bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficacy and safety of programmed cell death receptor 1 inhibition-based regimens in patients with pediatric malignancies: the real-world study in China
Authors: Hong Ye , Song Mengjia , Lan Yingxia , Wang Juan , Lu Suying , Zhang Yu , Zhu Jia , Sun Feifei , Huang Junting , Liu Juan , Xu Jiaqian , Wu Yanpeng , Guo Haixia , Cai Ruiqing , Zhen Zijun , Que Yi , Zhang Yizhuo
Published: June 2023

Background

Programmed death receptor 1 (PD-1) inhibition has shown durable response and mild adverse events (AEs) in adult malignancies. However, data on the clinical activity of PD-1 inhibition in pediatric patients are lacking. We comprehensively assessed the efficacy and safety of PD-1 inhibitor-based regimens for pediatric malignancies.

Methods

We conducted a real-world, multi-institutional, retrospective analysis of pediatric malignancies treated with PD-1 inhibitor-based regimens. The primary endpoints were objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints included disease control rate (DCR), duration of response (DOR), and AEs. The Kaplan–Meier method was used to calculate PFS and DOR. The National Cancer Institute Common Toxicity Criteria for AEs (version 5.0) were used to grade toxicity.

Results

A total of 93 and 109 patients were evaluated for efficacy and safety, respectively. For all efficacy-evaluable patients, PD-1 inhibitor monotherapy, combined chemotherapy, combined histone deacetylase inhibitor, and combined vascular endothelial growth factor receptor tyrosine kinase inhibitor cohorts, the ORR and DCR were 53.76%/81.72%, 56.67%/83.33%, 54.00%/80.00%, 100.00%/100.00%, and 12.50%/75.00%, respectively; the median PFS and DOR were 17.6/31.2 months, not achieved/not achieved, 14.9/31.2 months, 17.6/14.9 months, and 3.7/1.8 months, respectively; the incidence rate of AEs were 83.49%, 55.26%, 100.00%, 80.00%, and 100.00%, respectively. One patient in the PD-1 inhibitor-combined chemotherapy cohort discontinued treatment due to diabetic ketoacidosis.

Conclusions

This largest retrospective analysis demonstrate that PD-1 inhibitor-based regimens are potentially effective and tolerable in pediatric malignancies. Our findings provide references for future clinical trials and practice of PD-1 inhibitors in pediatric cancer patients.
Potency assays and biomarkers for cell-based advanced therapy medicinal products
Authors: Capelli Chiara , Cuofano Carolina , Pavoni Chiara , Frigerio Simona , Lisini Daniela , Nava Sara , Quaroni Michele , Colombo Valentina , Galli Francesco , Bezukladova Svetlana , Panina-Bordignon Paola , Gaipa Giuseppe , Comoli Patrizia , Cossu Giulio , Martino Gianvito , Biondi Andrea , Introna Martino , Golay Josée
Published: June 2023

Advanced Therapy Medicinal Products (ATMPs) based on somatic cells expanded in vitro, with or without genetic modification, is a rapidly growing area of drug development, even more so following the marketing approval of several such products. ATMPs are produced according to Good Manufacturing Practice (GMP) in authorized laboratories. Potency assays are a fundamental aspect of the quality control of the end cell products and ideally could become useful biomarkers of efficacy in vivo. Here we summarize the state of the art with regard to potency assays used for the assessment of the quality of the major ATMPs used clinic settings. We also review the data available on biomarkers that may substitute more complex functional potency tests and predict the efficacy in vivo of these cell-based drugs.
The axis of complement C1 and nucleolus in antinuclear autoimmunity
Authors: Wu Shan , Chen Junjie , Teo Boon Heng Dennis , Wee Seng Yin Kelly , Wong Ming Hui Millie , Cui Jianzhou , Chen Jinmiao , Leong Khai Pang , Lu Jinhua
Published: June 2023

Antinuclear autoantibodies (ANA) are heterogeneous self-reactive antibodies that target the chromatin network, the speckled, the nucleoli, and other nuclear regions. The immunological aberration for ANA production remains partially understood, but ANA are known to be pathogenic, especially, in systemic lupus erythematosus (SLE). Most SLE patients exhibit a highly polygenic disease involving multiple organs, but in rare complement C1q, C1r, or C1s deficiencies, the disease can become largely monogenic. Increasing evidence point to intrinsic autoimmunogenicity of the nuclei. Necrotic cells release fragmented chromatins as nucleosomes and the alarmin HMGB1 is associated with the nucleosomes to activate TLRs and confer anti-chromatin autoimmunogenecity. In speckled regions, the major ANA targets Sm/RNP and SSA/Ro contain snRNAs that confer autoimmunogenecity to Sm/RNP and SSA/Ro antigens. Recently, three GAR/RGG-containing alarmins have been identified in the nucleolus that helps explain its high autoimmunogenicity. Interestingly, C1q binds to the nucleoli exposed by necrotic cells to cause protease C1r and C1s activation. C1s cleaves HMGB1 to inactive its alarmin activity. C1 proteases also degrade many nucleolar autoantigens including nucleolin, a major GAR/RGG-containing autoantigen and alarmin. It appears that the different nuclear regions are intrinsically autoimmunogenic by containing autoantigens and alarmins. However, the extracellular complement C1 complex function to dampen nuclear autoimmunogenecity by degrading these nuclear proteins.
Preclinical immunogenicity and protective efficacy of a SARS-CoV-2 RBD-based vaccine produced with the thermophilic filamentous fungal expression system Thermothelomyces heterothallica C1
Authors: Gonzalez-Hernandez Mariana , Kaiser Franziska Karola , Steffen Imke , Ciurkiewicz Malgorzata , van Amerongen Geert , Tchelet Ronen , Emalfarb Mark , Saloheimo Markku , Wiebe Marilyn G. , Vitikainen Marika , Albulescu Irina C. , Bosch Berend-Jan , Baumgärtner Wolfgang , Haagmans Bart L. , Osterhaus Albert D. M. E.
Published: June 2023

Introduction

The emergency use of vaccines has been the most efficient way to control the coronavirus disease 19 (COVID-19) pandemic. However, the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern has reduced the efficacy of currently used vaccines. The receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein is the main target for virus neutralizing (VN) antibodies.

Methods

A SARS-CoV-2 RBD vaccine candidate was produced in the Thermothelomyces heterothallica (formerly, Myceliophthora thermophila) C1 protein expression system and coupled to a nanoparticle. Immunogenicity and efficacy of this vaccine candidate was tested using the Syrian golden hamster (Mesocricetus auratus) infection model.

Results

One dose of 10-μg RBD vaccine based on SARS-CoV-2 Wuhan strain, coupled to a nanoparticle in combination with aluminum hydroxide as adjuvant, efficiently induced VN antibodies and reduced viral load and lung damage upon SARS-CoV-2 challenge infection. The VN antibodies neutralized SARS-CoV-2 variants of concern: D614G, Alpha, Beta, Gamma, and Delta.

Discussion

Our results support the use of the Thermothelomyces heterothallica C1 protein expression system to produce recombinant vaccines against SARS-CoV-2 and other virus infections to help overcome limitations associated with the use of mammalian expression system.
Immunomodulatory role of decidual prolactin on the human fetal membranes and placenta
Authors: Flores-Espinosa Pilar , Méndez Isabel , Irles Claudine , Olmos-Ortiz Andrea , Helguera-Repetto Cecilia , Mancilla-Herrera Ismael , Ortuño-Sahagún Daniel , Goffin Vincent , Zaga-Clavellina Verónica
Published: June 2023

The close interaction between fetal and maternal cells during pregnancy requires multiple immune-endocrine mechanisms to provide the fetus with a tolerogenic environment and protection against any infectious challenge. The fetal membranes and placenta create a hyperprolactinemic milieu in which prolactin (PRL) synthesized by the maternal decidua is transported through the amnion-chorion and accumulated into the amniotic cavity, where the fetus is bedded in high concentrations during pregnancy. PRL is a pleiotropic immune-neuroendocrine hormone with multiple immunomodulatory functions mainly related to reproduction. However, the biological role of PRL at the maternal-fetal interface has yet to be fully elucidated. In this review, we have summarized the current information on the multiple effects of PRL, focusing on its immunological effects and biological significance for the immune privilege of the maternal-fetal interface.
Case report of cerebral cystic echinococcosis in a 5-year-old child
Authors: Menschaert Denis , Daron Aurore , Frere Julie
Published: June 2023

Cystic echinococcosis is a zoonosis caused by the larval form of the tapeworm Echinococcus granulosus. It has a worldwide distribution and represents a particularly significant economic and health burden in endemic areas. The most affected organs are the liver and the lungs. Cerebral involvement is relatively rare. This is a case study of a clinical presentation of cerebral cystic echinococcosis in a 5-year-old female patient of Moroccan origin who had developed recurrent seizures. Currently, diagnosis is based on radiological imaging in the context of anamnestic suspicion. Beyond the conclusions that can be drawn from the various case reports, there are no guidelines on management methods or randomized controlled trials that have compared management methods, and their absence can be deleterious for children. We present this clinical case report to add to the existing ones and to assist clinicians in their therapeutic decision-making while they await guidelines.
Incidence of harmful algal blooms in pristine subtropical ocean: a satellite remote sensing approach (Jeju Island)
Authors: Lee Min-Sun , Park Kyung-Ae , Kim Guebuem
Published: June 2023

Despite the increasing numbers of red tide events in the pristine subtropical ocean, a paucity of previous observations has limited understanding of harmful algae in the seas around the Korean Peninsula. Therefore, using six years (2012–2017) of Geostationary Ocean Color Imager (GOCI) satellite data, we characterized the red tides around Jeju Island, a volcanic island located near the paths of the Jeju Warm Current and Tsushima Warm Current, using the Normalized Red Tide Index (NRTI) method. The seawater around Jeju Island has for a long time been considered to be very clear, with relatively low suspended particulate matter concentrations and few harmful algae. Nonetheless, the satellite-based NRTI detection method used in this study detected and supported the existence of red tides in the coastal region around Jeju Island. Analysis of the red tide distribution showed that red tide first began to appear near the western coast of Jeju Island, then developed in the northern and eastern coastal regions, and finally vanished in the eastern coastal region. The monthly averages of the NRTI demonstrated a bloom event from April to May in every year. Additional fall blooms were detected in August–September, particularly in 2013 and 2016. The NRTI revealed strong interannual variations. The longest blooms occurred in 2015, and the most comprehensive and strongest event occurred in the spring of 2016. The latter three years (2015–2017) had much higher NRTI than the former three years (2012–2014). The probability of red tide occurrence at a given point during the 6-year study period revealed spatial differences. Relatively high probability of 0.3–0.5 was determined along the northern coastal region, whereas low probability of less than 0.2 was found along the southern region. Ground truth data also showed more frequent observations and higher red tide cell densities along the northern coast. Changes in NRTI in spring are positively correlated with changes in ENSO indices in winter. This study is the first to use a satellite-based approach with a vast long-term satellite database to elucidate the existence and probability of red tides near Jeju Island. We anticipate that this study will provide a useful strategy for remote monitoring of harmful algal blooms over wide regions using optical data.
Near infrared spectroscopy: a method for the monitoring and management of the commercial exploitation of the brown mussel (Perna perna) in southeastern Brazil
Authors: de Oliveira Amanda Gleyce Lima , Valladares Vanessa , Santos Cláudia Portes , Mello-Silva Clélia Christina
Published: June 2023

Perna perna (Linnaeus, 1758) is one of the most commercialized mollusk species in Brazil. The individuals with a shell length of at least 50 mm are considered to be adults and suitable for commercialization and human consumption. However, the lack of control over the size of extracted mussels is a recurrent and worrisome issue, which may compromise the long-term survival of natural stocks. The present study evaluated the potential to differentiate juvenile brown mussels from adult individuals by using Near Infrared Spectroscopy (NIRS). A total of 176 mussels were obtained from Jurujuba and Vermelha beaches, both located in Guanabara Bay, in the state of Rio de Janeiro, Brazil. Spectra were obtained from the muscle group and a specific part of the shell, with the specimens being separated by size (shell length < 50 mm or > 50 mm), following the current Brazilian legislation. The classification of the muscles by mussel size obtained a hit rate of 66.03%, while the hit rate of the shells was 78%. The two groups were also distinguished efficiently when the two localities were analyzed separately. The results reflect the influence of environmental factors on the chemical composition of the P. perna adults from different areas, with a 85.71% hit rate. The results indicate that NIRS is a potentially effective diagnostic tool for the monitoring and management of the commercial exploitation of natural P. perna stocks.
Antimicrobial mechanisms and secondary metabolite profiles of Streptomyces hygroscopicus subsp. hygroscopicus 5–4 against banana fusarium wilt disease using metabolomics
Authors: Yun Tianyan , Jing Tao , Zang Xiaoping , Zhou Dengbo , Li Kai , Zhao Yankun , Wang Wei , Xie Jianghui
Published: June 2023

Fusarium wilt of bananas (FWB) is seriously affecting the sustainable development of the banana industry and is caused by the devastating soil-borne fungus Fusarium oxysporum f. sp. cubense tropical race 4 (Foc TR4). Biological control is a promising strategy for controlling Fusarium wilt in bananas. We previously identified Streptomyces hygroscopicus subsp. hygroscopicus 5–4 with strong antifungal activity against the FWB. The most possible antimicrobial mechanism of strain 5–4 was explored using the metabolomics approach, light microscopy imaging, and transmission electron microscopy (TEM). The membrane integrity and ultrastructure of Foc TR4 was damaged after extract treatment, which was supported by the degradation of mycelium, soluble protein content, extracellular reducing sugar content, NADH oxidase activity, malondialdehyde content, mitochondrial membrane potential, and mitochondrial respiratory chain complex enzyme activity. The extracts of strain 5–4 cultivated at different times were characterized by a liquid chromatography–mass spectrometer (LC-MS). 647 known metabolites were detected in the extracts of strains 5–4. Hygromycin B, gluten exorphin B4, torvoside G, (z)-8-tetradecenal, piperitoside, sarmentosin, pubescenol, and other compounds were the main differential metabolites on fermentation culture for 7 days. Compared with strain 5–4 extracts, hygromycin B inhibited the mycelial growth of Foc TR4, and the EC50 concentration was 7.4 μg/mL. These results showed that strain 5–4 could destroy the cell membrane of Foc TR4 to inhibit the mycelial growth, and hygromycin B may be the key antimicrobial active metabolite. Streptomyces hygroscopicus subsp. hygroscopicus 5–4 might be a promising candidate strain to control the FWB and provide a scientific basis for the practical application of hygromycin B as a biological control agent.
Endophytic Streptomyces population induced by L-glutamic acid enhances plant resilience to abiotic stresses in tomato
Authors: Kim Da-Ran , Kwak Youn-Sig
Published: June 2023

Endophyte bacteria, which colonize plants including roots, stem, flower, and fruit, it can derive their nutrients from the host, are recognized for their mutualistic relationship with the host plant. They play a critical role in promoting host growth and modulating abiotic stress. Carbon and nitrogen have a significant impact on bacterial population and secondary metabolite production, which are highly specific in various categories such as bacterial growth regulation, anti-compounds production. Application of L-glutamic acid can significantly enhance Streptomyces globisporus population buildup in plants. However, the effectiveness of this population buildup against abiotic stresses such as salinity and drought has not been investigated. Therefore, in this study, we tested the bacteria and their prebiotic activity against salinity and drought stress in tomato plants. Three different amino acids were treated on the tomato plants, and it was observed that L-asparagine and L-proline had a negative effect on plant growth and phenotype, while L-glutamic acid promoted plant growth and increased bacteria population density. The bacteria were found to colonize the rhizosphere and root endosphere, with colonization being promoted by L-glutamic acid. Additionally, Streptomyces was found to have plant growth promotion effects and provided protection against abiotic stresses. Interestingly, L-glutamic acid reduced the damage caused by salinity stress, but not drought stress. These findings suggest that L-glutamic acid plays a role in providing tolerance to salinity stress with the core microbiota, thus the current study demonstrated their prebiotic activity in the agriculture system.
Antimicrobial photodynamic therapy against oral biofilm: influencing factors, mechanisms, and combined actions with other strategies
Authors: Li Yijun , Sun Guanwen , Xie Jingchan , Xiao Suli , Lin Chen
Published: June 2023

Oral biofilms are a prominent cause of a wide variety of oral infectious diseases which are still considered as growing public health problems worldwide. Oral biofilms harbor specific virulence factors that would aggravate the infectious process and present resistance to some traditional therapies. Antimicrobial photodynamic therapy (aPDT) has been proposed as a potential approach to eliminate oral biofilms via in situ-generated reactive oxygen species. Although numerous types of research have investigated the effectiveness of aPDT, few review articles have listed the antimicrobial mechanisms of aPDT on oral biofilms and new methods to improve the efficiency of aPDT. The review aims to summarize the virulence factors of oral biofilms, the progress of aPDT in various oral biofilm elimination, the mechanism mediated by aPDT, and combinatorial approaches of aPDT with other traditional agents.
Coraliomargarita parva sp. nov., isolated from mangrove sediment and genome-based analysis of the class Opitutae revealed five novel families: Coraliomargaritaceae fam. nov., Pelagicoccaceae fam. nov., Cerasicoccaeae fam. nov., Oceanipulchritudinaceae fam. nov., and Alterococcaeae fam. nov.
Authors: Min Lingli , Wang Wenzhuo , Oren Aharon , Lai Qiliang , Huang Zhaobin
Published: June 2023

Members of the class Opitutae are widely distributed in various environments such as rice paddy soil, freshwater lakes, seawater, marine sediment, and invertebrate digestive tracts. The class currently consists of two orders, Opitutales and Puniceicoccales, represented by the families Opitutaceae and Puniceicoccaceae, respectively, which are primarily delineated on the basis of 16S rRNA gene sequences and limited phenotypic characterizations of a few type strains. The scarcity of 16S rRNA gene and genome sequences generated from the type strains of the class Opitutae constrained our understanding of the ecological distribution and adequate resolution of its taxonomy. Here, an Opitutae strain designated WMMB3T, isolated from a mangrove sediment, was subjected to taxonomic characterization. The 16S rRNA gene of strain WMMB3T shared high sequence similarities with Coraliomargarita akajimensis DSM 45221T and C. sinensis WN38T of 96.1 and 95.9%, respectively. Phylogenetic analysis suggested that strain WMMB3T formed a monophyletic branch affiliated to the genus Coraliomargarita. The average nucleotide identity (ANI) values, digital DNA–DNA hybridization (dDDH) values and average amino acid identity (AAI) values of strain WMMB3T compared between Coraliomargarita members were 71.8–72.5, 20.7, and 68.2–68.7%, respectively, indicating that strain WMMB3T represented a novel species of Coraliomargarita. The genome of strain WMMB3T was 4.5 Mbp with a DNA G + C content of 56.0%. The respiratory quinone was menaquinone-7. The major fatty acids were iso-C14:0, and C18:1ω9c. Based on genomic, phenotypic, and chemotaxonomic characterizations, strain WMMB3T represents a novel species, and Coraliomargarita parva sp. nov. is proposed. Additionally, the phylogenomic analysis of more than 500 genomes of the class Opitutae, encompassing a majority of uncultivated bacteria and a few type strains, was performed using the Genome Taxonomic Database toolkit (GTDB-Tk) to present adequate resolution of the taxonomy. Combined with 16S rRNA gene sequence phylogeny and genomic relatedness, five novel families retrieved mainly from marine habitats were proposed: Coraliomargaritaceae fam. nov., Pelagicoccaceae fam. nov., Cerasicoccaeae fam. nov., Oceanipulchritudinaceae fam. nov., and Alterococcaeae fam. nov. AAI values of 58–60% could be considered as the boundary to delineate families of the class Opitutae. This study provided a new taxonomic framework of the class Opitutae based on the genomic data.
Physical pictures of rotation mechanisms of F1- and V1-ATPases: Leading roles of translational, configurational entropy of water
Authors: Yasuda Satoshi , Hayashi Tomohiko , Murata Takeshi , Kinoshita Masahiro
Published: June 2023

We aim to develop a theory based on a concept other than the chemo-mechanical coupling (transduction of chemical free energy of ATP to mechanical work) for an ATP-driven protein complex. Experimental results conflicting with the chemo-mechanical coupling have recently emerged. We claim that the system comprises not only the protein complex but also the aqueous solution in which the protein complex is immersed and the system performs essentially no mechanical work. We perform statistical-mechanical analyses on V1-ATPase (the A3B3DF complex) for which crystal structures in more different states are experimentally known than for F1-ATPase (the α3β3γ complex). Molecular and atomistic models are employed for water and the structure of V1-ATPase, respectively. The entropy originating from the translational displacement of water molecules in the system is treated as a pivotal factor. We find that the packing structure of the catalytic dwell state of V1-ATPase is constructed by the interplay of ATP bindings to two of the A subunits and incorporation of the DF subunit. The packing structure represents the nonuniformity with respect to the closeness of packing of the atoms in constituent proteins and protein interfaces. The physical picture of rotation mechanism of F1-ATPase recently constructed by Kinoshita is examined, and common points and differences between F1- and V1-ATPases are revealed. An ATP hydrolysis cycle comprises binding of ATP to the protein complex, hydrolysis of ATP into ADP and Pi in it, and dissociation of ADP and Pi from it. During each cycle, the chemical compounds bound to the three A or β subunits and the packing structure of the A3B3 or α3β3 complex are sequentially changed, which induces the unidirectional rotation of the central shaft for retaining the packing structure of the A3B3DF or α3β3γ complex stabilized for almost maximizing the water entropy. The torque driving the rotation is generated by water with no input of chemical free energy. The presence of ATP is indispensable as a trigger of the torque generation. The ATP hydrolysis or synthesis reaction is tightly coupled to the rotation of the central shaft in the normal or inverse direction through the water-entropy effect.
Constipation in multiple system atrophy: a pilot study in Chinese patients
Authors: Chen Yalan , Huang Hongyan , Zhang Peng , Xu Yanming , Chen Yangmei
Published: June 2023

Objective

This study aimed to investigate the prevalence and clinical characteristics of subjective constipation in Chinese patients with multiple system atrophy (MSA), as well as the timing of constipation onset relative to the occurrence of motor symptoms.

Methods

A total of 200 patients who were consecutively admitted to two large Chinese hospitals from February 2016 to June 2021 and subsequently diagnosed with probable MSA were enrolled in this cross-sectional study. Demographic and constipation-related clinical data were collected, and motor and non-motor symptoms were assessed using various scales and questionnaires. Subjective constipation was defined using ROME III criteria.

Results

The frequency of constipation was 53.5, 59.7, and 39.3% in MSA, MSA with predominately parkinsonism (MSA-P), and MSA with predominately cerebellar ataxia (MSA-C), respectively. MSA-P subtype and high total UMSARS scores were associated with constipation in MSA. Similarly, the high total UMSARS scores were associated with constipation in MSA-P and MSA-C patients. Among the 107 patients with constipation, 59.8% began experiencing it before the onset of motor symptoms, and the interval between constipation and occurrence of motor symptoms was significantly longer in these patients than in those who experienced constipation after onset of motor symptoms.

Conclusion

Constipation is a highly prevalent non-motor symptom in MSA and more often occurs before the onset of motor symptoms. The results of this study may help guide future research into MSA pathogenesis in its earliest stages.
The kynurenine pathway in traumatic brain injuries and concussion
Authors: Dehhaghi Mona , Heng Benjamin , Guillemin Gilles J.
Published: June 2023

Up to 10 million people per annum experience traumatic brain injury (TBI), 80–90% of which are categorized as mild. A hit to the brain can cause TBI, which can lead to secondary brain injuries within minutes to weeks after the initial injury through unknown mechanisms. However, it is assumed that neurochemical changes due to inflammation, excitotoxicity, reactive oxygen species, etc., that are triggered by TBI are associated with the emergence of secondary brain injuries. The kynurenine pathway (KP) is an important pathway that gets significantly overactivated during inflammation. Some KP metabolites such as QUIN have neurotoxic effects suggesting a possible mechanism through which TBI can cause secondary brain injury. That said, this review scrutinizes the potential association between KP and TBI. A more detailed understanding of the changes in KP metabolites during TBI is essential to prevent the onset or at least attenuate the severity of secondary brain injuries. Moreover, this information is crucial for the development of biomarker/s to probe the severity of TBI and predict the risk of secondary brain injuries. Overall, this review tries to fill the knowledge gap about the role of the KP in TBI and highlights the areas that need to be studied.
KCNC2 variants of uncertain significance are also associated to various forms of epilepsy
Authors: Seiffert Simone , Pendziwiat Manuela , Hedrich Ulrike B. S. , Helbig Ingo , Weber Yvonne , Schwarz Niklas
Published: June 2023

Recently, de novo variants in KCNC2, coding for the potassium channel subunit KV3.2, have been described as causative for various forms of epilepsy including genetic generalized epilepsy (GGE) and developmental and epileptic encephalopathy (DEE). Here, we report the functional characteristics of three additional KCNC2 variants of uncertain significance and one variant classified as pathogenic. Electrophysiological studies were performed in Xenopus laevis oocytes. The data presented here support that KCNC2 variants with uncertain significance may also be causative for various forms of epilepsy, as they show changes in the current amplitude and activation and deactivation kinetics of the channel, depending on the variant. In addition, we investigated the effect of valproic acid on KV3.2, as several patients carrying pathogenic variants in the KCNC2 gene achieved significant seizure reduction or seizure freedom with this drug. However, in our electrophysiological investigations, no change on the behavior of KV3.2 channels could be observed, suggesting that the therapeutic effect of VPA may be explained by other mechanisms.
Reduction of the vertical vestibular-ocular reflex in military aircraft pilots exposed to tactical, high-performance flight
Authors: Bertolini Giovanni , Pagnamenta Alberto , Kunz Andres , Del Torso Aleardo , Bron Denis
Published: June 2023

Background

Exposure to high-performance flight stresses the vestibular system and may lead to adaptive changes in the vestibular responses of pilots. We investigated the vestibular-ocular reflex of pilots with different histories of flight exposure both with respect to hours of flight and flight conditions (tactical, high-performance vs. non-high-performance) to evaluate if and how adaptative changes are observable.

Methods

We evaluated the vestibular-ocular reflex of aircraft pilots using the video Head Impulse Test. In study 1, we assessed three groups of military pilots: Group 1 had 68 pilots with few hours of flight experience (<300 h) in non-high-performance flight conditions; Group 2 had 15 pilots with many hours of flight (>3,000 h) and regularly flying tactical, high-performance flight conditions; Group 3 had eight pilots with many hours of flight (>3,000 h) but not exposed to tactical, high-performance flight conditions. In study 2, four trainee pilots were followed up and tested three times over a 4-year period: (1) <300 h of flight on civil aircraft; (2) shortly after exposure to aerobatic training and with <2,000 h of overall flight; and (3) after training on tactical, high-performance aircraft (F/A 18) and for more than 2,000 h of flight.

Results

Study 1: Pilots of tactical, high-performance aircrafts (Group 2) had significantly lower gain values (p < 0.05) as compared to Groups 1 and 3, selectively for the vertical semicircular canals. They also had a statistically (p = 0.022) higher proportion (0.53) of pathological values in at least one vertical semicircular canal as compared to the other groups. Study 2: A statistically significant (p < 0.05) decrease in the rVOR gains of all vertical semicircular canals, but not of the horizontal canals, was observed. Two pilots had a pathological value in at least one vertical semicircular canal in the third test.

Discussion

The results evidence a decrease in the gain of the vestibular-ocular reflex as measured with the video head impulse test for the vertical canals. This decrease appears to be associated with the exposure to tactical, high-performance flight rather than with the overall flight experience.
Gonadotropin-releasing hormone and growth hormone act as anti-inflammatory factors improving sensory recovery in female rats with thoracic spinal cord injury
Authors: Martínez-Moreno Carlos Guillermo , Calderón-Vallejo Denisse , Díaz-Galindo Carmen , Hernández-Jasso Irma , Olivares-Hernández Juan David , Ávila-Mendoza José , Epardo David , Balderas-Márquez Jerusa Elienai , Urban-Sosa Valeria Alejandra , Baltazar-Lara Rosario , Carranza Martha , Luna Maricela , Arámburo Carlos , Quintanar José Luis
Published: June 2023

The potential for novel applications of classical hormones, such as gonadotropin-releasing hormone (GnRH) and growth hormone (GH), to counteract neural harm is based on their demonstrated neurotrophic effects in both in vitro and in vivo experimental models and a growing number of clinical trials. This study aimed to investigate the effects of chronic administration of GnRH and/or GH on the expression of several proinflammatory and glial activity markers in damaged neural tissues, as well as on sensory recovery, in animals submitted to thoracic spinal cord injury (SCI). Additionally, the effect of a combined GnRH + GH treatment was examined in comparison with single hormone administration. Spinal cord damage was induced by compression using catheter insufflation at thoracic vertebrae 10 (T10), resulting in significant motor and sensory deficits in the hindlimbs. Following SCI, treatments (GnRH, 60 μg/kg/12 h, IM; GH, 150 μg/kg/24 h, SC; the combination of both; or vehicle) were administered during either 3 or 5 weeks, beginning 24 h after injury onset and ending 24 h before sample collection. Our results indicate that a chronic treatment with GH and/or GnRH significantly reduced the expression of proinflammatory (IL6, IL1B, and iNOS) and glial activity (Iba1, CD86, CD206, vimentin, and GFAP) markers in the spinal cord tissue and improved sensory recovery in the lesioned animals. Furthermore, we found that the caudal section of the spinal cord was particularly responsive to GnRH or GH treatment, as well as to their combination. These findings provide evidence of an anti-inflammatory and glial-modulatory effect of GnRH and GH in an experimental model of SCI and suggest that these hormones can modulate the response of microglia, astrocytes, and infiltrated immune cells in the spinal cord tissue following injury.
Characteristic analysis and identification of novel molecular biomarkers in elderly glioblastoma patients using the 2021 WHO Classification of Central Nervous System Tumors
Authors: Wang Yaning , Li Junlin , Cao Yaning , Chen Wenlin , Xing Hao , Guo Xiaopeng , Shi Yixin , Wang Yuekun , Liang Tingyu , Ye Liguo , Liu Delin , Yang Tianrui , Wang Yu , Ma Wenbin
Published: June 2023

Introduction

Elderly glioblastoma (GBM) patients is characterized by high incidence and poor prognosis. Currently, however, there is still a lack of adequate molecular characterization of elderly GBM patients. The fifth edition of the WHO Classification of Central Nervous System Tumors (WHO5) gives a new classification approach for GBM, and the molecular characteristics of elderly GBM patients need to be investigated under this new framework.

Methods

The clinical and radiological features of patients with different classifications and different ages were compared. Potential prognostic molecular markers in elderly GBM patients under the WHO5 classification were found using Univariate Cox regression and Kaplan–Meier survival analysis.

Results

A total of 226 patients were included in the study. The prognostic differences between younger and elderly GBM patients were more pronounced under the WHO5 classification. Neurological impairment was more common in elderly patients (p = 0.001), while intracranial hypertension (p = 0.034) and epilepsy (p = 0.038) were more common in younger patients. Elderly patients were more likely to have higher Ki-67(p = 0.013), and in elderly WHO5 GBM patients, KMT5B (p = 0.082), KRAS (p = 0.1) and PPM1D (p = 0.055) were each associated with overall survival (OS). Among them, KRAS and PPM1D were found to be prognostic features unique to WHO5 elderly GBM patients.

Conclusion

Our study demonstrates that WHO5 classification can better distinguish the prognosis of elderly and younger GBM. Furthermore, KRAS and PPM1D may be potential prognostic predictors in WHO5 elderly GBM patients. The specific mechanism of these two genes in elderly GBM remains to be further studied.
Association of leisure sedentary behavior and physical activity with the risk of nonalcoholic fatty liver disease: a two-sample Mendelian randomization study
Authors: Zhang Xicheng , Chen Keke , Yin Shangyu , Qian Mengao , Liu Changbao
Published: June 2023

Introduction

Previous observational studies have demonstrated the relationship between leisure sedentary behavior, physical activity, and nonalcoholic liver disease (NAFLD). However, whether these associations are causal or confounding factors remains unclear.

Methods

Pooled genetic data from the UK Biobank and other large genome-wide association studies (GWAS) were used to extract instrumental variables representing sedentary television watching, computer use, driving, vigorous physical activity (VPA), and moderate-to-vigorous physical activity (MVPA). The two-sample Mendelian randomization (MR) method was used to explain the causal relationship between them and NAFLD. The inverse variance of the weighted method was used as the main analysis method, and MR-Egger, weighted median, MR-PRESSO, and other supplementary methods were also used. A sensitivity analysis was also performed. Simultaneously, the common risk factors for NAFLD were further analyzed for potential mediating associations.

Results

We observed that sedentary television viewing (odds ratio (OR): 1.84; 95% confidence interval (CI): 1.09–3.10; p = 0.021) and genetically predicted VPA duration (OR: 0.0033; 95% CI: 0.000015–0.70; p = 0.036) were suggestively associated with the risk of NAFLD. Using a computer (OR: 1.51; 95% CI: 0.47–4.81; p = 0.484), driving (OR: 0.78; 95% CI: 0.05–11.94; p = 0.858), and MVPA time (OR: 0.168; 95% CI: 0.01–2.81; p = 0.214) were not significantly associated with NAFLD. The role of heterogeneity versus pleiotropy was limited in all the analyses.

Discussion

This study supports the association between sedentary television watching and an increased risk of NAFLD, along with vigorous physical activity as a possible protective factor for NAFLD.
Bioinformatics and pathway enrichment analysis identified hub genes and potential biomarker for gastric cancer prognosis
Authors: Darang Elham , Pezeshkian Zahra , Mirhoseini Seyed Ziaeddin , Ghovvati Shahrokh
Published: June 2023

Introduction

Gastric cancer is one of the most common cancers in the world. This study aimed to identify genes, biomarkers, and metabolic pathways affecting gastric cancer using bioinformatic analysis and meta-analysis.

Methods

Datasets containing gene expression profiles of tumor lesions and adjacent non-tumor mucosa samples were downloaded. Common differentially expressed genes between data sets were selected to identify hub genes and further analysis. Gene Expression Profiling and Interactive Analyses (GEPIA) and the Kaplan-Meier method were used to further validate the expression level of genes and plot the overall survivalcurve, respectively.

Results and disscussion

KEGG pathway analysis showed that the most important pathway was enriched in ECM-receptor interaction. Hub genes includingCOL1A2, FN1, BGN, THBS2, COL5A2, COL6A3, SPARC and COL12A1 wereidentified. The top interactive miRNAs including miR-29a-3p, miR-101-3p,miR-183-5p, and miR-15a-5p targeted the most hub genes. The survival chart showed an increase in mortality in patients with gastric cancer, which shows the importance of the role of these genes in the development of the disease and can be considered candidate genes in the prevention and early diagnosis of gastric cancer.
Myeloproliferative neoplasms – blurring the lines between cancer and chronic inflammatory disorder
Authors: Soyfer Eli M. , Fleischman Angela G.
Published: June 2023

Myeloproliferative Neoplasm (MPN) is a group of chronic blood cancers that arise from a hematopoietic stem cell (HSC) clone with somatic mutations causing constitutive activation of myeloid cytokine receptor signaling. In addition to elevated blood cell counts, MPN typically presents with increased inflammatory signaling and inflammation symptoms. Therefore, while being a clonally derived neoplasm, MPN has much in common with chronic non-cancerous inflammatory conditions, such as rheumatoid arthritis, lupus, and many more. MPN and chronic inflammatory disease (CID) share similar chronicity, symptoms, dependency on the immune system, environmental triggers, and treatments. Overall, we will highlight the similarities between an MPN and CID. We highlight that while MPN is classified as a cancer, its behavior is more aligned to that of a chronic inflammatory disease. We propose that MPN should inhabit a fluid/spectrum between auto-inflammatory disease and cancer.
Effect of neonatal breast crawl on breastfeeding: a prospective cohort study
Authors: Pang Yan , Wang Xin , Li Huimin , Tu Suhua
Published: June 2023

Aim

To analyse the effect of breast crawl on neonatal breastfeeding within 5 months of delivery.

Design

Prospective Cohort Study.

Methods

Neonates were divided into successful and failed groups, according to whether the newborn crawled to the breast and began sucking for the first time within 1 h after delivery. The initiation of lactation and breastfeeding duration of the two groups were analysed at 24 h, 48 h, 72 h, the feeding practices were followed-up on the 7th day, 42nd day, and 5th month in order to explore the long-term benefits of breast crawl on breastfeeding.

Results

A total of 163 neonates were included. The initiation time and the duration of first feeding, the lactation initiation in the successful group was earlier, the scores of first and in-hospital breastfeeding scales were higher.

Public Contribution

Breast crawl is the preferred method for mothers to begin breastfeeding. The delivery room is the place where the first breast crawl occurs immediately after delivery. The midwife is the key person to protect this valuable behavior. Therefore, the midwife needs provide valuable opportunities for the breast crawl of the newborn and promote this behavior.
Short-term anti-remodeling effects of gliflozins in diabetic patients with heart failure and reduced ejection fraction: an explainable artificial intelligence approach
Authors: Mele Marco , Imbrici Paola , Mele Antonietta , Togo Maria Vittoria , Dinoi Giorgia , Correale Michele , Brunetti Natale Daniele , Nicolotti Orazio , De Luca Annamaria , Altomare Cosimo Damiano , Liantonio Antonella , Amoroso Nicola
Published: June 2023

Introduction: Sodium-glucose cotransporter type 2 inhibitors (SGLT2i), gliflozins, play an emerging role for the treatment of heart failure with reduced left ventricular ejection fraction (HFrEF). Nevertheless, the effects of SGLT2i on ventricular remodeling and function have not been completely understood yet. Explainable artificial intelligence represents an unprecedented explorative option to clinical research in this field. Based on echocardiographic evaluations, we identified some key clinical responses to gliflozins by employing a machine learning approach.

Methods: Seventy-eight consecutive diabetic outpatients followed for HFrEF were enrolled in the study. Using a random forests classification, a single subject analysis was performed to define the profile of patients treated with gliflozins. An explainability analysis using Shapley values was used to outline clinical parameters that mostly improved after gliflozin therapy and machine learning runs highlighted specific variables predictive of gliflozin response.

Results: The five-fold cross-validation analyses showed that gliflozins patients can be identified with a 0.70 ± 0.03% accuracy. The most relevant parameters distinguishing gliflozins patients were Right Ventricular S'-Velocity, Left Ventricular End Systolic Diameter and E/e' ratio. In addition, low Tricuspid Annular Plane Systolic Excursion values along with high Left Ventricular End Systolic Diameter and End Diastolic Volume values were associated to lower gliflozin efficacy in terms of anti-remodeling effects.

Discussion: In conclusion, a machine learning analysis on a population of diabetic patients with HFrEF showed that SGLT2i treatment improved left ventricular remodeling, left ventricular diastolic and biventricular systolic function. This cardiovascular response may be predicted by routine echocardiographic parameters, with an explainable artificial intelligence approach, suggesting a lower efficacy in case of advanced stages of cardiac remodeling.
Exotic option pricing model of the Black–Scholes formula: a proactive investment strategy
Authors: Wu Jingyu , Wang Yaoping , Zhu Minting , Zheng Han , Li Lingfei
Published: June 2023

The option is an important derivative tool in financial market, and after decades of development, the option has emerged in various forms. This paper studies an exotic option with a proactive investment strategy. Compared with the classic option theory, we assume that the option holders continuously trade the underlying assets according to a predetermined investment strategy. Taking the European call option as an example, we first give some assumptions and define the loss function in terms of a logarithmic investment strategy. Then, the specific pricing expression of the exotic option is derived from the Black-Scholes option pricing formula. Next, numerical simulations are presented to visualize the mechanism of the exotic option in 2D and 3D forms by selecting appropriate parameters. The results indicate that the exotic option has a significant price advantage (up to 43.9% under specific parameter settings) over the classic option. Moreover, the empirical results illustrate a perfect fit between 50 ETF (issued by the Shanghai Stock Exchange) and our exotic option. The new proposed exotic option extends the Black-Scholes option theory from a no-trading condition (do not buy or sell underlying assets during the validity period) to a dynamic investment condition and has important practical significance in real life.
Adaptive command-filtered finite-time consensus tracking control for single-link flexible-joint robotic multi-agent systems
Authors: Liu Chao , Han Limin , Yan Bocheng , Niu Ben , Li Shengtao , Liu Xiaomei
Published: June 2023

This article presents a command-filtered finite-time consensus tracking control strategy for the considered single-link flexible-joint robotic multi-agent systems. First, each agent system considered in this article is a nonlinear nonstrict-feedback system with unknown nonlinearities, so the traditional backstepping method cannot be directly applied to the design controller. However, by applying the unique structure of the Gaussian function in radial basis function neural networks, the challenges in controller design caused by the aforementioned nonstrict-feedback system have been overcome. Second, the problem of unknown nonlinearities in the system is solved by the approximation property of radial basis function neural network technology. In addition, the traditional backstepping approach often leads to an “explosion of complexity” resulting from repeated derivation of virtual control signals. Our design addresses this issue by employing command filtering technology, which simplifies the controller design process. Meanwhile, new compensation signals are designed, which successfully eliminate the error influence posed by the filters. It is seen that the control strategy presented in this article can guarantee the tracking errors converge to a small neighborhood of origin in a finite time, and all signals in the closed-loop systems remain bounded. Eventually, the simulation results show the validity of the acquired control scheme.