bluuebunny/crossref_metadata_2025 huggingface dataset:
Mutations in Glycosyltransferases and Glycosidases: Implications for Associated Diseases
Authors: Gu Xiaotong , Kovacs Aaron S. , Myung Yoochan , Ascher David B.
Published: April 2024

Glycosylation, a crucial and the most common post-translational modification, coordinates a multitude of biological functions through the attachment of glycans to proteins and lipids. This process, predominantly governed by glycosyltransferases (GTs) and glycoside hydrolases (GHs), decides not only biomolecular functionality but also protein stability and solubility. Mutations in these enzymes have been implicated in a spectrum of diseases, prompting critical research into the structural and functional consequences of such genetic variations. This study compiles an extensive dataset from ClinVar and UniProt, providing a nuanced analysis of 2603 variants within 343 GT and GH genes. We conduct thorough MTR score analyses for the proteins with the most documented variants using MTR3D-AF2 via AlphaFold2 (AlphaFold v2.2.4) predicted protein structure, with the analyses indicating that pathogenic mutations frequently correlate with Beta Bridge secondary structures. Further, the calculation of the solvent accessibility score and variant visualisation show that pathogenic mutations exhibit reduced solvent accessibility, suggesting the mutated residues are likely buried and their localisation is within protein cores. We also find that pathogenic variants are often found proximal to active and binding sites, which may interfere with substrate interactions. We also incorporate computational predictions to assess the impact of these mutations on protein function, utilising tools such as mCSM to predict the destabilisation effect of variants. By identifying these critical regions that are prone to disease-associated mutations, our study opens avenues for designing small molecules or biologics that can modulate enzyme function or compensate for the loss of stability due to these mutations.
Technical Advances in Circulating Cell-Free DNA Detection and Analysis for Personalized Medicine in Patients’ Care
Authors: Sorbini Monica , Carradori Tullia , Togliatto Gabriele Maria , Vaisitti Tiziana , Deaglio Silvia
Published: April 2024

Circulating cell-free DNA (cfDNA) refers to small fragments of DNA molecules released after programmed cell death and necrosis in several body fluids such as blood, saliva, urine, and cerebrospinal fluid. The discovery of cfDNA has revolutionized the field of non-invasive diagnostics in the oncologic field, in prenatal testing, and in organ transplantation. Despite the potential of cfDNA and the solid results published in the recent literature, several challenges remain, represented by a low abundance, a need for highly sensitive assays, and analytical issues. In this review, the main technical advances in cfDNA analysis are presented and discussed, with a comprehensive examination of the current available methodologies applied in each field. Considering the potential advantages of cfDNA, this biomarker is increasing its consensus among clinicians, as it allows us to monitor patients’ conditions in an easy and non-invasive way, offering a more personalized care. Nevertheless, cfDNA analysis is still considered a diagnostic marker to be further validated, and very few centers are implementing its analysis in routine diagnostics. As technical improvements are enhancing the performances of cfDNA analysis, its application will transversally improve patients’ quality of life.
Mitochondrial DNA and Inflammation Are Associated with Cerebral Vessel Remodeling and Early Diabetic Kidney Disease in Patients with Type 2 Diabetes Mellitus
Authors: Petrica Ligia , Gadalean Florica , Muntean Danina Mirela , Jianu Dragos Catalin , Vlad Daliborca , Dumitrascu Victor , Bob Flaviu , Milas Oana , Suteanu-Simulescu Anca , Glavan Mihaela , Ursoniu Sorin , Balint Lavinia , Mogos-Stefan Maria , Ienciu Silvia , Cretu Octavian Marius , Popescu Roxana , Gluhovschi Cristina , Iancu Lavinia , Vlad Adrian
Published: April 2024

Cerebrovascular disease accounts for major neurologic disabilities in patients with type 2 diabetes mellitus (DM). A potential association of mitochondrial DNA (mtDNA) and inflammation with cerebral vessel remodeling in patients with type 2 DM was evaluated. A cohort of 150 patients and 30 healthy controls were assessed concerning urinary albumin/creatinine ratio (UACR), synaptopodin, podocalyxin, kidney injury molecule-1 (KIM-1), N-acetyl-β-(D)-glucosaminidase (NAG), interleukins IL-17A, IL-18, IL-10, tumor necrosis factor-alpha (TNFα), intercellular adhesion molecule-1 (ICAM-1). MtDNA-CN and nuclear DNA (nDNA) were quantified in peripheral blood and urine by qRT-PCR. Cytochrome b (CYTB) gene, subunit 2 of NADH dehydrogenase (ND2), and beta 2 microglobulin nuclear gene (B2M) were assessed by TaqMan assays. mtDNA-CN was defined as the ratio of the number of mtDNA/nDNA copies, through analysis of the CYTB/B2M and ND2/B2M ratio; cerebral Doppler ultrasound: intima-media thickness (IMT)—the common carotid arteries (CCAs), the pulsatility index (PI) and resistivity index (RI)- the internal carotid arteries (ICAs) and middle cerebral arteries (MCAs), the breath-holding index (BHI). The results showed direct correlations of CCAs-IMT, PI-ICAs, PI-MCAs, RI-ICAs, RI-MCAs with urinary mtDNA, IL-17A, IL-18, TNFα, ICAM-1, UACR, synaptopodin, podocalyxin, KIM-1, NAG, and indirect correlations with serum mtDNA, IL-10. BHI correlated directly with serum IL-10, and serum mtDNA, and negatively with serum IL-17A, serum ICAM-1, and NAG. In neurologically asymptomatic patients with type 2 DM cerebrovascular remodeling and impaired cerebrovascular reactivity may be associated with mtDNA variations and inflammation from the early stages of diabetic kidney disease.
Adenosine Triphosphate: The Primordial Molecule That Controls Protein Homeostasis and Shapes the Genome–Proteome Interface
Authors: Song Jianxing
Published: April 2024

Adenosine triphosphate (ATP) acts as the universal energy currency that drives various biological processes, while nucleic acids function to store and transmit genetic information for all living organisms. Liquid–liquid phase separation (LLPS) represents the common principle for the formation of membrane-less organelles (MLOs) composed of proteins rich in intrinsically disordered regions (IDRs) and nucleic acids. Currently, while IDRs are well recognized to facilitate LLPS through dynamic and multivalent interactions, the precise mechanisms by which ATP and nucleic acids affect LLPS still remain elusive. This review summarizes recent NMR results on the LLPS of human FUS, TDP-43, and the viral nucleocapsid (N) protein of SARS-CoV-2, as modulated by ATP and nucleic acids, revealing the following: (1) ATP binds to folded domains overlapping with nucleic-acid-binding interfaces; (2) ATP and nucleic acids interplay to biphasically modulate LLPS by competitively binding to overlapping pockets of folded domains and Arg/Lys within IDRs; (3) ATP energy-independently induces protein folding with the highest efficiency known so far. As ATP likely emerged in the prebiotic monomeric world, while LLPS represents a pivotal mechanism to concentrate and compartmentalize rare molecules for forming primordial cells, ATP appears to control protein homeostasis and shape genome–proteome interfaces throughout the evolutionary trajectory, from prebiotic origins to modern cells.
Management of Double-Seropositive Anti-Glomerular Basement Membrane and Anti-Neutrophil Cytoplasmic Antibodies with 100% Crescentic Glomerulonephritis and Nephrotic Range Proteinuria in a Young Female
Authors: Kunaprayoon Lalida , Scheffel Emily T. C. , Abdel-Rahman Emaad M.
Published: April 2024

Nephrotic range proteinuria in the setting of dual-positive anti-glomerular basement membrane (AGBM) and anti-neutrophil cytoplasmic antibodies (ANCAs) is rare. Furthermore, using rituximab as a primary immunosuppressant along with steroids and plasmapheresis has not been widely studied. We present a case of dual AGBM and ANCA with nephrotic range proteinuria in a young female, where rituximab was used as a primary immunosuppressant with partial recovery.
The Impact of Gut Microbiota Changes on Methotrexate-Induced Neurotoxicity in Developing Young Rats
Authors: Chen Yu-Chieh , Hou Chih-Yao , Hsu Mei-Hsin , Huang Li-Tung , Hsiao Chih-Cheng , Sheen Jiunn-Ming
Published: April 2024

Methotrexate (MTX) is an essential part of therapy in the treatment of acute lymphoblastic leukemia (ALL) in children, and inferior intellectual outcomes have been reported in children who are leukemia survivors. Although several studies have demonstrated that the interaction between gut microbiota changes and the brain plays a vital role in the pathogenesis of chemotherapy-induced brain injury, preexisting studies on the effect of MTX on gut microbiota changes focused on gastrointestinal toxicity only. Based on our previous studies, which revealed that MTX treatment resulted in inferior neurocognitive function in developing young rats, we built a young rat model mimicking MTX treatment in a child ALL protocol, trying to investigate the interactions between the gut and brain in response to MTX treatment. We found an association between gut microbiota changes and neurogenesis/repair processes in response to MTX treatment, which suggest that MTX treatment results in gut dysbiosis, which is considered to be related to MTX neurotoxicity through an alteration in gut–brain axis communication.
Whole-Body Dynamics for Humanoid Robot Fall Protection Trajectory Generation with Wall Support
Authors: Zuo Weilong , Gao Junyao , Liu Jiongnan , Wu Taiping , Xin Xilong
Published: April 2024

When humanoid robots work in human environments, they are prone to falling. However, when there are objects around that can be utilized, humanoid robots can leverage them to achieve balance. To address this issue, this paper established the state equation of a robot using a variable height-inverted pendulum model and implemented online trajectory optimization using model predictive control. For the arms’ optimal joint angles during movement, this paper took the distributed polygon method to calculate the arm postures. To ensure that the robot reached the target position smoothly and rapidly during its motion, this paper adopts a whole-body motion control approach, establishing a cost function for multi-objective constraints on the robot’s movement. These constraints include whole-body dynamics, center of mass constraints, arm’s end effector constraints, friction constraints, and center of pressure constraints. In the simulation, four sets of methods were compared, and the experimental results indicate that compared to free fall motion, adopting the method proposed in this paper reduces the maximum acceleration of the robot when it touches the wall to 69.1 m/s2, effectively reducing the impact force upon landing. Finally, in the actual experiment, we positioned the robot 0.85 m away from the wall and applied a forward pushing force. We observed that the robot could stably land on the wall, and the impact force was within the range acceptable to the robot, confirming the practical effectiveness of the proposed method.
Biomimetic Ultrasonic Vibrator with Broadband Characteristics Inspired by Leaf-Cutting Ants
Authors: Wu Wenshuai , Yao Guang , Zhang Mingshuo , Jiang Xinggang , Zhang Deyuan
Published: April 2024

Power ultrasound is widely used in industrial production, medical equipment, aerospace, and other fields. Currently, there are two main types of commonly used power generation devices: piezoelectric ultrasonic transducers and magnetostrictive ultrasonic transducers. However, in certain situations with limited external dimensions, the applications of existing power ultrasound devices are limited. In nature, leaf-cutting ants excite vibrations through their tiny organs. Inspired by the vibratory organs of leaf-cutting ants, a new type of biomimetic ultrasonic vibrator (BUV) comprising a scraper, dentate disc, and fixture system was proposed, fabricated, and tested in this study. The experimental results showed that the BUV could operate in the frequency range of 16.8–19 kHz. Within the working frequency range, the vibration of the BUV was stable and the amplitude of the vibration displacement was greater than 22 µm. The operating frequency band of the BUV was broader than those of the piezoelectric and magnetostrictive ultrasonic transducers. In addition, the BUV can cut soft rubber and pig tissues with sufficient output power and load-carrying capacity. The BUV, as a new type of power ultrasonic excitation device, is expected to be applied in high-power micro operating scenarios, such as minimally invasive surgical instruments.
SERS-Based Microneedle Biosensor for In Situ and Sensitive Detection of Tyrosinase
Authors: Gu Zimeng , Zhao Di , He Hongyan , Wang Zhenhui
Published: April 2024

Tyrosinase (TYR) emerges as a key enzyme that exerts a regulatory influence on the synthesis of melanin, thereby assuming the role of a critical biomarker for the detection of melanoma. Detecting the authentic concentration of TYR in the skin remains a primary challenge. Distinguished from ex vivo detection methods, this study introduces a novel sensor platform that integrates a microneedle (MN) biosensor with surface-enhanced Raman spectroscopy (SERS) technology for the in situ detection of TYR in human skin. The platform utilized dopamine (DA)-functionalized gold nanoparticles (Au NPs) as the capturing substrate and 4-mercaptophenylboronic acid (4-MPBA)-modified silver nanoparticles (Ag NPs) acting as the SERS probe. Here, the Au NPs were functionalized with mercaptosuccinic acid (MSA) for DA capture. In the presence of TYR, DA immobilized on the MN is preferentially oxidized to dopamine quinone (DQ), a process that results in a decreased density of SERS probes on the platform. TYR concentration was detected through variations in the signal intensity emitted by the phenylboronic acid. The detection system was able to evaluate TYR concentrations within a linear range of 0.05 U/mL to 200 U/mL and showed robust anti-interference capabilities. The proposed platform, integrating MN-based in situ sensing, SERS technology, and TYR responsiveness, holds significant importance for diagnosing cutaneous melanoma.
Optimizing Microfluidic Impedance Cytometry by Bypass Electrode Layout Design
Authors: Wu Guangzu , Zhang Zhiwei , Du Manman , Wu Dan , Zhou Junting , Hao Tianteng , Xie Xinwu
Published: April 2024

Microfluidic impedance cytometry (MIC) has emerged as a popular technique for single-cell analysis. Traditional MIC electrode designs consist of a pair of (or three) working electrodes, and their detection performance needs further improvements for microorganisms. In this study, we designed an 8-electrode MIC device in which the center pair was defined as the working electrode, and the connection status of bypass electrodes could be changed. This allowed us to compare the performance of layouts with no bypasses and those with floating or grounding electrodes by simulation and experiment. The results of detecting Φ 5 μm beads revealed that both the grounding and the floating electrode outperformed the no bypass electrode, and the grounding electrode demonstrated the best signal-to-noise ratio (SNR), coefficient of variation (CV), and detection sensitivity. Furthermore, the effects of different bypass grounding areas (numbers of grounding electrodes) were investigated. Finally, particles passing at high horizontal positions can be detected, and Φ 1 μm beads can be measured in a wide channel (150 μm) using a fully grounding electrode, with the sensitivity of bead volume detection reaching 0.00097%. This provides a general MIC electrode optimization technology for detecting smaller particles, even macromolecular proteins, viruses, and exosomes in the future.
Complete Neuron Reconstruction Based on Branch Confidence
Authors: Zeng Ying , Wang Yimin
Published: April 2024

In the past few years, significant advancements in microscopic imaging technology have led to the production of numerous high-resolution images capturing brain neurons at the micrometer scale. The reconstructed structure of neurons from neuronal images can serve as a valuable reference for research in brain diseases and neuroscience. Currently, there lacks an accurate and efficient method for neuron reconstruction. Manual reconstruction remains the primary approach, offering high accuracy but requiring significant time investment. While some automatic reconstruction methods are faster, they often sacrifice accuracy and cannot be directly relied upon. Therefore, the primary goal of this paper is to develop a neuron reconstruction tool that is both efficient and accurate. The tool aids users in reconstructing complete neurons by calculating the confidence of branches during the reconstruction process. The method models the neuron reconstruction as multiple Markov chains, and calculates the confidence of the connections between branches by simulating the reconstruction artifacts in the results. Users iteratively modify low-confidence branches to ensure precise and efficient neuron reconstruction. Experiments on both the publicly accessible BigNeuron dataset and a self-created Whole-Brain dataset demonstrate that the tool achieves high accuracy similar to manual reconstruction, while significantly reducing reconstruction time.
Impact of Empathic Concern on Prosocial Behavior in Gain and Loss Contexts: Evidence from Event-Related Potential
Authors: Luo Xi , Yu Taowen , Tan Min , Zhong Yiping
Published: April 2024

This study employs event-related potential (ERP) to examine the impact of empathic concern on prosocial decision-making with costs in both gain and loss contexts. In this experiment, participants can choose between two types of lottery tickets and pay lottery money to help the target person gain more money or lose less money. The behavioral results showed that regardless of the context of the decision (financial loss or gain), participants tended to help individuals who had induced high empathic concern. ERP results show that compared to the low-empathic-concern condition, the high-empathic-concern condition induced greater P3 amplitude in the gain context. However, this change in P3 amplitude caused by empathic concern did not occur in the context of loss. These findings indicate that empathic concern has different psychological mechanisms that moderate prosocial behavior in gain and loss contexts.
Design Analysis of Mass Timber and Volumetric Modular Strategies as Counterproposals for an Existing Reinforced Concrete Hotel
Authors: Filion Marie-Laure , Ménard Sylvain , Carbone Carlo , Bader Eddin Mohamad
Published: April 2024

Construction professionals work in silos and use traditional design and construction methods. The growing demand for rapidly built and high-quality construction is making off-site manufacturing mainstream. Studies have shown that collaboration among all stakeholders is a necessary component for success in the construction of such buildings. This multidisciplinary study of an existing concrete hotel aims to explore an alternative structural design in mass timber or volumetric modular construction. To this end, the reinforced concrete floor plan of Club Med de Charlevoix in Quebec, Canada, was used as a benchmark for two different structural systems. The first strategy investigated CLT (cross-laminated timber) and glulam columns to replicate the reinforced concrete system (column–slab), while the second involved maximum prefabrication (volumetric modular construction). Both mass timber and volumetric modular strategies can lead to a smaller carbon footprint. The main conclusion is that the plan should be designed from the outset to be either traditional or prefabricated since major changes are required if the choice is made to switch from one system to the other. Moreover, when structural systems maximize off-site construction, such as volumetric modular construction, the various professions need to be included during early planning. This is necessary to avoid task duplication and prevent the neglect of considerations such as manufacturable dimensions and partition organization.
An Updated Perspective of the Impact of the 1940 Vrancea Earthquake on Design and Construction Practices in Romania
Authors: Pavel Florin
Published: April 2024

This study presents an updated view of the effects of the 1940 Vrancea earthquake. Recently compiled studies in the literature from the time of the event, as well as other studies, present the opportunity to gain additional and relevant information regarding this large-magnitude event. The effects of this earthquake on various locations in Romania are compared to those observed after the subsequent large Vrancea earthquake of 1977. An assessment of the economic losses caused by the seismic event is also attempted. The seismic vulnerability of some building typologies commonly used before 1940 is assessed by employing the earthquake damage data and the well-known macroseismic method. The impact of this event on the design and construction practices in Romania is evaluated using the collected information as well. Finally, the policy of repair and strengthening of buildings applied after the event is also discussed, and case studies are presented.
Finite Element Analysis on the Seismic Performance of Concrete-Filled Steel Tube Columns with a Multiple-Chamber Round-Ended Cross-Section
Authors: Liu Jing , Yu Wenzhuo , Fang Yawei , Pan Zimao , Cao Guohui
Published: April 2024

This study proposes a form of concrete-filled steel tube column with a multiple-chamber round-ended cross-section (M-CFST). Longitudinal and transverse stiffening ribs divide the circular-ended section into different chambers, strengthening the steel tube’s confinement effect on the core concrete and improving the component’s seismic performance. A three-dimensional finite element (FE) solid model of the M-CFST is created by employing the FE software ABAQUS. Quasi-static analysis is conducted to investigate the influence of parameters, such as chamber arrangement, aspect ratio, and axial compression ratio, on flexural hysteresis performance. Moreover, the failure modes, hysteresis curves, skeleton curves, strain development, and energy dissipation of the components are analyzed. The results show the following: (1) The FE model presented in this study can simulate the quasi-static behavior of CFST columns accurately, and the calculated results are in good agreement with the measured values. (2) The seismic performance of the composite column is excellent, with a large number of chambers leading to a robust hysteresis curve for the composite columns, resulting in increased bearing capacity and energy dissipation capacity. However, the energy dissipation performance of the specimen with a two-chamber arrangement is slightly lower than that with a single-chamber arrangement. (3) The results of the finite element analysis suggest that the long and short sides of the CFST columns with a large length–width ratio should be arranged to be relatively close in length.
Innovative Use of UHF-RFID Wireless Sensors for Monitoring Cultural Heritage Structures
Authors: Gregori Amedeo , Castoro Chiara , Mercuri Micaela , Di Natale Antonio , Di Giampaolo Emidio
Published: April 2024

This paper reports a novel investigation in applying commercial Ultra High-Frequency RFID tags (UHF-RFID tags), which are widely used in logistics as sensing elements in civil engineering structures, particularly for monitoring out-of-plane displacements of brick masonry walls. Both laboratory tests and in situ experimental tests assessed the feasibility of the proposed application. Laboratory tests showed a very satisfactory response while the in situ experiments showed a weaker response. Nevertheless, the potential reliability of the proposed technique can be stated. The authors traced back the causes of the performance decrease to environmental interference, mainly due to the extensive presence of a rigid steel frame surrounding the out-of-plane loaded panels. Measurements of displacements, in fact, are obtained indirectly from the phase of UHF-RFID signals that strongly suffer from multipath generated by metallic surfaces. Despite some limitations, the proposed measurement technique permits a reliable and sustainable approach to the monitoring of structures. The use of commercial UHF-RFID wireless tags, in fact, assures easy and fast installation operations and assures the possibility of placing a large number of sensors over the structure with very low maintenance costs with respect to the more traditional monitoring techniques. Moreover, using very thin and small commercial UHR-RFID tags on cultural heritage structures can represent an opportunity for sustainable long-time monitoring with reduced costs. Overall, the results of this study are sufficiently satisfactory to be considered as the opening of new possible scenarios in wireless structural monitoring in the civil engineering field. The authors propose as future work to use UHF-RFID tags for the real-time monitoring of an existing masonry facade that, not being characterized by the presence of a steel frame, can potentially assure an adequate response and properly transmit the electromagnetic signal.
Rotational Stiffening Performance of Roof Folded Plates in Torsion Tests and the Stiffening Effect of Roof Folded Plates on the Lateral Buckling of H Beams in Steel Structures
Authors: Yoshino Yuki , Kimura Yoshihiro
Published: April 2024

Non-structural members, such as roofs and ceilings, become affixed to main beams that are known as structural members. When such main beams experience bending or compressive forces that lead to lateral buckling, non-structural members may act to restrain the resulting lateral buckling deformation. Nevertheless, neither Japanese nor European guidelines advocate for the utilization of non-structural members as lateral buckling stiffeners for beams. Additionally, local buckling ensues near the bolt apertures in the beam–roof folded plate connection due to the torsional deformation induced by the lateral buckling of the H beam, thereby reducing the rotational stiffness of the roof folded plate to a percentage of its ideal stiffness. This paper conducts torsional experiments on roof folded plates, and with various connection methods between these plates and the beams, to comprehend the deformation mechanism of roof folded plates and the relationship between their rotational stiffness and the torsional moment. Then, the relationship between the demand values against restraining the lateral buckling of the main beam and the experimentally determined bearing capacity of the roof folded plate is elucidated. Results indicate the efficacy of utilizing the roof folded plate as a continuous brace. The lateral buckling design capacity of H beams that are continuously stiffened by roof folded plates is elucidated via application of a connection method that ensures joint stiffness between the roof folded plate and the beam while using Japanese and European design codes.
Why Are PPP Projects Stagnating in China? An Evolutionary Analysis of China’s PPP Policies
Authors: Li Yougui , Xu Erman , Zhang Zhuoyou , He Shuxian , Jiang Xiaoyan , Skitmore Martin
Published: April 2024

The Public–Private Partnership (PPP) model has significantly contributed to global infrastructure and public service provision. The evolution of the PPP model closely aligns with policy directives. China’s PPP policy evolution has included five stages: budding (1986–2000), fluctuating (2001–2008), steady (2009–2012), expanding (2013–2018), and stagnating (2019–present). This study employs bibliometric analysis and co-word analysis to examine 407 policies enacted by the Chinese government from 1986 to 2018. By extracting policy text keywords at various stages and constructing a co-word network matrix, this study delineates the distinctive characteristics of Chinese PPP policies across different epochs. It can be found that critical areas such as “government credit”, “contract spirit”, and “power supervision” are still underappreciated. The challenges confronting China’s PPP model are multifaceted, stemming from policy gaps that have led to substantial project difficulties. Although the government proposed a new mechanism for franchising in 2023, the new mechanism is only for new PPP projects, and the difficulties of existing PPP projects have not been solved. This study advocates for enhancements in project bankability, regulatory clarity, institutional environment improvement, contract spirit defense, and the development of the PPP-REITs model to address these issues.
Advancements in Image-Based Models for High-Grade Gliomas Might Be Accelerated
Authors: Frosina Guido
Published: April 2024

The first half of 2022 saw the publication of several major research advances in image-based models and artificial intelligence applications to optimize treatment strategies for high-grade gliomas, the deadliest brain tumors. We review them and discuss the barriers that delay their entry into clinical practice; particularly, the small sample size and the heterogeneity of the study designs and methodologies used. We will also write about the poor and late palliation that patients suffering from high-grade glioma can count on at the end of life, as well as the current legislative instruments, with particular reference to Italy. We suggest measures to accelerate the gradual progress in image-based models and end of life care for patients with high-grade glioma.
The Role of Estrogen and Estrogen Receptors in Head and Neck Tumors
Authors: Kranjčević Jacqueline-Katrin , Čonkaš Josipa , Ozretić Petar
Published: April 2024

Head and neck squamous cell carcinoma (HNSCC) is the most common histological form of head and neck tumors (HNTs), which originate from the epithelium of the lips and oral cavity, pharynx, larynx, salivary glands, nasal cavity, and sinuses. The main risk factors include consumption of tobacco in all forms and alcohol, as well as infections with high-risk human papillomaviruses or the Epstein–Barr virus. Regardless of the etiological agent, the risk of developing different types of HNTs is from two to more than six times higher in males than in females. The reason for such disparities probably lies in a combination of both biological and psychosocial factors. Therefore, it is hypothesized that exposure to female sex hormones, primarily estrogen, provides women with protection against the formation and metastasis of HNTs. In this review, we synthesized available knowledge on the role of estrogen and estrogen receptors (ERs) in the development and progression of HNTs, with special emphasis on membrane ERs, which are much less studied. We can summarize that in addition to epidemiologic studies unequivocally pointing to the protective effect of estrogen in women, an increased expression of both nuclear ERs, ERα, and ERβ, and membrane ERs, ERα36, GPER1, and NaV1.2, was present in different types of HNSCC, for which anti-estrogens could be used as an effective therapeutic approach.
Preparation of High-Efficiency Fe/N-Doped Carbon Catalysts Derived from Graphite Phase Carbon Nitride for Reduction of Oxygen
Authors: Wang Yan , Liu Wuxin , Wang Rongzhe , Wang Qing , Luo Shaohua , Hou Pengqing , Zhang Yahui , Yan Shengxue , Liu Xin , Guo Jing
Published: April 2024

Fe/N-doped carbon (Fe-NC) is an excellent base-metal catalyst for use in an electrocatalytic oxygen reduction reaction (ORR) with high activity. In this paper, graphite phase carbon nitride (g-C3N4) was first obtained from the pyrolyzing of melamine, and then different proportions of FeCl3 were separately doped into g-C3N4 to further prepare the Fe-NC catalyst. The Fe-NC catalyst was applied in an ORR reaction, and the results show that the Fe-NC catalyst doped with 0.5 mmol FeCl3 possesses exceptional electrocatalytic performance, with an onset potential of 0.96 V and a half-wave potential of 0.81 V, which approaches that of a Pt/C catalyst. Meanwhile, the Fe-NC catalyst displays high stability and methanol resistance. The results supply a new way to prepare efficient ORR electrocatalysts.
From Hematopoietic Stem Cells to Platelets: Unifying Differentiation Pathways Identified by Lineage Tracing Mouse Models
Authors: Manso Bryce A. , Rodriguez y Baena Alessandra , Forsberg E. Camilla
Published: April 2024

Platelets are the terminal progeny of megakaryocytes, primarily produced in the bone marrow, and play critical roles in blood homeostasis, clotting, and wound healing. Traditionally, megakaryocytes and platelets are thought to arise from multipotent hematopoietic stem cells (HSCs) via multiple discrete progenitor populations with successive, lineage-restricting differentiation steps. However, this view has recently been challenged by studies suggesting that (1) some HSC clones are biased and/or restricted to the platelet lineage, (2) not all platelet generation follows the “canonical” megakaryocytic differentiation path of hematopoiesis, and (3) platelet output is the default program of steady-state hematopoiesis. Here, we specifically investigate the evidence that in vivo lineage tracing studies provide for the route(s) of platelet generation and investigate the involvement of various intermediate progenitor cell populations. We further identify the challenges that need to be overcome that are required to determine the presence, role, and kinetics of these possible alternate pathways.
Chemogenetic Manipulation of Amygdala Kappa Opioid Receptor Neurons Modulates Amygdala Neuronal Activity and Neuropathic Pain Behaviors
Authors: Ji Guangchen , Presto Peyton , Kiritoshi Takaki , Chen Yong , Navratilova Edita , Porreca Frank , Neugebauer Volker
Published: April 2024

Neuroplasticity in the central nucleus of the amygdala (CeA) plays a key role in the modulation of pain and its aversive component. The dynorphin/kappa opioid receptor (KOR) system in the amygdala is critical for averse-affective behaviors in pain conditions, but its mechanisms are not well understood. Here, we used chemogenetic manipulations of amygdala KOR-expressing neurons to analyze the behavioral consequences in a chronic neuropathic pain model. For the chemogenetic inhibition or activation of KOR neurons in the CeA, a Cre-inducible viral vector encoding Gi-DREADD (hM4Di) or Gq-DREADD (hM3Dq) was injected stereotaxically into the right CeA of transgenic KOR-Cre mice. The chemogenetic inhibition of KOR neurons expressing hM4Di with a selective DREADD actuator (deschloroclozapine, DCZ) in sham control mice significantly decreased inhibitory transmission, resulting in a shift of inhibition/excitation balance to promote excitation and induced pain behaviors. The chemogenetic activation of KOR neurons expressing hM3Dq with DCZ in neuropathic mice significantly increased inhibitory transmission, decreased excitability, and decreased neuropathic pain behaviors. These data suggest that amygdala KOR neurons modulate pain behaviors by exerting an inhibitory tone on downstream CeA neurons. Therefore, activation of these interneurons or blockade of inhibitory KOR signaling in these neurons could restore control of amygdala output and mitigate pain.
Flow Cytometry-Based Assay to Detect Alpha Galactosidase Enzymatic Activity at the Cellular Level
Authors: Fekete Nóra , Li Luca Kamilla , Kozma Gergely Tibor , Fekete György , Pállinger Éva , Kovács Árpád Ferenc
Published: April 2024

Background: Fabry disease is a progressive, X chromosome-linked lysosomal storage disorder with multiple organ dysfunction. Due to the absence or reduced activity of alpha-galactosidase A (AGAL), glycosphingolipids, primarily globotriaosyl-ceramide (Gb3), concentrate in cells. In heterozygous women, symptomatology is heterogenous and currently routinely used fluorometry-based assays measuring mean activity mostly fail to uncover AGAL dysfunction. The aim was the development of a flow cytometry assay to measure AGAL activity in individual cells. Methods: Conventional and multispectral imaging flow cytometry was used to detect AGAL activity. Specificity was validated using the GLA knockout (KO) Jurkat cell line and AGAL inhibitor 1-deoxygalactonojirimycin. The GLA KO cell line was generated via CRISPR-Cas9-based transfection, validated with exome sequencing, gene expression and substrate accumulation. Results: Flow cytometric detection of specific AGAL activity is feasible with fluorescently labelled Gb3. In the case of Jurkat cells, a substrate concentration of 2.83 nmol/mL and 6 h of incubation are required. Quenching of the aspecific exofacial binding of Gb3 with 20% trypan blue solution is necessary for the specific detection of lysosomal substrate accumulation. Conclusion: A flow cytometry-based assay was developed for the quantitative detection of AGAL activity at the single-cell level, which may contribute to the diagnosis of Fabry patients.
Lineage Reprogramming: Genetic, Chemical, and Physical Cues for Cell Fate Conversion with a Focus on Neuronal Direct Reprogramming and Pluripotency Reprogramming
Authors: Umeyama Taichi , Matsuda Taito , Nakashima Kinichi
Published: April 2024

Although lineage reprogramming from one cell type to another is becoming a breakthrough technology for cell-based therapy, several limitations remain to be overcome, including the low conversion efficiency and subtype specificity. To address these, many studies have been conducted using genetics, chemistry, physics, and cell biology to control transcriptional networks, signaling cascades, and epigenetic modifications during reprogramming. Here, we summarize recent advances in cellular reprogramming and discuss future directions.
GW501516-Mediated Targeting of Tetraspanin 15 Regulates ADAM10-Dependent N-Cadherin Cleavage in Invasive Bladder Cancer Cells
Authors: Barbaud Alexandre , Lascombe Isabelle , Péchery Adeline , Arslan Sergen , Kleinclauss François , Fauconnet Sylvie
Published: April 2024

Bladder cancer aggressiveness is correlated with abnormal N-cadherin transmembrane glycoprotein expression. This protein is cleaved by the metalloprotease ADAM10 and the γ-secretase complex releasing a pro-angiogenic N-terminal fragment (NTF) and a proliferation-activating soluble C-terminal fragment (CTF2). Tetraspanin 15 (Tspan15) is identified as an ADAM10-interacting protein to induce selective N-cadherin cleavage. We first demonstrated, in invasive T24 bladder cancer cells, that N-cadherin was cleaved by ADAM10 generating NTF in the extracellular environment and leaving a membrane-anchored CTF1 fragment and that Tspan15 is required for ADAM10 to induce the selective N-cadherin cleavage. Targeting N-cadherin function in cancer is relevant to preventing tumor progression and metastases. For antitumor molecules to inhibit N-cadherin function, they should be complete and not cleaved. We first showed that the GW501516, an agonist of the nuclear receptor PPARβ/δ, decreased Tspan15 and prevented N-cadherin cleavage thus decreasing NTF. Interestingly, the drug did not modify ADAM10 expression, which was important because it could limit side effects since ADAM10 cleaves numerous substrates. By targeting Tspan15 to block ADAM10 activity on N-cadherin, GW501516 could prevent NTF pro-tumoral effects and be a promising molecule to treat bladder cancer. More interestingly, it could optimize the effects of the N-cadherin antagonists those such as ADH-1 that target the N-cadherin ectodomain.
Hematopoietic Stem Cells as an Integrative Hub Linking Lifestyle to Cardiovascular Health
Authors: Chen Xinliang , Liu Chaonan , Wang Junping , Du Changhong
Published: April 2024

Despite breakthroughs in modern medical care, the incidence of cardiovascular disease (CVD) is even more prevalent globally. Increasing epidemiologic evidence indicates that emerging cardiovascular risk factors arising from the modern lifestyle, including psychosocial stress, sleep problems, unhealthy diet patterns, physical inactivity/sedentary behavior, alcohol consumption, and tobacco smoking, contribute significantly to this worldwide epidemic, while its underpinning mechanisms are enigmatic. Hematological and immune systems were recently demonstrated to play integrative roles in linking lifestyle to cardiovascular health. In particular, alterations in hematopoietic stem cell (HSC) homeostasis, which is usually characterized by proliferation, expansion, mobilization, megakaryocyte/myeloid-biased differentiation, and/or the pro-inflammatory priming of HSCs, have been shown to be involved in the persistent overproduction of pro-inflammatory myeloid leukocytes and platelets, the cellular protagonists of cardiovascular inflammation and thrombosis, respectively. Furthermore, certain lifestyle factors, such as a healthy diet pattern and physical exercise, have been documented to exert cardiovascular protective effects through promoting quiescence, bone marrow retention, balanced differentiation, and/or the anti-inflammatory priming of HSCs. Here, we review the current understanding of and progression in research on the mechanistic interrelationships among lifestyle, HSC homeostasis, and cardiovascular health. Given that adhering to a healthy lifestyle has become a mainstream primary preventative approach to lowering the cardiovascular burden, unmasking the causal links between lifestyle and cardiovascular health from the perspective of hematopoiesis would open new opportunities to prevent and treat CVD in the present age.
Correction: Won et al. Ex Vivo Perfusion Using a Mathematical Modeled, Controlled Gas Exchange Self-Contained Bioreactor Can Maintain a Mouse Kidney for Seven Days. Cells 2022, 11, 1822
Authors: Won Natalie , Castillo-Prado Jorge , Tan Xinzhu , Ford John , Heath David , Mazilescu Laura Ioana , Selzner Markus , Rogers Ian M.
Published: April 2024

In the original publication [...]
5-Hydroxymethylcytosine in Cell-Free DNA Predicts Immunotherapy Response in Lung Cancer
Authors: Shao Jianming , Xu Yitian , Olsen Randall J. , Kasparian Saro , Sun Kai , Mathur Sunil , Zhang Jun , He Chuan , Chen Shu-Hsia , Bernicker Eric H. , Li Zejuan
Published: April 2024

Immune checkpoint inhibitors (ICIs) drastically improve therapeutic outcomes for lung cancer, but accurately predicting individual patient responses to ICIs remains a challenge. We performed the genome-wide profiling of 5-hydroxymethylcytosine (5hmC) in 85 plasma cell-free DNA (cfDNA) samples from lung cancer patients and developed a 5hmC signature that was significantly associated with progression-free survival (PFS). We built a 5hmC predictive model to quantify the 5hmC level and validated the model in the validation, test, and control sets. Low weighted predictive scores (wp-scores) were significantly associated with a longer PFS compared to high wp-scores in the validation [median 7.6 versus 1.8 months; p = 0.0012; hazard ratio (HR) 0.12; 95% confidence interval (CI), 0.03–0.54] and test (median 14.9 versus 3.3 months; p = 0.00074; HR 0.10; 95% CI, 0.02–0.50) sets. Objective response rates in patients with a low or high wp-score were 75.0% (95% CI, 42.8–94.5%) versus 0.0% (95% CI, 0.0–60.2%) in the validation set (p = 0.019) and 80.0% (95% CI, 44.4–97.5%) versus 0.0% (95% CI, 0.0–36.9%) in the test set (p = 0.0011). The wp-scores were also significantly associated with PFS in patients receiving single-agent ICI treatment (p < 0.05). In addition, the 5hmC predictive signature demonstrated superior predictive capability to tumor programmed death-ligand 1 and specificity to ICI treatment response prediction. Moreover, we identified novel 5hmC-associated genes and signaling pathways integral to ICI treatment response in lung cancer. This study provides proof-of-concept evidence that the cfDNA 5hmC signature is a robust biomarker for predicting ICI treatment response in lung cancer.
Speech Sounds Production, Narrative Skills, and Verbal Memory of Children with 22q11.2 Microdeletion
Authors: Rakonjac Marijana , Cuturilo Goran , Kovacevic-Grujicic Natasa , Simeunovic Ivana , Kostic Jovana , Stevanovic Milena , Drakulic Danijela
Published: April 2024

22q11.2 deletion syndrome (22q11.2DS), the most frequent microdeletion syndrome in humans, is related to a high risk of developing neurodevelopmental disorders. About 95% of patients with 22q11.2DS have speech and language impairments. Global articulation, story generation, and verbal memory tests were applied to compare articulatory characteristics of speech sounds, spontaneous language abilities, and immediate verbal memory between four groups of Serbian-speaking children: patients with 22q11.2DS, children with clinical presentation of 22q11.2DS that do not have the microdeletion, children with non-syndromic congenital heart defects, and their peers with typical speech–sound development. The obtained results showed that children with this microdeletion have impaired articulation skills and expressive language abilities. However, we did not observe weaker receptive language skills and immediate verbal memory compared to healthy controls. Children with 22q11.2DS should be considered a risk category for the development of speech–sound pathology and expressive language abilities. Since speech intelligibility is an instrument of cognition and adequate peer socialization, and language impairment in school-aged children with 22q11DS might be an indicator of increased risk for later psychotic symptoms, patients with 22q11.2 microdeletion should be included in a program of early stimulation of speech–language development immediately after diagnosis is established.
An Update on Pharmacologic Management of Neonatal Hypotension: When, Why, and Which Medication
Authors: Agakidou Eleni , Chatziioannidis Ilias , Kontou Angeliki , Stathopoulou Theodora , Chotas William , Sarafidis Kosmas
Published: April 2024

Anti-hypotensive treatment, which includes dopamine, dobutamine, epinephrine, norepinephrine, milrinone, vasopressin, terlipressin, levosimendan, and glucocorticoids, is a long-established intervention in neonates with arterial hypotension (AH). However, there are still gaps in knowledge and issues that need clarification. The main questions and challenges that neonatologists face relate to the reference ranges of arterial blood pressure in presumably healthy neonates in relation to gestational and postnatal age; the arterial blood pressure level that potentially affects perfusion of critical organs; the incorporation of targeted echocardiography and near-infrared spectroscopy for assessing heart function and cerebral perfusion in clinical practice; the indication, timing, and choice of medication for each individual patient; the limited randomized clinical trials in neonates with sometimes conflicting results; and the sparse data regarding the potential effect of early hypotension or anti-hypotensive medications on long-term neurodevelopment. In this review, after a short review of AH definitions used in neonates and existing data on pathophysiology of AH, we discuss currently available data on pharmacokinetic and hemodynamic effects, as well as the effectiveness and safety of anti-hypotensive medications in neonates. In addition, data on the comparisons between anti-hypotensive medications and current suggestions for the main indications of each medication are discussed.