bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the causal relationships between human blood metabolites and the risk of NAFLD: A comprehensive mendelian randomization study
Authors: Guo Ziwei , Zhang Tingyu , Yun Zhangjun , Jin Qian , Cao Xu , Kong Deming , Yao Yuhao , Li Xiaoke , Zhang Jiaxin , Ye Yong’An
Published: March 2023

Background: Non-alcoholic fatty liver disease (NAFLD) is a liver disease associated with obesity, insulin resistance, type 2 diabetes mellitus (T2DM), and metabolic syndrome. The risk factors for NAFLD have not been identified. Metabolic dysfunction has been found to be an important factor in the pathogenesis and progression of NAFLD. However, the causal impact of blood metabolites on NAFLD is unclear.

Methods: We performed a two-sample Mendelian randomization (MR) study. A genome-wide association study (GWAS) with 7824 participants provided data on 486 human blood metabolites. Outcome information was obtained from a large-scale GWAS meta-analysis of NAFLD, which contained 8,434 cases and 770,180 controls of Europeans. The inverse variance weighted (IVW) model was chosen as the primary two-sample MR analysis approach, followed by sensitivity analyses such as the heterogeneity test, horizontal pleiotropy test, and leave-one-out analysis. In addition, we performed replication, meta-analysis, and metabolic pathway analysis. We further conducted colocalization analysis to deeply reflect the causality.

Results: After rigorous genetic variant selection, IVW, sensitivity analysis, replication, and meta-analysis, two known metabolites were identified as being associated with the development of NAFLD [biliverdin: OR = 1.45; 95% CI 1.20-1.75; p = 0.0001; myristoleate: OR = 0.57; 95% CI 0.39-0.83; p = 0.0030].

Conclusion: By combining genomics with metabolomics, our findings provide a new perspective on the underlying mechanisms of NAFLD and have important implications for the screening and prevention of NAFLD.
Comprehensive analysis of epigenetics mechanisms in osteoporosis
Authors: Chen Yuzhu , Sun Yumiao , Xue Xiangyu , Ma Huanzhi
Published: March 2023

Epigenetic modification pertains to the alteration of genetic-expression, which could be transferred to the next generations, without any alteration in the fundamental DNA sequence. Epigenetic modification could include various processes such as DNA methylation, histone alteration, non-coding RNAs (ncRNAs), and chromatin adjustment are among its primary operations. Osteoporosis is a metabolic disorder that bones become more fragile due to the decrease in mineral density, which could result in a higher risk of fracturing. Recently, as the investigation of the causal pathology of osteoporosis has been progressed, remarkable improvement has been made in epigenetic research. Recent literatures have illustrated that epigenetics is estimated to be one of the most contributing factors to the emergence and progression of osteoporosis. This dissertation primarily focuses on indicating the research progresses of epigenetic mechanisms and also the regulation of bone metabolism and the pathogenesis of osteoporosis in light of the significance of epigenetic mechanisms. In addition, it aims to provide new intelligence for the treatment of diseases related to bone metabolism.
The roles of toll-like receptor 4, CD33, CD68, CD69, or CD147/EMMPRIN for monocyte activation by the DAMP S100A8/S100A9
Authors: Möller Alexander , Jauch-Speer Saskia-Larissa , Gandhi Shrey , Vogl Thomas , Roth Johannes , Fehler Olesja
Published: March 2023

The S100A8/A9 heterocomplex is an abundant damage-associated molecular pattern and mainly expressed by monocytes, inflammatory activated keratinocytes and neutrophilic granulocytes. The heterocomplex as well as the heterotetramer are involved in a variety of diseases and tumorous processes. However, their detailed mode of action and especially which receptors are involved hereby remains to be fully revealed. Several cell surface receptors are reported to interact with S100A8 and/or S100A9, the best studied being the pattern recognition receptor TLR4. RAGE, CD33, CD68, CD69, and CD147, all of them are involved as receptors in various inflammatory processes, are also among these putative binding partners for S100A8 and S100A9. Interactions between S100 proteins and these receptors described so far come from a wide variety of cell culture systems but their biological relevance in vivo for the inflammatory response of myeloid immune cells is not yet clear. In this study, we compared the effect of CRISPR/Cas9 mediated targeted deletion of CD33, CD68, CD69, and CD147 in ER-Hoxb8 monocytes on S100A8 or S100A9 induced cytokine release with TLR4 knockout monocytes. Whereas deletion of TLR4 abolished the S100-induced inflammatory response in monocyte stimulation experiments with both S100A8 and S100A9, knockouts of CD33, CD68, CD69, or CD147 revealed no effect on the cytokine response in monocytes. Thus, TLR4 is the dominant receptor for S100-triggered inflammatory activation of monocytes.
Immunotherapy efficacy predictive tool for lung adenocarcinoma based on neural network
Authors: Li Wei , Fu Siyun , Gao Xiang , Lu Zhendong , Jin Renjing , Qin Na , Zhang Xinyong , Wu Yuhua , Li Weiying , Wang Jinghui
Published: March 2023

Background

Remarkably, the anti-cancer efficacy of immunotherapy in lung adenocarcinoma (LUAD) has been demonstrated. However, predicting the beneficiaries of this expensive treatment is still a challenge.

Materials and methods

A group of patients (N = 250) diagnosed with LUAD and receiving immunotherapy were retrospectively studied. They were randomly divided into a training dataset (80%) and a test dataset (20%). The training dataset was utilized to train neural network models to predict patients’ objective response rate (ORR), disease control rate (DCR), responders (progression-free survival time > 6 months), and overall survival (OS) possibility, which were validated by both the training and test datasets and packaged into a tool later.

Results

In the training dataset, the tool scored 0.9016 area under the receiver operating characteristic (AUC) curve on ORR judgment, 0.8570 on DCR, and 0.8395 on responder prediction. In the test dataset, the tool scored 0.8173 AUC on ORR, 0.8244 on DCR, and 0.8214 on responder determination. As for OS prediction, the tool scored 0.6627 AUC in the training dataset and 0.6357 in the test dataset.

Conclusions

This immunotherapy efficacy predictive tool for LUAD patients based on neural networks could predict their ORR, DCR, and responder well.
Combined analysis of bulk and single-cell RNA sequencing reveals novel natural killer cell-related prognostic biomarkers for predicting immunotherapeutic response in hepatocellular carcinoma
Authors: Zhang Kai , Yuan Enwu
Published: March 2023

Introduction

Natural killer (NK) cells play an irreplaceable and important role as a subtype of innate immune cells in the contemporary setting of antitumor immunity.

Methods

We chose a total of 1,196 samples for this analysis from the public dataset’s six separate cohorts. To identify 42 NK cell marker genes, we first carried out a thorough study of single-cell RNA sequencing data from the GSE149614 cohort of hepatocellular carcinoma (HCC).

Results

Using the NK cell marker genes in the TCGA cohort, we next created a seven-gene prognostic signature, separating the patients into two categories with distinct survival patterns. This signature’s prognostic prediction ability was well verified across several validation cohorts. Patients with high scores had higher TIDE scores but lower immune cell infiltration percentages. Importantly, low-scoring patients had superior immunotherapy response and prognosis than high-scoring patients in an independent immunotherapy cohort (IMvigor210). Finally, we used CD56 and TUBA1B antibodies for immunohistochemical labeling of HCC tissue sections, and we discovered a lower number of CD56+ cells in the HCC tissue sections with high TUBA1B expression.

Discussion

In summary, our research created a unique prognostic profile based on NK cell marker genes that may accurately predict how well immunotherapy would work for HCC patients.
Characterization of TLR1 and expression profiling of TLR signaling pathway related genes in response to Aeromonas hydrophila challenge in hybrid yellow catfish (Pelteobagrus fulvidraco ♀ × P. vachelli ♂)
Authors: Guo Shengtao , Gao Wenxue , Zeng Mengsha , Liu Fenglin , Yang Qingzhuoma , Chen Lei , Wang Zesong , Jin Yanjun , Xiang Peng , Chen Hanxi , Wen Zhengyong , Shi Qiong , Song Zhaobin
Published: March 2023

Toll‐like receptor 1 (TLR1) mediates the innate immune response to a variety of microbes through recognizing cell wall components (such as bacterial lipoproteins) in mammals. However, the detailed molecular mechanism of TLR1 involved in pathogen immunity in the representative hybrid yellow catfish (Pelteobagrus fulvidraco ♀ × P. vachelli ♂) has not been well studied. In the present study, we identified the TLR1 gene from the hybrid yellow catfish, and further comparative synteny data from multiple species confirmed that the TLR1 gene is highly conserved in teleosts. Phylogenetic analysis revealed distinguishable TLR1s in diverse taxa, suggesting consistence in evolution of the TLR1 proteins with various species. Structural prediction indicated that the three-dimensional structures of TLR1 proteins are relatively conserved among different taxa. Positive selection analysis showed that purifying selection dominated the evolutionary process of TLR1s and TLR1-TIR domain in both vertebrates and invertebrates. Expression pattern analysis based on the tissue distribution showed that TLR1 mainly transcribed in the gonad, gallbladder and kidney, and the mRNA levels of TLR1 in kidney were remarkably up-regulated after Aeromonas hydrophila stimulation, indicating that TLR1 participates in the inflammatory responses to exogenous pathogen infection in hybrid yellow catfish. Homologous sequence alignment and chromosomal location indicated that the TLR signaling pathway is very conserved in the hybrid yellow catfish. The expression patterns of TLR signaling pathway related genes (TLR1- TLR2 - MyD88 - FADD - Caspase 8) were consistent after pathogen stimulation, revealing that the TLR signaling pathway is triggered and activated after A. hydrophila infection. Our findings will lay a solid foundation for better understanding the immune roles of TLR1 in teleosts, as well as provide basic data for developing strategies to control disease outbreak in hybrid yellow catfish.
Methane release effects on foraminiferal tests in northern South China Sea
Authors: Cen Yue , Wang Jiasheng , Algeo Thomas J. , Wang Zhou , Ma Xiaochen , Chen Can
Published: March 2023

Upward diffusing methane in gas hydrate geological systems is consumed in the sediment and water column by a series of biogeochemical reactions, which not only affect living foraminifera but also lead to early diagenetic alteration of buried foraminiferal tests. Previous studies of the impact of methane release events on fossil foraminifera focused mainly on carbon and oxygen isotopes, with little attention given to other geochemical proxies to date. Here, we examine the test wall microstructure and analyze the elemental and stable carbon-oxygen isotopic compositions of buried foraminifera from gas hydrate-bearing sediments at Site GMGS2-16 in the northern South China Sea. Our results show that diagenetic alteration of foraminiferal tests at Site GMGS2-16 is mainly linked to high-Mg calcite overgrowths. Test δ13C covaries negatively with the degree of diagenetic alteration (based on petrographic characteristics) but positively with Mg/Ca ratios. With increasing diagenetic alteration, Ba/Ca, Mn/Ca, Fe/Ca, Mo/Ca, U/Ca, V/Ca, Ni/Ca and Co/Ca also generally increase, but Sr/Ca and Cu/Ca exhibit variable changes. We infer that foraminiferal tests are highly susceptible to alteration by methane-bearing fluids, and that the elemental ratios of diagenetically altered tests are potentially reliable proxies for paleo-methane release events. At Site GMGS2-16, the overall pattern of diagenetic alteration of foraminiferal tests records frequent vertical fluctuations of the sulfate-methane transition zone (SMTZ) caused by variable fluid flux and methane release rates, with two discrete large-scale methane release events having maximum ages of ~0.47 ka and ~170 ka.
Global, regional, and national burden of chronic respiratory diseases and associated risk factors, 1990–2019: Results from the Global Burden of Disease Study 2019
Authors: Chen Xiang , Zhou Cheng-Wei , Fu Yang-Yang , Li Yao-Zhe , Chen Lei , Zhang Qing-Wei , Chen Yan-Fan
Published: March 2023

Background

The burden of chronic respiratory diseases has changed over the three decades. This study aims to describe the spatiotemporal trends of prevalence, mortality, and disability-adjusted life years (DALY) due to chronic respiratory diseases (CRDs) worldwide during 1990–2019 using data from the Global Burden of Disease Study 2019 (GBD 2019).

Methods

The prevalence, mortality, and DALY attributable to CRDs and risk factors from 1990 to 2019 were estimated. We also assessed the driving factors and potentiality for improvement with decomposition and frontier analyses, respectively.

Results

In 2019, 454.56 [95% uncertainty interval (UI): 417.35–499.14] million individuals worldwide had a CRD, showing a 39·8% increase compared with 1990. Deaths due to CRDs were 3.97 (95%UI: 3.58–4.30) million, and DALY in 2019 was 103.53 (95%UI: 94.79–112.27) million. Declines by average annual percent change (AAPC) were observed in age-standardized prevalence rates (ASPR) (0.64% decrease), age-standardized mortality rates (ASMR) (1.92%), and age-standardized DALY rates (ASDR) (1.72%) globally and in 5 socio-demographic index (SDI) regions. Decomposition analyses represented that the increase in overall CRDs DALY was driven by aging and population growth. However, chronic obstructive pulmonary disease (COPD) was the leading driver of increased DALY worldwide. Frontier analyses witnessed significant improvement opportunities at all levels of the development spectrum. Smoking remained a leading risk factor (RF) for mortality and DALY, although it showed a downward trend. Air pollution, a growing factor especially in relatively low SDI regions, deserves our attention.

Conclusion

Our study clarified that CRDs remain the leading causes of prevalence, mortality, and DALY worldwide, with growth in absolute numbers but declines in several age-standardized estimators since 1990. The estimated contribution of risk factors to mortality and DALY demands the need for urgent measures to improve them.

Systematic review registration

http://ghdx.healthdata.org/gbd-results-tool.
3D interaction homology: The hydrophobic residues alanine, isoleucine, leucine, proline and valine play different structural roles in soluble and membrane proteins
Authors: AL Mughram Mohammed H. , Catalano Claudio , Herrington Noah B. , Safo Martin K. , Kellogg Glen E.
Published: March 2023

The aliphatic hydrophobic amino acid residues—alanine, isoleucine, leucine, proline and valine—are among the most common found in proteins. Their structural role in proteins is seemingly obvious: engage in hydrophobic interactions to stabilize secondary, and to a lesser extent, tertiary and quaternary structure. However, favorable hydrophobic interactions involving the sidechains of these residue types are generally less significant than the unfavorable set arising from interactions with polar atoms. Importantly, the constellation of interactions between residue sidechains and their environments can be recorded as three-dimensional maps that, in turn, can be clustered. The clustered average map sets compose a library of interaction profiles encoding interaction strengths, interaction types and the optimal 3D position for the interacting partners. This library is backbone angle-dependent and suggests solvent and lipid accessibility for each unique interaction profile. In this work, in addition to analysis of soluble proteins, a large set of membrane proteins that contained optimized artificial lipids were evaluated by parsing the structures into three distinct components: soluble extramembrane domain, lipid facing transmembrane domain, core transmembrane domain. The aliphatic residues were extracted from each of these sets and passed through our calculation protocol. Notable observations include: the roles of aliphatic residues in soluble proteins and in the membrane protein’s soluble domains are nearly identical, although the latter are slightly more solvent accessible; by comparing maps calculated with sidechain-lipid interactions to maps ignoring those interactions, the potential extent of residue-lipid and residue-interactions can be assessed and likely exploited in structure prediction and modeling; amongst these residue types, the levels of lipid engagement show isoleucine as the most engaged, while the other residues are largely interacting with neighboring helical residues.
The alterations in multiple neurophysiological procedures are associated with frailty phenotype in older adults
Authors: Jiang Xin , Zhou Junhong , Yu Chengyuan , Chen Wenbo , Huang Baofeng , Chen Yurong , Zhong Lilian , Guo Yi , Geng Qingshan , Cai Yurun
Published: March 2023

Background

Older adults oftentimes suffer from the conditions in multiple physiologic systems, interfering with their daily function and thus contributing to physical frailty. The contributions of such multisystem conditions to physical frailty have not been well characterized.

Methods

In this study, 442 (mean age = 71.4 ± 8.1 years, 235 women) participants completed the assessment of frailty syndromes, including unintentional weight loss, exhaustion, slowness, low activity, and weakness, and were categorized into frail (≥3 conditions), pre-frail (1 or 2 conditions), and robust (no condition) status. Multisystem conditions including cardiovascular diseases, vascular function, hypertension, diabetes, sleep disorders, sarcopenia, cognitive impairment, and chronic pain were assessed. Structural equation modeling examined the interrelationships between these conditions and their associations with frailty syndromes.

Results

Fifty (11.3%) participants were frail, 212 (48.0%) were pre-frail, and 180 (40.7%) were robust. We observed that worse vascular function was directly associated with higher risk of slowness [standardized coefficient (SC) = −0.419, p < 0.001], weakness (SC = −0.367, p < 0.001), and exhaustion (SC = −0.347, p < 0.001). Sarcopenia was associated with both slowness (SC = 0.132, p = 0.011) and weakness (SC = 0.217, p = 0.001). Chronic pain, poor sleep quality, and cognitive impairment were associated with exhaustion (SC = 0.263, p < 0.001; SC = 0.143, p = 0.016; SC = 0.178, p = 0.004, respectively). The multinomial logistic regression showed that greater number of these conditions were associated with increased probability of being frail (odds ratio>1.23, p < 0.032).

Conclusion

These findings in this pilot study provide novel insights into how multisystem conditions are associated with each other and with frailty in older adults. Future longitudinal studies are warranted to explore how the changes in these health conditions alter frailty status.
Porphyromonas gingivalis-induced periodontitis could contribute to cognitive impairment in Sprague–Dawley rats via the P38 MAPK signaling pathway
Authors: Jin Ru , Ning Xiaoqiao , Liu Xiang , Zhao Yueyang , Ye Guo
Published: March 2023

Background

Periodontitis is one of the most common oral diseases and has been shown to be a risk factor for systemic diseases. Our aim was to investigate the relationship between periodontitis and cognitive impairment and to explore the role of the P38 MAPK signaling pathway in this process.

Methods

We established a periodontitis model by ligating the first molars of SD rats with silk thread and injecting Porphyromonas gingivalis (P. gingivalis) or P. gingivalis plus the P38 MAPK inhibitor SB203580 at the same time for ten weeks. We assessed alveolar bone resorption and spatial learning and memory using microcomputed tomography and the Morris water maze test, respectively. We used transcriptome sequencing to explore the genetic differences between the groups. The gingival tissue, peripheral blood and hippocampal tissue were assessed for the cytokines TNF-α, IL-1β, IL-6, IL-8 and C reactive protein (CRP) with enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT–PCR). We observed the presence of P. gingivalis in the hippocampus of rats by paraffin-fluorescence in situ hybridization (FISH). We determined the activation of microglia by immunofluorescence. Finally, Western blot analysis was employed to determine the expression of amyloid precursor protein (APP), β-site APP-cleaving enzyme 1 (BACE1) and P38MAPK pathway activation.

Results

We demonstrated that silk ligature-induced periodontitis plus injection of P. gingivalis into subgingival tissue could lead to memory and cognitive impairment. Transcriptome sequencing results suggested that there were neurodegenerative diseases in the P. gingivalis group, and the MWM test showed that periodontitis reduced the spatial learning and memory ability of mild cognitive impairment (MCI) model rats. We found high levels of inflammatory factors (TNF-α, IL-1β, IL-6, and IL-8) and CRP in the gingiva, peripheral blood and hippocampus, and the expression of APP and BACE1 was upregulated, as was the P38 MAPK pathway activation. Activated microglia and the presence of P. gingivalis were also found in the hippocampus. P38 MAPK inhibitors mitigated all of these changes.

Conclusion

Our findings strongly suggest that topical application of P. gingivalis increases the inflammatory burden in the peripheral and central nervous systems (CNS) and that neuroinflammation induced by activation of P38 MAPK leads to impaired learning and memory in SD rats. It can also modulate APP processing. Therefore, P38 MAPK may serve as a linking pathway between periodontitis and cognitive impairment.
Application of multi-task transfer learning: The combination of EA and optimized subband regularized CSP to classification of 8-channel EEG signals with small dataset
Authors: Long Taixue , Wan Min , Jian Wenjuan , Dai Honghui , Nie Wenbing , Xu Jianzhong
Published: March 2023

Introduction

The volume conduction effect and high dimensional characteristics triggered by the excessive number of channels of EEG cap-acquired signals in BCI systems can increase the difficulty of classifying EEG signals and the lead time of signal acquisition. We aim to combine transfer learning to decode EEG signals in the few-channel case, improve the classification performance of the motor imagery BCI system across subject cases, reduce the cost of signal acquisition performed by the BCI system, and improve the usefulness of the system.

Methods

Dataset2a from BCI CompetitionIV(2008) was used as Dataset1, and our team's self-collected dataset was used as Dataset2. Dataset1 acquired EEG signals from 9 subjects using a 22-channel device with a sampling frequency of 250 Hz. Dataset2 acquired EEG signals from 10 healthy subjects (8 males and 2 females; age distribution between 21-30 years old; mean age 25 years old) using an 8-channel system with a sampling frequency of 1000 Hz. We introduced EA in the data preprocessing process to reduce the signal differences between subjects and proposed VFB-RCSP in combination with RCSP and FBCSP to optimize the effect of feature extraction.

Results

Experiments were conducted on Dataset1 with EEG data containing only 8 channels and achieved an accuracy of 78.01 and a kappa coefficient of 0.54. The accuracy exceeded most of the other methods proposed in recent years, even though the number of channels used was significantly reduced. On Dataset 2, an accuracy of 59.77 and a Kappa coefficient of 0.34 were achieved, which is a significant improvement compared to other poorly improved classical protocols.

Discussion

Our work effectively improves the classification of few-channel EEG data. It overcomes the dependence of existing algorithms on the number of channels, the number of samples, and the frequency band, which is significant for reducing the complexity of BCI models and improving the user-friendliness of BCI systems.
Impact of localized fine tuning in the performance of segmentation and classification of lung nodules from computed tomography scans using deep learning
Authors: Cai Jingwei , Guo Lin , Zhu Litong , Xia Li , Qian Lingjun , Lure Yuan-Ming Fleming , Yin Xiaoping
Published: March 2023

Background

Algorithm malfunction may occur when there is a performance mismatch between the dataset with which it was developed and the dataset on which it was deployed.

Methods

A baseline segmentation algorithm and a baseline classification algorithm were developed using public dataset of Lung Image Database Consortium to detect benign and malignant nodules, and two additional external datasets (i.e., HB and XZ) including 542 cases and 486 cases were involved for the independent validation of these two algorithms. To explore the impact of localized fine tuning on the individual segmentation and classification process, the baseline algorithms were fine tuned with CT scans of HB and XZ datasets, respectively, and the performance of the fine tuned algorithms was tested to compare with the baseline algorithms.

Results

The proposed baseline algorithms of both segmentation and classification experienced a drop when directly deployed in external HB and XZ datasets. Comparing with the baseline validation results in nodule segmentation, the fine tuned segmentation algorithm obtained better performance in Dice coefficient, Intersection over Union, and Average Surface Distance in HB dataset (0.593 vs. 0.444; 0.450 vs. 0.348; 0.283 vs. 0.304) and XZ dataset (0.601 vs. 0.486; 0.482 vs. 0.378; 0.225 vs. 0.358). Similarly, comparing with the baseline validation results in benign and malignant nodule classification, the fine tuned classification algorithm had improved area under the receiver operating characteristic curve value, accuracy, and F1 score in HB dataset (0.851 vs. 0.812; 0.813 vs. 0.769; 0.852 vs. 0.822) and XZ dataset (0.724 vs. 0.668; 0.696 vs. 0.617; 0.737 vs. 0.668).

Conclusions

The external validation performance of localized fine tuned algorithms outperformed the baseline algorithms in both segmentation process and classification process, which showed that localized fine tuning may be an effective way to enable a baseline algorithm generalize to site-specific use.
Identification of a cuproptosis and copper metabolism gene–related lncRNAs prognostic signature associated with clinical and immunological characteristics of hepatocellular carcinoma
Authors: Yuan Wei , Xiao Jun-hao , Zhang Jian-song , Mao Ben-liang , Wang Peng-zhen , Wang Bai-lin
Published: March 2023

Background

The relationship between cuproptosis and HCC is still in the exploratory stage. Long noncoding RNAs (lncRNAs) have recently been linked to the progression of hepatocellular carcinoma (HCC). However, the clinical significance of lncRNAs associated with cuproptosis remains unclear.

Methods

Based on The Cancer Genome Atlas (TCGA) liver hepatocellular carcinoma (LIHC) dataset, we identified characteristic prognostic lncRNAs by univariate, LASSO, and multifactorial regression analysis, and constructed a prognostic signature of cuproptosis-related lncRNAs in HCC. The role of lncRNAs were identified through CCK-8, clone formation in Huh-7 cells with high expression of FDX1. Prognostic potential of the characteristic lncRNAs was evaluated in each of the two cohorts created by randomly dividing the TCGA cohort into a training cohort and a test cohort in a 1:1 ratio. Immune profiles in defined subgroups of cuproptosis-related lncRNA features as well as drug sensitivity were analyzed.

Results

We constructed a multigene signature based on four characteristic prognostic lncRNAs (AL590705.3, LINC02870, KDM4A-AS1, MKLN1-AS). These four lncRNAs participated in the development of cuproptosis. HCC patients were classified into high-risk and low-risk groups based on the median value of the risk score. The receiver operating characteristic curve area under the curve values for 1-, 3-, and 5-year survival were 0.773, 0.728, and 0.647, respectively, for the training cohort, and 0.764, 0.671, and 0.662, respectively, for the test cohort. Univariate and multifactorial regression analyses indicated that this prognostic feature was an independent prognostic factor for HCC. Principal component analysis plots clearly distinguished between low- and high-risk patients in terms of their probability of survival. Furthermore, gene set enrichment analysis showed that a variety of processes associated with tumor proliferation and progression were enriched in the high-risk group compared with the low-risk group. Moreover, there were significant differences in the expression of immune cell subpopulations, immune checkpoint genes, and potential drug screening, which provided distinct therapeutic recommendations for individuals with various risks.

Conclusions

We constructed a novel cuproptosis-associated lncRNA signature with a significant predictive value for the prognosis of patients with HCC. Cuproptosis-associated lncRNAs are associated with the tumor immune microenvironment of HCC and even the efficacy of tumor immunotherapy.
Automatic tumor segmentation and metachronous single-organ metastasis prediction of nasopharyngeal carcinoma patients based on multi-sequence magnetic resonance imaging
Authors: Huang Yecai , Zhu Yuxin , Yang Qiang , Luo Yangkun , Zhang Peng , Yang Xuegang , Ren Jing , Ren Yazhou , Lang Jinyi , Xu Guohui
Published: March 2023

Background

Distant metastases is the main failure mode of nasopharyngeal carcinoma. However, early prediction of distant metastases in NPC is extremely challenging. Deep learning has made great progress in recent years. Relying on the rich data features of radiomics and the advantages of deep learning in image representation and intelligent learning, this study intends to explore and construct the metachronous single-organ metastases (MSOM) based on multimodal magnetic resonance imaging.

Patients and methods

The magnetic resonance imaging data of 186 patients with nasopharyngeal carcinoma before treatment were collected, and the gross tumor volume (GTV) and metastatic lymph nodes (GTVln) prior to treatment were defined on T1WI, T2WI, and CE-T1WI. After image normalization, the deep learning platform Python (version 3.9.12) was used in Ubuntu 20.04.1 LTS to construct automatic tumor detection and the MSOM prediction model.

Results

There were 85 of 186 patients who had MSOM (including 32 liver metastases, 25 lung metastases, and 28 bone metastases). The median time to MSOM was 13 months after treatment (7–36 months). The patients were randomly assigned to the training set (N = 140) and validation set (N = 46). By comparison, we found that the overall performance of the automatic tumor detection model based on CE-T1WI was the best (6). The performance of automatic detection for primary tumor (GTV) and lymph node gross tumor volume (GTVln) based on the CE-T1WI model was better than that of models based on T1WI and T2WI (AP@0.5 is 59.6 and 55.6). The prediction model based on CE-T1WI for MSOM prediction achieved the best overall performance, and it obtained the largest AUC value (AUC = 0.733) in the validation set. The precision, recall, precision, and AUC of the prediction model based on CE-T1WI are 0.727, 0.533, 0.730, and 0.733 (95% CI 0.557–0.909), respectively. When clinical data were added to the deep learning prediction model, a better performance of the model could be obtained; the AUC of the integrated model based on T2WI, T1WI, and CE-T1WI were 0.719, 0.738, and 0.775, respectively. By comparing the 3-year survival of high-risk and low-risk patients based on the fusion model, we found that the 3-year DMFS of low and high MSOM risk patients were 95% and 11.4%, respectively (p < 0.001).

Conclusion

The intelligent prediction model based on magnetic resonance imaging alone or combined with clinical data achieves excellent performance in automatic tumor detection and MSOM prediction for NPC patients and is worthy of clinical application.
Effectiveness of pegfilgrastim prophylaxis in preventing febrile neutropenia during R-FC chemoimmunotherapy for chronic lymphocytic leukemia: A multicenter prospective phase II study
Authors: Jeon Youngwoo , Yang Duk-Hwan , Oh Suk-Joong , Park Jin-Hee , Kim Jung-Ah , Kim Sung-Young , Choi Chul-Won , Lee Won-Sik , Kim In-Ho , Mun Yeung-Chul , Min Gi June , Eom Ki-Seong , Cho Seok-Goo
Published: March 2023

Background

A chemotherapy of rituximab, fludarabine and cyclophosphamide (R-FC) has been accepted as a promising frontline chemotherapy in selected patients with chronic lymphocytic leukemia (CLL). Although R-FC regimen is a relatively dose-dense regimen and neutropenia incidence is more than 50%, primary prophylactic pegfilgrastim was not fully recommended in the clinical field. Therefore, the study evaluated the prophylactic effectiveness of pegfilgrastim to reduce the incidence of febrile neutropenia associated with R-FC of patients with CLL.

Patients and methods

A single-arm, multicenter, prospective phase II study was designed to assess the efficacy of prophylactic pegfilgrastim. Thirty-four CLL patients were enrolled and analyzed for neutropenia and other related factors, and comparative analysis was performed with historical cohort.

Results

Compared with our historical cohort, incidence of grade 3-4 neutropenia and febrile neutropenia was remarkably reduced during any cycle of chemotherapy (14.7% vs. 48.2% of study cohort vs. historical cohort during C1, 5.9% vs. 65.8% during C2, 12.9% vs. 80.6% during C3, 10% vs. 84.6% during C4, 3.4% vs. 83.6% during C5, and 10.7% vs. 85.7% during C6, p <0.001). Also, cumulative incidence of disrupted chemotherapy was noticeably reduced in study cohort on any cycles of R-FC regimen (8.8% vs. 22.2% of study cohort vs. historical cohort on C2, 9.7% vs. 25.2% on C3, 13.4% vs. 26.9% on C4, 13.8% vs. 45.2% on C5, 17.9% vs. 47.3% on C6, p=0.007). In addition, treatment-related mortality was 5.9%, which significantly reduced compared to 9.6% of our historical cohort (HR 0.64, 95% CI 0.42–0.79, P = 0.032).

Conclusion

Primary prophylactic pegfilgrastim is effective in the prevention of neutropenia/febrile neutropenia, and infection-related mortality during R-FC regimen in patients with CLL.
Dimethyl fumarate abrogates striatal endoplasmic reticulum stress in experimentally induced late-stage Huntington’s disease: Focus on the IRE1α/JNK and PERK/CHOP trajectories
Authors: Hassab Lina Y. , Abbas Samah S. , Mohammed Reham A. , Abdallah Dalaal M.
Published: March 2023

Introduction: Dimethyl fumarate (DMF) is FDA-approved for use in patients with relapsing multiple sclerosis, and it processes neuroprotection in several experimental settings; however, its impact on combating Huntington’s disease (HD) remains elusive. This study aimed to explore the role of DMF post-treatment on HD mediated endoplasmic reticulum (ER) stress response in a selective striatal degeneration HD model.

Methods: Rats, exposed to 3-nitropropionic acid, were either left untreated or post-treated with DMF for 14 days.

Results and Discussion: DMF reduced locomotion deficits in both the open field and beam walk paradigms, boosted the striatal dopamine (DA) content, improved its architecture at the microscopic level, and hindered astrogliosis. Mechanistically, DMF limited the activation of two of the ER stress arms in the striatum by reducing p-IRE1α, p-JNK, and p-PERK protein expressions besides the CHOP/GADD153 content. Downstream from both ER stress arms’ suppression, DMF inhibited the intrinsic apoptotic pathway, as shown by the decrease in Bax and active caspase-3 while raising Bcl-2. DMF also decreased oxidative stress markers indicated by a decline in both reactive oxygen species and malondialdehyde while boosting glutathione. Meanwhile, it enhanced p-AKT to activate /phosphorylate mTOR and stimulate the CREB/BDNF/TrkB trajectory, which, in a positive feedforward loop, activates AKT again. DMF also downregulated the expression of miRNA-634, which negatively regulates AKT, to foster survival kinase activation.

Conclusion: This study features a focal novel point on the DMF therapeutic ability to reduce HD motor manifestations via its ability to enhance DA and suppress the IRE1α/JNK and PERK/CHOP/GADD153 hubs to inhibit the mitochondrial apoptotic pathway through activating the AKT/mTOR and BDNF/TrkB/AKT/CREB signaling pathways and abating miRNA-634 and oxidative stress.
Triple-gene deletion for osteocalcin significantly impairs the alignment of hydroxyapatite crystals and collagen in mice
Authors: Xu Zihan , Yang Chao , Wu Feng , Tan Xiaowen , Guo Yaxiu , Zhang Hongyu , Wang Hailong , Sui Xiukun , Xu Zi , Zhao Minbo , Jiang Siyu , Dai Zhongquan , Li Yinghui
Published: March 2023

Osteocalcin (Ocn), also known as bone Gla protein, is synthesized by osteoblasts and thought to regulate energy metabolism, testosterone synthesis and brain development. However, its function in bone is not fully understood. Mice have three Ocn genes: Bglap, Bglap2 and Bglap3. Due to the long span of these genes in the mouse genome and the low expression of Bglap3 in bone, researchers commonly use Bglap and Bglap2 knockout mice to investigate the function of Ocn. However, it is unclear whether Bglap3 has any compensatory mechanisms when Bglap and Bglap2 are knocked out. Considering the controversy surrounding the role of Ocn in bone, we constructed an Ocn-deficient mouse model by knocking out all three genes (Ocn−/−) and analyzed bone quality by Raman spectroscopy (RS), Scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR) and MicroCT (μCT). The RS test showed that the alignment of hydroxyapatite crystals and collagen fibers was significantly poorer in Ocn−/− mice than in wild-type (WT) mice. Ocn deficiency resulted in a looser surface structure of bone particles and a larger gap area proportion. FTIR analysis showed few differences in bone mineral index between WT and Ocn−/− mice, while μCT analysis showed no significant difference in cortical and trabecular regions. However, under tail-suspension simulating bone loss condition, the disorder of hydroxyapatite and collagen fiber alignment in Ocn−/− mice led to more obvious changes in bone mineral composition. Collectively, our results revealed that Ocn is necessary for regulating the alignment of minerals parallel to collagen fibrils.
High fish intake rich in n-3 polyunsaturated fatty acids reduces cardiovascular disease incidence in healthy adults: The ATTICA cohort study (2002-2022)
Authors: Critselis Elena , Tsiampalis Thomas , Damigou Evangelia , Georgousopoulou Ekavi , Barkas Fotios , Chrysohoou Christina , Skoumas John , Pitsavos Christos , Liberopoulos Evangelos , Tsioufis Costas , Sfikakis Petros P. , Panagiotakos Demosthenes
Published: March 2023

Background: The long-term effects of high fish intake rich in n-3 fatty acids for deterring cardiovascular disease (CVD) and related adverse outcomes in healthy individuals have not been yet elucidated.

Purpose: To evaluate the association between total seafood, as well as small fish, intake on 10- and 20-year CVD incidence and mortality in healthy adults.

Methods: A prospective cohort study (n = 2,020) was conducted in healthy community dwelling adults in Athens, Greece, selected following age- and sex-based random multistage sampling (mean ± SD age at baseline: 45.2 ± 14.0 years). Seafood (high (>2 servings/week) vs. low (≤2 servings/week) intake), including small fish rich in n-3 fatty acids (high (>1 serving/week) vs. low (≤1 serving/week) intake), consumption was evaluated by semi-quantitative food frequency questionnaire at baseline. The occurrence of non-fatal and/or fatal CVD events (ICD-10) was assessed during 10- and 20-year follow-up periods.

Results: Only 32.7% and 9.6% of participants had high seafood and small fish intakes, respectively. Participants with high seafood intake had 27% decreased 10-year CVD risk (adj. HR:0.73; 95% CI:0.55-0.98) and 74% lower attributable mortality (adj. HR:0.26; 95% CI:0.11-0.58). Participants with high seafood intake also sustained a 24% lower 20-year risk of CVD mortality (adj. HR: 0.76; 95% CI: 0.55-0.98). Moreover, participants with high small fish intake had a lower 10-year CVD risk and 76% decreased risk of 10-year CVD mortality (adj. HR:0.24; 95% CI:0.06-0.99), even among normotensive individuals (adj. HR:0.31; 95% CI:0.13-0.73). When analogous analyses focused on 20-year CVD incidence and mortality, similar but not significant associations were observed (all p-values >0.10).

Conclusion: High intake of seafood, and particularly small fish rich in n-3 fatty acids, was associated with a lower risk of 10-year fatal and non-fatal CVD. Thus, public health interventions aimed at enhancing small fish consumption may most effectively deter long-term CVD outcomes, particularly among low risk normotensive individuals.
Quantitative trait loci associated with apple endophytes during pathogen infection
Authors: Karlström Amanda , Papp-Rupar Matevz , Passey Tom A. J. , Deakin Greg , Xu Xiangming
Published: March 2023

The plant phyllosphere is colonized by microbial communities that can influence the fitness and growth of their host, including the host’s resilience to plant pathogens.There are multiple factors involved in shaping the assemblages of bacterial and fungal endophytes within the phyllosphere, including host genetics and environment. In this work, the role of host genetics in plant-microbiome assembly was studied in a full-sibling family of apple (Malus x domestica) trees infected with the fungal pathogen Neonectria ditissima. A Quantitative Trait Loci (QTL) analysis showed that there are multiple loci which influence the abundance of individual endophytic taxa, with the majority of QTL having a moderate to large effect (20-40%) on endophyte abundance. QTL regions on LG 1, 3, 4, 5, 10, 12, 13, 14 and 15 were shown to affect multiple taxa. Only a small proportion of the variation in overall taxonomic composition was affected by host genotype, with significant QTL hits for principal components explaining <8% and <7.4% of the total variance in bacterial and fungal composition, respectively. Four of the identified QTL colocalised with previously identified regions associated with tolerance to Neonectria ditissima. These results suggest that there is a genetic basis shaping apple endophyte composition and that microbe-host associations in apple could be tailored through breeding.
Insights into the genetic determination of tuber shape and eye depth in potato natural population based on autotetraploid potato genome
Authors: Zhao Long , Zou Meiling , Deng Ke , Xia Chengcai , Jiang Sirong , Zhang Chenji , Ma Yongzhen , Dong Xiaorui , He Miaohua , Na Tiancang , Wang Jian , Xia Zhiqiang , Wang Fang
Published: March 2023

Potato is one of the world’s most important food crops, with a time-consuming breeding process. In this study, we performed a genome-wide association (GWAS) analysis of the two important traits of potato tuber shape and eye depth, using the tetraploid potato genome (2n=4x=48) as a reference. A total of 370 potatoes were divided into three subgroups based on the principal component analysis and evolutionary tree analysis. The genetic diversity within subgroups is low (5.18×10-5, 4.36×10-5 and 4.24×10-5). Genome-wide linkage disequilibrium (LD) analysis showed that their LD is about 60 Kb. GWAS analysis identified that 146 significant single nucleotide polymorphism (SNP) loci at Chr01A1:34.44−35.25 Mb and Chr02A1:28.35−28.54 Mb regions are significantly associated with potato tuber shape, and that three candidate genes that might be related to potato tuber traits, PLATZ transcription factor, UTP-glucose-1-phosphate uridylyltransferase and FAR1 DNA-binding domain, are in the association region of Chr02A1. GWAS analysis identified 53 significant SNP loci at Chr05A2: 49.644-50.146 Mb and Chr06A2: 25.866-26.384 Mb regions with robust associations with potato tuber eye depth. Hydrolase and methyltransferases are present in the association region of Chr05A2, and three CYPs are present in the association region of Chr06A2. Our findings suggested that these genes are closely associated with potato tuber shape and eye depth. Our study identified molecular markers and candidate genes for improving tetraploid potato tuber shape and eye depth and provided ideas and insights for tetraploid potato breeding.
Two salivary proteins Sm10 and SmC002 from grain aphid Sitobion miscanthi modulate wheat defense and enhance aphid performance
Authors: Fu Yu , Liu Xiaobei , Wang Qian , Liu Huan , Cheng Yumeng , Li Hongmei , Zhang Yong , Chen Julian
Published: March 2023

The grain aphid Sitobion miscanthi is a serious pest of wheat that causes severe economic damage by sucking phloem sap and transmitting plant viruses. Here, two putative salivary effector homologs from S. miscanthi (Sm10 and SmC002) were selected based on sequence similarity to other characterized aphid candidate effectors. These effectors were then delivered into wheat cells separately via the type III secretion system of Pseudomonas fluorescens to elucidate their functions in the regulation of plant defenses and host fitness. The results showed that the delivery of either Sm10 or SmC002 into wheat plants significantly suppressed callose deposition and affected the transcript levels of callose synthase genes. The expression levels of salicylic acid (SA)-associated defense genes were upregulated significantly in wheat leaves carrying either Sm10 or SmC002. Moreover, LC-MS/MS analysis revealed that wheat SA levels significantly increased after the delivery of the two effectors. The results of aphid bioassays conducted on the wheat plants carrying Sm10 or SmC002 showed significant increases in the survival and fecundity of S. miscanthi. This study demonstrated that the Sm10 and SmC002 salivary effectors of S. miscanthi enhanced host plant susceptibility and benefited S. miscanthi performance by regulating wheat defense signaling pathways.
Correlation among some phenological and biochemical traits in date palm (Phoenix dactylifera L.) germplasm
Authors: Ahmad Riaz , Ali Hayssam M. , Lisek Anna , Mosa Walid F. A. , Ercisli Sezai , Anjum Muhammad Akbar
Published: March 2023

Date palm is an economically important fruit crop in the arid and semi-arid regions of the world. The knowledge of genetic variation, genotype-by-traits comparison, as well as the relationship among several phenological traits is effective for developing breeding populations by choosing the best allelic combinations and employing selection approaches. Information regarding the genetic variability and inter-relationships among fruit characteristics is facilitating the plant breeders to efficiently exploit the date palm germplasm for the introduction of elite genotypes. The present study was conducted to examine genetic variation among different date palm cultivars -collected from two different research stations in Pakistan as well as the relationship among their phenological and biochemical characteristics. Biplot analysis revealed that the cultivars ‘Dhakki’, ‘Chohara’, and ‘Kupra’ possessed the highest fruit and pulp weights. Moreover, the fruits of the cultivars ‘Champa Kali’ and ‘Shakri’ had the maximum TSS (total soluble solids) and total sugar content. Similar variations were observed in the mean values of the studied phenological and biochemical characteristics as in the biplot analysis. Cluster analysis on the basis of phenological and biochemical characteristics divided 50 cultivars into seven clusters, showing differences in the studied characters. A correlation matrix revealed that pulp weight had a strong relationship with fruit weight, length, and diameter. A strong correlation also existed among antioxidant capacity, antioxidant activity, and total phenolic content. These results demonstrated a huge diversity in phenological and biochemical characteristics of date palm cultivars as well as a correlation among several characteristics of the studied germplasm, which can be exploited in future breeding programs.