bluuebunny/crossref_metadata_2025 huggingface dataset:
Hepcidin Gene Co-Option Balancing Paternal Immune Protection and Male Pregnancy
Authors: Xiao Wanghong , Chen Zelin , Zhang Yanhong , Wu Yongli , Jiang Han , Zhang Huixian , Qu Meng , Lin Qiang , Qin Geng
Published: April 2022

Viviparity has originated independently more than 150 times in vertebrates, while the male pregnancy only emerged in Syngnathidae fishes, such as seahorses. The typical male pregnancy seahorses have closed sophisticated brood pouch that act as both uterus and placenta, representing an excellent model system for studying the evolutionary process of paternal immune protection. Phylogenetic analysis indicated that the hampII gene family has multiple tandem duplicated genes and shows independent lineage-specific expansion in seahorses, and they had the highest ratio of nonsynonymous substitutions to synonymous substitutions (dN/dS) in the seahorse phylogenetic branch. The expression levels of hampIIs in the brood pouch placenta were significantly higher during pregnancy than non-pregnancy. Both LPS stimulation test in vivo and cytotoxicity test in vitro proved the immunological protection function of hampIIs against pathogen infection in seahorse. Besides, seahorse hampII peptides exhibit weaker antibacterial function, but stronger agglutination and free endotoxin inhibition. We assumed that the modified immunological function seemed to be a trade-off between the resistance to microbial attack and offspring protection. In brief, this study suggests that the rapid co-option of hampIIs contributes to the evolutionary adaption to paternal immune care during male pregnancy.
Concentration of Serum Matrix Metalloproteinase-3 in Patients With Primary Biliary Cholangitis
Authors: Bauer Alicja , Habior Andrzej
Published: April 2022

Background and Aims

Metalloproteinases (MMPs) are involved in many distinct processes in the liver. Matrix metalloproteinase-3 (MMP-3) plays an important role in connective tissue remodeling, degradation of collagen (types II, III, IV, IX, and X), proteoglycans, fibronectin, laminin, and elastin. In addition, MMP-3 can also activate other MMPs such as MMP-1, MMP-7, and MMP-9. Primary biliary cholangitis (PBC) is a cholestatic, autoimmune liver disease, characterized by the progressive destruction of intrahepatic bile ducts, leading to cholestasis, fibrosis, cirrhosis, and liver failure. Fibrosis is the result of an imbalance between production and degradation of the extracellular matrix surrounding hepatocytes. Our aim in the present study was to determine whether the measurement of serum MMP-3 is clinically useful for assessing ongoing liver fibrosis in patients with PBC.

Methods

The MMP-3 concentration was determined in 182 PBC patients and 80 non-PBC controls using a commercially available ELISA kit.

Results

Higher concentrations of MMP-3 were found in 61% of PBC patients. PBC subjects had greater MMP-3 levels than controls: 68.9 ± 62.6 vs 21.3 ± 7.4 ng/mL, p < 0.001 for healthy subjects; 68.9 ± 62.6 vs 22.7 ± 7.6 ng/mL, p = 0.022 for autoimmune hepatitis controls; and 68.9 ± 62.6 vs 37.2 ± 17.4 ng/mL, p = 0.002 for primary sclerosing cholangitis controls. The serum MMP-3 concentration was significantly elevated in patients with higher bilirubin concentration (107.6 ± 85.8 vs 61.6 ± 46.1 ng/mL, p < 0.001) and was correlated with the level of antimitochondrial antibodies specific for PBC. The concentration of MMP-3 in sera of PBC patients was also found to correlate with the state of liver fibrosis (OR = 4.3; p < 0.01).

Conclusions

Our study demonstrated significantly higher MMP-3 levels in PBC patients than in healthy and pathological controls. Increased MMP-3 concentrations were positively correlated with various clinical and immunological parameters, and advanced liver fibrosis. The level of MMP-3 was associated with hepatic dysfunction and could play a role in the pathophysiology of hepatic fibrosis in PBC.
Trade-Offs and Synergies Between Seagrass Ecosystems and Fishing Activities: A Global Literature Review
Authors: Herrera Mariana , Tubío Ana , Pita Pablo , Vázquez Elsa , Olabarria Celia , Duarte Carlos M. , Villasante Sebastián
Published: April 2022

Seagrass ecosystems support human well-being by delivering a wide range of ecosystem services. Particularly important is the significant role they play in food provisioning by supporting fisheries worldwide. Despite their socio-economic importance, it is only recently when they have been considered as important social-ecological systems worldwide. Research focused on the interactions between seagrasses and human activities have been understudied and never addressed from a global approach, even though this knowledge is essential to create relevant policy and management plans, and to promote governance systems, which consider fishers’ needs and rights. Thus, we carried out a global systematic review on trade-offs and/or synergies between seagrasses and fishing activities, aiming to analyse the current state of the art on these interactions, to identify potential gaps in knowledge, and to pinpoint key research priorities. We found a total of 94 publications assessing the relationship between seagrass ecosystems and fisheries, which have tripled between 2001-2021, being most of them empirical studies (90%) with ecological scope (a total of 68). Socioeconomic studies (3%) on the subject were identified as a knowledge gap. Most studies (72%) were carried out in northern hemisphere countries, with an underrepresentation of studies in tropical regions. The studies reporting trade-off (a total of 69) interactions almost tripled those reporting synergies (a total of 31) between seagrass ecosystems and fisheries. Mechanical damage to seagrasses by fishing gear is the main source (51%) of trade-offs, followed by overfishing (28%), while aquaculture cages’ emissions (20%) are also a relevant source of trade-offs. Seafood market demand and conflicts of use were the main drivers for trade-offs. When assessing synergistic interactions, most studies (27 out of 31) reported a larger abundance or recruitment of species with commercial interest mediated by seagrass habitat provision. Globally, seagrass ecosystems are mainly affected by industrial and small-scale fisheries, including aquaculture and shellfisheries, and to a lesser extent, by recreational fisheries. Fisheries management system is not specified in more than half (53) of the reviewed publications, which represents a key knowledge gap with implications for sustainable management. Nevertheless, we document a fast increase in studies covering fishery-seagrass interactions, which, if accompanied by better reporting of the nature of the interactions and the socio-economic context of the fishery, would help improve the sustainable management of both systems.
COI Metabarcoding of Zooplankton Species Diversity for Time-Series Monitoring of the NW Atlantic Continental Shelf
Authors: Bucklin Ann , Batta-Lona Paola G. , Questel Jennifer M. , Wiebe Peter H. , Richardson David E. , Copley Nancy J. , O’Brien Todd D.
Published: April 2022

Marine zooplankton are rapid-responders and useful indicators of environmental variability and climate change impacts on pelagic ecosystems on time scales ranging from seasons to years to decades. The systematic complexity and taxonomic diversity of the zooplankton assemblage has presented significant challenges for routine morphological (microscopic) identification of species in samples collected during ecosystem monitoring and fisheries management surveys. Metabarcoding using the mitochondrial Cytochrome Oxidase I (COI) gene region has shown promise for detecting and identifying species of some – but not all – taxonomic groups in samples of marine zooplankton. This study examined species diversity of zooplankton on the Northwest Atlantic Continental Shelf using 27 samples collected in 2002-2012 from the Gulf of Maine, Georges Bank, and Mid-Atlantic Bight during Ecosystem Monitoring (EcoMon) Surveys by the NOAA NMFS Northeast Fisheries Science Center. COI metabarcodes were identified using the MetaZooGene Barcode Atlas and Database (https://metazoogene.org/MZGdb) specific to the North Atlantic Ocean. A total of 181 species across 23 taxonomic groups were detected, including a number of sibling and cryptic species that were not discriminated by morphological taxonomic analysis of EcoMon samples. In all, 67 species of 15 taxonomic groups had ≥ 50 COI sequences; 23 species had >1,000 COI sequences. Comparative analysis of molecular and morphological data showed significant correlations between COI sequence numbers and microscopic counts for 5 of 6 taxonomic groups and for 5 of 7 species with >1,000 COI sequences for which both types of data were available. Multivariate statistical analysis showed clustering of samples within each region based on both COI sequence numbers and EcoMon counts, although differences among the three regions were not statistically significant. The results demonstrate the power and potential of COI metabarcoding for identification of species of metazoan zooplankton in the context of ecosystem monitoring.
A Delphi Based Approach to the Assessment of New Marine Litter Reduction and Processing Technologies
Authors: Cunha Maria C. , Marques João , Dias Luis C. , Cotera Ignacio Rada , Triantaphyllidis George
Published: April 2022

This work presents the most important aspects that should be considered for assessing new marine litter reduction and processing technologies. The most relevant technology features are highlighted using a Delphi method capable of gathering and handling a large quantity of valuable data in areas where information is lacking. This relies on judgements provided by recognized experts in a particular area of knowledge, through an organized procedure based on a structured questionnaire and its reiterations. The Delphi process developed in this study completed two rounds. In the first round, a questionnaire with 55 statements (potentially important aspects) was shared with experts and stakeholders from different types of institutions (Administrations, Marinas and Ports; Associations; Companies; Universities; and Research Centers). Appropriate statistical analysis of the responses determined the degree of consensus and the level of importance perceived for each aspect. Feedback information based on analysis of the answers provided during the first round was included in a second round of the survey that focused on the statements that did not gather enough consensus, and therefore needed to be reevaluated by the expert group. After checking the stability of the results between rounds, the conclusions are set out and a list of the aspects to be considered in different decision-making contexts is drawn (from technology development, investment to marketing and policy making) taking into account technical, environmental, socio-economic, and political issues.
Predictive Utility of Mortality by Aging Measures at Different Hierarchical Levels and the Response to Modifiable Life Style Factors: Implications for Geroprotective Programs
Authors: Zhang Jingyun , Cao Xingqi , Chen Chen , He Liu , Ren Ziyang , Xiao Junhua , Han Liyuan , Wu Xifeng , Liu Zuyun
Published: April 2022

Background

Aging, as a multi-dimensional process, can be measured at different hierarchical levels including biological, phenotypic, and functional levels. The aims of this study were to: (1) compare the predictive utility of mortality by three aging measures at three hierarchical levels; (2) develop a composite aging measure that integrated aging measures at different hierarchical levels; and (3) evaluate the response of these aging measures to modifiable life style factors.

Methods

Data from National Health and Nutrition Examination Survey 1999–2002 were used. Three aging measures included telomere length (TL, biological level), Phenotypic Age (PA, phenotypic level), and frailty index (FI, functional level). Mortality information was collected until December 2015. Cox proportional hazards regression and multiple linear regression models were performed.

Results

A total of 3,249 participants (20–84 years) were included. Both accelerations (accounting for chronological age) of PA and FI were significantly associated with mortality, with HRs of 1.67 [95% confidence interval (CI) = 1.41–1.98] and 1.59 (95% CI = 1.35–1.87), respectively, while that of TL showed non-significant associations. We thus developed a new composite aging measure (named PC1) integrating the accelerations of PA and FI, and demonstrated its better predictive utility relative to each single aging measure. PC1, as well as the accelerations of PA and FI, were responsive to several life style factors including smoking status, body mass index, alcohol consumption, and leisure-time physical activity.

Conclusion

This study demonstrates that both phenotypic (i.e., PA) and functional (i.e., FI) aging measures can capture mortality risk and respond to modifiable life style factors, despite their inherent differences. Furthermore, the PC1 that integrated phenotypic and functional aging measures outperforms in predicting mortality risk in comparison with each single aging measure, and strongly responds to modifiable life style factors. The findings suggest the complementary of aging measures at different hierarchical levels and highlight the potential of life style-targeted interventions as geroprotective programs.
Deep Learning-Based Universal Expert-Level Recognizing Pathological Images of Hepatocellular Carcinoma and Beyond
Authors: Chen Wei-Ming , Fu Min , Zhang Cheng-Ju , Xing Qing-Qing , Zhou Fei , Lin Meng-Jie , Dong Xuan , Huang Jiaofeng , Lin Su , Hong Mei-Zhu , Zheng Qi-Zhong , Pan Jin-Shui
Published: April 2022

Background and Aims

We aim to develop a diagnostic tool for pathological-image classification using transfer learning that can be applied to diverse tumor types.

Methods

Microscopic images of liver tissue with and without hepatocellular carcinoma (HCC) were used to train and validate the classification framework based on a convolutional neural network. To evaluate the universal classification performance of the artificial intelligence (AI) framework, histological images from colorectal tissue and the breast were collected. Images for the training and validation sets were obtained from the Xiamen Hospital of Traditional Chinese Medicine, and those for the test set were collected from Zhongshan Hospital Xiamen University. The accuracy, sensitivity, and specificity values for the proposed framework were reported and compared with those of human image interpretation.

Results

In the human–machine comparisons, the sensitivity, and specificity for the AI algorithm were 98.0, and 99.0%, whereas for the human experts, the sensitivity ranged between 86.0 and 97.0%, while the specificity ranged between 91.0 and 100%. Based on transfer learning, the accuracies of the AI framework in classifying colorectal carcinoma and breast invasive ductal carcinoma were 96.8 and 96.0%, respectively.

Conclusion

The performance of the proposed AI framework in classifying histological images with HCC was comparable to the classification performance achieved by human experts, indicating that extending the proposed AI’s application to diagnoses and treatment recommendations is a promising area for future investigation.
Prevalence of Prefrailty and Frailty Among Older Adults in Germany: A Systematic Review, Meta-Analysis and Meta-Regression
Authors: Hajek André , Kretzler Benedikt , König Hans-Helmut
Published: April 2022

Background

Various studies have identified the prevalence of prefrailty and frailty among older adults in Germany. Nevertheless, there is no review systematically synthesizing these studies. Thus, our aim was to close this gap in knowledge. Moreover, another aim was to perform a meta-analysis to synthesize the pooled prevalence of prefrailty and frailty. A further aim was to explore potential sources of heterogeneity based on a meta-regression.

Methods

A number of three electronic databases (PubMed, PsycINFO, and CINAHL) were searched (plus an additional hand search). The observational studies that determine the prevalence of frailty among older adults aged 65 years and above in Germany were included, whereas disease-specific samples were excluded. Data extraction included the description of the sample, operationalization of frailty, statistical analysis, sample characteristics and main findings. The established Joanna Briggs Institute (JBI) standardized critical appraisal instrument for prevalence studies was used for evaluating the quality of the studies. Important steps were performed by two reviewers.

Results

In sum, a number of 12 studies were included. The prevalence of frailty varied from about 2.4 to 25.6%. The pooled prevalence of frailty was 13.7% (95% CI: 9.0 to 18.5%). There was a significant heterogeneity among the studies (I2 = 98.9%, p < 0.001). The pooled prevalence of prefrailty was 40.2% (95% CI: 28.3 to 52.1%; I2 = 99.6%, p < 0.001). Some evidence of a publication bias exists. Meta-regressions showed that some of the heterogeneity was explained by the tool to quantify frailty and the average age of the respective sample.

Conclusion

Particularly, the high prevalence of prefrailty should be highlighted since it is important to prevent individuals in old age from developing to frail status. This knowledge is important for the German society as a whole and for relevant stakeholders.

Systematic Review Registration

PROSPERO, identifier: CRD42021293648.
Bacterial Community and Fermentation Quality of Ensiling Alfalfa With Commercial Lactic Acid Bacterial Additives
Authors: Na Na , Qili Moge , Wu Nier , Sun Lin , Xu Haiwen , Zhao Yi , Wei Xiaobin , Xue Yanlin , Tao Ya
Published: April 2022

The aim of this study was to determine the effects of six common commercial lactic acid bacteria (LAB) additives [A1, Lactobacillus plantarum, L. buchneri, and Enterococcus faecalis; A2, L. plantarum and L. casei; A3, L. plantarum and L. buchneri; A4, L. plantarum, L. buchneri, L. casei, and Pediococcus acidilactici; A5, L. plantarum (producing feruloyl esterase); and A6, L. buchneri, P. acidilactici, β-glucanase, and xylanase] on the bacterial community and fermentation quality of alfalfa silage. Alfalfa was harvested at the squaring stage, wilted in the field for 24 h, and ensiled without any additives (Control) or with A1, A2, A3, A4, A5, or A6. Microbial counts, bacterial community, fermentation parameters, and nutritional composition were determined after ensiling for 90 days. The total abundance of LAB genera on alfalfa pre-ensiling was 0.38% in bacterial community. The abundances of Lactobacillus, Enterococcus, and Pediococcus in the Control silage were 42.18, 40.18, and 8.09% of abundance, respectively. The abundances of Lactobacillus in A1-, A2-, A3-, A4-, and A5-treatments were 89.32, 92.93, 92.87, 81.12, and 80.44%, respectively. The abundances of Pediococcus and Lactobacillus in A6-treatment were 70.14 and 24.86%, respectively. Compared with Control silage, LAB-treated silage had lower pH and less ammonia nitrogen and water-soluble carbohydrates concentrations (p < 0.05). Further, the A5- and A6-treatments contained lower neutral detergent fiber, acid detergent fiber, and hemicellulose than other treatments (p < 0.05). Overall, LAB genera were presented as minor taxa in alfalfa pre-ensiling and as dominant taxa in alfalfa silage. Adding LAB additives improved the fermentation quality and altered the bacterial community of alfalfa silage. The main bacterial genera in Control silage were Lactobacillus, Enterococcus, and Pediococcus. Lactobacillus dominated the bacterial communities of A1-, A2-, A3-, A4-, and A5-treatments, while Pediococcus and Lactobacillus were dominant bacterial genera in A6-treatment. Inoculating A5 and A6 degraded the fiber in alfalfa silage. It is necessary to ensile alfalfa with LAB inoculants.
Physicochemical and Biological Insights Into the Molecular Interactions Between Extracellular DNA and Exopolysaccharides in Myxococcus xanthus Biofilms
Authors: Wang Yan , Li Tingyi , Xue Weiwei , Zheng Yue , Wang Yipeng , Zhang Ning , Zhao Yue , Wang Jing , Li Yuezhong , Wang Chuandong , Hu Wei
Published: April 2022

Extracellular DNA (eDNA) is a critical component in the extracellular matrix (ECM) of bacterial biofilms, while little is known about the mechanisms underlying how eDNA integrates into the ECM through potential macromolecular interactions. Myxococcus xanthus biofilm was employed as a suitable model for the investigation due to the co-distribution of eDNA and exopolysaccharides (EPS) owing to their direct interactions in the ECM. DNA is able to combine with M. xanthus EPS to form a macromolecular conjugate, which is dominated by the electrostatic forces participating in the polymer-polymer interactions. Without intercalation binding, DNA-EPS interactions exhibit a certain degree of reversibility. Acting as a strong extracellular framework during biofilm formation process, the eDNA-EPS complex not only facilitates the initial cell adhesion and subsequent establishment of ECM architecture, but also renders cells within biofilms stress resistances that are relevant to the survival of M. xanthus in some hostile environments. Furthermore, the EPS protects the conjugated DNA from the degradation by nucleic acid hydrolases, which leads to the continuous and stable existence of eDNA in the native ECM of M. xanthus biofilms. These results will shed light on developing prevention and treatment strategies against biofilm-related risks.
Neuronal Redevelopment and the Regeneration of Neuromodulatory Axons in the Adult Mammalian Central Nervous System
Authors: Cooke Patrick , Janowitz Haley , Dougherty Sarah E.
Published: April 2022

One reason that many central nervous system injuries, including those arising from traumatic brain injury, spinal cord injury, and stroke, have limited recovery of function is that neurons within the adult mammalian CNS lack the ability to regenerate their axons following trauma. This stands in contrast to neurons of the adult mammalian peripheral nervous system (PNS). New evidence, provided by single-cell expression profiling, suggests that, following injury, both mammalian central and peripheral neurons can revert to an embryonic-like growth state which is permissive for axon regeneration. This “redevelopment” strategy could both facilitate a damage response necessary to isolate and repair the acute damage from injury and provide the intracellular machinery necessary for axon regrowth. Interestingly, serotonin neurons of the rostral group of raphe nuclei, which project their axons into the forebrain, display a robust ability to regenerate their axons unaided, counter to the widely held view that CNS axons cannot regenerate without experimental intervention after injury. Furthermore, initial evidence suggests that norepinephrine neurons within the locus coeruleus possess similar regenerative abilities. Several morphological characteristics of serotonin axon regeneration in adult mammals, observable using longitudinal in vivo imaging, are distinct from the known characteristics of unaided peripheral nerve regeneration, or of the regeneration seen in the spinal cord and optic nerve that occurs with experimental intervention. These results suggest that there is an alternative CNS program for axon regeneration that likely differs from that displayed by the PNS.
Long-Term Potentiation-Like Visual Synaptic Plasticity Is Negatively Associated With Self-Reported Symptoms of Depression and Stress in Healthy Adults
Authors: Rygvold Trine Waage , Hatlestad-Hall Christoffer , Elvsåshagen Torbjørn , Moberget Torgeir , Andersson Stein
Published: April 2022

Long-term potentiation (LTP) is one of the most extensively studied forms of neuroplasticity and is considered the strongest candidate mechanism for memory and learning. The use of event-related potentials and sensory stimulation paradigms has allowed for the translation from animal studies to non-invasive studies of LTP-like synaptic plasticity in humans. Accumulating evidence suggests that synaptic plasticity as measured by stimulus-specific response modulation is reduced in neuropsychiatric disorders such as major depressive disorder (MDD), bipolar disorders and schizophrenia, suggesting that impaired synaptic plasticity plays a part in the underlying pathophysiology of these disorders. This is in line with the neuroplasticity hypothesis of depression, which postulate that deficits in neuroplasticity might be a common pathway underlying depressive disorders. The current study aims to replicate and confirm earlier reports that visual stimulus-specific response modulation is a viable probe into LTP-like synaptic plasticity in a large sample of healthy adults (n = 111). Further, this study explores whether impairments in LTP-like synaptic plasticity is associated with self-reported subclinical depressive symptoms and stress in a healthy population. Consistent with prior research, the current study replicated and confirmed reports demonstrating significant modulation of visual evoked potentials (VEP) following visual high-frequency stimulation. Current results further indicate that reduced LTP-like synaptic plasticity is associated with higher levels of self-reported symptoms of depression and perceived stress. This indicate that LTP-like plasticity is sensitive to sub-clinical levels of psychological distress, and might represent a vulnerability marker for the development of depressive symptoms.
Transcranial Magnetic Stimulation for Improving Dysphagia After Stroke: A Meta-Analysis of Randomized Controlled Trials
Authors: Xie Yu-lei , Wang Shan , Jia Jia-meng , Xie Yu-han , Chen Xin , Qing Wu , Wang Yin-xu
Published: April 2022

Background

Rehabilitation of post-stroke dysphagia is an urgent clinical problem, and repetitive transcranial magnetic stimulation (rTMS) has been widely used in the study of post-stroke function. However, there is no reliable evidence-based medicine to support the effect of rTMS on post-stroke dysphagia. This review aims to evaluate the effectiveness and safety of rTMS on post-stroke dysphagia.

Methods

English-language literature published before December 20, 2021, were searched in six electronic databases. Identified articles were screened, data were extracted, and the methodological quality of included trials was assessed. Meta-analysis was performed using RevMan 5.3 software. The GRADE method was used to assess the quality of the evidence.

Results

A total of 10 studies with 246 patients were included. Meta-analysis showed that rTMS significantly improved overall swallowing function (standardized mean difference [SMD]−0.76, 95% confidence interval (CI)−1.07 to−0.46, p < 0.0001, n = 206; moderate-quality evidence), Penetration Aspiration Scale (PAS) (mean difference [MD]−1.03, 95% CI−1.51 to−0.55, p < 0.0001, n = 161; low-quality evidence) and Barthel index scale (BI) (MD 23.86, 95% CI 12.73 to 34.99, p < 0.0001, n = 136; moderate-quality evidence). Subgroup analyses revealed that (1) rTMS targeting the affected hemisphere and targeting both hemispheres significantly enhanced overall swallowing function and reduced aspiration. (2) Low-frequency rTMS significantly enhanced overall swallowing function and reduced aspiration, and there was no significant difference between high-frequency rTMS and control group in reducing aspiration (p = 0.09). (3) There was no statistical difference in the dropout rate (low-quality evidence) and adverse effects (moderate-quality evidence) between the rTMS group and the control group.

Conclusion

rTMS improved overall swallowing function and activity of daily living ability and reduced aspiration in post-stroke patients with good acceptability and mild adverse effects.
Learning Deficits and Attenuated Adaptive Stress Response After Early-Life Seizures in Zebrafish
Authors: Singh Harsimran , Ramon Alfonsina , Finore Dana , Burnham Kaleigh , McRobert Scott , Lippman-Bell Jocelyn
Published: April 2022

Early-life seizures (ELS) are often associated with the development of cognitive deficits. However, methods to predict and prevent these deficits are lacking. To increase the range of research models available to study cognitive consequences of ELS, we investigated whether seizures in larval zebrafish (Danio rerio) lead to behavioral deficits later in life. We thus modified the existing pentylenetetrazole (PTZ)-induced seizure model in larval zebrafish, exposing zebrafish to PTZ daily from 5 to 7 days post-fertilization (dpf). We then compared later-life learning, social behavior (shoaling), and behavioral and chemical measures of anxiety in the PTZ-exposed zebrafish (PTZ group) to that of naïve clutchmates (untouched controls, UC) and to a second control group (handling control, HC) that experienced the same handling as the PTZ group, but without PTZ exposure. We observed that only the PTZ group displayed a significant deficit in a y-maze learning task, while only the HC group displayed a social deficit of decreased shoaling. HC fish also showed an increased frequency of behavioral freezing and elevated cortisol responses to netting, heightened stress responses not seen in the PTZ fish. Since mild stressors, such as the handling the HC fish experienced, can lead to learned, advantageous responses to stress later in life, we tested escape response in the HC fish using an acoustic startle stimulus. The HC group showed an enhanced startle response, swimming significantly farther than either the PTZ or UC group immediately after being startled. Taken together, these results indicate that seizures in larval zebrafish impair learning and the development of an adaptive, heightened stress response after early-life stress. These findings expand the behavioral characterization of the larval zebrafish seizure model, strengthening the power of this model for ELS research.
Prediction of Response to Induction Chemotherapy Plus Concurrent Chemoradiotherapy for Nasopharyngeal Carcinoma Based on MRI Radiomics and Delta Radiomics: A Two-Center Retrospective Study
Authors: Xi Yuzhen , Ge Xiuhong , Ji Haiming , Wang Luoyu , Duan Shaofeng , Chen Haonan , Wang Mengze , Hu Hongjie , Jiang Feng , Ding Zhongxiang
Published: April 2022

Objective

We aimed to establish an MRI radiomics model and a Delta radiomics model to predict tumor retraction after induction chemotherapy (IC) combined with concurrent chemoradiotherapy (CCRT) for primary nasopharyngeal carcinoma (NPC) in non-endemic areas and to validate its efficacy.

Methods

A total of 272 patients (155 in the training set, 66 in the internal validation set, and 51 in the external validation set) with biopsy pathologically confirmed primary NPC who were screened for pretreatment MRI were retrospectively collected. The NPC tumor was delineated as a region of interest in the two sequenced images of MRI before treatment and after IC, followed by radiomics feature extraction. With the use of maximum relevance minimum redundancy (mRMR) and least absolute shrinkage and selection operator (LASSO) algorithms, logistic regression was performed to establish pretreatment MRI radiomics and pre- and post-IC Delta radiomics models. The optimal Youden’s index was taken; the receiver operating characteristic (ROC) curve, calibration curve, and decision curve were drawn to evaluate the predictive efficacy of different models.

Results

Seven optimal feature subsets were selected from the pretreatment MRI radiomics model, and twelve optimal subsets were selected from the Delta radiomics model. The area under the ROC curve, accuracy, sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of the MRI radiomics model were 0.865, 0.827, 0.837, 0.813, 0.776, and 0.865, respectively; the corresponding indicators of the Delta radiomics model were 0.941, 0.883, 0.793, 0.968, 0.833, and 0.958, respectively.

Conclusion

The pretreatment MRI radiomics model and pre- and post-IC Delta radiomics models could predict the IC-CCRT response of NPC in non-epidemic areas.
MiR-29b-3p Inhibits Migration and Invasion of Papillary Thyroid Carcinoma by Downregulating COL1A1 and COL5A1
Authors: Wang Congjun , Wang Ye , Fu Zhao , Huang Weijia , Yu Zhu , Wang Jiancheng , Zheng Kaitian , Zhang Siwen , Li Shen , Chen Junqiang
Published: April 2022

Introduction

MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate genetic expression and are also vital for tumor initiation and development. MiR-29b-3p was found to be involved in regulating various biological processes of tumors, including tumor cell proliferation, metastasis, and apoptosis inhibition; however, the biofunction and molecule-level mechanisms of miR-29b-3p inpapillary thyroid carcinoma (PTC) remain unclear.

Methods

The expression of miR-29b-3p in PTC samples was tested via qRT-PCR. Cellular proliferation was analyzed by CCK-8 and EdU assays, and cellular migratory and invasive abilities were assessed utilizing wound-healing and Transwell assays. In addition, protein expressions of COL1A1, COL5A1, E-cadherin, N-cadherin, Snail, and Vimentin were identified via Western blot (WB) assay. Bioinformatics, qRT-PCR, WB, and dual luciferase reporter assays were completed to identify whether miR-29b-3p targeted COL1A1 and COL5A1. In addition, our team explored the treatment effects of miR-29b-3p on a murine heterograft model.

Results

Our findings revealed that miR-29b-3p proved much more regulated downward in PTC tissue specimens than in adjacent non-cancerous tissues. Meanwhile, decreased expression of miR-29b-3p was strongly related to the TNM stage of PTC patients (p<0.001), while overexpression of miR-29b-3p in PTC cells suppressed cellular migration, invasion, proliferation, and EMT. Conversely, silencing miR-29b-3p yielded the opposite effect. COL1A1 and COL5A1 were affirmed as the target of miR-29b-3p. Additionally, the COL1A1 and COL5A1 were highly expressed in PTC tumor samples than in contrast to neighboring healthy samples. Functional assays revealed that overexpression of COL1A1 or COL5A1 reversed the suppressive role of miR-29b-3p in migration, invasion, and EMT of PTC cells. Finally, miR-29b-3p agomir treatment dramatically inhibited Xenograft tumor growth in the animal model.

Conclusions

These findings document that miR-29b-3p inhibited PTC cells invasion and metastasis by targeting COL1A1 and COL5A1; this study also sparks new ideas for risk assessment and miRNA replacement therapy in PTC.
Immortal Time Bias-Corrected Effectiveness of Traditional Chinese Medicine in Non-Small Cell Lung Cancer (C-EVID): A Prospective Cohort Study
Authors: Zhang Xing , Guo Qiujun , Li Conghuang , Liu Rui , Xu Tao , Jin Zhichao , Xi Yupeng , Qin Yinggang , Li Weidong , Chen Shuntai , Xu Ling , Lin Lizhu , Shao Kang , Wang Shenyu , Xie Ying , Sun Hong , Li Ping , Chu Xiangyang , Chai Kequn , Shu Qijin , Liu Yanqing , Zhang Yue , Hu Jiaqi , Shi Bolun , Zhang Xiwen , Zhang Zhenhua , Jiang Juling , He Shulin , He Jie , Sun Mingxi , Zhang Ying , Zhang Meiying , Zheng Honggang , Hou Wei , Hua Baojin
Published: April 2022

Background

Relatively little is known about the effect of traditional Chinese medicine (TCM) on prognosis of non-small cell lung cancer (NSCLC).

Methods

In this nationwide, multicenter, prospective, cohort study, eligible patients aged 18-75 years with radical resection, and histologically confirmed stage II-IIIA NSCLC were enrolled. All patients received 4 cycles of standard adjuvant chemotherapy. Patients who received Chinese herbal decoction and (or) oral Chinese patent medicine for a cumulative period of not less than 6 months were defined as TCM group, otherwise they were considered as control group. The primary endpoint was DFS calculated using the Kaplan–Meier method. A time-dependent Cox proportional hazards model was used to correct immortal time bias. The secondary endpoints included DFS in patients of different characteristics, and safety analyses. This study was registered with the Chinese Clinical Trial Registry (ChiCTR1800015776).

Results

A total of 507 patients were included (230 patients in the TCM group; 277 patients in the control group). The median follow-up was 32.1 months. 101 (44%) in the TCM group and 186 (67%) in the control group had disease relapse. The median DFS was not reached in the TCM group and was 19.4 months (95% CI, 14.2 to 24.6) in the control group. The adjusted time-dependent HR was 0.61 (95% CI, 0.47 to 0.78), equalling to a 39% reduction in the risk of disease recurrence with TCM. the number needed to treat to prevent one patient from relapsing was 4.29 (95% CI, 3.15 to 6.73) at 5 years. Similar results were observed in most of subgroups. Patients had a significant improvement in white blood cell decrease, nausea, decreased appetite, diarrhea, pain, and fatigue in the TCM group.

Conclusion

TCM may improves DFS and has a better tolerability profile in patients with stage II-IIIA NSCLC receiving standard chemotherapy after complete resection compared with those receiving standard chemotherapy alone. Further studies are warranted.
The Predictive Value of PD-L1 Expression Level in Evaluating the Cost-Effectiveness of Atezolizumab/Pembrolizumab
Authors: Lin Shen , Li Yiyuan , Gu Dian , Luo Shaohong , Huang Xiaoting , Dong Liangliang , Xu Xiongwei , Lin Peili , Weng Xiuhua
Published: April 2022

Objective

Recently, the significant improvement of atezolizumab and pembrolizumab over chemotherapy for treatment-naïve stage IV non-small cell lung cancer (NSCLC) has been demonstrated, but the cost-effectiveness of these regimens remains unknown.

Methods

A Markov model was adapted from the US healthcare perspective to assess the cost-effectiveness of atezolizumab, pembrolizumab, and chemotherapy in treatment-naïve NSCLC. Pseudo-individual patient data were generated from digitized Kaplan–Meier curves. Direct medical costs and utility values were sourced from the database and literature. Quality-adjusted life-years (QALYs), total costs, and incremental cost-effectiveness ratios (ICERs) were computed. Sensitivity analyses and budgetary impact analyses were calculated.

Results

In any and high programmed cell death 1-ligand 1 (PD-L1) expression populations, with chemotherapy, atezolizumab provided ICERs of $234,990 and $130,804 per QALY, while pembrolizumab yielded ICERs of $424,797 and $140,873 per QALY. The ICER of atezolizumab vs. pembrolizumab was $56,635 and $115,511.82 in any and high PD-L1 expression population, respectively. The critical drivers of ICERs included the cost of atezolizumab and pembrolizumab. The accumulated incremental budgetary impact of atezolizumab vs. chemotherapy increased to approximately $39.1 million in high PD-L1 expression patients over 5 years.

Conclusions

In the high PD-L1 expression population, both atezolizumab and pembrolizumab were cost-effective for stage IV NSCLC compared to chemotherapy, which is contrary to that in any PD-L1 expression population. Atezolizumab shows a higher acceptability in both populations. Treating with immune checkpoint inhibitors (ICIs) has a substantial budgetary impact on the medical burden. The PD-L1 expression level has the potential to be a predictor for the economics of ICIs.
RNA Demethylase ALKBH5 Prevents Lung Cancer Progression by Regulating EMT and Stemness via Regulating p53
Authors: Liu Xiangli , Wang Ziyi , Yang Qiwei , Hu Xiaohai , Fu Qiang , Zhang Xinyu , Li Wenya
Published: April 2022

Background

Although N6-methyladenosine (m6A) RNA methylation is the most abundant reversible methylation of mRNA, which plays a critical role in regulating cancer processing, few studies have examined the role of m6A in nonsmall-cell lung cancer-derived cancer stem-like cells (CSCs).

Methods

CSCs were enriched by culturing NSCLC cells in a serum-free medium, and stem factors, including CD24, CD44, ALDH1, Nanog, Oct4, and Sox2 were detected by Western blot. ALKBH5 expression was measured by employing a tissue array. Global m6A methylation was measured after ALKBH5 knockdown. Malignances of CSCs were detected by performing CCK-8 assay, invasion assay, cell cycle analysis, and tumor formation in vitro and in vivo.

Results

m6A demethylase ALKBH5 is highly expressed in CSCs derived from NSCLC. Knockdown of ALKBH5 increased global m6A level, and also increased E-cadherin, decreased stem hallmarkers, Nanog and Oct4, and inhibited stemness of CSCs. In lung carcinoma, ALKBH5 is found to be positively correlated with p53 by using Gene Expression Profiling Interactive Analysis (GEPIA) online tool. P53 transcriptionally regulates ALKBH5 and subsequently regulates the global m6A methylation level. Knockdown of p53 or inhibition of p53’s transcriptional activity by addition of its specific inhibitor PFT-α decreased expression of ALKBH5 and CSCs’ malignancies, including proliferation, invasion, and tumor formation ability, indicating that p53 may partially regulate CSC’s malignancies via ALKBH5. Furthermore, we also found p53 transcriptionally regulates PRRX1, which is consistent with our previous report.

Conclusion

Collectively, our findings indicate the pivotal role of ALKBH5 in CSCs derived from NSCLC and highlight the regulatory function of the p53/ALKBH5 axis in modulating CSC progression, which could be a promising therapeutic target for NSCLC.
Prognostic Factors at Diagnosis Associated With Damage Accrual in Childhood-Onset Systemic Lupus Erythematosus Patients
Authors: Rodríguez-Lozano Ana Luisa , Rivas-Larrauri Francisco Eduardo , García-de la Puente Silvestre , Alcivar-Arteaga Daniel Alfredo , González-Garay Alejandro Gabriel
Published: April 2022

Objectives

To associate prognostic factors present at diagnosis with damage accrual in childhood-onset systemic lupus erythematosus (cSLE) patients.

Methods

We designed a cohort study of eligible children age 16 or younger who fulfilled the 1997 American College of Rheumatology (ACR) classification criteria for SLE. Excluded were those with previous treatment of steroids or immunosuppressants. The diagnosis date was cohort entry. We followed up on all subjects prospectively for at least 2 years. Two experts assessed the disease activity with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and Mexican-SLEDAI (MEX-SLEDAI) every 3–6 months. Damage was measured annually, applying Pediatric Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) to their last visit. We analyzed prognostic factors by relative risks (RR) and used logistic regression to construct the clinimetric table.

Results

Ninety patients with a median age of 11.8 years at diagnosis had a SLEDAI score of 15.5 (2–40) and a MEX-SLEDAI score of 12 (2–29); and of them, forty-eight children (53%) had SDI ≥ 2. The associated variables to damage (SDI ≥ 2) are as follows: neurologic disease RR 9.55 [95% CI 1.411–64.621]; vasculitis RR 2.81 [95% CI 0.991–7.973], and hemolytic anemia RR 2.09 [95% CI 1.280–3.415]. When these three features are present at diagnosis, the probability of damage ascends to 98.97%.

Conclusion

At diagnosis, we identified neurologic disease, vasculitis, and hemolytic anemia as prognostic factors related to the development of damage in cSLE. Their presence should lead to a closer follow-up to reduce the likelihood of damage development.
Mass Spectrometry-Based Targeted Lipidomics and Supervised Machine Learning Algorithms in Detecting Disease, Cultivar, and Treatment Biomarkers in Xylella fastidiosa subsp. pauca-Infected Olive Trees
Authors: Scala Valeria , Salustri Manuel , Loreti Stefania , Pucci Nicoletta , Cacciotti Andrea , Tatulli Giuseppe , Scortichini Marco , Reverberi Massimo
Published: April 2022

In 2013, Xylella fastidiosa (Xf) was detected for the first time in Apulia and, subsequently, recognized as the causal agent of the olive quick decline syndrome (OQDS). To contain the disease, the olive germplasm was evaluated for resistance to Xf, identifying cultivars with different susceptibility to the pathogen. Regarding this, the resistant cultivar Leccino has generally a lower bacterial titer compared with the susceptible cultivar Ogliarola salentina. Among biomolecules, lipids could have a pivotal role in the interaction of Xf with its host. In the grapevine Pierce’s disease, fatty acid molecules, the diffusible signaling factors (DSFs), act as regulators of Xf lifestyle and are crucial for its virulence. Other lipid compounds derived from fatty acid oxidation, namely, oxylipins, can affect, in vitro, biofilm formation in Xf subsp. pauca (Xfp) strain De Donno, that is, the strain causing OQDS. In this study, we combined high-performance liquid chromatography-mass spectrometry-MS-based targeted lipidomics with supervised learning algorithms (random forest, support vector machine, and neural networks) to classify olive tree samples from Salento. The dataset included samples from either OQDS-positive or OQDS-negative olive trees belonging either to cultivar Ogliarola salentina or Leccino treated or not with the zinc-copper-citric acid biocomplex Dentamet®. We built classifiers using the relative differences in lipid species able to discriminate olive tree samples, namely, (1) infected and non-infected, (2) belonging to different cultivars, and (3) treated or untreated with Dentamet®. Lipid entities emerging as predictors of the thesis are free fatty acids (C16:1, C18:1, C18:2, C18:3); the LOX-derived oxylipins 9- and 13-HPOD/TrE; the DOX-derived oxylipin 10-HPOME; and diacylglyceride DAG36:4(18:1/18:3).
Optimized Transformation and Gene Editing of the B104 Public Maize Inbred by Improved Tissue Culture and Use of Morphogenic Regulators
Authors: Aesaert Stijn , Impens Lennert , Coussens Griet , Van Lerberge Els , Vanderhaeghen Rudy , Desmet Laurence , Vanhevel Yasmine , Bossuyt Shari , Wambua Angeline Ndele , Van Lijsebettens Mieke , Inzé Dirk , De Keyser Ellen , Jacobs Thomas B. , Karimi Mansour , Pauwels Laurens
Published: April 2022

Plant transformation is a bottleneck for the application of gene editing in plants. In Zea mays (maize), a breakthrough was made using co-transformation of the morphogenic transcription factors BABY BOOM (BBM) and WUSCHEL (WUS) to induce somatic embryogenesis. Together with adapted tissue culture media, this was shown to increase transformation efficiency significantly. However, use of the method has not been reported widely, despite a clear need for increased transformation capacity in academic settings. Here, we explore use of the method for the public maize inbred B104 that is widely used for transformation by the research community. We find that only modifying tissue culture media already boosts transformation efficiency significantly and can reduce the time in tissue culture by 1 month. On average, production of independent transgenic plants per starting embryo increased from 1 to 4% using BIALAPHOS RESISTANCE (BAR) as a selection marker. In addition, we reconstructed the BBM-WUS morphogenic gene cassette and evaluated its functionality in B104. Expression of the morphogenic genes under tissue- and development stage-specific promoters led to direct somatic embryo formation on the scutellum of zygotic embryos. However, eight out of ten resulting transgenic plants showed pleiotropic developmental defects and were not fertile. This undesirable phenotype was positively correlated with the copy number of the morphogenic gene cassette. Use of constructs in which morphogenic genes are flanked by a developmentally controlled Cre/LoxP recombination system led to reduced T-DNA copy number and fertile T0 plants, while increasing transformation efficiency from 1 to 5% using HIGHLY-RESISTANT ACETOLACTATE SYNTHASE as a selection marker. Addition of a CRISPR/Cas9 module confirmed functionality for gene editing applications, as exemplified by editing the gene VIRESCENT YELLOW-LIKE (VYL) that can act as a visual marker for gene editing in maize. The constructs, methods, and insights produced in this work will be valuable to translate the use of BBM-WUS and other emerging morphogenic regulators (MRs) to other genotypes and crops.