bluuebunny/crossref_metadata_2025 huggingface dataset:
RNA-seq data science: From raw data to effective interpretation
Authors: Deshpande Dhrithi , Chhugani Karishma , Chang Yutong , Karlsberg Aaron , Loeffler Caitlin , Zhang Jinyang , Muszyńska Agata , Munteanu Viorel , Yang Harry , Rotman Jeremy , Tao Laura , Balliu Brunilda , Tseng Elizabeth , Eskin Eleazar , Zhao Fangqing , Mohammadi Pejman , P. Łabaj Paweł , Mangul Serghei
Published: March 2023

RNA sequencing (RNA-seq) has become an exemplary technology in modern biology and clinical science. Its immense popularity is due in large part to the continuous efforts of the bioinformatics community to develop accurate and scalable computational tools to analyze the enormous amounts of transcriptomic data that it produces. RNA-seq analysis enables genes and their corresponding transcripts to be probed for a variety of purposes, such as detecting novel exons or whole transcripts, assessing expression of genes and alternative transcripts, and studying alternative splicing structure. It can be a challenge, however, to obtain meaningful biological signals from raw RNA-seq data because of the enormous scale of the data as well as the inherent limitations of different sequencing technologies, such as amplification bias or biases of library preparation. The need to overcome these technical challenges has pushed the rapid development of novel computational tools, which have evolved and diversified in accordance with technological advancements, leading to the current myriad of RNA-seq tools. These tools, combined with the diverse computational skill sets of biomedical researchers, help to unlock the full potential of RNA-seq. The purpose of this review is to explain basic concepts in the computational analysis of RNA-seq data and define discipline-specific jargon.
Zetomipzomib (KZR-616) attenuates lupus in mice via modulation of innate and adaptive immune responses
Authors: Muchamuel Tony , Fan R. Andrea , Anderl Janet L. , Bomba Darrin J. , Johnson Henry W. B. , Lowe Eric , Tuch Brian B. , McMinn Dustin L. , Millare Beatriz , Kirk Christopher J.
Published: March 2023

Zetomipzomib (KZR-616) is a selective inhibitor of the immunoproteasome currently undergoing clinical investigation in autoimmune disorders. Here, we characterized KZR-616 in vitro and in vivo using multiplexed cytokine analysis, lymphocyte activation and differentiation, and differential gene expression analysis. KZR-616 blocked production of >30 pro-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs), polarization of T helper (Th) cells, and formation of plasmablasts. In the NZB/W F1 mouse model of lupus nephritis (LN), KZR-616 treatment resulted in complete resolution of proteinuria that was maintained at least 8 weeks after the cessation of dosing and was mediated in part by alterations in T and B cell activation, including reduced numbers of short and long-lived plasma cells. Gene expression analysis of human PBMCs and tissues from diseased mice revealed a consistent and broad response focused on inhibition of T, B, and plasma cell function and the Type I interferon pathway and promotion of hematopoietic cell lineages and tissue remodeling. In healthy volunteers, KZR-616 administration resulted in selective inhibition of the immunoproteasome and blockade of cytokine production following ex vivo stimulation. These data support the ongoing development of KZR-616 in autoimmune disorders such as systemic lupus erythematosus (SLE)/LN.
Culture density influences the functional phenotype of human macrophages
Authors: Ruder Adele V. , Temmerman Lieve , van Dommelen Joep M.A. , Nagenborg Jan , Lu Chang , Sluimer Judith C. , Goossens Pieter , Biessen Erik A.L.
Published: March 2023

Macrophages (MΦ) are commonly cultured in vitro as a model of their biology and functions in tissues. Recent evidence suggests MΦ to engage in quorum sensing, adapting their functions in response to cues about the proximity of neighboring cells. However, culture density is frequently overlooked in the standardization of culture protocols as well as the interpretation of results obtained in vitro. In this study, we investigated how the functional phenotype of MΦ was influenced by culture density. We assessed 10 core functions of human MΦ derived from the THP-1 cell line as well as primary monocyte-derived MΦ. THP-1 MΦ showed increasing phagocytic activity and proliferation with increasing density but decreasing lipid uptake, inflammasome activation, mitochondrial stress, and secretion of cytokines IL-10, IL-6, IL-1β, IL-8, and TNF-α. For THP-1 MΦ, the functional profile displayed a consistent trajectory with increasing density when exceeding a threshold (of 0.2 x 103 cells/mm2), as visualized by principal component analysis. Culture density was also found to affect monocyte-derived MΦ, with functional implications that were distinct from those observed in THP-1 MΦ, suggesting particular relevance of density effects for cell lines. With increasing density, monocyte-derived MΦ exhibited progressively increased phagocytosis, increased inflammasome activation, and decreased mitochondrial stress, whereas lipid uptake was unaffected. These different findings in THP-1 MΦ and monocyte-derived MΦ could be attributed to the colony-forming growth pattern of THP-1 MΦ. At the lowest density, the distance to the closest neighboring cells showed greater influence on THP-1 MΦ than monocyte-derived MΦ. In addition, functional differences between monocyte-derived MΦ from different donors could at least partly be attributed to differences in culture density. Our findings demonstrate the importance of culture density for MΦ function and demand for awareness of culture density when conducting and interpreting in vitro experiments.
Fatty acid transport protein inhibition sensitizes breast and ovarian cancers to oncolytic virus therapy via lipid modulation of the tumor microenvironment
Authors: Surendran Abera , Jamalkhah Monire , Poutou Joanna , Birtch Rayanna , Lawson Christine , Dave Jaahnavi , Crupi Mathieu J. F. , Mayer Justin , Taylor Victoria , Petryk Julia , de Souza Christiano Tanese , Moodie Neil , Billingsley Jacob Lecompte , Austin Bradley , Cormack Nicole , Blamey Natalie , Rezaei Reza , McCloskey Curtis W. , Fekete Emily E. F. , Birdi Harsimrat K. , Neault Serge , Jamieson Taylor R. , Wylie Brenna , Tucker Sarah , Azad Taha , Vanderhyden Barbara , Tai Lee-Hwa , Bell John C. , Ilkow Carolina S.
Published: March 2023

Introduction

Adipocytes in the tumour microenvironment are highly dynamic cells that have an established role in tumour progression, but their impact on anti-cancer therapy resistance is becoming increasingly difficult to overlook.

Methods

We investigated the role of adipose tissue and adipocytes in response to oncolytic virus (OV) therapy in adipose-rich tumours such as breast and ovarian neoplasms.

Results

We show that secreted products in adipocyte-conditioned medium significantly impairs productive virus infection and OV-driven cell death. This effect was not due to the direct neutralization of virions or inhibition of OV entry into host cells. Instead, further investigation of adipocyte secreted factors demonstrated that adipocyte-mediated OV resistance is primarily a lipid-driven phenomenon. When lipid moieties are depleted from the adipocyte-conditioned medium, cancer cells are re-sensitized to OV-mediated destruction. We further demonstrated that blocking fatty acid uptake by cancer cells, in a combinatorial strategy with virotherapy, has clinical translational potential to overcome adipocyte-mediated OV resistance.

Discussion

Our findings indicate that while adipocyte secreted factors can impede OV infection, the impairment of OV treatment efficacy can be overcome by modulating lipid flux in the tumour milieu.
Neutrophil extracellular traps in tumor progression and immunotherapy
Authors: Yan Meina , Gu Yifeng , Sun Hongxia , Ge Qinghong
Published: March 2023

Tumor immunity is a growing field of research that involves immune cells within the tumor microenvironment. Neutrophil extracellular traps (NETs) are neutrophil-derived extracellular web-like chromatin structures that are composed of histones and granule proteins. Initially discovered as the predominant host defense against pathogens, NETs have attracted increasing attention due to they have also been tightly associated with tumor. Excessive NET formation has been linked to increased tumor growth, metastasis, and drug resistance. Moreover, through direct and/or indirect effects on immune cells, an abnormal increase in NETs benefits immune exclusion and inhibits T-cell mediated antitumor immune responses. In this review, we summarize the recent but rapid progress in understanding the pivotal roles of NETs in tumor and anti-tumor immunity, highlighting the most relevant challenges in the field. We believe that NETs may be a promising therapeutic target for tumor immunotherapy.
Genetically predicted levels of folate, vitamin B12, and risk of autoimmune diseases: A Mendelian randomization study
Authors: Yang Hong , Song Jie , Li Aole , Lv Linshuoshuo , Sun Xiaohui , Mao Yingying , Ye Ding
Published: March 2023

Background

Evidence from observational studies on the association of folate and vitamin B12with autoimmune diseases are conflicting.

Objective

We aimed to investigate the relationship of folate and vitamin B12with autoimmune diseases using Mendelian randomization (MR).

Materials and methods

We selected single-nucleotide polymorphisms associated with folate and vitamin B12at the genome-wide significance level. Summary-level data for four common autoimmune diseases (vitiligo, inflammatory bowel disease, rheumatoid arthritis, and systemic lupus erythematosus) were obtained from large-scale genome-wide association studies, with a sample size of 44,266, 86,640, 58,284, and 23,210, respectively. MR analyses were conducted using the inverse variance weighted (IVW) approach, and sensitivity analyses were further performed to test the robustness.

Results

We found that a higher genetically determined serum folate level per one standard deviation (SD) was associated with a decreased risk of vitiligo by the IVW method [odds ratios (OR) = 0.47; 95% confidence interval (CI): 0.32–0.69;P= 1.33 × 10-4]. Sensitivity analyses using alternative methods showed similar associations, and no evidence of pleiotropy was detected by MR-Egger regression (P= 0.919). In addition, we observed that vitamin B12per one SD was positively associated with IBD (IVW: OR = 1.14, 95% CI: 1.03–1.26,P= 0.010; maximum likelihood: OR = 1.14, 95% CI: 1.01–1.29,P= 0.035; MR-PRESSO: OR = 1.14, 95% CI:1.01–1.28,P=0.037), while the association was not significant after Bonferroni correction.

Conclusion

The study provides convincing evidence for an inverse association between serum folate level and risk of vitiligo. Further studies are warranted to elucidate the possible association between vitamin B12and risk of IBD.
Spatial-temporal transformer network for multi-year ENSO prediction
Authors: Song Dan , Su Xinqi , Li Wenhui , Sun Zhengya , Ren Tongwei , Liu Wen , Liu An-An
Published: March 2023

The El Niño-Southern Oscillation (ENSO) is a quasi-periodic climate type that occurs near the equatorial Pacific Ocean. Extreme periods of this climate type can cause terrible weather and climate anomalies on a global scale. Therefore, it is critical to accurately, quickly, and effectively predict the occurrence of ENSO events. Most existing research methods rely on the powerful data-fitting capability of deep learning which does not fully consider the spatio-temporal evolution of ENSO and its quasi-periodic character, resulting in neural networks with complex structures but a poor prediction. Moreover, due to the large magnitude of ocean climate variability over long intervals, they also ignored nearby prediction results when predicting the Niño 3.4 index for the next month, which led to large errors. To solve these problem, we propose a spatio-temporal transformer network to model the inherent characteristics of the sea surface temperature anomaly map and heat content anomaly map along with the changes in space and time by designing an effective attention mechanism, and innovatively incorporate temporal index into the feature learning procedure to model the influence of seasonal variation on the prediction of the ENSO phenomenon. More importantly, to better conduct long-term prediction, we propose an effective recurrent prediction strategy using previous prediction as prior knowledge to enhance the reliability of long-term prediction. Extensive experimental results show that our model can provide an 18-month valid ENSO prediction, which validates the effectiveness of our method.
An experimental study on nonlinear wave dynamics for freak waves over an uneven bottom
Authors: He Yanli , Wu Guanglin , Mao Hongfei , Chen Hongzhou , Lin Jinbo , Dong Guohai
Published: March 2023

The effect of the non-uniform bathymetry on the nonlinear wave dynamics for the freak wave is investigated experimentally, with emphasis on the interrelations between different nonlinear behaviors resulting from various geometric parameters and spectral analysis. Both the frequency modulation and the nonlinear phase coupling can be provoked by the decreasing water depth and weakened after the top peak of the bar, the nonlinear exhibition for transferring energy to high-frequency contents over shoal supports that frequency modulation can reflect nonlinear phase coupling well. The consistent change of the Hilbert energy spectrum and the bicoherence shows that the main nonlinear interaction in the process of wave propagation in shallowing water is quadratic nonlinearity. In addition, the geometric study is conducted to investigate the effect of the water depth on the parametric variations, the research results show that the mean asymmetry and kurtosis change abruptly when the wave approaches the top peak of the bar. As the wave propagates along the water flume, freak waves can be generated at various locations, however, they appear more frequently as waves propagate close to the shallowest water depth, and the maximum probability of occurrence for a freak wave can be up to about 1%.
Evaluation of corneal dendritic cell density and subbasal nerve density in contact lens wearers using IVCM: A systematic review and meta-analysis
Authors: Guo Rongjie , Jiang Jiaxuan , Zhang Yanan , Liang Qi , Chen Taige , Hu Kai
Published: March 2023

Purpose

To evaluate the subclinical changes in corneal dendritic cell density (CDCD) and corneal subbasal nerve density (CSND) in asymptomatic contact lens (CL) wearers.

Methods

Databases including PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials were searched for trials and studies reporting the changes of corneal CDCD and CSND in contact lens wearers published until 25 June 2022. PRISMA guidelines as well as recommended meta-analysis practices were followed. Meta-analysis was conducted using RevMan V.5.3 software.

Results

After the screening, 10 studies with 587 eyes of 459 participants were included. Seven studies reported the data of CDCD. Compared with the control group, CDCD in the CL wearers was higher (18.19, 95% CI 18.8–27.57, p = 0.0001). Type of in vivo confocal microscopy (IVCM), wear duration, and frequency of lens change were sources of heterogeneity. The difference in CSND between CL wearers and the control group was insignificant, and subgroup analysis did not reveal a source of heterogeneity.

Conclusion

Overall, CDCD increased in CL wears, while CSND did not show significant differences. IVCM is a feasible tool to assess subclinical changes in CL wearers.
β-Lactam potentiators to re-sensitize resistant pathogens: Discovery, development, clinical use and the way forward
Authors: Narendrakumar Lekshmi , Chakraborty Medha , Kumari Shashi , Paul Deepjyoti , Das Bhabatosh
Published: March 2023

β-lactam antibiotics are one of the most widely used and diverse classes of antimicrobial agents for treating both Gram-negative and Gram-positive bacterial infections. The β-lactam antibiotics, which include penicillins, cephalosporins, monobactams and carbapenems, exert their antibacterial activity by inhibiting the bacterial cell wall synthesis and have a global positive impact in treating serious bacterial infections. Today, β-lactam antibiotics are the most frequently prescribed antimicrobial across the globe. However, due to the widespread use and misapplication of β-lactam antibiotics in fields such as human medicine and animal agriculture, resistance to this superlative drug class has emerged in the majority of clinically important bacterial pathogens. This heightened antibiotic resistance prompted researchers to explore novel strategies to restore the activity of β-lactam antibiotics, which led to the discovery of β-lactamase inhibitors (BLIs) and other β-lactam potentiators. Although there are several successful β-lactam-β-lactamase inhibitor combinations in use, the emergence of novel resistance mechanisms and variants of β-lactamases have put the quest of new β-lactam potentiators beyond precedence. This review summarizes the success stories of β-lactamase inhibitors in use, prospective β-lactam potentiators in various phases of clinical trials and the different strategies used to identify novel β-lactam potentiators. Furthermore, this review discusses the various challenges in taking these β-lactam potentiators from bench to bedside and expounds other mechanisms that could be investigated to reduce the global antimicrobial resistance (AMR) burden.
Classification and prediction of cognitive trajectories of cognitively unimpaired individuals
Authors: Kim Young Ju , Kim Si Eun , Hahn Alice , Jang Hyemin , Kim Jun Pyo , Kim Hee Jin , Na Duk L. , Chin Juhee , Seo Sang Won
Published: March 2023

Objectives

Efforts to prevent Alzheimer’s disease (AD) would benefit from identifying cognitively unimpaired (CU) individuals who are liable to progress to cognitive impairment. Therefore, we aimed to develop a model to predict cognitive decline among CU individuals in two independent cohorts.

Methods

A total of 407 CU individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and 285 CU individuals from the Samsung Medical Center (SMC) were recruited in this study. We assessed cognitive outcomes by using neuropsychological composite scores in the ADNI and SMC cohorts. We performed latent growth mixture modeling and developed the predictive model.

Results

Growth mixture modeling identified 13.8 and 13.0% of CU individuals in the ADNI and SMC cohorts, respectively, as the “declining group.” In the ADNI cohort, multivariable logistic regression modeling showed that increased amyloid-β (Aβ) uptake (β [SE]: 4.852 [0.862], p < 0.001), low baseline cognitive composite scores (β [SE]: −0.274 [0.070], p < 0.001), and reduced hippocampal volume (β [SE]: −0.952 [0.302], p = 0.002) were predictive of cognitive decline. In the SMC cohort, increased Aβ uptake (β [SE]: 2.007 [0.549], p < 0.001) and low baseline cognitive composite scores (β [SE]: −4.464 [0.758], p < 0.001) predicted cognitive decline. Finally, predictive models of cognitive decline showed good to excellent discrimination and calibration capabilities (C-statistic = 0.85 for the ADNI model and 0.94 for the SMC model).

Conclusion

Our study provides novel insights into the cognitive trajectories of CU individuals. Furthermore, the predictive model can facilitate the classification of CU individuals in future primary prevention trials.
Basilar artery plaque distribution is associated with pontine infarction and vertebrobasilar artery geometry
Authors: Zheng Jinmei , Sun Bin , Lin Ruolan , Teng Yongqi , Zheng Enshuang , Zhao Xihai , Xue Yunjing
Published: March 2023

Background

Basilar artery (BA) atherosclerosis is a common cause of posterior-circulation ischemic stroke. In this study, we investigate the relationship between BA plaque distribution and pontine infarction (PI), further, explore the influence of vertebrobasilar artery (VBA) geometries on BA plaque distribution.

Materials and methods

303 patients were performed with MRI in this study, patients were divided into three groups: no cerebral infarction (NCI), anterior circulation cerebral infarction (ACCI), and posterior circulation cerebral infarction (PCCI), the VBA geometry was classified into four configurations: Walking, Tuning Fork, Lambda, and No Confluence. The AP-Mid-BA, Lateral-Mid-BA, and VA-BA angles were measured on three-dimensional time-of-flight magnetic resonance angiography. Patients underwent high-resolution magnetic resonance imaging to evaluate the BA plaque distribution (either anterior, posterior, or lateral wall). Acute and subacute cerebral infarction [including pontine infarction (PI)] were identified by T2 weighted imaging-fluid-attenuated inversion recovery and diffusion-weighted imaging.

Results

The presence of BA plaque (P < 0.001) were associated with PCCI. Eighty-six patients all with BA plaque were further analyzed, compared with patients without pontine infarction, patients with pontine infarction were more likely to have plaque distributed at the posterior wall (P = 0.009) and have larger VA-BA anger (38.72° ± 26.01° vs. 26.59° ± 17.33°, P = 0.035). BA plaques in patients with pontine infarction were more frequently located at the posterior wall (50.00%) than at the anterior (10.00%) and lateral (37.50%) walls (P = 0.028). In Walking, Lambda and No Confluence geometry, BA plaques were prone to located at the lateral wall than at the anterior and posterior walls (all P ≤ 0.05). In the Tuning Fork group, BA plaques were evenly distributed.

Conclusion

BA plaque was related to PCCI, BA plaque distribution was associated with PI, and VBA configuration strongly influences BA plaque distribution.
Tracking auditory mismatch negativity responses during full conscious state and coma
Authors: Herrera-Diaz Adianes , Boshra Rober , Tavakoli Paniz , Lin Chia-Yu A. , Pajankar Netri , Bagheri Elham , Kolesar Richard , Fox-Robichaud Alison , Hamielec Cindy , Reilly James P. , Connolly John F.
Published: March 2023

The mismatch negativity (MMN) is considered the electrophysiological change-detection response of the brain, and therefore a valuable clinical tool for monitoring functional changes associated with return to consciousness after severe brain injury. Using an auditory multi-deviant oddball paradigm, we tracked auditory MMN responses in seventeen healthy controls over a 12-h period, and in three comatose patients assessed over 24 h at two time points. We investigated whether the MMN responses show fluctuations in detectability over time in full conscious awareness, or whether such fluctuations are rather a feature of coma. Three methods of analysis were utilized to determine whether the MMN and subsequent event-related potential (ERP) components could be identified: traditional visual analysis, permutation t-test, and Bayesian analysis. The results showed that the MMN responses elicited to the duration deviant-stimuli are elicited and reliably detected over the course of several hours in healthy controls, at both group and single-subject levels. Preliminary findings in three comatose patients provide further evidence that the MMN is often present in coma, varying within a single patient from easily detectable to undetectable at different times. This highlights the fact that regular and repeated assessments are extremely important when using MMN as a neurophysiological predictor of coma emergence.
Corticosteroids in childhood epilepsies: A systematic review
Authors: Becker Lena-Luise , Kaindl Angela M.
Published: March 2023

Corticosteroids have been used for the treatment of patients with epilepsy for more than 6 decades, based on the hypothesis of inflammation in the genesis and/or promotion of epilepsy. We, therefore, aimed to provide a systematic overview of the use of corticosteroid regimes in childhood epilepsies in line with the PRISMA guidelines. We performed a structured literature search via PubMed and identified 160 papers with only three randomized controlled trials excluding the substantial trials on epileptic spasms. Corticosteroid regimes, duration of treatment (days to several months), and dosage protocols were highly variable in these studies. Evidence supports the use of steroids in epileptic spasms; however, there is only limited evidence for a positive effect for other epilepsy syndromes, e.g., epileptic encephalopathy with spike-and-wave activity in sleep [(D)EE-SWAS] or drug-resistant epilepsies (DREs). In (D)EE-SWAS (nine studies, 126 patients), 64% of patients showed an improvement either in the EEG or in their language/cognition following various steroid treatment regimes. In DRE (15 studies, 436 patients), a positive effect with a seizure reduction in 50% of pediatric and adult patients and seizure freedom in 15% was identified; however, no recommendation can be drawn due to the heterozygous cohort. This review highlights the immense need for controlled studies using steroids, especially in DRE, to offer patients new treatment options.
Frontal midline theta rhythm and gamma activity measured by sheet-type wearable EEG device
Authors: Ueno Keita , Ishii Ryouhei , Ueda Masaya , Yuri Takuma , Shiroma China , Hata Masahiro , Naito Yasuo
Published: March 2023

Introduction

The current study measured the frontal midline theta rhythm (Fmθ), which appears in the frontal midline region during the attentional focus state, using the sheet-type wearable electroencephalograph (EEG) device HARU-1, and examined the modulation of frontal gamma band activity by cognitive tasks.

Methods

We measured the frontal EEG of 20 healthy subjects using HARU-1 for 2 min during the rest eyes-closed condition and simple mental calculation task condition, respectively. Statistical analyses were conducted using permutation testing based on t-test and cluster analysis to compare the results between the resting state and the task condition.

Results

Twelve of 20 subjects showed Fmθ during the task condition. The 12 subjects with Fmθ showed significantly higher activity of the theta and gamma bands, and significantly low activity of the alpha band during the task condition compared to the resting condition. In the eight subjects without Fmθ were significantly low activity of the alpha and beta bands and no significant activity in the theta and gamma band activity during the task condition compared to the resting condition.

Discussion

These results indicate that it is possible to measure Fmθ using HARU-1. A novel finding was the gamma band activity appearing with Fmθ in the left and right frontal forehead regions, suggesting that it reflects the function of the prefrontal cortex in working memory tasks.
Establishment of a new prognostic risk model of MAPK pathway-related molecules in kidney renal clear cell carcinoma based on genomes and transcriptomes analysis
Authors: Zhang Peizhi , Li Jiayi , Wang Zicheng , Zhao Leizuo , Qiu Jiechuan , Xu Yingkun , Wu Guangzhen , Xia Qinghua
Published: March 2023

Purpose

The mitogen-activated protein kinase (MAPK) signaling pathway is often studied in oncology as the most easily mentioned signaling pathway. This study aims to establish a new prognostic risk model of MAPK pathway related molecules in kidney renal clear cell carcinoma (KIRC) based on genome and transcriptome analysis.

Methods

In our study, RNA-seq data were acquired from the KIRC dataset of The Cancer Genome Atlas (TCGA) database. MAPK signaling pathway-related genes were obtained from the gene enrichment analysis (GSEA) database. We used “glmnet” and the “survival” extension package for LASSO (Least absolute shrinkage and selection operator) regression curve analysis and constructed a prognosis-related risk model. The survival curve and the COX regression analysis were used the “survival” expansion packages. The ROC curve was plotted using the “survival ROC” extension package. We then used the “rms” expansion package to construct a nomogram plot. We performed a pan-cancer analysis of CNV (copy number variation), SNV (single nucleotide variant), drug sensitivity, immune infiltration, and overall survival (OS) of 14 MAPK signaling pathway-related genes using several analysis websites, such as GEPIA website and TIMER database. Besides, the immunohistochemistry and pathway enrichment analysis used The Human Protein Atlas (THPA) database and the GSEA method. Finally, the mRNA expression of risk model genes in clinical renal cancer tissues versus adjacent normal tissues was further verified by real-time quantitative reverse transcription (qRT-PCR).

Results

We performed Lasso regression analysis using 14 genes and created a new KIRC prognosis-related risk model. High-risk scores suggested that KIRC patients with lower-risk scores had a significantly worse prognosis. Based on the multivariate Cox analysis, we found that the risk score of this model could serve as an independent risk factor for KIRC patients. In addition, we used the THPA database to verify the differential expression of proteins between normal kidney tissues and KIRC tumor tissues. Finally, the results of qRT-PCR experiments suggested large differences in the mRNA expression of risk model genes.

Conclusions

This study constructs a KIRC prognosis prediction model involving 14 MAPK signaling pathway-related genes, which is essential for exploring potential biomarkers for KIRC diagnosis.
Perioperative and long-term survival outcomes of laparoscopic versus open hepatectomy for BCLC stage A large hepatocellular carcinoma patients in difficult segments: A two-centre, propensity score matching analysis
Authors: Ding Dong-yang , Liu Lei , Lin Kong-ying , Gan Xiao-jie , Guo Xing-gang , Ding Wen-bin , Sun Da-peng , Li Wen , Tao Qi-fei , Gu Fang-ming , Guo Wei-xing , Zeng Yong-yi , Zhou Wei-ping , Yuan Sheng-xian
Published: March 2023

Background

The differences in short- and long-term outcome between laparoscopic liver resection (LLR) and open liver resection (OLR) for BCLC stage A large hepatocellular carcinoma (HCC) in difficult segments (I, IVa, VII, VIII) remain unclear. This PSM two-centre study aimed to compare perioperative and long-term survival outcomes of LLR with OLR for this HCC.

Methods

HCC patients with BCLC stage A who underwent OLR or LLR in two medical centres were enrolled in the study. PSM analysis was performed to match patients between the LLR cohort and OLR cohort. Survival was analysed based on the Kaplan–Meier method. Independent risk factors were identified by Cox regression.

Results

After PSM, 35 patients remained in the LLR cohort, and 84 remained in the OLR cohort. Patients in the LLR cohort had more intraoperative blood loss (p=0.036) and shorter hospital stays after surgery (p<0.001). The LLR cohort and OLR cohort had no difference in intraoperative blood transfusion, surgical margin or postoperative short-term outcomes. The OS and RFS were not significantly different between the two cohorts. The OS and RFS of these two cohorts were not different in the subgroup analysis. Surgical margin was identified as an independent risk factor for tumour recurrence.

Conclusion

For BCLC stage A large HCC patients with lesions in difficult segments, LLR was feasible and had shorter hospital stay than OLR. In addition, a surgical margin ≥1 cm could significantly decrease the recurrence probability for large HCC located in different segments without compromising short-term outcomes.
Non-canonical Wnt/Ca2+ signaling is essential to promote self-renewal and proliferation in colon cancer stem cells
Authors: Sarabia-Sánchez Miguel Angel , Moreno-Londoño Angela Patricia , Castañeda-Patlán María Cristina , Alvarado-Ortiz Eduardo , Martínez-Morales Juan Carlos , Robles-Flores Martha
Published: March 2023

Introduction

Cancer Stem Cells (CSC) are responsible for maintaining tumor growth, chemoresistance, and metastasis. Therefore, understanding their characteristics is critical to progress in cancer therapy. While the contribution of the canonical Wnt/b-catenin signaling in both normal and CSCs had been well established, the function of non-canonical Wnt signaling cascades in stem cells is unclear. Recently, we reported that Wnt ligands trigger complex signaling in which the canonical and non-canonical responses can be simultaneously activated by one ligand in colon cancer cells, suggesting, therefore, that noncanonical Wnt pathways may also be important in CSCs.

Methods

The present work aimed to know the role of the Wnt/Ca2+ pathway in colon CSCs. We used tumorspheres as a model of CSCs enrichment of CRC cell lines with different Wnt/b-catenin contexts.

Results

Using Wnt3a and Wnt5a as prototype ligands to activate the canonical or the non-canonical pathways, respectively, we found that both Wnt3a and Wnt5a promote sphere-formation capacity and proliferation without stimulating b-catenin-dependent transcription. Upregulation of sphere formation by Wnt5a or Wnt3a requires the downstream activation of Phospholipase C and transcriptional factor NFAT. Moreover, the single specific inhibition of PLC or NFAT, using U73122 and 11R-VIVIT, respectively, leads to impaired sphere formation.

Discussion

Our results indicate that both types of ligands activate the Wnt/Ca2+ signaling axis to induce/maintain the self-renewal efficiency of CSCs, demonstrating to be essential for the functions of CSC in colon cancer.
Risk factors for length of NICU stay of newborns: A systematic review
Authors: Fu Maoling , Song Wenshuai , Yu Genzhen , Yu Yaqi , Yang Qiaoyue
Published: March 2023

Background

The improvement in survival of preterm infants is accompanied by an increase in neonatal intensive care unit (NICU) admissions. Prolonged length of stay in the NICU (LOS-NICU) increases the incidence of neonatal complications and even mortality and places a significant economic burden on families and strain on healthcare systems. This review aims to identify risk factors influencing LOS-NICU of newborns and to provide a basis for interventions to shorten LOS-NICU and avoid prolonged LOS-NICU.

Methods

A systematic literature search was conducted in PubMed, Web of Science, Embase, and Cochrane library for studies that were published in English from January 1994 to October 2022. The PRISMA guidelines were followed in all phases of this systematic review. The Quality in Prognostic Studies (QUIPS) tool was used to assess methodological quality.

Results

Twenty-three studies were included, 5 of which were of high quality and 18 of moderate quality, with no low-quality literature. The studies reported 58 possible risk factors in six broad categories (inherent factors; antenatal treatment and maternal factors; diseases and adverse conditions of the newborn; treatment of the newborn; clinical scores and laboratory indicators; organizational factors).

Conclusions

We identified several of the most critical risk factors affecting LOS-NICU, including birth weight, gestational age, sepsis, necrotizing enterocolitis, bronchopulmonary dysplasia, and retinopathy of prematurity. As only a few high-quality studies are available at present, well-designed and more extensive prospective studies investigating the risk factors affecting LOS-NICU are still needed in the future.
Exosomes: The role in mammalian reproductive regulation and pregnancy-related diseases
Authors: Guo Xing-Ru , Ma Yun , Ma Zi-Ming , Dai Tian-Shu , Wei Shi-Hao , Chu Yuan-Kui , Dan Xin-Gang
Published: March 2023

Exosomes are a kind of extracellular vesicles that are produced and secreted by different mammalian cells. They serve as cargo proteins and can transfer different kinds of biomolecules, including proteins, lipids, and nucleic acids, which consequently act on target cells to exert different biological effects. Recent years have witnessed a significant increase in the number of studies on exosomes due to the potential effects of exosomes in the diagnosis and treatment of cancers, neurodegenerative diseases, and immune disorders. Previous studies have demonstrated that exosomal contents, especially miRNAs, are implicated in numerous physiological processes such as reproduction, and are crucial regulators of mammalian reproduction and pregnancy-related diseases. Here, we describe the origin, composition, and intercellular communication of exosomes, and discuss their functions in follicular development, early embryonic development, embryonic implantation, male reproduction and development of pregnancy-related diseases in humans and animals. We believe this study will provide a foundation for revealing the mechanism of exosomes in regulating mammalian reproduction, and providing new approaches and ideas for the diagnosis and treatment of pregnancy-related diseases.
Normalizing salt content by mixing native human airway mucus samples normalizes sample rheology
Authors: Markovetz Matthew R. , Hibbard Jacob E. , Plott Lucas M. , Bacudio Lawrence G. , Kissner William J. , Ghio Andrew , Kumar Priya A. , Arora Harendra , Hill David B.
Published: March 2023

Across the globe, millions of people are affected by muco-obstructive pulmonary diseases like cystic fibrosis, asthma, and chronic obstructive pulmonary disease. In MOPDs, the airway mucus becomes hyperconcentrated, increasing viscoelasticity and impairing mucus clearance. Research focused on treatment of MOPDs requires relevant sources of airway mucus both as a control sample type and as a basis for manipulation to study the effects of additional hyperconcentration, inflammatory milieu, and biofilm growth on the biochemical and biophysical properties of mucus. Endotracheal tube mucus has been identified as a prospective source of native airway mucus given its several advantages over sputum and airway cell culture mucus such as ease of access and in vivo production that includes surface airway and submucosal gland secretions. Still, many ETT samples suffer from altered tonicity and composition from either dehydration, salivary dilution, or other contamination. Herein, the biochemical compositions of ETT mucus from healthy human subjects were determined. Samples were characterized in terms of tonicity, pooled, and restored to normal tonicity. Salt-normalized ETT mucus exhibited similar concentration-dependent rheologic properties as originally isotonic mucus. This rheology agreed across spatial scales and with previous reports of the biophysics of ETT mucus. This work affirms previous reports of the importance of salt concentration on mucus rheology and presents methodology to increase yield native airway mucus samples for laboratory use and manipulation.
Voluntary exercise modulates pathways associated with amelioration of retinal degenerative diseases
Authors: Chu-Tan Joshua A. , Cioanca Adrian V. , Wooff Yvette , Kirkby Max , Ellis Marissa , Gulati Pranay , Karl Tim , Boatright Jeffrey H. , Bales Katie , Nickerson John , Natoli Riccardo
Published: March 2023

Background: Exercise has been shown to promote a healthier and longer life and linked to a reduced risk of developing neurodegenerative diseases including retinal degenerations. However, the molecular pathways underpinning exercise-induced cellular protection are not well understood. In this work we aim to profile the molecular changes underlying exercise-induced retinal protection and investigate how exercise-induced inflammatory pathway modulation may slow the progression of retinal degenerations.

Methods: Female C57Bl/6J mice at 6 weeks old were given free access to open voluntary running wheels for a period of 28 days and then subjected to 5 days of photo-oxidative damage (PD)-induced retinal degeneration. Following, retinal function (electroretinography; ERG), morphology (optical coherence tomography; OCT) and measures of cell death (TUNEL) and inflammation (IBA1) were analysed and compared to sedentary controls. To decipher global gene expression changes as a result of voluntary exercise, RNA sequencing and pathway and modular gene co-expression analyses were performed on retinal lysates of exercised and sedentary mice that were subjected to PD, as well as healthy dim-reared controls.

Results: Following 5 days of PD, exercised mice had significantly preserved retinal function, integrity and reduced levels of retinal cell death and inflammation, compared to sedentary controls. In response to voluntary exercise, inflammatory and extracellular matrix integrity pathways were significantly modulated, with the gene expression profile of exercised mice more closely trending towards that of a healthy dim-reared retina.

Conclusion: We suggest that voluntary exercise may mediate retinal protection by influencing key pathways involved in regulating retinal health and shifting the transcriptomic profile to a healthy phenotype.
In silico analysis of the contribution of cardiomyocyte-fibroblast electromechanical interaction to the arrhythmia
Authors: Kursanov Alexander , Balakina-Vikulova Nathalie A. , Solovyova Olga , Panfilov Alexander , Katsnelson Leonid B.
Published: March 2023

Although fibroblasts are about 5–10 times smaller than cardiomyocytes, their number in the ventricle is about twice that of cardiomyocytes. The high density of fibroblasts in myocardial tissue leads to a noticeable effect of their electromechanical interaction with cardiomyocytes on the electrical and mechanical functions of the latter. Our work focuses on the analysis of the mechanisms of spontaneous electrical and mechanical activity of the fibroblast-coupled cardiomyocyte during its calcium overload, which occurs in a variety of pathologies, including acute ischemia. For this study, we developed a mathematical model of the electromechanical interaction between cardiomyocyte and fibroblasts and used it to simulate the impact of overloading cardiomyocytes. In contrast to modeling only the electrical interaction between cardiomyocyte and fibroblasts, the following new features emerge in simulations with the model that accounts for both electrical and mechanical coupling and mechano-electrical feedback loops in the interacting cells. First, the activity of mechanosensitive ion channels in the coupled fibroblasts depolarizes their resting potential. Second, this additional depolarization increases the resting potential of the coupled myocyte, thus augmenting its susceptibility to triggered activity. The triggered activity associated with the cardiomyocyte calcium overload manifests itself in the model either as early afterdepolarizations or as extrasystoles, i.e., extra action potentials and extra contractions. Analysis of the model simulations showed that mechanics contribute significantly to the proarrhythmic effects in the cardiomyocyte overloaded with calcium and coupled with fibroblasts, and that mechano-electrical feedback loops in both the cardiomyocyte and fibroblasts play a key role in this phenomenon.
ZnO nanoparticles efficiently enhance drought tolerance in Dracocephalum kotschyi through altering physiological, biochemical and elemental contents
Authors: Karimian Zahra , Samiei Leila
Published: March 2023

Using nanofertilizers in certain concentrations can be a novel method to alleviate drought stress effects in plants as a global climate problem. We aimed to determine the impacts of zinc nanoparticles (ZnO-N) and zinc sulfate (ZnSO4) fertilizers on the improvement of drought tolerance in Dracocephalum kotschyi as a medicinal-ornamental plant. Plants were treated with three doses of ZnO-N and ZnSO4 (0, 10, and 20 mg/l) under two levels of drought stress [50% and 100% field capacity (FC)]. Relative water content (RWC), electrolyte conductivity (EC), chlorophyll, sugar, proline, protein, superoxide dismutase (SOD), polyphenol oxidase (PPO) and, guaiacol peroxidase (GPO) were measured. Moreover, the concentration of some elements interacting with Zn was reported using the SEM-EDX method. Results indicated that foliar fertilization of D. kotschyi under drought stress with ZnO-N decreased EC, while ZnSO4 application was less effective. Moreover, sugar and proline content as well as activity of SOD and GPO (and to some extent PPO) in treated plants by 50% FC, increased under the influence of ZnO-N. ZnSO4 application could increase chlorophyll and protein content and PPO activity in this plant under drought stress. Based on the results, ZnO-N and then ZnSO4 improved the drought tolerance of D. kotschyi through their positive effects on physiological and biochemical attributes changing the concentration of Zn, P, Cu, and Fe. Accordingly, due to the increased sugar and proline content and also antioxidant enzyme activity (SOD, GPO, and to some extent PPO) on enhancing drought tolerance in this plant, ZnO-N fertilization is advisable.
Phenotyping grapevine red blotch virus and grapevine leafroll-associated viruses before and after symptom expression through machine-learning analysis of hyperspectral images
Authors: Sawyer Erica , Laroche-Pinel Eve , Flasco Madison , Cooper Monica L. , Corrales Benjamin , Fuchs Marc , Brillante Luca
Published: March 2023

Introduction

Grapevine leafroll-associated viruses (GLRaVs) and grapevine red blotch virus (GRBV) cause substantial economic losses and concern to North America’s grape and wine industries. Fast and accurate identification of these two groups of viruses is key to informing disease management strategies and limiting their spread by insect vectors in the vineyard. Hyperspectral imaging offers new opportunities for virus disease scouting.

Methods

Here we used two machine learning methods, i.e., Random Forest (RF) and 3D-Convolutional Neural Network (CNN), to identify and distinguish leaves from red blotch-infected vines, leafroll-infected vines, and vines co-infected with both viruses using spatiospectral information in the visible domain (510-710nm). We captured hyperspectral images of about 500 leaves from 250 vines at two sampling times during the growing season (a pre-symptomatic stage at veraison and a symptomatic stage at mid-ripening). Concurrently, viral infections were determined in leaf petioles by polymerase chain reaction (PCR) based assays using virus-specific primers and by visual assessment of disease symptoms.

Results

When binarily classifying infected vs. non-infected leaves, the CNN model reaches an overall maximum accuracy of 87% versus 82.8% for the RF model. Using the symptomatic dataset lowers the rate of false negatives. Based on a multiclass categorization of leaves, the CNN and RF models had a maximum accuracy of 77.7% and 76.9% (averaged across both healthy and infected leaf categories). Both CNN and RF outperformed visual assessment of symptoms by experts when using RGB segmented images. Interpretation of the RF data showed that the most important wavelengths were in the green, orange, and red subregions.

Discussion

While differentiation between plants co-infected with GLRaVs and GRBV proved to be relatively challenging, both models showed promising accuracies across infection categories.