bluuebunny/crossref_metadata_2025 huggingface dataset:
Bridging Size and Charge Effects of Mesoporous Silica Nanoparticles for Crossing the Blood–Brain Barrier
Authors: Chen Yi-Ping , Chou Chih-Ming , Chang Tsu-Yuan , Ting Hao , Dembélé Julien , Chu You-Tai , Liu Tsang-Pai , Changou Chun A. , Liu Chien-Wei , Chen Chien-Tsu
Published: June 2022

The blood–brain barrier (BBB) is a highly selective cellular barrier that tightly controls the microenvironment of the central nervous system to restrict the passage of substances, which is a primary challenge in delivering therapeutic drugs to treat brain diseases. This study aimed to develop simple surface modifications of mesoporous silica nanoparticles (MSNs) without external stimuli or receptor protein conjugation, which exhibited a critical surface charge and size allowing them to cross the BBB. A series of MSNs with various charges and two different sizes of 50 and 200 nm were synthesized, which showed a uniform mesoporous structure with various surface zeta potentials ranging from +42.3 to −51.6 mV. Confocal microscopic results showed that 50 nm of strongly negatively charged N4-RMSN50@PEG/THPMP (∼−40 mV) could be significantly observed outside blood vessels of the brain in Tg(zfli1:EGFP) transgenic zebrafish embryos superior to the other negatively charged MSNs. However, very few positively charged MSNs were found in the brain, indicating that negatively charged MSNs could successfully penetrate the BBB. The data were confirmed by high-resolution images of 3D deconvoluted confocal microscopy and two-photon microscopy and zebrafish brain tissue sections. In addition, while increasing the size to 200 nm but maintaining the similar negative charge (∼40 mV), MSNs could not be detected in the brain of zebrafish, suggesting that transport across the BBB based on MSNs occurred in charge- and size-dependent manners. No obvious cytotoxicity was observed in the CTX-TNA2 astrocyte cell line and U87-MG glioma cell line treated with MSNs. After doxorubicin (Dox) loading, N4-RMSN50@PEG/THPMP/Dox enabled drug delivery and pH-responsive release. The toxicity assay showed that N4-RMSN50@PEG/THPMP could reduce Dox release, resulting in the increase of the survival rate in zebrafish. Flow cytometry demonstrated N4-RMSN50@PEG/THPMP had few cellular uptakes. Protein corona analysis revealed three transporter proteins, such as afamin, apolipoprotein E, and basigin, could contribute to BBB penetration, validating the possible mechanism of N4-RMSN50@PEG/THPMP crossing the BBB. With this simple approach, MSNs with critical negative charge and size could overcome the BBB-limiting characteristics of therapeutic drug molecules; furthermore, their use may also cause drug sustained-release in the brain, decreasing peripheral toxicity.
Genetic Predisposition of Anti-Cytomegalovirus Immunoglobulin G Levels and the Risk of 9 Cardiovascular Diseases
Authors: Tan Jiang-Shan , Ren Jia-Meng , Fan Luyun , Wei Yuhao , Hu Song , Zhu Sheng-Song , Yang Yanmin , Cai Jun
Published: June 2022

Background

Accumulating evidence has indicated that persistent human cytomegalovirus (HCMV) infection is associated with several cardiovascular diseases including atherosclerosis and coronary artery disease. However, whether there is a causal association between the level of anti-HCMV immune response and the risk of cardiovascular diseases remains unknown.

Methods

Single-nucleotide polymorphisms associated with anti-cytomegalovirus immunoglobulin (Ig) G levels were used as instrumental variables to estimate the causal effect of anti-cytomegalovirus IgG levels on 9 cardiovascular diseases (including atrial fibrillation, coronary artery disease, hypertension, heart failure, peripheral artery disease, pulmonary embolism, deep vein thrombosis of the lower extremities, rheumatic valve diseases, and non-rheumatic valve diseases). For each cardiovascular disease, Mendelian randomization (MR) analyses were performed. Inverse variance-weighted meta-analysis (IVW) with a random-effects model was used as a principal analysis. In addition to this, the weighted median approach and MR-Egger method were used for further sensitivity analysis.

Results

In the IVW analysis, genetically predicted anti-cytomegalovirus IgG levels were suggestively associated with coronary artery disease with an odds ratio (OR) of 1.076 [95% CI, 1.009–1.147; p = 0.025], peripheral artery disease (OR 1.709; 95% CI, 1.039–2.812; p = 0.035), and deep vein thrombosis (OR 1.002; 95% CI, 1.000–1.004; p = 0.025). In the further analysis, similar causal associations were obtained from weighted median analysis and MR-Egger analysis with lower precision. No notable heterogeneities and horizontal pleiotropies were observed (p > 0.05).

Conclusions/Interpretation

Our findings first provide direct evidence that genetic predisposition of anti-cytomegalovirus IgG levels increases the risk of coronary artery disease, peripheral artery disease, and deep vein thrombosis.
Fecal Microbiota Transplantation and Health Outcomes: An Umbrella Review of Meta-Analyses of Randomized Controlled Trials
Authors: Li Yapeng , Zhang Tingting , Sun Jiahui , Liu Nanyang
Published: June 2022

Background

Meta-analysis of randomized clinical trials (RCT) demonstrated several health benefits of fecal microbiota transplantation (FMT). However, there has been little comprehensive assessment of the strength and quality of evidence. We conducted an umbrella review to summarize the evidence of the association between FMT and health outcomes.

Methods

PubMed, Embase, and Cochrane library databases were searched from inception to August 6, 2021. The random-effects model was applied to recalculate the effect estimates. We used AMSTAR 2 and GRADE to assess the methodological quality and to grade the evidence.

Results

A total of 7 meta-analyses comprising 26 RCTs (median [IQR] primary study, 6 [2-7]; median [IQR] sample size, 267 [147-431] participants) were included in the current umbrella review describing 45 unique associations. There were 22 statistically significant associations (49%) demonstrating beneficial outcomes of FMT for antibiotic resistance burden, functional constipation, inflammatory bowel disease, and C. difficile infection. FMT does not appear to be associated with positive outcomes in irritable bowel syndrome and metabolic syndrome. Eight significant associations (36%) were supported by moderate-quality evidence, nine associations (41%) were supported by low-quality evidence, and the remaining associations found to be significant were supported by very low-quality evidence.

Conclusion

Although we found that FMT was positively associated with several outcomes, caution should be exercised in choosing this approach, given the insufficient number of primary studies, low methodological quality, and low quality of evidence. Further high-quality randomized controlled trials with long-term follow-up are needed to improve the strength and credibility of the evidence base.
Chimonanthus nitens Oliv. Leaf Granule Ameliorates DSS-Induced Acute Colitis Through Treg Cell Improvement, Oxidative Stress Reduction, and Gut Microflora Modulation
Authors: Huang Jia-Qi , Wei Si-Yi , Cheng Nian , Zhong You-Bao , Yu Fei-Hao , Li Ming-Da , Liu Duan-Yong , Li Shan-Shan , Zhao Hai-Mei
Published: June 2022

The rising incidence of ulcerative colitis has become a new challenge for public health. Chimonanthus nitens Oliv. leaf granule (COG) is a natural medicine used for the treatment of respiratory diseases, which has excellent anti-inflammatory and antioxidant effects. However, the therapeutic effect of COG in ulcerative colitis (UC) has not been reported. Here, the experimental colitis was treated with dextran sodium sulfate (DSS) and COG. After treatment with high (30 g/kg), medium (15 g/kg), and low (7.5 g/kg) doses of COG for 11 consecutive days, the body weight, disease activity index (DAI) score, colon length, colon weight index, and the pathological score of mice were effectively improved. COG significantly reduced the levels of inflammatory cytokines in UC mice in vitro and in vivo and restored the secretion levels of IL-6 and IL-10 in the colon. Meanwhile, compared to mice with colitis, COG-treated mice showed lower levels of MDA, MPO, NO, and eNOS and higher levels of GSH-Px and MAO, which indicated that oxidative stress damage in colitic mice was alleviated by COG. Moreover, less Th17 and more Tregs were observed in the COG-treated groups. In addition, COG improved the diversity and relative abundance of gut microflora in the colon of colitic mice, and Lachnospiraceae_NK4A136_group and Lachnospiraceae_UCG-006 were obviously regulated at the genus level. In summary, COG has a protective effect on DSS-induced experimental colitis, mainly through inhibition of immune-inflammatory responses and oxidative stress and regulation of mTreg cell responses and intestinal flora composition.
High-Risk Human Papillomavirus Oncogenic E6/E7 mRNAs Splicing Regulation
Authors: Zheng Yunji , Li Xue , Jiao Yisheng , Wu Chengjun
Published: June 2022

High-risk human papillomavirus infection may develop into a persistent infection that is highly related to the progression of various cancers, including cervical cancer and head and neck squamous cell carcinomas. The most common high-risk subtypes are HPV16 and HPV18. The oncogenic viral proteins expressed by high-risk HPVs E6/E7 are tightly involved in cell proliferation, differentiation, and cancerous transformation since E6/E7 mRNAs are derived from the same pre-mRNA. Hence, the alternative splicing in the E6/E7-coding region affects the balance of the E6/E7 expression level. Interrupting the balance of E6 and E7 levels results in cell apoptosis. Therefore, it is crucial to understand the regulation of E6/E7 splice site selection and the interaction of splicing enhancers and silencers with cellular splicing factors. In this review, we concluded the relationship of different E6/E7 transcripts with cancer progression, the known splicing sites, and the identified cis-regulatory elements within high-risk HPV E6/E7-coding region. Finally, we also reviewed the role of various splicing factors in the regulation of high-risk HPV oncogenic E6/E7 mRNA splicing.
Horizon Scan on the Benefits of Ocean Seasonal Forecasting in a Future of Increasing Marine Heatwaves for Aotearoa New Zealand
Authors: Stevens Craig L. , Spillman Claire M. , Behrens Erik , Broekhuizen Niall , Holland Paula , Matthews Yvonne , Noll Ben , O'Callaghan Joanne M. , Rampal Neelesh , Smith Robert Owain , Soltanzadeh Iman , Tait Leigh W. , Taylor David I. , Thoral François , Williams Erica
Published: June 2022

With climate heating, Aotearoa New Zealand is expected to experience more marine heatwaves (MHW) in the coming decades. These extreme events are already impacting the island nation's marine and coastal environments and marine industries at a variety of scales. There will potentially be substantial benefits in developing an early warning system–specifically ocean seasonal forecast tools. This near-term 2,030 horizon scan reviews studies supporting the development of this capability and notes work needed to enable stakeholders to benefit from this knowledge. Review findings congregate around six themes; (1) MHW impacts, (2) mechanistic understanding, (3) observational basis, (4) seasonal forecast tools, (5) supporting Te Tiriti (The Treaty of Waitangi) and Māori aspirations, and (6) end-user engagement. The primary recommendation is a cross-institutional, cross-sector MHW Taskforce that would address, in a coordinated and effective fashion, the real, multi-faceted challenges associated with the committed pathway of warming. A range of sub-recommendations follow that connect with the United Nations Ocean Decade initiative.
Effects of Solar Proton Events Associated With X-Ray Flares on Near-Earth Electron and Proton Fluxes Based on ZH-1 Satellite Observations
Authors: Wang Lu , Zhang Zhenxia , Shen Xunhui , Li Xinqiao , Liang Xiaohua , Zhima Zeren , Chu Wei , Guo Feng , Zhou Na , Chen Huaran , Wei Daihui
Published: June 2022

Solar eruptions can cause violent effects on the space environment. Electromagnetic radiation from solar flares will be the first to arrive on the Earth at the speed of light, followed by solar energetic charged particles. The last to appear will be coronal mass ejections and geomagnetic storms. Based on observations of ZH-1 satellite, we report three strong disturbed space environment events, all of them with solar proton events (SPEs), and analyze the driving mechanisms: 1) On 29 November 2020, an M4.4 flare accompanied with a full halo CME caused a gradual SPE, which was mainly driven by CME shocks. 2) On 28 May 2021, a C9.4 flare brought an impulsive SPE, which was accelerated by the flare. The heliolongitude of this small flare was 63°W, near the footpoint of the magnetic field line leading from the Sun to the Earth. 3) On 28 October 2021, a full-halo CME accompanied with an X1.1 flare brought a gradual SPE. On 2 November 2021, another fast full halo CME accompanied with flare was ejected. The faster CME of November 2 caught up and swept up the slower CME of November 1, and subsequently caused a severe geomagnetic storm (minimum Dst = -101) and a high-energy electron storm on November 4. The observations of the above three space environmental events confirm that the data quality of the high-energy particle package (HEPP) from ZH-1 is highly reliable and accurate and is highly advantageous to monitoring the variation of energetic particles and X-rays in the radiation belt of the Earth during solar activities.
Evaluation of the State of Health of Lithium-Ion Battery Based on the Temporal Convolution Network
Authors: Zhang Dan , Zhao Weihua , Wang Long , Chang Xucheng , Li Xiang , Wu Peng
Published: June 2022

The state of health (SOH) of lithium-ion batteries is an important part of the battery management system (BMS). Accurately grasping the SOH of the lithium-ion battery will help replace the battery in time, to avoid accidents. Aiming at the problems of complex BMS management and high calculation cost caused by too many inputs/attributes, this study used feature engineering to mine the higher temperature variety rate associated with degraded capacity as the input of temporal convolutional networks (TCNs) and SOH as the output to establish the TCN model. On this basis, three lithium-ion batteries, namely, as B0005, B0007, and B0018 are verified, and the mean absolute error (MAE) and root mean square error (RMSE) of predicted SOH are not more than 1.455% and 1.800%, respectively. To further obtain the uncertain expression of predicted SOH, this study adopts the sampling method to obtain the confidence interval of lithium-ion battery SOH prediction results.
Temporal Difference-Based Graph Transformer Networks For Air Quality PM2.5 Prediction: A Case Study in China
Authors: Zhang Zhen , Zhang Shiqing , Zhao Xiaoming , Chen Linjian , Yao Jun
Published: June 2022

Air quality PM2.5 prediction is an effective approach for providing early warning of air pollution. This paper proposes a new deep learning model called temporal difference-based graph transformer networks (TDGTN) to learn long-term temporal dependencies and complex relationships from time series PM2.5 data for air quality PM2.5 prediction. The proposed TDGTN comprises of encoder and decoder layers associated with the developed graph attention mechanism. In particular, considering the similarity of different time moments and the importance of temporal difference between two adjacent moments for air quality PM2.5prediction, we first construct graph-structured data from original time series PM2.5 data at different moments without explicit graph structure. Then we improve the self-attention mechanism with the temporal difference information, and develop a new graph attention mechanism. Finally, the developed graph attention mechanism is embedded into the encoder and decoder layers of the proposed TDGTN to learn long-term temporal dependencies and complex relationships from a graph prospective on air quality PM2.5 prediction tasks. Experiment results on two collected real-world datasets in China, such as Beijing and Taizhou PM2.5 datasets, show that the proposed method outperforms other used methods on both short-term and long-term air quality PM2.5 prediction tasks.
Illness-Death Model as a Framework for Chronic Disease Burden Projection: Application to Mental Health Epidemiology
Authors: Ito Chisato , Kurth Tobias , Baune Bernhard T. , Brinks Ralph
Published: June 2022

Introduction

Estimates of future disease burden supports public health decision-making. Multistate modeling of chronic diseases is still limited despite a long history of mathematical modeling of diseases. We introduce a discrete time approach to the illness-death model and a recursion formula, which can be utilized to project chronic disease burden. We further illustrate an example of the technique applied to anxiety disorders in Germany.

Materials and Equipment

The illness-death model is a multistate model that relates prevalence, incidence, mortality, and remission. A basic recursion formula that considers prevalence, incidence, mortality among the susceptible, and mortality among the diseased can be applied to irreversible chronic diseases such as diabetes. Among several mental disorders, remission plays a key role and thus an extended recursion formula taking remission into account is derived.

Methods

Using the Global Burden of Disease Study 2019 data and population projections from the Federal Statistical Office of Germany, a total number of individuals with anxiety disorders by sex in Germany from 2019 to 2030 was projected. Regression models were fitted to historical data for prevalence and incidence. Differential mortality risks were modeled based on empirical evidence. Remission was estimated from prevalence, incidence, and mortality, applying the extended recursion formula. Sex- and age-specific prevalence of 2019 was given as the initial value to estimate the total number of individuals with anxiety disorders for each year up to 2030. Projections were also made through simple extrapolation of prevalence for comparison.

Results

From 2019 to 2030, we estimated a decrease of 52,114 (−1.3%) individuals with anxiety disorders among women, and an increase of 166,870 (+8.5%) cases among men, through the illness-death model approach. With prevalence extrapolation, an increase of 381,770 (+9.7%) among women and an increase of 272,446 (+13.9%) among men were estimated.

Discussion

Application of the illness-death model with discrete time steps is possible for both irreversible chronic diseases and diseases with possible remissions, such as anxiety disorders. The technique provides a framework for disease burden prediction. The example provided here can form a basis for running simulations under varying transition probabilities.
Herbivory and Drought Reduce the Temporal Stability of Herbaceous Cover by Increasing Synchrony in a Semi-arid Savanna
Authors: Ebel Carmen R. , Case Madelon F. , Werner Chhaya M. , Porensky Lauren M. , Veblen Kari E. , Wells Harry B. M. , Kimuyu Duncan M. , Langendorf Ryan E. , Young Truman P. , Hallett Lauren M.
Published: June 2022

Ecological stability in plant communities is shaped by bottom-up processes like environmental resource fluctuations and top-down controls such as herbivory, each of which have demonstrated direct effects but may also act indirectly by altering plant community dynamics. These indirect effects, called biotic stability mechanisms, have been studied across environmental gradients, but few studies have assessed the importance of top-down controls on biotic stability mechanisms in conjunction with bottom-up processes. Here we use a long-term herbivore exclusion experiment in central Kenya to explore the joint effects of drought and herbivory (bottom-up and top-down limitation, respectively) on three biotic stability mechanisms: (1) species asynchrony, in which a decline in one species is compensated for by a rise in another, (2) stable dominant species driving overall stability, and (3) the portfolio effect, in which a community property is distributed among multiple species. We calculated the temporal stability of herbaceous cover and biotic stability mechanisms over a 22-year time series and with a moving window to examine changes through time. Both drought and herbivory additively reduced asynchronous dynamics, leading to lower stability during droughts and under high herbivore pressure. This effect is likely attributed to a reduction in palatable dominant species under higher herbivory, which creates space for subordinate species to fluctuate synchronously in response to rainfall variability. Dominant species population stability promoted community stability, an effect that did not vary with precipitation but depended on herbivory. The portfolio effect was not important for stability in this system. Our results demonstrate that this system is naturally dynamic, and a future of increasing drought may reduce its stability. However, these effects will in turn be amplified or buffered depending on changes in herbivore communities and their direct and indirect impacts on plant community dynamics.
Increased Virulence and Large-Scale Reduction in Genome Size of Tetraploid Candida albicans Evolved in Nematode Hosts
Authors: Smith Amanda C. , Rizvi Hassan , Hickman Meleah A. , Morran Levi T.
Published: June 2022

Candida albicans is an opportunistic fungal pathogen of humans, yet the within-host dynamics of C. albicans infection are not clear. While C. albicans is commonly diploid, it exhibits a range of ploidies, including tetraploidy. Previous work found that tetraploid C. albicans populations exhibited rapid adaptation and significant genome instability when evolved in vitro. Host immune function alters the rate and magnitude of C. albicans virulence evolution, but the effects of the host immunity on tetraploid C. albicans populations are unclear. Here, we tested the effects of the host immunity on genome stability and virulence evolution of tetraploid C. albicans using experimental evolution. We selected for C. albicans increased virulence within either immunocompetent or immunocompromised Caenorhabditis elegans hosts. After nine passages we observed a response to selection for increased virulence. Both populations exposed to either immunocompetent or immunocompromised hosts increased virulence after passage through C. elegans hosts. However, the C. albicans populations passaged through immunocompetent hosts under selection exhibited unique temporal dynamics, a rapid increase in virulence and then subsequent loss of virulence. Most C. albicans populations exhibited genome size reduction within six passages, however populations exposed to immunocompetent hosts exhibited the most rapid transition to ~diploid. Therefore, we found that tetraploids rapidly increase in virulence and decrease genome size within host environments. Further, the combination of selection for greater virulence in the presence of immunocompetent hosts results in major virulence fluctuations and genome size changes. Thus, host immunity significantly impacts the evolutionary trajectories of tetraploid C. albicans.
Effects of Automated Emergency Braking and Seatbelt Pre-Pretensioning on Occupant Injury Risks in High-Severity Frontal Crashes
Authors: Mishra Ekant , Mroz Krystoffer , Pipkorn Bengt , Lubbe Nils
Published: June 2022

In high-severity crashes, occupant protection is challenging. Automated Emergency Braking (AEB) and seatbelt pre-pretensioning (PPT) are means to improve occupant protection; the purpose of this study was to quantify their effects on occupant injury risks in high-severity full-frontal crashes by Finite Element (FE) simulations. The SAFER Active average male Human Body Model was used as an occupant substitute. The crash pulses used were from separate full-frontal crash simulations using a Honda Accord FE model. The vehicle interior model comprised a seat, an instrument panel, a three-point pretensioned seatbelt system with a load-limiter of 3.1 kN force level, and a frontal passenger airbag. The effects of AEB and PPT were evaluated by simulating a 1 g pre-crash braking scenario for 0.5 s, with and without AEB, for three different PPT force levels: 0, 300, and 600 N. The impact speed of 80 km/h was reduced to 69 km/h by AEB. When neither system was activated, the predicted risk for an occupant to sustain two or more fractured ribs (NFR2+) was 100% for both 45- and 65-year-old male occupants. The risks were reduced when the AEB was activated, particularly for the 45-year-old occupant. When the AEB was activated, the risks of concussion and rib fractures were reduced; upper neck tension forces, pelvis Anterior Superior Iliac Spine (ASIS) forces, and lower extremity forces were also reduced. Increasing the PPT forces reduced the rib fracture risk further (to about 48% for a 45-year-old occupant with 600 N PPT force). The reduced speed due to AEB resulted in a lower concussion risk (from 71.3% to 31%). However, the concussion risk increased slightly with increased PPT forces.
Heterogeneous Distribution of Genetic Mutations in Myosin Binding Protein-C Paralogs
Authors: Desai Darshini A. , Rao Vinay J. , Jegga Anil G. , Dhandapany Perundurai S. , Sadayappan Sakthivel
Published: June 2022

Myosin binding protein-C (MyBP-C) is a sarcomeric protein which regulates the force of contraction in striated muscles. Mutations in the MYBPC family of genes, including slow skeletal (MYBPC1), fast skeletal (MYBPC2) and cardiac (MYBPC3), can result in cardiac and skeletal myopathies. Nonetheless, their evolutionary pattern, pathogenicity and impact on MyBP-C protein structure remain to be elucidated. Therefore, the present study aimed to systematically assess the evolutionarily conserved and epigenetic patterns of MYBPC family mutations. Leveraging a machine learning (ML) approach, the Genome Aggregation Database (gnomAD) provided variants in MYBPC1, MYBPC2, and MYBPC3 genes. This was followed by an analysis with Ensembl’s variant effect predictor (VEP), resulting in the identification of 8,618, 3,871, and 3,071 variants in MYBPC1, MYBPC2, and MYBPC3, respectively. Missense variants comprised 61%–66% of total variants in which the third nucleotide positions in the codons were highly altered. Arginine was the most mutated amino acid, important because most disease-causing mutations in MyBP-C proteins are arginine in origin. Domains C5 and C6 of MyBP-C were found to be hotspots for most mutations in the MyBP-C family of proteins. A high percentage of truncated mutations in cMyBP-C cause cardiomyopathies. Arginine and glutamate were the top hits in fMyBP-C and cMyBP-C, respectively, and tryptophan and tyrosine were the most common among the three paralogs changing to premature stop codons and causing protein truncations at the carboxyl terminus. A heterogeneous epigenetic pattern was identified among the three MYBP-C paralogs. Overall, it was shown that databases using computational approaches can facilitate diagnosis and drug discovery to treat muscle disorders caused by MYBPC mutations.
Comprehensive Characterization of a Novel E3-Related Gene Signature With Implications in Prognosis and Immunotherapy of Low-Grade Gliomas
Authors: Tan Shichuan , Spear Ryan , Zhao Juan , Sun Xiulian , Wang Pin
Published: June 2022

Gliomas, a type of primary brain tumor, have emerged as a threat to global mortality due to their high heterogeneity and mortality. A low-grade glioma (LGG), although less aggressive compared with glioblastoma, still exhibits high recurrence and malignant progression. Ubiquitination is one of the most important posttranslational modifications that contribute to carcinogenesis and cancer recurrence. E3-related genes (E3RGs) play essential roles in the process of ubiquitination. Yet, the biological function and clinical significance of E3RGs in LGGs need further exploration. In this study, differentially expressed genes (DEGs) were screened by three differential expression analyses of LGG samples from The Cancer Genome Atlas (TCGA) database. DEGs with prognostic significance were selected by the univariate Cox regression analysis and log-rank statistical test. The LASSO-COX method was performed to identify an E3-related prognostic signature consisting of seven genes AURKA, PCGF2, MAP3K1, TRIM34, PRKN, TLE3, and TRIM17. The Chinese Glioma Genome Atlas (CGGA) dataset was used as the validation cohort. Kaplan–Meier survival analysis showed that LGG patients in the low-risk group had significantly higher overall survival time than those in the high-risk group in both TCGA and CGGA cohorts. Furthermore, multivariate Cox regression analysis revealed that the E3RG signature could be used as an independent prognostic factor. A nomogram based on the E3RG signature was then established and provided the prediction of the 1-, 3-, and 5-year survival probability of patients with LGGs. Moreover, DEGs were analyzed based on the risk signature, on which function analyses were performed. GO and KEGG analyses uncovered gene enrichment in extracellular matrix–related functions and immune-related biological processes in the high-risk group. GSEA revealed high enrichment in pathways that promote tumorigenesis and progression in the high-risk group. Furthermore, ESTIMATE algorithm analysis showed a significant difference in immune and stroma activity between high- and low-risk groups. Positive correlations between the risk signature and the tumor microenvironment immune cell infiltration and immune checkpoint molecules were also observed, implying that patients with the high-risk score may have better responses to immunotherapy. Overall, our findings might provide potential diagnostic and prognostic markers for LGG patients and offer meaningful insight for individualized treatment.
High Expression of TMEM33 Predicts Poor Prognosis and Promotes Cell Proliferation in Cervical Cancer
Authors: Chen Hanxiang , Zhao Xia , Li Yongqing , Zhang Shaoming , Wang Yunshan , Wang Lili , Ma Wanshan
Published: June 2022

Background: The prognosis of patients with advanced cervical cancer remains unsatisfactory. A study indicated that transmembrane protein 33 (TMEM33) was implicated in tumor recurrence, while its role in cervical cancer has not been elucidated.

Methods: TMEM33 expression in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) was primarily screened in The Cancer Genome Atlas (TCGA), and further validated in Gene Expression Omnibus (GEO) database. The Kaplan–Meier plotter analysis and Cox regression were constructed to evaluate the prognostic value of TMEM33 in CESC. Functional enrichment analysis was performed with GO, KEGG and GSEA tools. CCK-8 assay and colony formation assay were performed to investigate the carcinogenesis role of TMEM33 in cervical cancer cell proliferation.

Results: TMEM33 expression was significantly elevated in CESC compared with normal tissues. High expression of TMEM33 was associated with poor prognostic clinical characteristics in CESC patients. KM-plotter analysis revealed that patients with increased TMEM33 had shorter overall survival (OS), progress free interval (PFI), and disease specific survival (DSS). Moreover, Multivariate Cox analysis confirmed that high TMEM33 expression was an independent risk factor for OS in patients with CESC. TMEM33 was associated with immune infiltrates, and its expression was correlated with tumorigenesis-related genes RNF4, OCIAD1, TMED5, DHX15, MED28 and LETM1. More importantly, knockdown of TMEM33 in cervical cancer cells decreased the expression of those genes and inhibited cell proliferation.

Conclusion: Increased TMEM33 in cervical cancer can serve as an independent prognostic marker and might play a role in tumorigenesis by promoting cell proliferation.
Tacrolimus CYP3A Single-Nucleotide Polymorphisms and Preformed T- and B-Cell Alloimmune Memory Improve Current Pretransplant Rejection-Risk Stratification in Kidney Transplantation
Authors: Crespo Elena , Vidal-Alabró Anna , Jouve Thomas , Fontova Pere , Stein Maik , Mocka Sonila , Meneghini Maria , Sefrin Anett , Hruba Petra , Gomà Montserrat , Torija Alba , Donadeu Laura , Favà Alex , Cruzado Josep M. , Melilli Edoardo , Moreso Francesc , Viklicky Ondrej , Bemelman Frederike , Reinke Petra , Grinyó Josep , Lloberas Nuria , Bestard Oriol
Published: June 2022

Achieving fast immunosuppression blood exposure after kidney transplantation is key to abrogating both preformed and de novo anti-donor humoral and cellular alloresponses. However, while tacrolimus (TAC) is the cornerstone immunosuppressant inhibiting adaptive alloimmunity, its blood exposure is directly impacted by different single-nucleotide polymorphisms (SNPs) in CYP3A TAC-metabolizing enzymes. Here, we investigated how functional TAC-CYP3A genetic variants (CYP3A4*22/CYP3A5*3) influence the main baseline clinical and immunological risk factors of biopsy-proven acute rejection (BPAR) by means of preformed donor-specific antibodies (DSAs) and donor-specific alloreactive T cells (DSTs) in a large European cohort of 447 kidney transplants receiving TAC-based immunosuppression. A total of 70 (15.7%) patients developed BPAR. Preformed DSAs and DSTs were observed in 12 (2.7%) and 227 (50.8%) patients, respectively. According to the different CYP3A4*22 and CYP3A5*3 functional allele variants, we found 4 differential new clusters impacting fasting TAC exposure after transplantation; 7 (1.6%) were classified as high metabolizers 1 (HM1), 71 (15.9%) as HM2, 324 (72.5%) as intermediate (IM), and 45 (10.1%) as poor metabolizers (PM1). HM1/2 showed significantly lower TAC trough levels and higher dose requirements than IM and PM (p < 0.001) and more frequently showed TAC underexposure (<5 ng/ml). Multivariate Cox regression analyses revealed that CYP3A HM1 and IM pharmacogenetic phenotypes (hazard ratio (HR) 12.566, 95% CI 1.99–79.36, p = 0.007, and HR 4.532, 95% CI 1.10–18.60, p = 0.036, respectively), preformed DSTs (HR 3.482, 95% CI 1.99–6.08, p < 0.001), DSAs (HR 4.421, 95% CI 1.63–11.98, p = 0.003), and delayed graft function (DGF) (HR 2.023, 95% CI 1.22–3.36, p = 0.006) independently predicted BPAR. Notably, a significant interaction between T-cell depletion and TAC underexposure was observed, showing a reduction of the BPAR risk (HR 0.264, 95% CI 0.08–0.92, p = 0.037). Such variables except for DSAs displayed a higher predictive risk for the development of T cell-mediated rejection (TCMR). Refinement of pretransplant monitoring by incorporating TAC CYP3A SNPs with preformed DSAs as well as DSTs may improve current rejection-risk stratification and help induction treatment decision-making.
Th2 to Th1 Transition Is Required for Induction of Skin Lesions in an Inducible and Recurrent Murine Model of Cutaneous Lupus–Like Inflammation
Authors: Haddadi Nazgol-Sadat , Mande Purvi , Brodeur Tia Y. , Hao Kaiyuan , Ryan Grace E. , Moses Stephanie , Subramanian Sharon , Picari Xhuliana , Afshari Khashayar , Marshak-Rothstein Ann , Richmond Jillian M.
Published: June 2022

Cutaneous lupus erythematosus (CLE) is an autoimmune skin disease characterized by a strong IFN signature, normally associated with type I IFNs. However, increasing evidence points to an additional role for IFNγ, or at least a pathogenic T effector subset dependent on IFNγ, for disease progression. Nevertheless, Th2 effector subsets have also been implicated in CLE. We have now assessed the role of specific T cell subsets in the initiation and persistence of skin disease using a T cell-inducible murine model of CLE, dependent on KJ1-26 T cell recognition of an ovalbumin fusion protein. We found that only Th2-skewed cells, and not Th1-skewed cells, induced the development of skin lesions. However, we provide strong evidence that the Th2 disease-initiating cells convert to a more Th1-like functional phenotypein vivoby the time the skin lesions are apparent. This phenotype is maintained and potentiates over time, as T cells isolated from the skin, following a second induction of self-antigen, expressed more IFN-γ than T cells isolated at the time of the initial response. Transcriptional analysis identified additional changes in the KJ1-26 T cells at four weeks post injection, with higher expression levels of interferon stimulated genes (ISGs) includingCXCL9, IRF5, IFIH1, andMX1. Further, injection of IFN-γ-/- T cells faied to induce skin disease in mice. We concluded that Th2 cells trigger skin lesion formation in CLE, and these cells switch to a Th1-like phenotype in the context of a TLR7-driven immune environment that is stable within the T cell memory compartment.
Myocarditis Following COVID-19 Vaccine Use: Can It Play a Role for Conditioning Immunization Schedules?
Authors: Esposito Susanna , Caminiti Caterina , Giordano Rosanna , Argentiero Alberto , Ramundo Greta , Principi Nicola
Published: June 2022

Myocarditis (MYO) is a relatively uncommon inflammatory disease that involves the heart muscle. It can be a very severe disease as it can lead to the development of acute or chronic heart failure and, in a not marginal number of cases, to death. Most of the cases are diagnosed in healthy people younger than 30 years of age. Moreover, males are affected about twice as much as females. Viruses are among the most common causes of MYO, but how viral infection can lead to MYO development is not precisely defined. After COVID-19 pandemic declaration, incidence rate of MYO has significantly increased worldwide because of the SARS-CoV-2 infection. After the introduction of anti-COVID-19 vaccines, reports of post-immunization MYO have emerged, suggesting that a further cause of MYO together with the SARS-CoV-2 infection could increase the risk of heart damage during pandemic. Main aim of this study is to discuss present knowledge regarding etiopathogenesis and clinical findings of MYO associated with COVID-19 vaccine administration and whether the risk of this adverse events can modify the initially suggested recommendation for the use of COVID-19 vaccines in pediatric age. Literature analysis showed that MYO is an adverse event that can follow the COVID-19 immunization with mRNA vaccines in few persons, particularly young adults, adolescents, and older children. It is generally a mild disease that should not modify the present recommendations for immunization with the authorized COVID-19 mRNA vaccines. Despite this, further studies are needed to evaluate presently undefined aspects of MYO development after COVID-19 vaccine administration and reduce the risk of development of this kind of vaccine complication. Together with a better definition of the true incidence of MYO and the exact role of the various factors in conditioning incidence variations, it is essential to establish long-term evolution of acute COVID-19 related MYO.
The m6A/m5C/m1A Regulated Gene Signature Predicts the Prognosis and Correlates With the Immune Status of Hepatocellular Carcinoma
Authors: Li Dan , Li Kai , Zhang Wei , Yang Kong-Wu , Mu De-An , Jiang Guo-Jun , Shi Rong-Shu , Ke Di
Published: June 2022

RNA modification of m6A/m5C/m1A contributes to the occurrence and development of cancer. Consequently, this study aimed to investigate the functions of m6A/m5C/m1A regulated genes in the prognosis and immune microenvironment of hepatocellular carcinoma (HCC). The expression levels of 45 m6A/m5C/m1A regulated genes in HCC tissues were determined. The functional mechanisms and protein–protein interaction network of m6A/m5C/m1A regulated genes were investigated. The Cancer Genome Atlas (TCGA) HCC gene set was categorized based on 45 m6A/m5C/m1A regulated genes, and survival analysis was used to determine the relationship between the overall survival of HCC patients in subgroups. Cox and least absolute shrinkage and selection operator (LASSO) regression analyses were used to construct the risk model and nomogram for m6A/m5C/m1A regulated genes. The relationships between m6A/m5C/m1A regulated gene subsets and risk model and immune cell infiltration were analyzed using CIBERSORT. m6A/m5C/m1A regulated genes were involved in mRNA and RNA modifications, mRNA and RNA methylation, mRNA and RNA stability, and other processes. There was a statistically significant difference between cluster1 and cluster2 groups of genes regulated by m6A/m5C/m1A. The prognosis of cluster1 patients was significantly better than that of cluster2 patients. There were statistically significant differences between the two cluster groups in terms of fustat status, grade, clinical stage, and T stage of HCC patients. The risk model comprised the overexpression of YBX1, ZC3H13, YTHDF1, TRMT10C, YTHDF2, RRP8, TRMT6, LRPPRC, and IGF2BP3, which contributed to the poor prognosis of HCC patients. The high-risk score was associated with prognosis, fustat status, grade, clinical stage, T stage, and M stage and was an independent risk factor for poor prognosis in HCC patients. High-risk score mechanisms included spliceosome, RNA degradation, and DNA replication, among others, and high-risk was closely related to stromal score, CD4 memory resting T cells, M0 macrophages, M1 macrophages, resting mast cells, CD4 memory activated T cells, and follicular helper T cells. In conclusion, the cluster subgroup and risk model of m6A/m5C/m1A regulated genes were associated with the poor prognosis and immune microenvironment in HCC and are expected to be the new tools for assessing the prognosis of HCC patients.
Regulatory Roles of Phospholipase A2 Enzymes and Bioactive Lipids in Mast Cell Biology
Authors: Taketomi Yoshitaka , Murakami Makoto
Published: June 2022

Lipids play fundamental roles in life as an essential component of cell membranes, as a major source of energy, as a body surface barrier, and as signaling molecules that transmit intracellular and intercellular signals. Lipid mediators, a group of bioactive lipids that mediates intercellular signals, are producedviaspecific biosynthetic enzymes and transmit signalsviaspecific receptors. Mast cells, a tissue-resident immune cell population, produce several lipid mediators that contribute to exacerbation or amelioration of allergic responses and also non-allergic inflammation, host defense, cancer and fibrosis by controlling the functions of microenvironmental cells as well as mast cell themselves in paracrine and autocrine fashions. Additionally, several bioactive lipids produced by stromal cells regulate the differentiation, maturation and activation of neighboring mast cells. Many of the bioactive lipids are stored in membrane phospholipids as precursor forms and released spatiotemporally by phospholipase A2(PLA2) enzymes. Through a series of studies employing gene targeting and lipidomics, several enzymes belonging to the PLA2superfamily have been demonstrated to participate in mast cell-related diseases by mobilizing unique bioactive lipids in multiple ways. In this review, we provide an overview of our current understanding of the regulatory roles of several PLA2-driven lipid pathways in mast cell biology.
Anti-MDA5 Antibody Linking COVID-19, Type I Interferon, and Autoimmunity: A Case Report and Systematic Literature Review
Authors: Tonutti Antonio , Motta Francesca , Ceribelli Angela , Isailovic Natasa , Selmi Carlo , De Santis Maria
Published: June 2022

Introduction

The SARS-CoV-2 infection has been advocated as an environmental trigger for autoimmune diseases, and a paradigmatic example comes from similarities between COVID-19 and the myositis-spectrum disease associated with antibodies against the melanoma differentiation antigen 5 (MDA5) in terms of clinical features, lung involvement, and immune mechanisms, particularly type I interferons (IFN).

Case Report

We report a case of anti-MDA5 syndrome with skin manifestations, constitutional symptoms, and cardiomyopathy following a proven SARS-CoV-2 infection.

Systematic Literature Review

We systematically searched for publications on inflammatory myositis associated with COVID-19. We describe the main clinical, immunological, and demographic features, focusing our attention on the anti-MDA5 syndrome.

Discussion

MDA5 is a pattern recognition receptor essential in the immune response against viruses and this may contribute to explain the production of anti-MDA5 antibodies in some SARS-CoV-2 infected patients. The activation of MDA5 induces the synthesis of type I IFN with an antiviral role, inversely correlated with COVID-19 severity. Conversely, elevated type I IFN levels correlate with disease activity in anti-MDA5 syndrome. While recognizing this ia broad area of uncertainty, we speculate that the strong type I IFN response observed in patients with anti-MDA5 syndrome, might harbor protective effects against viral infections, including COVID-19.
The Mineralization of Molluscan Shells: Some Unsolved Problems and Special Considerations
Authors: Huang Jingliang , Zhang Rongqing
Published: June 2022

The field of biomineralization is an inspiration for human design across disciplines, e.g. biomimetic materials, environmental and biomedical treatments, etc. Having a coherent understanding of the basic science sets the pillars for these fields that will impact human welfare. Intensive studies lead to great progress in unraveling the molecular mechanism underlying molluscan shell formation, especially in the past three decades. However, some problems remain, and discrepancy exists in varied studies. In this review, we pay attention to some issues which have been overlooked and warranted more in-depth studies, and pointed out that considerations should be seriously taken when looking into the cellular and molecular events in shell formation. We first consider the evolution of shell mineralogy and organic matrix by emphasizing the great impact of sea water chemistry. Secondly, we discussed the recent progress on the shell matrix protein (SMP) characterization and pointed out environmental and physiological conditions should be taken into account when studying the SMP functions. Finally, we highlighted some ambiguous issues in the less studied mineralizing tissues and cells, and the underlying cellular control on shell formation. New researchers in this field should keep in mind that early geochemistry in vitro research has mostly failed to address the in vivo context of biomineralization in cells and tissues. Therefore, the more biologically relevant experiments are still needed for future research.
The State of the Art of Radiotherapy for Non-melanoma Skin Cancer: A Review of the Literature
Authors: Benkhaled Sofian , Van Gestel Dirk , Gomes da Silveira Cauduro Carolina , Palumbo Samuel , Marmol Veronique del , Desmet Antoine
Published: June 2022

Due to the general aging population and the fashion trend of sun exposure, non-melanoma skin cancer (NMSC) is rising. The management of NMSC is difficult and necessitates a multidisciplinary team (i.e., pathologists, dermatologists, medical oncologists, surgeons, and radiation oncologists). When surgery is not an option or will cause unacceptably functional morbidity, radiation therapy (RT) may be a preferable tissue-preserving option. Whether used alone or in conjunction with other treatments, RT has been shown to be quite effective in terms of cosmetic results and local control. Contact hypofractionated RT, brachytherapy, and electronic brachytherapy are all promising new treatments. However, rigorous, randomized trials are missing, explaining the disparity in dose, fractionation, and technique recommendations. Therefore, it is essential that interdisciplinary teams better understand RT modalities, benefits, and drawbacks. Our review will provide the role and indications for RT in patients with NMSC.