariskina Elena V. , Kovalchuk Sergey I. , Mineev Konstantin S. , Babenko Vladislav V. , Sergiev Petr V. , Lukianov Dmitrii A. , Terekhov Stanislav S.
Published: December 2024

Puromycin (Puro) is a natural aminonucleoside antibiotic that inhibits protein synthesis by its incorporation into elongating peptide chains. The unique mechanism of Puro finds diverse applications in molecular biology, including the selection of genetically engineered cell lines, in situ protein synthesis monitoring, and studying ribosome functions. However, the key step of Puro biosynthesis remains enigmatic. In this work, pur6-guided genome mining is carried out to explore the natural diversity of Puro-like antibiotics. The diversity of biosynthetic gene cluster (BGC) architectures suggests the existence of distinct structural analogs of puromycin encoded by pur-like clusters. Moreover, the presence of tRNACys in some BGCs, i.e., cst-like clusters, leads us to the hypothesis that Pur6 utilizes aminoacylated tRNA as an activated peptidyl precursor, resulting in cysteine-based analogs. Detailed metabolomic analysis of Streptomyces sp. VKM Ac-502 containing cst-like BGC revealed the production of a cysteinyl-based analog of Puro—cystocin (Cst). Similar to puromycin, cystocin inhibits both prokaryotic and eukaryotic translation by the same mechanism. Aminonucleoside N-acetyltransferase CstC inactivated Cst, mediating antibiotic resistance in genetically modified bacteria and human cells. The substrate specificity of CstC originated from the steric hindrance of its active site. We believe that novel aminonucleosides and their inactivating enzymes can be developed through the directed evolution of the discovered biosynthetic machinery.
Mef2c- and Nkx2-5-Divergent Transcriptional Regulation of Chick WT1_76127 and Mouse Gm14014 lncRNAs and Their Implication in Epicardial Cell Migration
Authors: Caño-Carrillo Sheila , Garcia-Padilla Carlos , Aranega Amelia E. , Lozano-Velasco Estefania , Franco Diego
Published: December 2024

Cardiac development is a complex developmental process. The early cardiac straight tube is composed of an external myocardial layer and an internal endocardial lining. Soon after rightward looping, the embryonic heart becomes externally covered by a new epithelial lining, the embryonic epicardium. A subset of these embryonic epicardial cells migrate and colonize the embryonic myocardium, contributing to the formation of distinct cell types. In recent years, our understanding of the molecular mechanisms that govern proepicardium and embryonic epicardium formation has greatly increased. We have recently witnessed the discovery of a novel layer of complexity governing gene regulation with the discovery of non-coding RNAs. Our laboratory recently identified three distinct lncRNAs, adjacent to the Wt1, Bmp4 and Fgf8 chicken gene loci, with enhanced expression in the proepicardium that are distinctly regulated by Bmp, Fgf and thymosin β4, providing support for their plausible implication in epicardial formation. The expression of lncRNAs was analyzed in different chicken and mouse tissues as well as their subcellular distribution in chicken proepicardial, epicardial, ventricle explants and in different murine cardiac cell types. lncRNA transcriptional regulation was analyzed by using siRNAs and expression vectors of different transcription factors in chicken and mouse models, whereas antisense oligonucleotides were used to inhibit Gm14014 expression. Furthermore, RT-qPCR, immunocytochemistry, RNA pulldown, Western blot, viability and cell migration assays were conducted to investigate the biological functions of Wt1_76127 and Gm14014. We demonstrated that Wt1_76127 in chicken and its putative conserved homologue Gm14014 in mice are widely distributed in different embryonic and adult tissues and distinctly regulated by cardiac-enriched transcription factors, particularly Mef2c and Nkx2.5. Furthermore, silencing assays demonstrated that mouse Gm14014, but not chicken Wt1_76127, is essential for epicardial, but not endocardial or myocardial, cell migration. Such processes are governed by partnering with Myl9, promoting cytoskeletal remodeling. Our data show that Gm14014 plays a pivotal role in epicardial cell migration essential for heart regeneration under these experimental conditions.
Cinnamaldehyde-Mediated Suppression of MMP-13, COX-2, and IL-6 Through MAPK and NF-κB Signaling Inhibition in Chondrocytes and Synoviocytes Under Inflammatory Conditions
Authors: Sankaranarayanan Jaishree , Lee Seok Cheol , Kim Hyung Keun , Kang Ju Yeon , Kuppa Sree Samanvitha , Seon Jong Keun
Published: December 2024

Inflammatory disorders encompass a range of conditions, including osteoarthritis (OA), characterized by the body’s heightened immune response to diverse stimuli. OA is a prevalent degenerative joint disease characterized by the progressive deterioration of joint cartilage and subchondral bone, leading to pain, limited mobility, and physical disability. Synovitis, the inflammation of the synovial membrane, is increasingly recognized as a critical factor in OA pathogenesis and progression. This study evaluates the therapeutic potential of cinnamaldehyde (CA), a bioactive compound derived from cinnamon, on synovial and articular inflammation in OA. Given CA’s established anti-inflammatory, antioxidant, and antibacterial properties, this research explores its specific impact on OA and synovitis. The cytotoxicity of CA was assessed using a CCK-8 assay in human IL-1β pretreated chondrocytes and synoviocytes, which serve as in vitro models of OA and synovitis. The study further examined the effects of CA on the expression of proinflammatory cytokines, including IL-6, COX-2, and TNF-α, utilizing multiple analytical techniques. Additionally, the production of matrix metalloproteinases (MMP-3 and MMP-13) and the activation of the NF-κB signaling pathway, particularly the phosphorylation of p65 (pp65), were investigated. The role of the NF-κB inhibitor 5HPP-33 and its downstream effects on gene expression, including COX-2 and IL-6, as well as the MAPK pathway components (p38, ERK, and JNK), were also explored. An MEK inhibitor (U0126) was employed to assess its downstream impact on COX-2 and IL-6 expressions. The results demonstrated that CA significantly inhibited the expression of proinflammatory cytokines and suppressed NF-κB activation in IL-1β pretreated chondrocytes and synoviocytes. These findings suggest that CA, in a dose-dependent manner, may serve as an effective therapeutic agent for preventing OA and synovitis, offering valuable insights into its potential role in managing synovial inflammation and OA.
The Role of Fetuin-A in Tumor Cell Growth, Prognosis, and Dissemination
Authors: Odiase Peace , Ma Jonathan , Ranganathan Sruthi , Ogunkua Olugbemiga , Turner Winston B. , Marshall Dana , Ochieng Josiah
Published: December 2024

Fetuin-A, also known as alpha-2-Heremans-Schmid-glycoprotein (Ahsg), is a multifunctional molecule with diverse roles in biological processes such as mineralization, tumor growth, and inflammation. This review explores the involvement of Ahsg in various cancers, including liver, breast, prostate, colorectal, brain, osteosarcoma, and lung cancers. In many cancer types, Ahsg promotes tumor growth, invasion, and metastasis through various mechanisms, including cellular adhesion, spreading, chemotaxis, and modulation of cell-growth signaling pathways. Additionally, Ahsg has been implicated in the regulation of inflammatory cytokine production, making it a potential marker of inflammation in cancer. The complex interplay between Ahsg and cancer progression highlights its potential as a diagnostic biomarker and therapeutic target in various cancers. However, further research is needed to fully elucidate the mechanisms of action of Ahsg in cancer and to explore its clinical implications in cancer diagnosis, prognosis, and treatment.
Zero-Order Kinetics Release of Lamivudine from Layer-by-Layer Coated Macromolecular Prodrug Particles
Authors: Urbaniak Tomasz , Milasheuski Yauheni , Musiał Witold
Published: December 2024

To reduce the risk of side effects and enhance therapeutic efficiency, drug delivery systems that offer precise control over active ingredient release while minimizing burst effects are considered advantageous. In this study, a novel approach for the controlled release of lamivudine (LV) was explored through the fabrication of polyelectrolyte-coated microparticles. LV was covalently attached to poly(ε-caprolactone) via ring-opening polymerization, resulting in a macromolecular prodrug (LV-PCL) with a hydrolytic release mechanism. The LV-PCL particles were subsequently coated using the layer-by-layer (LbL) technique, with polyelectrolyte multilayers assembled to potentially modify the carrier’s properties. The LbL assembly process was comprehensively analyzed, including assessments of shell thickness, changes in ζ-potential, and thermodynamic properties, to provide insights into the multilayer structure and interactions. The sustained LV release over 7 weeks was observed, following zero-order kinetics (R2 > 0.99), indicating a controlled and predictable release mechanism. Carriers coated with polyethylene imine/heparin and chitosan/heparin tetralayers exhibited a distinct increase in the release rate after 6 weeks and 10 weeks, respectively, suggesting that this coating can facilitate the autocatalytic degradation of the polyester microparticles. These findings indicate the potential of this system for long-term, localized drug delivery applications, requiring sustained release with minimal burst effects.
Diagnostic Accuracy of Lipid Transfer Proteins (LTPs) Specific IgE Assay in Food Allergy: A Systematic Review
Authors: Bellia Chiara , Sardina Davide , Scazzone Concetta , Lio Domenico , Scola Letizia , Uasuf Carina
Published: December 2024

The aim of this systematic review was to evaluate the diagnostic accuracy of molecular-based LTPs serum sIgE for the diagnosis of food allergies in patients with suspected allergy to one of the LTPs-containing foods. Cohort, prospective or retrospective cross-sectional studies were considered for inclusion in this review. Oral food challenge (both open and double-blind placebo-controlled) was the reference standard for the diagnosis. PubMed (MEDLINE), Web of Science, Scopus, and ClinicalTrial.org were searched for relevant papers. The risk of bias was assigned by the QUADAS-2 tool. Data were reported as the sensitivity and specificity. The study protocol was registered in the PROSPERO database (CRD42022321985). Fifteen articles, including 2395 individuals, were included. The sensitivity of Ara h 9 for peanut allergy diagnosis ranged from 6 to 61%; the specificity ranged from 57 to 100%. The Cor a 8 sensitivity ranged from 11 to 43%, with the specificity ranging from 59 to 94%. Ara h 9 and Cor a 8 serum sIgE may be useful for confirming the diagnosis of peanut and hazelnut allergy in symptomatic patients, although the diagnostic accuracy is limited by the low sensitivity. More investigation on other LTPs and in adult populations may be important to define the clinical role of this test in food allergy diagnostics.
A 2.9 Mb Chromosomal Segment Deletion Is Responsible for Early Ripening and Deep Red Fruit in Citrus sinensis
Authors: Chen Jianmei , Chen Zhenmin , Xie Quming , Wu Xiaotong , Pei Qingyu , Lin Yi , Chen Qiong , Wan Shubei
Published: December 2024

Sweet orange (Citrus sinensis) is an economically important fruit crop worldwide. Mining for genes associated with ripening periods and fruit color traits is crucial for plant genetics and for the improvement of external fruit quality traits. The present study identified a novel navel orange accession, designated as Ganhong, with early ripening and deep red fruit traits. DNA sequence analysis showed a 2.9 Mb deletion in one copy of chromosome 7 in Ganhong navel orange. Flesh samples from Ganhong and its parental variety, Newhall navel orange, were sampled for RNA sequence analysis 200 days after flowering; 958 differentially expressed genes (DEGs) were identified between the two varieties. Functional enrichment analysis indicated that these DEGs were mainly enriched in phytohormones, particularly abscisic acid (ABA), related to fruit ripening. The deletion interval has 343 annotated genes, among which 4 genes (Cs_ont_7g018990, Cs_ont_7g019400, Cs_ont_7g019650, and Cs_ont_7g019820) were inferred to be candidate causal genes for early ripening and deep red fruit traits based on gene functionality and gene expression analysis. The present study laid a foundation for further elucidation of the mechanisms underlying the early ripening and deep red fruit trait in Ganhong navel orange.
Turner Syndrome and the Thyroid Function—A Systematic and Critical Review
Authors: Lacka Katarzyna , Pempera Nikola , Główka Alicja , Mariowska Agnieszka , Miedziaszczyk Miłosz
Published: December 2024

Turner syndrome (TS) is associated with thyroid disorders. Since the rate of thyroid disease among patients with this syndrome is significantly higher as compared to the general population, it seems vital to explore this particular area. This systematic and critical review was performed to evaluate thyroid function and autoimmunity in patients with Turner syndrome. Four databases were searched: PubMed, Scopus, Google Scholar, and Cochrane Library from the onset of the study to July 2024. Two independent researchers manually searched databases for the following keywords: “Turner syndrome”, “anti-TPO”, “anti-Tg”, “autoimmune thyroid disorders”, “TSH”, and “hypothyroidism”, which were entered into the search engine in isolation, as well as in combinations. Criteria incorporating information on thyroid-stimulating hormone (TSH), triiodothyronine (total—TT3), and thyroxine (free and total—fT4, TT4) concentrations among patients and control groups were also included. Thyroid diseases are common in patients with Turner syndrome. Women with TS present both higher TSH levels and positive thyroid antibodies concentrations. Typical thyroid ultrasound heterogeneity with a hypogenic or mixed echopattern was also observed. As a result, it is essential to monitor thyroid hormone levels in this group, in order to detect hypothyroidism earlier and initiate appropriate replacement therapy. Thyroid diseases in women with TS may remain underdiagnosed for a number of years, due to the lack of screening. Therefore, the authors suggest a thyroid screening regimen for TS patients, which allows for early detection of the disease and implementation of treatment.
Genetic Diversity Analysis and Identification of Candidate Genes for Growth Traits in Chengkou Mountain Chicken
Authors: Liu Lingbin , Wang Yi , Huang Yu , Wang Zhen , Wang Qigui , Wang Haiwei
Published: December 2024

Growth traits constitute critical factors in the breeding program of broiler chickens. The Chengkou mountain chicken A-lineage (CMC-A) represents a breed specifically bred for meat production. To further explore the growth performance of the CMC-A population, this study conducted whole-genome sequencing on 464 CMC-A roosters to systematically evaluate their genetic diversity. Additionally, runs of homozygosity (ROH) islands and genome-wide association studies (GWASs) were employed to identify the loci and functional genes influencing the growth traits in Chengkou mountain chickens. The results revealed a high level of genetic diversity and low levels of inbreeding in Chengkou mountain chickens. Several genes associated with stress resistance, muscle growth, and fat deposition were pinpointed through ROH island identification. Moreover, 52 SNP loci were detected, along with 71 candidate genes. These findings enhance our understanding of the genetic architecture underlying the growth traits in Chengkou mountain chickens and provide a theoretical foundation for subsequent breeding endeavors.
Innovative Insights into Single-Cell Technologies and Multi-Omics Integration in Livestock and Poultry
Authors: Lu Ying , Li Mengfei , Gao Zhendong , Ma Hongming , Chong Yuqing , Hong Jieyun , Wu Jiao , Wu Dongwang , Xi Dongmei , Deng Weidong
Published: December 2024

In recent years, single-cell RNA sequencing (scRNA-seq) has marked significant strides in livestock and poultry research, especially when integrated with multi-omics approaches. These advancements provide a nuanced view into complex regulatory networks and cellular dynamics. This review outlines the application of scRNA-seq in key species, including poultry, swine, and ruminants, with a focus on outcomes related to cellular heterogeneity, developmental biology, and reproductive mechanisms. We emphasize the synergistic power of combining scRNA-seq with epigenomic, proteomic, and spatial transcriptomic data, enhancing molecular breeding precision, optimizing health management strategies, and refining production traits in livestock and poultry. The integration of these technologies offers a multidimensional approach that not only broadens the scope of data analysis but also provides actionable insights for improving animal health and productivity.
High-Pressure Processing Influences Antibiotic Resistance Gene Transfer in Listeria monocytogenes Isolated from Food and Processing Environments
Authors: Wiśniewski Patryk , Chajęcka-Wierzchowska Wioleta , Zadernowska Anna
Published: December 2024

The study aimed to assess the high-pressure processing (HPP) impact on antibiotic resistance gene transfer in L. monocytogenes from food and food processing environments, both in vitro (in microbiological medium) and in situ (in carrot juice), using the membrane filter method. Survival, recovery, and frequency of antibiotic resistance gene transfer analyses were performed by treating samples with HPP at different pressures (200 MPa and 400 MPa). The results showed that the higher pressure (400 MPa) had a significant effect on increasing the transfer frequency of genes such as fosX, encoding fosfomycin resistance, and tet_A1, tet_A3, tetC, responsible for tetracycline resistance, both in vitro and in situ. In contrast, the Lde gene (the gene encoding ciprofloxacin resistance) was not transferred under any conditions. In the food matrix (carrot juice), greater variability in results was observed, suggesting that food matrices may have a protective effect on bacteria and modify HPP efficacy. In general, an increase in MIC values for antibiotics was noted in transconjugants compared to donors. Genotypic analysis of transconjugants showed differences in genetic structure, especially after exposure to 400 MPa pressure, indicating genotypic changes induced by pressure stress. The study confirms the possibility of antibiotic resistance genes transfer in the food environment, even from strains showing initial susceptibility to antibiotics carrying so-called silent antibiotic resistance genes, highlighting the public health risk of the potential spread of antibiotic-resistant strains through the food chain. The findings suggest that high-pressure processing can increase and decrease the frequency of resistance gene transfer depending on the strain, antibiotic combination, and processing conditions.
Transcriptomic Analysis Reveals the Potential Mechanism of Cardamine circaeoides Hook.f. & Thomson in Lowering Serum Uric Acid by Reducing Inflammatory State Through CCR7 Target
Authors: Di Songrui , Li Yipeng , Fu Xiangchen , Xie Chenyu , Jiang Yanxin , Liang Weican , Wang Zixu , Wang Chun , Wang Linyuan , Zhu Yingli , Zhang Jianjun
Published: December 2024

Cardamine circaeoides Hook.f. & Thomson (CC) is a traditional medicinal herb with multiple biological activities. In previous studies, we have identified its serum uric acid (SUA) lowering effects and speculated that Cardamine circaeoides water extract (CCE) may exert anti-hyperuricemia effects related to its anti-inflammatory activity. This study aims to further investigate the molecular mechanism underlying these effects at the mRNA level through transcriptomic analysis, quantitative reverse transcription polymerase chain reaction (RT-qPCR), molecular docking, and Western blotting. CCE effectively reduced SUA and improved renal function in a dose-dependent manner in hyperuricemia rats. Cytokine–cytokine receptor interaction pathway was significantly altered by CCE. An additional study identified a number of genes (IL27, Inhbe, CCR7, CXCR3, IL12RB1, CXCR5, Mstn, and GDF5) as regulators of the inflammatory response. Meanwhile, three key targets (IL27, Inhbe, and CCR7) were found to be significantly expressed at the mRNA level and have strong binding affinity with 22 components, among which Kaempferol 3-sophoroside 7-glucoside, Kaempferol-3-O-sophoroside, and Quercetin 3-sophoroside 7-glucoside have strong binding activities. Following this, Western blotting showed a significant increase in CCR7 expression. Our findings indicated that CCE regulated the cytokine–cytokine receptor interaction pathway through CCR7 to reduce the inflammatory state and exert an SUA-lowering effect.
AlphaFold2-Based Characterization of Apo and Holo Protein Structures and Conformational Ensembles Using Randomized Alanine Sequence Scanning Adaptation: Capturing Shared Signature Dynamics and Ligand-Induced Conformational Changes
Authors: Raisinghani Nishank , Parikh Vedant , Foley Brandon , Verkhivker Gennady
Published: December 2024

Proteins often exist in multiple conformational states, influenced by the binding of ligands or substrates. The study of these states, particularly the apo (unbound) and holo (ligand-bound) forms, is crucial for understanding protein function, dynamics, and interactions. In the current study, we use AlphaFold2, which combines randomized alanine sequence masking with shallow multiple sequence alignment subsampling to expand the conformational diversity of the predicted structural ensembles and capture conformational changes between apo and holo protein forms. Using several well-established datasets of structurally diverse apo-holo protein pairs, the proposed approach enables robust predictions of apo and holo structures and conformational ensembles, while also displaying notably similar dynamics distributions. These observations are consistent with the view that the intrinsic dynamics of allosteric proteins are defined by the structural topology of the fold and favor conserved conformational motions driven by soft modes. Our findings provide evidence that AlphaFold2 combined with randomized alanine sequence masking can yield accurate and consistent results in predicting moderate conformational adjustments between apo and holo states, especially for proteins with localized changes upon ligand binding. For large hinge-like domain movements, the proposed approach can predict functional conformations characteristic of both apo and ligand-bound holo ensembles in the absence of ligand information. These results are relevant for using this AlphaFold adaptation for probing conformational selection mechanisms according to which proteins can adopt multiple conformations, including those that are competent for ligand binding. The results of this study indicate that robust modeling of functional protein states may require more accurate characterization of flexible regions in functional conformations and the detection of high-energy conformations. By incorporating a wider variety of protein structures in training datasets, including both apo and holo forms, the model can learn to recognize and predict the structural changes that occur upon ligand binding.
The Microenvironment in an Experimental Model of Acute Pancreatitis Can Modify the Formation of the Protein Corona of sEVs, with Implications on Their Biological Function
Authors: Armengol-Badia Olga , Maggi Jaxaira , Casal Carme , Cortés Roser , Abián Joaquín , Carrascal Montserrat , Closa Daniel
Published: December 2024

A considerable number of the physiological functions of extracellular vesicles are conditioned by the protein corona attached to their surface. The composition of this corona is initially defined during their intracellular synthesis, but it can be subsequently modified by interactions with the microenvironment. Here, we evaluated how the corona of small extracellular vesicles exposed to the inflammatory environment generated in acute pancreatitis is modified and what functional changes occur as a result of these modifications. Small extracellular vesicles obtained from a pancreatic cell line were incubated with the ascitic fluid generated in experimental acute pancreatitis in rats. Using proteomic techniques, we detected the appearance of new proteins and an increase the uptake of extracellular vesicles by certain cell types and the response induced in inflammatory cells. The inhibition of different pattern recognition receptors reversed this activation, indicating that some of these effects could be due to binding of damage-associated molecular patterns to the corona. All of this indicates that in pathologies such as acute pancreatitis, characterized by an inflammatory response and intense tissue damage, the microenvironment substantially influences the corona of extracellular vesicles, thus altering their behavior and enhancing their inflammatory activity.
A Risk Factor for Attention Deficit Hyperactivity Disorder Induces Marked Long-Term Anatomical Changes at GABAergic-Dopaminergic Synapses in the Rat Ventral Tegmental Area
Authors: Seo Steve , Parr-Brownlie Louise C. , Wicky Hollie E. , Bilkey David K. , Hughes Stephanie M. , Oorschot Dorothy E.
Published: December 2024

Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. However, the core biology of the disorder that leads to the hypofunctioning of the cerebral dopaminergic network requires further elucidation. We investigated midbrain synaptic changes in male rats exposed to repeated hypoxia during the equivalent of extreme prematurity, which is a new animal model of the hyperactive/impulsive presentation of ADHD. We used a novel combination of a lentiviral vector, peroxidase-immunonanogold double-labelling, three-dimensional serial section transmission electron microscopy and stereological techniques to investigate the synapses formed between GABAergic axons of the rostromedial tegmental nucleus (RMTg) and dopaminergic neurons of the posterior ventral tegmental area (pVTA). This is a key site that sends extensive dopaminergic projections to the forebrain. We also compared the results to our previous study on a schizophrenia risk factor that produces cerebral hyperdopaminergia. In total, 117 reconstructed synapses were compared. Repeated hypoxic rats had a significantly thicker (22%) and longer (18%) postsynaptic density at RMTg GABAergic-pVTA dopaminergic synapses compared to their controls. These results were opposite to those previously observed in rats exposed to a schizophrenia risk factor. These findings for repeated hypoxic rats suggest that the enhanced inhibition of pVTA dopaminergic neurons may contribute to hypodopaminergia in ADHD motor hyperactivity. Synaptic triads, a key component of pVTA circuitry, were not detected in repeated hypoxic rats, indicating a marked deficit. The current knowledge may guide development in males of novel, site-specific ADHD drugs, which is necessary due to the rising prevalence of ADHD, the chronic nature of ADHD symptoms and the limitations of the currently available medications.
The Effects of Resistance Training on Pain, Strength, and Function in Osteoarthritis: Systematic Review and Meta-Analysis
Authors: Lim Jaehyun , Choi Ahyoung , Kim Byeonggeun
Published: December 2024

Background/Objectives: Pain is the most common symptom of osteoarthritis (OA), and it leads to functional decline, such as decreased mobility and limitations in activities of daily living, which leads to difficulties in social participation, increased social isolation, and economic burden. Muscle weakness can be a cause of OA symptoms. The purpose was to analyze the effects of resistance training on improving pain, strength, and function in OA and to analyze the effects by intervention duration and joint. Methods: The study search was conducted on 14 September 2024, and the period of study inclusion covered studies available in the databases from their inception to the search date. The databases used were PubMed, CHINAL, Cochrane Library, and Embase. Inclusion criteria were studies that targeted OA and compared a resistance training intervention with a no resistance training intervention group and measured pain, strength, and function. Subgroup analysis was used to analyze the effects by intervention duration (4 weeks or less, 5 to 8 weeks, 9 weeks or more) and joint (knee, hip). Results: A total of 27 studies included 1712 subjects, and significant improvements were observed in pain (SMD: −0.48, CI: −0.58~−0.37, I2: 45%), strength (SMD: 0.4, CI: 0.32~0.47, I2: 0%), and function (SMD: −0.56, CI: −0.65~−0.47, I2: 30%). In the effects by intervention duration, both pain and strength showed significant improvements, but no effect on function was observed for less than 4 weeks. For effects by joint, both the knee and hip showed significant improvements. Conclusions: Resistance training was effective in improving pain, strength, and function in patients with knee and hip OA.
Assessing Postural Stability in Gastrointestinal Endoscopic Procedures with a Belt-like Endoscope Holder Using a MoCap Camera System
Authors: Durič Tadej , Hejda Jan , Volf Petr , Sokol Marek , Kutílek Patrik , Hajer Jan
Published: December 2024

Background/Objectives: As musculoskeletal injuries in gastroenterologists related to the performance of endoscopic procedures are on the rise, solutions and new approaches are needed to prevent these undesired outcomes. In our study, we evaluated an approach to ergonomic challenges in the form of a belt-like endoscope holder designed to redistribute the weight of the endoscope across the whole body of the practitioner. The aim of the study was to determine how the use of this holder affected the body posture of practitioners during endoscopy. Methods: We designed a special endoscopic model that emulates basic endoscopic movement and maneuvers. With the use of the MoCap camera system, we recorded experienced endoscopists exercising a standardized set of tasks with and without the holder. Results: Following video and statistical analyses, the most significant differences were observed in the position of the left arm which pointed to a more relaxed arm position. Conclusions: The ergonomic benefits of the belt holder in this model merit testing in the clinical setting to evaluate its effectiveness and prevention of musculoskeletal injuries in GI endoscopy.
Up-to-Date Snapshot of Current and Emerging Medical Therapies in Primary Biliary Cholangitis
Authors: Warsop Zakary , Anand Nikhil , Al Maliki Husam , De Souza Shuell , Kamyab Arya , Al Hadad Amin , Alrubaiy Laith
Published: December 2024

Background/Objectives: Primary biliary cholangitis (PBC) is an autoimmune chronic cholestatic disease of the liver that symptomatically can present with pruritus and fatigue. Its established first- and second-line therapies are ursodeoxycholic acid (UDCA) and obeticholic acid (OCA) although they provide limited symptom management. Liver transplantation offers a potentially curative therapeutic option in refractory cases progressing to cirrhosis. Novel research published after the current guidelines highlights the importance of providing an up-to-date analysis of treatment options available. Methods: In this study, we conducted a literature search using Pubmed, Ovid Medline, and SCOPUS to provide a narrative review of first-line, second-line, and emerging therapies in PBC. Results: UDCA has been well established as a long-term, safe therapy within the literature although it is possible that treatment dosage can be further optimised in refractory patients. It has a favourable side effect profile. Despite improving biochemical markers, histopathological profile, and overall outcomes, up to 30–40% of patients are refractory to it. Age and sex are highlighted as independent indicators of non-responsiveness. This necessitates effective second-line therapies. Future trials could aim to investigate UDCA as a co-first-line therapy. Further supporting results for OCA were found in the interim extension trial of the seminal POISE study. The long-term phase 4 COBOLT trial is still awaiting results to further assess the complications, adherence, and potential adverse effects. It is a viable option in UDCA-refractory patients. The high incidence rate of dose-related pruritis indicates that alternative second-line options are needed. Bezafibrate is an off-label antilipemic agent that shows promise as a prospective second-line therapy option. The landmark BEZURSO trial alleviated some efficacy and safety concerns, but it remains associated with elevated serum creatinine; thus, it should be considered with caution. Other prospective second-line therapies are budesonide, triple therapy, and novel agents such as seladelpar and elafibranor. Conclusions: UDCA should remain the treatment of choice for PBC, though perhaps not as monotherapy. With further investigation, BF shows promise as a new second-line therapy alongside OCA, which it may outperform.
Inter-Fraction Motion and Dosimetric Analysis of Volumetric Modulated Arc Therapy for Craniospinal Irradiation in Adult Medulloblastoma Patients
Authors: Bonaparte Ilaria , Di Guglielmo Fiorella Cristina , Fragnoli Federica , Cuscito Rosilda , Indellicati Chiara , De Pascali Christian , Surgo Alessia , Carbonara Roberta , Davì Valerio , Gentile Maria Annunziata , Calbi Roberto , Caliandro Morena , Sanfrancesco Giuseppe , Aga Alberto , Cardetta Pietro , Antonicelli Michele , Ciocia Annarita , Curci Domenico , Ciliberti Maria Paola , Fiorentino Alba
Published: December 2024

Background/Objectives. Adult medulloblastoma (AMB) patients should receive postoperative craniospinal irradiation (CSI) as a standard treatment. Volumetric intensity-modulated arc therapy (VMAT) is a promising method for CSI. This report summarizes the repositioning and dosimetric data outcomes for six AMB patients. Methods. Complete CSI and posterior cranial fossa irradiation, or tumor bed boost irradiation with Linac-based VMAT, was performed and evaluated. Patients were immobilized in the supine position with two thermoplastic masks (head-neck and abdomen). To ensure inter-fraction reproducibility during radiotherapy (RT), a single cone-beam CT (CBCT) scan for each isocenter and real-time surface-guided RT using AlignRT® were performed daily before and during the RT session. Match values of all three translational axes (x = lateral, y = longitudinal, z = vertical) were recorded. Results. From August 2022 to September 2023, six AMB patients were treated with CSI: three women and three men with a median age of 32 (22–42). All cases were classical MB, four were low risk, and two were defined as high risk due to the metastatic disease. All patients underwent surgery; two received a gross total resection. Low-risk patients received 36 Gy for CSI and a 54 Gy boost, while high-risk patients received 39 Gy for CSI. No significant toxicities greater than G2 were observed during RT, and only two cases reported decreased platelet counts. The dose to the organs at risk was low and acceptable. The mean dose to the heart, lungs, eyes, stomach, and thyroid were 4.4 Gy, 8.5 Gy, 12 Gy, 8.7 Gy, and 11 Gy, respectively. In terms of repositioning data, 124 CBCT scans were analyzed. Inter-fraction CBCT mean values for the study population in all translational directions were inferior to 2 mm in more than 90% of cases. Conclusions. VMAT is a convenient and effective treatment for AMB. Positioning and immobilization with masks (head and neck plus abdomen) reduce inter-fraction motion.
Effects of Environmental Changes on Flood Patterns in the Jing River Basin: A Case Study from the Loess Plateau, China
Authors: Lyu Jiqiang , Yang Yuhao , Yin Shanshan , Yang Zhizhou , Zhou Zhaohui , Wang Yan , Luo Pingping , Jiao Meng , Huo Aidi
Published: December 2024

Human activities and climate change have significantly influenced the water cycle, impacting flood risks and water security. This study centers on the Jing River Basin in the Chinese Loess Plateau, analyzing hydrological patterns and flood progression using the HEC-HMS model under changing conditions. The findings indicate that climate change substantially affects flood predictions, increasing peak flows and volumes by up to 10.9% and 11.1%, respectively. It is essential to recognize that traditional flood models may underestimate the risks posed by these changes, emphasizing the necessity for updated methods incorporating climatic and human factors. Changes in land use, such as the expansion of grasslands and forests, have reduced peak discharges and flood volumes. Consequently, the combined impacts of climate and land use changes have intensified flood frequencies, necessitating updated strategies to manage risks effectively. The dynamics of flooding are significantly impacted by changes in climate and land use, particularly in minor floods that occur frequently, highlighting the influence of climate change on flooding trends. Within the Jing River Basin, hydrological patterns have been shaped by both climatic variations and human activities, leading to an increase in extreme hydrological events and concerns regarding water security. Using the HEC-HMS model, this study examines the hydrology of the Jing River Basin, focusing on the design of storm events and analyzing various flood characteristics under different scenarios. Climate change has resulted in higher peak discharges and volume surges ranging from 6.3% to 10.9%, while shifts in land use, such as decreases in farmland and the expansion of grasslands, have caused declines ranging from 7.2% to 4.7% in peak flows and volumes. The combined effects of climate variation and land utilization have complex implications for flood patterns, with milder to moderate floods showing a more significant impact and shorter return periods facing increased consequences. These findings underscore the interconnected nature of climate change, land use, and flooding dynamics in the Jing River Basin, highlighting the need for comprehensive strategies to address these challenges and ensure sustainable water management in the region.
Determinants of Dockless Bicycle-Sharing Adoption and Usage Intensity for Commuting and Errands: Evidence from Disadvantaged Neighborhoods
Authors: Wang Hongyu , Dong Yu , Ma Liang
Published: December 2024

The emergence of dockless bicycle sharing has transformed urban transportation, particularly in China, by offering a flexible and accessible travel option. However, understanding the factors driving its adoption and usage in disadvantaged neighborhoods is crucial, as these areas often face unique mobility challenges. This study explores these determinants, providing a more comprehensive analysis than prior research by focusing specifically on disadvantaged communities. Using survey data from four such neighborhoods in Xi’an, China, we apply Structural Equation Modeling to investigate the factors influencing individuals’ decisions to adopt and intensively use dockless bicycle sharing for commuting and errands. The results reveal key determinants, including psychological factors, demographic characteristics, and spatial and social contexts, and their interaction mechanisms. Attitudes are found to have a substantial impact on bicycle-sharing behavior for both commuting and errands, while social norms and perceived behavioral control (PBC) mainly influence usage for errands. Interestingly, PBC affects adoption but not usage frequency. The findings also highlight that proximity to schools, subways, and neighborhood aesthetics positively correlate with bicycle-sharing adoption for errands, whereas bicycling infrastructure significantly influences usage intensity. However, none of the neighborhood environment factors were found to significantly affect adoption for commuting purposes. These insights are especially valuable for developing targeted strategies to promote bicycle sharing as a sustainable transportation solution in disadvantaged neighborhoods, where improved access can significantly enhance mobility and quality of life.
Identification of Priority Areas for Ecological Restoration Based on Ecosystem Service Bundles and Human Activity Footprint in Western Jilin, China
Authors: Shang Yi , Wang Dongyan , Li Hong
Published: December 2024

As a typical ecologically fragile region in the north of China, ecosystems in western Jilin Province have been severely damaged by a combination of natural factors and human activities. Ecological restoration sites need to be identified and viable strategies need to be developed to maximize the restoration of ecosystem functions and enhance human well-being. This study used the InVEST model, K-means clustering, and spatial statistical tools to identify priority sites for ecological restoration in western Jilin Province based on the change in ecosystem service bundles and in the human activity footprint. The results showed that provisioning services continued to increase and other services decreased and then increased during the study period. The provisioning service bundles and provisioning-regulating bundles increased continuously, the regulating service bundles, cultural service bundles and the service synergy bundles decreased continuously, and the supporting service bundles first increased and then decreased. Out of 48,005 evaluation units, 10,203 were prioritized for ecological restoration, accounting for 21.25% of the total. This study provides a scientific basis for restoring regional ecosystems and improving the supply of ecosystem services.
Assessment of Placental Antioxidant Defense Markers in Vaccinated and Unvaccinated COVID-19 Third-Trimester Pregnancies
Authors: Rolfo Alessandro , Cosma Stefano , Nuzzo Anna Maria , Moretti Laura , Tancredi Annalisa , Canosa Stefano , Revelli Alberto , Benedetto Chiara
Published: December 2024

Background: Pregnancy has been identified as a risk factor for severe COVID-19, leading to maternal and neonatal complications. The safety and effects of the SARS-CoV-2 vaccination during pregnancy, particularly on placental function and oxidative stress (OxS), remain underexplored. We investigated the impact of vaccination on third-trimester placental antioxidant defense markers. Methods: Ninety full-term pregnant women were divided into the following groups: vaccinated (n = 27) and unvaccinated (n = 25) COVID-19-positive pregnant women; control subgroups were composed of vaccinated (n = 19) or unvaccinated (n = 19) COVID-19-negative women with a healthy term singleton pregnancy with no signs of COVID-19. Placental samples were collected after delivery. Lipid peroxidation (TBARS), gene expression of HIF-1α, and catalase (CAT), superoxide dismutase-1 (SOD1) and CAT-SOD1 enzymatic activity were measured. Results: COVID-19-positive placentae exhibited significantly higher TBARS and HIF-1α levels compared to controls, regardless of vaccination status. Vaccination significantly increased placental CAT and SOD1 expression and activity in COVID-19-positive women, suggesting enhanced antioxidant defense. Unvaccinated women showed a higher incidence of COVID-19 symptoms and lower antioxidant enzyme activity. Conclusions: SARS-CoV-2 infection induced placental OxS, which is countered by a placental adaptive antioxidant response. Vaccination during pregnancy enhances placental defense, further supporting the safety and benefits of COVID-19 vaccination in preventing complications and protecting fetal development.
Osteogenic CpG Oligodeoxynucleotide, iSN40, Inhibits Osteoclastogenesis in a TLR9-Dependent Manner
Authors: Ikeda Rena , Kimura Chihaya , Nihashi Yuma , Umezawa Koji , Shimosato Takeshi , Takaya Tomohide
Published: December 2024

A CpG oligodeoxynucleotide (CpG-ODN), iSN40, was originally identified as promoting the mineralization and differentiation of osteoblasts, independent of Toll-like receptor 9 (TLR9). Since CpG ODNs are often recognized by TLR9 and inhibit osteoclastogenesis, this study investigated the TLR9 dependence and anti-osteoclastogenic effect of iSN40 to validate its potential as an osteoporosis drug. The murine monocyte/macrophage cell line RAW264.7 was treated with the receptor activator of nuclear factor-κB ligand (RANKL) to induce osteoclast differentiation, then the effect of iSN40 on was quantified by tartrate-resistant acid phosphatase (TRAP) staining and real-time RT-PCR. iSN40 completely inhibited RANKL-induced differentiation into TRAP+ multinucleated osteoclasts by suppressing osteoclastogenic genes and inducing anti-/non-osteoclastogenic genes. Treatment with a TLR9 inhibitor, E6446, or a mutation in the CpG motif of iSN40 abolished the intracellular uptake and anti-osteoclastogenic effect of iSN40. These results demonstrate that iSN40 is subcellularly internalized and is recognized by TLR9 via its CpG motif, modulates RANKL-dependent osteoclastogenic gene expression, and ultimately inhibits osteoclastogenesis. Finally, iSN40 was confirmed to inhibit the osteoclastogenesis of RAW264.7 cells cocultured with the murine osteoblast cell line MC3T3-E1, presenting a model of bone remodeling. This study demonstrates that iSN40, which exerts both pro-osteogenic and anti-osteoclastogenic effects, may be a promising nucleic acid drug for osteoporosis.