bluuebunny/crossref_metadata_2025 huggingface dataset:
Young and old persons' subjective feelings when facing with a non-human computer-graphics-based agent's emotional responses in consideration of differences in emotion perception
Authors: Numata Takashi , Asa Yasuhiro , Hashimoto Takaaki , Karasawa Kaori
Published: January 2024

Virtual agents (computer-graphics-based agents) have been developed for many purposes such as supporting the social life, mental care, education, and entertainment of both young and old people individuals. Promoting affective communication between young/old users and agents requires clarifying subjective feelings induced by an agent's expressions. However, an emotional response model of agents to induce positive feelings has not been fully understood due to differences in emotion perception between young and old adults. We investigated subjective feelings induced when facing with a non-human computer-graphics-based agent's emotional responses in consideration of differences of emotion perception between young adults and old adults. To emphasize the differences in emotion perception, the agent's expressions were developed by adopting exaggerated human expressions. The differences in their emotion perception of happy, sadness, and angry between young and old participants were then identified through a preliminary experiment. Considering the differences in emotion perception, induced feelings when facing with the agent's expressions were analyzed from the three types of emotion sources of the participant, agent, and other, which was defined as subject and responsibility of induced emotion. The subjective feelings were evaluated using a subjective rating task with 139 young and 211 old participants. The response of the agent that most induced positive feelings was happy when participants felt happy, and that was sad when participants felt sad, regardless emotion sources in both young and old groups. The response that most induced positive feelings was sad when participants felt angry and emotion sources were participant and the agent, and that was angry when the emotion source was other. The emotion types of the response to induce most positive feelings were the same between the young and old participants, and the way to induce most positive feelings was not always to mimic the emotional expressions, which is a typical tendency of human responses. These findings suggest that a common agent response model can be developed for young and old people by combining an emotional mimicry model with a response model to induce positive feelings in users and promote natural and affective communication, considering age characteristics of emotion perception.
Facial emotion recognition through artificial intelligence
Authors: Ballesteros Jesús A. , Ramírez V. Gabriel M. , Moreira Fernando , Solano Andrés , Pelaez Carlos A.
Published: January 2024

This paper introduces a study employing artificial intelligence (AI) to utilize computer vision algorithms for detecting human emotions in video content during user interactions with diverse visual stimuli. The research aims to unveil the creation of software capable of emotion detection by leveraging AI algorithms and image processing pipelines to identify users' facial expressions. The process involves assessing users through images and facilitating the implementation of computer vision algorithms aligned with psychological theories defining emotions and their recognizable features. The study demonstrates the feasibility of emotion recognition through convolutional neural networks (CNN) and software development and training based on facial expressions. The results highlight successful emotion identification; however, precision improvement necessitates further training for contexts with more diverse images and additional algorithms to distinguish closely related emotional patterns. The discussion and conclusions emphasize the potential of A.I. and computer vision algorithms in emotion detection, providing insights into software development, ongoing training, and the evolving landscape of emotion recognition technology. Further training is necessary for contexts with more diverse images, alongside additional algorithms that can effectively distinguish between facial expressions depicting closely related emotional patterns, enhancing certainty and accuracy.
Exercise training outcomes in patients with chronic heart failure with reduced ejection fraction depend on patient background
Authors: Soejima Yukako , Yoshioka Hideki , Guro Sayuri , Sato Hiromi , Hatakeyama Hiroto , Sato Yasunori , Fujimoto Yoshihide , Anzai Naohiko , Hisaka Akihiro
Published: January 2024

Background

The aim of this study was to identify significant factors affecting the effectiveness of exercise training using information of the HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) study.

Methods

Background factors influencing the effect of exercise training were comprehensively surveyed for 2,130 patients by multivariable Cox regression analysis with the stepwise variable selection, and only significant factors were selected that were statistically distinguished from dummy noise factors using the Boruta method.

Results

The analysis suggested that the use of beta-blockers, pulse pressure, hemoglobin level, electrocardiography findings, body mass index, and history of stroke at baseline potentially influenced the exercise effect on all-cause death (AD). Therefore, a hypothetical score to estimate the effect of exercise training was constructed based on the analysis. The analysis suggested that the score is useful in identifying patients for whom exercise training may be significantly effective in reducing all-caused death and hospitalization (ADH) as well as AD. Such a subpopulation accounted for approximately 40% of the overall study population. On the other hand, in approximately 45% of patients, the effect of exercise was unclear on either AD or ADH. In the remaining 15% of patients, it was estimated that the effect of exercise might be unclear for ADH and potentially rather increase AD.

Conclusions

This study is the first analysis to comprehensively evaluate the effects of various factors on the outcome of exercise training in chronic heart failure, underscoring the need to carefully consider the patient's background before recommending exercise training. However, it should be noted that exercise training can improve many outcomes in a wide variety of diseases. Therefore, given the limitations involved in post-hoc analyses of a single clinical trial, the characteristics of patients to whom the results of this analysis can be applied need attention, and also further research is necessary on the relationship between the degree of exercise and the outcomes. A new clinical trial would be needed to confirm the factors detected and the appropriateness of the score.
Three-dimensional modeling and geostatistical structural analysis for ore deposit prospecting trend and wisdom mining: a case study in the Jiaoxibei gold field, China
Authors: Liu Xiaoning , Wang Gongwen , Lv Jingyi , Peng Yongming , Zhao Xianyong
Published: January 2024

The orientation of deep-seated orebodies was observed shifted from the northwest to north at the Xincheng deposit in the Jiaoxibei gold field during the mining operations. To make informed decisions, understanding the geological factors influencing this directional change is crucial for mining engineers. Prior research suggested that the ore-controlling fault morphology might correlate with the orebody positions and the thickness of alteration zones. Hence, the morphology of fault structures emerges as a key point in this work. First, we constructed a three-dimensional (3D) fault surface model. A large fault framework was interpreted using gravity–magnetic–electrical geophysical datasets, and then, the local details of the fault surfaces were characterized using an interpolation method based on the drillhole fault gouge data. Subsequently, we statistically assessed the spatial association between fault morphology and orebody positioning using the standardized C-values method and demarcated the ore-controlling structures on fault surfaces using quantitative indicators. The indicators of fault dips, fault azimuths, and the second-order trend residuals of fault surfaces represented the fault morphology. The drillhole grade data (Σsampling grade * sampling length) were used to describe the scale of mineralization zones, and the cumulative thickness of the pyrite–sericite altered rocks indicated the intensity of alteration zones. Finally, a geostatistical structural analysis was used to depict the mineralization orientation at different locations. Through these methods, we aim to propose a potential pattern of how ore-controlling fault morphology spatially influences the positions and orientations of orebodies. This comprehensive approach offers valuable insights into exploring deep-seated mineralization at the Xincheng deposit, aiding in a better understanding of the deposit’s geological dynamics for future mining endeavors.
Arc-related Alaskan type magmatism: evidence from pyroxenites associated with the Pakkanadu alkaline-ultramafic complex, Southern India
Authors: Pattnaik Jiten , Ashutosh Ankur , Janaarthanan P. A. , Viljoen Fanus , Srivastava Rajesh K. , Ueckermann Henriette
Published: January 2024

Petrological and major-trace element mineral chemistry studies have been carried out on pyroxenites from the Pakkanadu alkaline-ultramafic complex from the southern India to understand their origin and nature of magma responsible for ultramafic magmatism in the area. Pyroxenites display cumulus texture and consist of clinopyroxenes (cpx) and amphiboles (amp) as dominant phases with a subordinate amount of apatite, biotite, ilmenite, magnetite, pyrite, sphene, and calcite. Mineral chemistry classifies cpx as augite and diopside, whereas amp falls under tremolite-actinolite and hornblende-actinolite fields. Cpx are alkaline to sub-alkaline in composition and Mg# - Al2O3 compositions suggest their crystallization under high-pressure conditions. A negative correlation between Mg# and TiO2 in cpx suggests early crystallization of magnetite and pyrite; high Mg# (76–92) suggests its link with the Alaskan-type intrusions, which may be crystallized through fractionation-accumulation Processes. Tectonic discrimination diagrams for cpx argue for the magmatic emplacements under an arc-tholeiitic environment in a subduction zone setting. Amp mineral chemistry (high SiO2 and low TiO2) indicate as the products of hydrothermal alteration of clinopyroxenes. A Low Al/Si ratio in the cpx suggests their derivation from silica-oversaturated magma, whereas low-Ti contents reflect slow cooling rate of the magma. Positive Rb, Ba and U anomalies in the multi-element patterns of the cpx probably signifying varying degrees of hydrothermal alteration in the studied samples. However, consistent Nb-Ta depletion can also be attributed to an enriched mantle source of the magma from which pyroxenites were crystallized. Moreover, single-cpx geothermobarometry yielded a crystallization temperature of 905 to 911°C under moderate to high pressure of 3–9 kbar.
Affective, behavioural, and cognitive engagement with written feedback on second language writing: a systematic methodological review
Authors: Pearson William S.
Published: January 2024

There is growing interest in multi-dimensional approaches for investigating student engagement with written feedback (WF), drawing and building on prior theoretical work carried out both within and beyond second language teaching and learning. It is thought that understandings of developing L2 writers’ affective, behavioural, and cognitive processes and responses explain the utility they gain from WF. The present study constitutes a systematic methodological review of 35 empirical studies of student engagement, reviewing their conceptual orientations, methodologies and methods, contexts and sampling approaches, written texts, and WF. The study identified a pre-eminent methodological approach constituting mixed method case studies (often situated in Chinese tertiary settings) involving the triangulation of textual measures with student verbal reports (usually semi-structured or stimulated recall interviews), albeit with variations in the operationalisation of behavioural and cognitive engagement. Teachers constituted the main feedback provider queried (frequently for the purposes of examining engagement with corrective feedback), although were seldom recruited as informants to provide their perspectives on student engagement. Relatively few studies contrasted engagement across multiple feedback sources, such as peers or AWE applications. Texts subject to written feedback tended to be short (and perhaps elicited for the purposes of research), with fewer studies investigating engagement with WF on authentic high-stakes or longer-form writing (e.g., theses drafts, research articles). Methodological limitations of existing scholarship are posited and suggestions for future research outlined.
Soil organic matter on arid saline-alkali land drives greenhouse gas emissions from artificial and natural grasslands in different directions
Authors: Wei Ziwen , Cheng Yunxiang , Hou Fujiang
Published: January 2024

Reducing greenhouse gas (GHG) emissions and mitigating the pace of global warming are crucial to achieving a balance between economic development and ecological protection. However, research on GHG emissions from different types of artificial grasslands is limited. This study aimed to elucidate the dynamics of GHG emission fluxes in three types of artificial grasslands and natural saline meadow grassland (NG). Meteorological and soil data were collected to determine the correlations between GHG fluxes and environmental variables. All grasslands were sources of CO2 and N2O. Artificial grasslands were sinks of CH4, whereas NG was a CH4 source. FCO2 was the main source of GHGs in grasslands. The average emissions of FCO2 and FN2O in artificial grasslands were higher than those in NG. Soil temperature had a positive effect on GHG emissions in all grasslands and soil organic matter content was the main factor affecting all grassland GHG fluxes.
Genome-wide genetic architecture for plant maturity and drought tolerance in diploid potatoes
Authors: Fofana Bourlaye , Soto-Cerda Braulio , Zaidi Moshin , Main David , Fillmore Sherry
Published: January 2024

Cultivated potato (Solanum tuberosum) is known to be highly susceptible to drought. With climate change and its frequent episodes of drought, potato growers will face increased challenges to achieving their yield goals. Currently, a high proportion of untapped potato germplasm remains within the diploid potato relatives, and the genetic architecture of the drought tolerance and maturity traits of diploid potatoes is still unknown. As such, a panel of 384 ethyl methanesulfonate-mutagenized diploid potato clones were evaluated for drought tolerance and plant maturity under field conditions. Genome-wide association studies (GWAS) were conducted to dissect the genetic architecture of the traits. The results obtained from the genetic structure analysis of the panel showed five main groups and seven subgroups. Using the Genome Association and Prediction Integrated Tool–mixed linear model GWAS statistical model, 34 and 17 significant quantitative trait nucleotides (QTNs) were found associated with maturity and drought traits, respectively. Chromosome 5 carried most of the QTNs, some of which were also detected by using the restricted two-stage multi-locus multi-allele-GWAS haploblock-based model, and two QTNs were found to be pleiotropic for both maturity and drought traits. Using the non-parametric U-test, one and three QTNs, with 5.13%–7.4% phenotypic variations explained, showed favorable allelic effects that increase the maturity and drought trait values. The quantitaive trait loci (QTLs)/QTNs associated with maturity and drought trait were found co-located in narrow (0.5–1 kb) genomic regions with 56 candidate genes playing roles in plant development and senescence and in abiotic stress responses. A total of 127 potato clones were found to be late maturing and tolerant to drought, while nine were early to moderate–late maturing and tolerant to drought. Taken together, the data show that the studied germplasm panel and the identified candidate genes are prime genetic resources for breeders and biologists in conventional breeding and targeted gene editing as climate adaptation tools.
Case report: Identification of a novel variant p.Gly215Arg in the CHN1 gene causing Moebius syndrome
Authors: Manso-Bazús Carmen , Spataro Nino , Gabau Elisabeth , Beltrán-Salazar Viviana P. , Trujillo-Quintero Juan Pablo , Capdevila Nuria , Brunet-Vega Anna , Baena Neus , Jeyaprakash A Arockia , Martinez-Glez Victor , Ruiz Anna
Published: January 2024

Background: Moebius Syndrome (MBS) is a rare congenital neurological disorder characterized by paralysis of facial nerves, impairment of ocular abduction and other variable abnormalities. MBS has been attributed to both environmental and genetic factors as potential causes. Until now only two genes, PLXND1 and REV3L have been identified to cause MBS.

Results: We present a 9-year-old male clinically diagnosed with MBS, presenting facial palsy, altered ocular mobility, microglossia, dental anomalies and congenital torticollis. Radiologically, he lacks both abducens nerves and shows altered symmetry of both facial and vestibulocochlear nerves. Whole-exome sequence identified a de novo missense variant c.643G>A; p.Gly215Arg in CHN1, encoding the α2-chimaerin protein. The p.Gly215Arg variant is located in the C1 domain of CHN1 where other pathogenic gain of function variants have been reported. Bioinformatic analysis and molecular structural modelling predict a deleterious effect of the missense variant on the protein function.

Conclusion: Our findings support that pathogenic variants in the CHN1 gene may be responsible for different cranial congenital dysinnervation syndromes, including Moebius and Duane retraction syndromes. We propose to include CHN1 in the genetic diagnoses of MBS.
Environmental DNA metabarcoding of foraminifera for biological monitoring of bottom water and sediments on the Takuyo-Daigo Seamount in the northwestern Pacific
Authors: Maeda Ayumi , Nishijima Miyuki , Iguchi Akira , Ota Yuki , Suzumura Masahiro , Suzuki Atsushi
Published: January 2024

Foraminifera are adapted to a wide range of environments, and environmental DNA (eDNA) metabarcoding of foraminifera should facilitate development of new environmental indicators. In this study, we used eDNA metabarcoding to evaluate the discrepancy between planktic and benthic foraminifera molecular communities identified in bottom water and short sediment cores. The molecular community was compared to foraminiferal shells in sediment traps set on the seafloor. Samples were collected in June and August around the Takuyo-Daigo Seamount in the western subtropical Pacific Ocean. Approximately 40% of amplicon sequence variants (ASVs) pertained to unknown foraminiferal lineages in sediment samples, compared with only 22% in bottom water. Bottom water contained benthic foraminifera and taxonomically unassigned lineages, which were attributed to resuspended particles. In bottom water, 100 ASVs were assigned to planktic foraminifera. ASVs assigned to Candeina nitida were most abundant and accounted for 36%–86% of planktic foraminiferal ASVs. In sedimentary DNA, Globigerinita glutinata was the most abundant among 33 ASVs of planktic foraminifera. However, transparent shells in sediment traps contained more spinose species, such as Globigerinoides ruber, whereas C. nitida was not found and few G. glutinata were detected. This discrepancy between the three samples may be due to the species-specific preservation, to polymerase chain reaction biases, and/or to low abundance of planktic foraminifers. In sedimentary DNA, 893 ASVs were assigned to high-level foraminiferal taxa. Among benthic foraminiferal lineages, monothalamids were most abundant, as reported in other deep-sea regions. Molecular communities formed one cluster above the boundary at which ASVs sharply decrease across the three cores. Our results suggest that depth within the sediment core can affect foraminiferal ASVs, but the distance between sites up to 200 m did not strongly affect ASVs of sedimentary DNA at least above the boundary at which ASVs sharply decrease. Sequences of foraminiferal DNA in sediment decreased linearly in core PC02-A1, but exponentially in core PC03-B3. The decline of foraminiferal ASVs may reflect both the decreases in numbers of living foraminifera and degradation of DNA in sediment, related to the particle mixing depth.
A comparison of adenosine triphosphate with other metrics of microbial biomass in a gradient from the North Atlantic to the Chesapeake Bay
Authors: Bochdansky Alexander B. , Beecher Amber A. , Calderon Joshua R. , Stouffer Alison N. , Washington NyJaee N.
Published: January 2024

A new, simplified protocol for determining particulate adenosine triphosphate (ATP) levels allows for the assessment of microbial biomass distribution in aquatic systems at a high temporal and spatial resolution. A comparison of ATP data with related variables, such as particulate carbon, nitrogen, chlorophyll, and turbidity in pelagic samples, yielded significant and strong correlations in a gradient from the tributaries of the Chesapeake Bay (sigma-t = 8) to the open North Atlantic (sigma-t = 29). Correlations varied between ATP and biomass depending on the microscopic method employed. Despite the much greater effort involved, biomass determined by microscopy correlated poorly with other indicator variables including carbon, nitrogen, and chlorophyll. The ATP values presented here fit well within the range of ATP biomass estimates in the literature for similar environments. A compilation of prior research data from a wide range of marine habitats demonstrated that ATP values can be ranked according to broad trophic gradients, from the deep sea to eutrophic inland waters. Using a mass-based conversion factor of 250, the contribution of biomass to overall particulate organic carbon (POC) ranged from 15% to 30% along the gradient, from the open ocean to locations in the Chesapeake Bay respectively. Our data corroborate the notion that ATP, due to its consistency and simplicity, is a promising high-throughput indicator of cytoplasm volume with distinct benefits over cell counts and measures of chlorophyll or POC.
Trichoderma spp. promotes ginseng biomass by influencing the soil microbial community
Authors: Zhang Linlin , Jin Qiao , Guan Yiming , Liu Zhengbo , Pan Xiaoxi , Zhang Yue , Zhang Yayu , Wang Qiuxia
Published: January 2024

Introduction

Ginseng (Panax ginseng C.A. Meyer) has multiple effects on human health; however, soil degradation seriously affects its yield. Trichoderma spp. play an important role in improving plant biomass by influencing the soil environment. Therefore, it is necessary to screen efficient Trichoderma strains that can increase ginseng biomass and determine their mechanisms.

Methods

Herein, we selected six Trichoderma species (T. brevicompactum, T. velutinum, T. viridescens, T. atroviride, T. koningiopsis, and T. saturnisporum) isolated from ginseng rhizosphere soil, and evaluated their growth promoting effects on ginseng and their influence on the microbiome and chemical attributes of the ginseng rhizosphere soil.

Results

Except for T. saturnisporum (F), compared with the control, the other five species increased ginseng biomass. In terms of chemical properties, the pH value, available potassium content, and available phosphorus content in the ginseng rhizosphere soil increased by 1.16–5.85%, 0.16–14.03%, and 3.92–38.64%, respectively, after root irrigation with spores of Trichoderma species. For the soil microbiome, fungal Chao1 and Ace richness indices decreased. Application of Trichoderma enhanced the relative level of Proteobacteria, but reduced the relative level of Ascomycota. At the genus level, application of Trichoderma enhanced the relative levels of Sphingomonas, Blastomonas, and Trichoderma, but reduced the relative level of Fusarium. Available K and available P were the most important elements that affected the structure of the bacterial community, while total K was the most influential element for the structure of the fungal community structure.

Conclusion

The results indicated that the application of Trichoderma spp. could increase soil nutrients and regulate the structure and composition of the soil microbial community, thereby enhancing the biomass of ginseng. The results will provide guidance for soil improvement in ginseng cultivation.
Development of a minimal PBPK-QSP modeling platform for LNP-mRNA based therapeutics to study tissue disposition and protein expression dynamics
Authors: Miyazawa Kenji , Liu Yun , Bazzazi Hojjat
Published: January 2024

Physiologically based pharmacokinetic models have gained significant recognition as effective mathematical models that enable deeper mechanistic investigation of drug delivery and tissue disposition. Here we describe the development of a platform PBPK-quantitative systems pharmacology (QSP) model to study tissue delivery of lipid nanoparticle (LNP) based mRNA therapeutics. The model is calibrated to published data in the context of Crigler-Najjar syndrome. Sensitivity analyses were performed to explore factors that influence protein expression and pharmacodynamic response following LNP-mRNA liver disposition. The most sensitive determinants of protein exposures were mRNA stability, translation, and cellular uptake rate, while the liver influx rate of lipid nanoparticle did not appreciably impact protein expression. Indeed, protein expression level may be tuned by modulation of mRNA degradation rate. However, simulations predicted that when the intrinsic half-life of the translated protein falls below a certain threshold, lowering mRNA degradation rate may not rescue protein exposure, a design feature that should be considered in optimal design of mRNA therapeutics. Additionally, interplay of LNP degradation rate and mRNA escape rate from endosomes was found to be crucial in modulation of protein expression. Simulations predicted that at a given LNP degradation rate, protein exposure varied linearly with mRNA escape rate. We further extended the model by incorporating LNP recycling to identify conditions necessary for observing a second peak in mRNA pharmacokinetics (PK). Simulations predict that with a fast recycling and slow tissue re-uptake rates, a robust second peak is observed in the plasma mRNA concentration curve. The amplitude and timing of the second peak could be tuned with recycling and re-uptake rates. Modeling results indicate that within the context of non-secreted mRNA mediated enzyme replacement therapy, recycling may depress or improve protein exposure depending on the re-uptake rate of the recycled LNP. The model is subsequently used to generate virtual animal cohorts to investigate optimal dosing and schedule of the compound. Virtual instances of the model were then employed to identify design principles that potentially reduce dosing frequency while maintaining efficacy. This study demonstrates the potential applications of coupled PBPK-QSP model for LNP based mRNA therapeutics as a translational platform.
Research on eight machine learning algorithms applicability on different characteristics data sets in medical classification tasks
Authors: Zhang Yiyan , Li Qin , Xin Yi
Published: January 2024

With the vigorous development of data mining field, more and more algorithms have been proposed or improved. How to quickly select a data mining algorithm that is suitable for data sets in medical field is a challenge for some medical workers. The purpose of this paper is to study the comparative characteristics of the general medical data set and the general data sets in other fields, and find the applicability rules of the data mining algorithm suitable for the characteristics of the current research data set. The study quantified characteristics of the research data set with 26 indicators, including simple indicators, statistical indicators and information theory indicators. Eight machine learning algorithms with high maturity, low user involvement and strong family representation were selected as the base algorithms. The algorithm performances were evaluated by three aspects: prediction accuracy, running speed and memory consumption. By constructing decision tree and stepwise regression model to learn the above metadata, the algorithm applicability knowledge of medical data set is obtained. Through cross-verification, the accuracy of all the algorithm applicability prediction models is above 75%, which proves the validity and feasibility of the applicability knowledge.
Insights into refractory chronic inflammatory demyelinating polyneuropathy: a comprehensive real-world study
Authors: Zheng Yongsheng , Hu Jianian , Sun Chong , Qiao Kai , Zhao Yanyin , Liu Bingyou , Sun Jian , Xi Jianying , Luo Sushan , Lu Jiahong , Zhao Chongbo , Lin Jie
Published: January 2024

Background

Refractory chronic inflammatory demyelinating polyneuropathy (CIDP) is a challenging subset of CIDP. It does not respond well to immune therapy and causes substantial disability. A comprehensive understanding of its clinical profile, electrophysiological characteristics and potential risk factors associated with refractoriness remains to be further elucidated.

Methods

Data in this cross-sectional study was collected and reviewed from the Huashan Peripheral Neuropathy Database (HSPN). Included patients were categorized into refractory CIDP and non-refractory CIDP groups based on treatment response. The clinical and electrophysiological characteristics were compared between refractory and non-refractory CIDP groups. Potential risk factors associated with refractory CIDP were explored with a multivariate logistic regression model.

Results

Fifty-eight patients with CIDP were included. Four disease course patterns of refractory CIDP are described: a relapsing–remitting form, a stable form, a secondary progressive form and a primary progressive form. Compared to non-refractory CIDP patients, refractory CIDP exhibited a longer disease duration (48.96 ± 33.72 vs. 28.33 ± 13.72 months, p = 0.038) and worse functional impairment (MRC sum score, 46.08 ± 12.69 vs. 52.81 ± 7.34, p = 0.018; mRS, 2.76 ± 0.93 vs. 2.33 ± 0.99, p = 0.082; INCAT, 3.68 ± 1.76 vs. 3.03 ± 2.28, p = 0.056, respectively). Electrophysiological studies further revealed greater axonal impairment (4.15 ± 2.0 vs. 5.94 ± 2.77 mv, p = 0.011, ulnar CMAP) and more severe demyelination (5.56 ± 2.86 vs. 4.18 ± 3.71 ms, p = 0.008, ulnar distal latency, 7.94 ± 5.62 vs. 6.52 ± 6.64 ms, p = 0.035, median distal latency; 30.21 ± 12.59 vs. 37.48 ± 12.44 m/s, p = 0.035, median conduction velocity; 58.66 ± 25.73 vs. 42.30 ± 13.77 ms, p = 0.033, median F-wave latency), compared to non-refractory CIDP. Disease duration was shown to be an independent risk factor for refractory CIDP (p < 0.05, 95%CI [0.007, 0.076]).

Conclusion

This study provided a comprehensive description of refractory CIDP, addressing its clinical features, classification of clinical course, electrophysiological characteristics, and prognostic factors, effectively elucidating its various aspects. These findings contribute to a better understanding of this challenging subset of CIDP and might be informative for management and treatment strategies.
Case report: A lung squamous cell carcinoma patient with a rare EGFR G719X mutation and high PD-L1 expression showed a good response to anti-PD1 therapy
Authors: Zhu Zhen-feng , Bao Xu-xia , Shi Hong-yan , Gu Xi-xi
Published: January 2024

Lung cancer treatment has transitioned fully into the era of immunotherapy, yielding substantial improvements in survival rate for patients with advanced non-small cell lung cancer (NSCLC). In this report, we present a case featuring a rare epidermal growth factor receptor (EGFR) mutation accompanied by high programmed death-ligand 1 (PD-L1) expression, demonstrating remarkable therapeutic efficacy through a combination of immunotherapy and chemotherapy. A 77-year-old male with no family history of cancer suffered from upper abdominal pain for more than half months in August 2020 and was diagnosed with stage IV (cT3N3M1c) lung squamous cell carcinoma (LUSC) harboring both a rare EGFR p.G719C mutation and high expression of PD-L1 (tumor proportion score [TPS] = 90%). Treatment with the second-generation targeted therapy drug Afatinib was initiated on September 25, 2020. However, resistance ensued after 1.5 months of treatment. On November 17, 2020, immunotherapy was combined with chemotherapy (Sintilimab + Albumin-bound paclitaxel + Cisplatin), and a CT scan conducted three months later revealed significant tumor regression with a favorable therapeutic effect. Subsequently, the patient received one year of maintenance therapy with Sintilimab, with follow-up CT scans demonstrating subtle tumor shrinkage (stable disease). This case provides evidence for the feasibility and efficacy of immunotherapy combined with chemotherapy in the treatment of EGFR-mutated and PD-L1 highly expressed LUSC.
Roles of transmembrane protein 135 in mitochondrial and peroxisomal functions - implications for age-related retinal disease
Authors: Landowski Michael , Gogoi Purnima , Ikeda Sakae , Ikeda Akihiro
Published: January 2024

Aging is the most significant risk factor for age-related diseases in general, which is true for age-related diseases in the eye including age-related macular degeneration (AMD). Therefore, in order to identify potential therapeutic targets for these diseases, it is crucial to understand the normal aging process and how its mis-regulation could cause age-related diseases at the molecular level. Recently, abnormal lipid metabolism has emerged as one major aspect of age-related symptoms in the retina. Animal models provide excellent means to identify and study factors that regulate lipid metabolism in relation to age-related symptoms. Central to this review is the role of transmembrane protein 135 (TMEM135) in the retina. TMEM135 was identified through the characterization of a mutant mouse strain exhibiting accelerated retinal aging and positional cloning of the responsible mutation within the gene, indicating the crucial role of TMEM135 in regulating the normal aging process in the retina. Over the past decade, the molecular functions of TMEM135 have been explored in various models and tissues, providing insights into the regulation of metabolism, particularly lipid metabolism, through its action in multiple organelles. Studies indicated that TMEM135 is a significant regulator of peroxisomes, mitochondria, and their interaction. Here, we provide an overview of the molecular functions of TMEM135 which is crucial for regulating mitochondria, peroxisomes, and lipids. The review also discusses the age-dependent phenotypes in mice with TMEM135 perturbations, emphasizing the importance of a balanced TMEM135 function for the health of the retina and other tissues including the heart, liver, and adipose tissue. Finally, we explore the potential roles of TMEM135 in human age-related retinal diseases, connecting its functions to the pathobiology of AMD.
Generation and characterization of a zebrafish gain-of-function ACOX1 Mitchell disease model
Authors: Raas Quentin , Wood Austin , Stevenson Tamara J. , Swartwood Shanna , Liu Suzanne , Kannan Rangaramanujam M. , Kannan Sujatha , Bonkowsky Joshua L.
Published: January 2024

Background

Mitchell syndrome is a rare, neurodegenerative disease caused by an ACOX1 gain-of-function mutation (c.710A>G; p.N237S), with fewer than 20 reported cases. Affected patients present with leukodystrophy, seizures, and hearing loss. ACOX1 serves as the rate-limiting enzyme in peroxisomal beta-oxidation of very long-chain fatty acids. The N237S substitution has been shown to stabilize the active ACOX1 dimer, resulting in dysregulated enzymatic activity, increased oxidative stress, and glial damage. Mitchell syndrome lacks a vertebrate model, limiting insights into the pathophysiology of ACOX1-driven white matter damage and neuroinflammatory insults.

Methods

We report a patient presenting with rapidly progressive white matter damage and neurological decline, who was eventually diagnosed with an ACOX1 N237S mutation through whole genome sequencing. We developed a zebrafish model of Mitchell syndrome using transient ubiquitous overexpression of the human ACOX1 N237S variant tagged with GFP. We assayed zebrafish behavior, oligodendrocyte numbers, expression of white matter and inflammatory transcripts, and analysis of peroxisome counts.

Results

The patient experienced progressive leukodystrophy and died 2 years after presentation. The transgenic zebrafish showed a decreased swimming ability, which was restored with the reactive microglia-targeted antioxidant dendrimer-N-acetyl-cysteine conjugate. The mutants showed no effect on oligodendrocyte counts but did display activation of the integrated stress response (ISR). Using a novel SKL-targeted mCherry reporter, we found that mutants had reduced density of peroxisomes.

Conclusions

We developed a vertebrate (zebrafish) model of Mitchell syndrome using transient ubiquitous overexpression of the human ACOX1 N237S variant. The transgenic mutants exhibited motor impairment and showed signs of activated ISR, but interestingly, there were no changes in oligodendrocyte counts. However, the mutants exhibited a deficiency in the number of peroxisomes, suggesting a possible shared mechanism with the Zellweger spectrum disorders.
Barriers, enablers and motivators of the “I’m an active Hero” physical activity intervention for preschool children: a qualitative study
Authors: Al-walah Mosfer A. , Donnelly Michael , Heron Neil
Published: January 2024

Background

Insufficient physical activity (PA) in early childhood is linked to adverse health outcomes and a heightened risk of obesity. Successful PA programmes often require input from key stakeholders, such as parents and educators. However, research on stakeholders’ perspectives regarding PA programmes for preschool children is limited, impeding effective programme design and implementation.

Objectives

This study aims to explore the perspectives of key stakeholders to gain insights into the challenges, facilitators, and motivators that influence the planning, execution, and sustainability of the “I'm an Active Hero (IAAH) intervention component,” a preschool-based initiative designed to promote PA among young children.

Methods

Semi-structured interviews were conducted in Saudi Arabia with individual preschool principals (n = 2), and focus group discussions were held, respectively, with preschool staff members (n = 4, all female) and parents (4 mothers, 5 fathers).

Results

A thematic analysis identified four main themes: (1) Barriers to parental involvement in preschool PA interventions, such as time constraints, lack of flexibility, limited space, and a shortage of trained staff; (2) Risks and benefits of children's programme participation; (3) Motivators including rewards, non-financial incentives, and concerns about childhood obesity and a sedentary lifestyle; (4) Facilitating factors for overcoming barriers, including staff training, time reallocation, staff coordination, space optimization, non-financial incentives, and sustaining partnerships.

Conclusion

This study's findings are crucial for childcare professionals, preschools, education authorities, and policymakers, offering valuable insights for future research. However, further collaboration with key stakeholders is essential to enhance individual attitudes and preschool policies for effective intervention implementation.
Chaihu Shugan prevents cholesterol gallstone formation by ameliorating the microbiota dysbiosis and metabolic disturbance in mice
Authors: Wang Wei , Zhang Kun , Liu Bin , Zhou Tong , Tang Yu , Li Yuliang
Published: January 2024

Introduction: Cholesterol gallstone (CGS) is a biliary tract disorder requiring treatment in approximately 20% of patients. The efficacy of Chaihu Shugan in preventing CGS recurrence after successful treatment remains uncertain.

Methods: We examined the in vivo preventive efficacy of Chaihu Shugan using a CGS mouse model and used multi-omics to study the interplay between gut microbiota, metabolism, and gene expression.

Results: The intestinal microbiota was severely dysregulated during the formation of CGS, showing a marked decrease in the abundance of beneficial microbiota, especially Lactobacillus and Akkermansia. Chaihu Shugan prevented CGS formation by restoring the composition of the gut microbiota and reversing the metabolic disturbances caused by dysbiosis. This preventive effect of Chaihu Shugan was paralleled by changes in the expression of metabolism-related genes in the liver. A network pharmacology analysis of Chaihu Shugan revealed that obacunone may be the key active metabolite in regulating bile acid metabolism. Multi-omics and correlation analyses elucidated the interplay between gut microbiota, metabolism, and gene alterations in the dose-dependent effect of Chaihu Shugan.

Conclusion: Our data show that Chaihu Shugan can prevent CGS and indicate its mechanisms of action.
Contrastive analysis on the safety of brand and generic nebivolol: a real-world pharmacovigilance study based on the FDA adverse event reporting system
Authors: Wang Hongli , Zhong Guizun , Ji Huanhuan , Chen Siqi , Xie Qinqin , Shen Zhengze , Jia Yuntao
Published: January 2024

Background:The equivalence of generic drugs to their brand-name counterparts is a controversial issue. Current literature indicates disparities between the generic nebivolol (GN) and the brand nebivolol (BN).

Aim:The study is designed to investigate the safety difference between GN and BN and provide reference information for clinical practice.

Methods:We reviewed adverse event (AE) reports that recorded nebivolol as the primary suspect drug in the FDA Adverse Event Reporting System (FAERS) database from 2004 to 2022, conducted a disproportional analysis to detect signals for the GN and BN respectively, and compared the AE heterogeneity between them using the Breslow-Day test.

Results:A total of 2613 AE reports of nebivolol were recorded in the FAERS database from 2004 to 2022, of which 2,200 were classified as BN, 346 as GN, and 67 unclassifiable AE reports were excluded. The signals of 37 AEs distributed in cardiac, gastrointestinal, psychiatric, and nervous systems were detected in disproportional analysis. 33 out of 37 AEs were positive signals, with 21 not previously listed on the drug label, indicating an unrecognized risk with nebivolol. In the heterogeneity analysis of AE signals between GN and BN, the GN generally showed a higher AE signal value than BN, especially 15 AEs distributed in the cardiac, neurological, and psychiatric systems that showed statistically significantly higher risk by taking GN.

Conclusion:Our study shows some previously overlooked adverse effects of nebivolol. It suggests that the risk of GN’s adverse effects may be higher than those in BN, which deserves further attention and investigation by healthcare professionals, regulators, and others.
From genomic spectrum of NTRK genes to adverse effects of its inhibitors, a comprehensive genome-based and real-world pharmacovigilance analysis
Authors: Cui Zhiwei , Zhai Zhen , Xie De , Wang Lihui , Cheng Feiyan , Lou Siyu , Zou Fan , Pan Rumeng , Chang Shixue , Yao Haoyan , She Jing , Zhang Yidan , Yang Xinyuan
Published: January 2024

Introduction: The discovery of neurotrophic tyrosine receptor kinase (NTRK) gene fusions has facilitated the development of precision oncology. Two first-generation NTRK inhibitors (larotrectinib and entrectinib) are currently approved for the treatment of patients with solid tumors harboring NTRK gene fusions. Nevertheless, comprehensive NTRK profiling at the pan-cancer genomic level and real-world studies pertaining to the adverse events of NTRK inhibitors are lacking.

Methods: We characterize the genome of NTRK at the pan-cancer level through multi-omics databases such as The Cancer Genome Atlas (TCGA). Through the FDA Adverse Event Reporting System (FAERS) database, we collect reports of entrectinib and larotrectinib-induced adverse events and perform a pharmacovigilance analysis using various disproportionality methods.

Results:NTRK1/2/3 expression is lower in most tumor tissues, while they have higher methylation levels. NTRK gene expression has prognostic value in some cancer types, such as breast invasive carcinoma (BRCA). The cancer type with highest NTRK alteration frequency is skin cutaneous melanoma (SKCM) (31.98%). Thyroid carcinoma (THCA) has the largest number of NTRK fusion cases, and the most common fusion pair is ETV6-NTRK3. Adverse drug events (ADEs) obtained from the FAERS database for larotrectinib and entrectinib are 524 and 563, respectively. At the System Organ Class (SOC) level, both drugs have positive signal value for “nervous system disorder”. Other positive signals for entrectinib include “cardiac disorders”, “metabolism and nutrition disorders”, while for larotrectinib, it is “hepatobiliary disorders”. The unexpected signals are also listed in detail. ADEs of the two NTRK inhibitors mainly occur in the first month. The median onset time of ADEs for entrectinib and larotrectinib was 16 days (interquartile range [IQR] 6–86.5) and 44 days ([IQR] 7–136), respectively.

Conclusion: Our analysis provides a broad molecular view of the NTRK family. The real-world adverse drug event analysis of entrectinib and larotrectinib contributes to more refined medication management.
The crisis is over, long live the crisis: mental health in emerging adulthood during the course of the COVID-19 pandemic
Authors: Wirkner Janine , Brakemeier Eva-Lotta
Published: January 2024

Introduction

As a multidimensional stressor, the COVID-19 pandemic posed a significant threat to mental health, with studies showing younger age groups to be particularly vulnerable. Thus, this study aimed to monitor mental health, potential risk/protective factors, and pandemic-related variables among young university students during the pandemic.

Methods

Students of the University of Greifswald (M age = 23.0 years, 73.9% female) participated in five cross-sectional online surveys in December 2020 (N = 1,127), March 2021 (N = 760), June/July 2021 (N = 531), December 2021 (N = 1,226), and December 2022 (N = 814). Sociodemographic data, depression and anxiety severity, loneliness, quality of life, coping strategies, resilience, self-esteem, and emotion regulation were measured. First, results from December 2020 were compared to pre-pandemic normative data. Second, the time course during the pandemic was analyzed. Third, linear models were calculated to examine the influence of risk and protective factures on depression and anxiety severity.

Results

Higher levels of depression, anxiety, and loneliness, as well as lower levels of self-esteem, physical and mental health, social relationships and well-being were found in December 2020 compared to pre-pandemic. Levels of depression and anxiety severity peaked in December 2022. Female sex, loneliness, and previous mental treatment showed associations with higher depression and anxiety severity, while higher self-esteem, resilience and use of reappraisal strategies appeared to act as protective factors.

Discussion

The study indicates the pandemic’s detrimental impact on students’ mental health and quality of life. Identified risk and protective factors provide guidance for tailored prevention and treatment, as well as the design of measures for future pandemics and other crisis.