bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting the microRNA-34a as a Novel Therapeutic Strategy for Cardiovascular Diseases
Authors: Hua Cun-Cun , Liu Xin-Ming , Liang Li-Rong , Wang Le-Feng , Zhong Jiu-Chang
Published: January 2022

Cardiovascular diseases (CVDs) are still the main cause of morbidity and mortality worldwide and include a group of disorders varying from vasculature, myocardium, arrhythmias and cardiac development. MicroRNAs (miRs) are endogenous non-coding RNAs with 18–23 nucleotides that regulate gene expression. The miR-34 family, including miR-34a/b/c, plays a vital role in the regulation of myocardial physiology and pathophysiological processes. Recently, miR-34a has been implicated in cardiovascular fibrosis, dysfunction and related cardiovascular disorders as an essential regulator. Interestingly, there is a pivotal link among miR-34a, cardiovascular fibrosis, and Smad4/TGF-β1 signaling. Notably, both loss-of-function and gain-of-function approaches identified the critical roles of miR-34a in cardiovascular apoptosis, autophagy, inflammation, senescence and remodeling by modulating multifunctional signaling pathways. In this article, we focus on the current understanding of miR-34a in biogenesis, its biological effects and its implications for cardiac pathologies including myocardial infarction, heart failure, ischaemia reperfusion injury, cardiomyopathy, atherosclerosis, hypertension and atrial fibrillation. Thus, further understanding of the effects of miR-34a on cardiovascular diseases will aid the development of effective interventions. Targeting for miR-34a has emerged as a potential therapeutic target for cardiovascular dysfunction and related diseases.
Recent Progress in in vitro Models for Atherosclerosis Studies
Authors: Chen Jun , Zhang Xixi , Millican Reid , Lynd Tyler , Gangasani Manas , Malhotra Shubh , Sherwood Jennifer , Hwang Patrick Taejoon , Cho Younghye , Brott Brigitta C. , Qin Gangjian , Jo Hanjoong , Yoon Young-sup , Jun Ho-Wook
Published: January 2022

Atherosclerosis is the primary cause of hardening and narrowing arteries, leading to cardiovascular disease accounting for the high mortality in the United States. For developing effective treatments for atherosclerosis, considerable efforts have been devoted to developing in vitro models. Compared to animal models, in vitro models can provide great opportunities to obtain data more efficiently, economically. Therefore, this review discusses the recent progress in in vitro models for atherosclerosis studies, including traditional two-dimensional (2D) systems cultured on the tissue culture plate, 2D cell sheets, and recently emerged microfluidic chip models with 2D culture. In addition, advanced in vitro three-dimensional models such as spheroids, cell-laden hydrogel constructs, tissue-engineered blood vessels, and vessel-on-a-chip will also be covered. Moreover, the functions of these models are also summarized along with model discussion. Lastly, the future perspectives of this field are discussed.
Macrophages Can Drive Sympathetic Excitability in the Early Stages of Hypertension
Authors: Neely Oliver C. , Domingos Ana I. , Paterson David J.
Published: January 2022

Hypertension is a major health burden worldwide with many cases resistant to current treatments. Hyperactivity of the sympathetic nervous contributes to the etiology and progression of the disease, where emerging evidence suggests that inflammation may underpin the development of sympathetic dysautonomia. This study examined whether macrophages could drive the sympathetic phenotype in Spontaneously Hypertensive Rats (SHR) before animals develop high pressure. Stellate neurons from wild-type control Wistar rats and SHRs were co-cultured with blood leukocytes from their own strain, and also crossed cultured between strains. The calcium transient response to nicotinic stimulation was recorded using Fura-2 calcium imaging, where SHR neurons had a greater calcium transient compared with Wistar neurons. However, when co-cultured with leukocytes, Wistar neurons began to phenocopy the SHR sympathetic hyperactivity, while the SHR neurons themselves were unaltered. Resident leukocyte populations of the SHR and Wistar stellate ganglia were then compared using flow cytometry, where there was a shift in monocyte-macrophage subset proportions. While classical monocyte-macrophages were predominant in the Wistar, there were relatively more of the non-classical subset in the SHR, which have been implicated in pro-inflammatory roles in a number of diseases. When bone marrow-derived macrophages (BMDMs) were co-cultured with stellate neurons, they made Wistar neurons recapitulate the SHR nicotinic stimulated calcium transient. Wistar BMDMs however, had no effect on SHR neurons, even though SHR BMDMs increased SHR neuron responsiveness further above their hyper-responsive state. Taken together, these findings show that macrophages can be potent enhancers of sympathetic neuronal calcium responsiveness, and thus could conceivably play a role in peripheral sympathetic hyperactivity observed in the early stages of hypertension.
Mitral and Aortic Regurgitation in Patients Undergoing Kidney Transplantation: The Natural Course and Factors Associated With Progression
Authors: Kim Minjeong , Kim Darae , Lee Juhan , Kim Dae-Young , Seo Jiwon , Cho Iksung , Huh Kyu Ha , Hong Geu-Ru , Ha Jong-Won , Shim Chi Young
Published: January 2022

Background

Valve regurgitation can decrease with resolution of hemodynamic loads on the left ventricle (LV) after kidney transplantation (KT). We aimed to investigate the natural course of left-side valve regurgitation after KT and factors associated with progression.

Methods

Among patients who underwent KT in two tertiary centers, 430 (224 men, mean age 50 ± 13 years) were examined by echocardiography within 3 months before KT and between 6 and 36 months after KT. Mitral regurgitation (MR) and aortic regurgitation (AR) were graded according to the current guidelines. Regression was defined as a decrease in regurgitation by one or more steps, and progression was an increase in one or more steps after KT. Clinical and echocardiographic factors associated with progression of MR and AR were analyzed.

Results

Mild or greater MR was observed in 216 (50%) patients before KT, and mild or greater AR was observed in 99 (23%). During the follow-up period of 23.4 ± 9.9 months, most patients experienced regression or no change in regurgitation after KT, but 34 patients (7.9%) showed MR progression and 37 (8.6%) revealed AR progression. Patients who showed MR progression were more likely to receive a second KT, have mitral annular calcifications, and show a smaller decrease in LV end-systolic dimension. Patients who showed AR progression were more likely to have persistent hypertension after KT, aortic valve calcifications, and a smaller reduction of LV end-systolic dimension.

Conclusions

Risk factors for progression of MR after KT include a second KT, MAC and a smaller decrease in LV end-systolic dimension after KT. Risk factors for progression of AR include valve calcification, persistent hypertension and a smaller decrease in LV end-systolic dimension after KT. Further echocardiographic surveillance and risk factor management after KT are warranted in these patients.
CT Segmentation of Dinosaur Fossils by Deep Learning
Authors: Yu Congyu , Qin Fangbo , Li Ying , Qin Zichuan , Norell Mark
Published: January 2022

Recently, deep learning has reached significant advancements in various image-related tasks, particularly in medical sciences. Deep neural networks have been used to facilitate diagnosing medical images generated from various observation techniques including CT (computed tomography) scans. As a non-destructive 3D imaging technique, CT scan has also been widely used in paleontological research, which provides the solid foundation for taxon identification, comparative anatomy, functional morphology, etc. However, the labeling and segmentation of CT images are often laborious, prone to error, and subject to researchers own judgements. It is essential to set a benchmark in CT imaging processing of fossils and reduce the time cost from manual processing. Since fossils from the same localities usually share similar sedimentary environments, we constructed a dataset comprising CT slices of protoceratopsian dinosaurs from the Gobi Desert, Mongolia. Here we tested the fossil segmentation performances of U-net, a classic deep neural network for image segmentation, and constructed a modified DeepLab v3+ network, which included MobileNet v1 as feature extractor and practiced an atrous convolutional method that can capture features from various scales. The results show that deep neural network can efficiently segment protoceratopsian dinosaur fossils, which can save significant time from current manual segmentation. But further test on a dataset generated by other vertebrate fossils, even from similar localities, is largely limited.
Predictors and a Prediction Model for Central Cervical Lymph Node Metastasis in Papillary Thyroid Carcinoma (cN0)
Authors: Gao Xin , Luo Wenpei , He Lingyun , Cheng Juan , Yang Lu
Published: January 2022

Objectives

To screen out the predictors of central cervical lymph node metastasis (CLNM) for papillary thyroid carcinoma (PTC) and establish a prediction model to guide the operation of PTC patients (cN0).

Methods

Data from 296 PTC patients (cN0) who underwent thyroid operation at the Second Affiliated Hospital of Chongqing Medical University were collected and retrospectively analyzed. They were divided into two groups in accordance with central CLNM or not. Their information, including ultrasound (US) features, BRAFV600E status, and other characteristics of the two groups, was analyzed and compared using univariate and multivariate logistic regression analyses, and the independent predictors were selected to construct a nomogram. The calibration plot, C-index, and decision curve analysis were used to assess the prediction model’s calibration, discrimination, and clinical usefulness.

Results

A total of 37.8% (112/296) of PTC patients had central CLNM, and 62.2% (184/296) did not. The two groups were compared using a univariate logistic regression analysis, and there were no significant differences between the two groups in sex, aspect ratio, boundary, morphology, hypoechoic nodule, thyroid peroxidase antibody, or tumor location (P>0.05), and there were significant differences between age, tumor size, capsule contact, microcalcifications, blood flow signal, thyroglobulin antibodies (TgAb), and BRAF gene status (P<0.05). A multivariate logistic regression analysis was performed to further clarify the correlation of these indices. However, only tumor size (OR=2.814, 95% Cl=1.634~4.848, P<0.001), microcalcifications (OR=2.839, 95% Cl=1,684~4.787, P<0.001) and TgAb (OR=1.964, 95% Cl=1.039~3,711, P=0.038) were independent predictors of central CLNM and were incorporated and used to construct the prediction nomogram. The model had good discrimination with a C-index of 0.715. An ROC curve analysis was performed to evaluate the accuracy of this model. The decision curve analysis showed that the model was clinically useful when intervention was decided in the threshold range of 16% to 80%.

Conclusion

In conclusion, three independent predictors of central CLNM, including tumor size (> 1.0 cm), US features (microcalcifications), and TgAb (positive), were screened out. A visualized nomogram model was established based on the three predictors in this study, which could be used as a basis of central cervical lymph node dissection (CLND) for PTC patients (cN0).
Deep Learning Algorithm for Automated Detection of Polycystic Ovary Syndrome Using Scleral Images
Authors: Lv Wenqi , Song Ying , Fu Rongxin , Lin Xue , Su Ya , Jin Xiangyu , Yang Han , Shan Xiaohui , Du Wenli , Huang Qin , Zhong Hao , Jiang Kai , Zhang Zhi , Wang Lina , Huang Guoliang
Published: January 2022

The high prevalence of polycystic ovary syndrome (PCOS) among reproductive-aged women has attracted more and more attention. As a common disorder that is likely to threaten women’s health physically and mentally, the detection of PCOS is a growing public health concern worldwide. In this paper, we proposed an automated deep learning algorithm for the auxiliary detection of PCOS, which explores the potential of scleral changes in PCOS detection. The algorithm was applied to the dataset that contains the full-eye images of 721 Chinese women, among which 388 are PCOS patients. Inputs of the proposed algorithm are scleral images segmented from full-eye images using an improved U-Net, and then a Resnet model was applied to extract deep features from scleral images. Finally, a multi-instance model was developed to achieve classification. Various performance indices such as AUC, classification accuracy, precision, recall, precision, and F1-score were adopted to assess the performance of our algorithm. Results show that our method achieves an average AUC of 0.979 and a classification accuracy of 0.929, which indicates the great potential of deep learning in the detection of PCOS.
The Urinary Glucose Excretion by Sodium–Glucose Cotransporter 2 Inhibitor in Patients With Different Levels of Renal Function: A Systematic Review and Meta-Analysis
Authors: Hu Suiyuan , Lin Chu , Cai Xiaoling , Zhu Xingyun , Lv Fang , Nie Lin , Ji Linong
Published: January 2022

Objective

Previous evidence suggested that sodium–glucose cotransporter 2 inhibitor (SGLT2i)-mediated urinary glucose excretion (UGE) appeared to be reduced with a decrease in glomerular filtration rate. Thus, we conducted a systematic review and meta‐analysis to compare SGLT2i-mediated UGE among individuals with different levels of renal function.

Methods

We conducted systematic searches in PubMed, Medline, Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrial.gov from inception to May 2021. Clinical studies of SGLT2i with reports of UGE changes in predefined different levels of renal function were included. The results were expressed as pooled effect sizes with 95% confidence interval (CI). A random-effects model was used to calculate the pooled effect sizes.

Results

In total, eight eligible studies were included. Significant differences were observed in the post-treatment UGE level among subgroups stratified by renal function (P <0.001 for subgroup difference), which were gradually decreased along with the severity of impaired renal function. Consistently, changes in UGE before and after SGLT2i treatment were also decreased along with the severity of impaired renal function [67.52 g/day (95%CI: 55.58 to 79.47 g/day) for individuals with normal renal function, 52.41 g/day (95%CI: 38.83 to 65.99 g/day) for individuals with mild renal function impairment, 35.11 g/day (95%CI: 19.79 to 50.43 g/day) for individuals with moderate renal function impairment, and 13.53 g/day (95%CI: 7.20 to 19.86 g/day) for individuals with severe renal function impairment; P <0.001 for subgroup differences].

Conclusions

SGLT2i-mediated UGE was renal function dependent, which was decreased with the extent of renal function impairment.
Flexible Power and Biomass-To-Methanol Plants With Different Gasification Technologies
Authors: Poluzzi A. , Guandalini G. , Guffanti S. , Martinelli M. , Moioli S. , Huttenhuis P. , Rexwinkel G. , Palonen J. , Martelli E. , Groppi G. , Romano M. C.
Published: January 2022

The competitiveness of biofuels may be increased by integrating biomass gasification plants with electrolysis units, which generate hydrogen to be combined with carbon-rich syngas. This option allows increasing the yield of the final product by retaining a higher amount of biogenic carbon and improving the resilience of the energy sector by favoring electric grid services and sector coupling. This article illustrates a techno-economic comparative analysis of three flexible power and biomass to methanol plants based on different gasification technologies: direct gasification, indirect gasification, and sorption-enhanced gasification. The design and operational criteria of each plant are conceived to operate both without green hydrogen addition (baseline mode) and with hydrogen addition (enhanced mode), following an intermittent use of the electrolysis system, which is turned on when the electricity price allows an economically viable hydrogen production. The methanol production plants include a gasification section, syngas cleaning, conditioning and compression section, methanol synthesis and purification, and heat recovery steam cycle to be flexibly operated. Due to the high oxygen demand in the gasifier, the direct gasification-based plant obtains a great advantage to be operated between a minimum load to satisfy the oxygen demand at high electricity prices and a maximum load to maximize methanol production at low electricity prices. This allows avoiding large oxygen storages with significant benefits for Capex and safety issues. The analysis reports specific fixed-capital investments between 1823 and 2048 €/kW of methanol output in the enhanced operation and LCOFs between 29.7 and 31.7 €/GJLHV. Economic advantages may be derived from a decrease in the electrolysis capital investment, especially for the direct gasification-based plants, which employ the greatest sized electrolyzer. Methanol breakeven selling prices range between 545 and 582 €/t with the 2019 reference Denmark electricity price curve and between 484 and 535 €/t with an assumed modified electricity price curve of a future energy mix with increased penetration of intermittent renewables.
Multi-Time Scale Harmonic Mitigation for High Proportion Electronic Grid
Authors: Suo Lian , Lin LiJuan , Xing Licheng , Jia Qingquan
Published: January 2022

As new energies integrated into grid, the harmonics in the grid are more serious, and the Voltage Detection Active Power Filter (VDAPF) has been used as the mitigation equipment to solve the harmonic problems in power electronic distribution network. The global optimization method generally utilizes 15 min to mitigate harmonic which is named long-time-scale, and it is impossible to mitigate harmonic timely. This paper studies a multi-time-scale harmonic mitigation method which adds 5 min prediction to the global optimization method which is named multi-time-scale. The objective is to correct the deviation of harmonic caused by the long-time-scale harmonic prediction error. This paper utilizes MPC to predict the amplitude and phase variation of the harmonics in short time scale, and utilizes distributed VDAPF to optimize harmonic in long time scale. The IEEE 33 nodes system was used as an example to conduct a comparative analysis of mitigation effects in two different harmonic injection scenarios which injected separately 10 and 20%. The results shows that the mitigating effect of the global optimization method is limited under two different harmonic injection scenarios, and it needs to combine with short time scale harmonic prediction information to ensure the effectiveness and rationality of the mitigation results. When the harmonic current fluctuates, there are unqualified voltage distortion nodes in each region, and the voltage distortion rate is larger. But the MPC can change harmonic prediction in a short time, so every harmonic of each VDAPF conductance values is set bigger, and harmonic conductance of the higher harmonics is relatively lower.
Why Do Agroforestry Systems Enhance Biodiversity? Evidence From Habitat Amount Hypothesis Predictions
Authors: Santos Mário , Cajaiba Reinaldo Lucas , Bastos Rita , Gonzalez Darinka , Petrescu Bakış Alis-Luciana , Ferreira Daniel , Leote Pedro , Barreto da Silva Wully , Cabral João Alexandre , Gonçalves Berta , Mosquera-Losada Maria Rosa
Published: January 2022

Considering the present ecological crisis, land use-biodiversity relationships have become a major topic in landscape planning, ecosystem management and ecological restoration. In this scope, consistent patterns of outstanding biodiversity have been identified in agroforestry systems within diverse biogeographic regions and types of management. Empirical work has revealed that agroforestry higher structural complexity, when compared with current simplified agricultural systems, might be partially responsible for the observed patterns. The recently developed Habitat Amount Hypothesis predicts diversity for a local habitat patch, from the amount of the same habitat within the local landscape. We have expanded the previous hypothesis to the landscape level, computing the influence of the dominant land uses on the diversity of coexisting guilds. As a case study, we have considered archetypal landscapes dominated (or co-dominated) by crops or trees, which were compared using normalized diversities. The results obtained show that agroforestry systems substantially increase functional diversity and overall biodiversity within landscapes. We highlight that the normalized values should be parametrized to real conditions where the type of crop, tree and agroecological management will make a difference. Most importantly, our findings provide additional evidence that agroforestry has a critical role in enhancing biodiversity in agricultural landscapes and, in this way, should be regarded as a priority measure in European Agri-environmental funding schemes.
Spatio-Temporal Patterns of Joshua Tree Stand Structure and Regeneration Following Mojave Desert Wildfires
Authors: St. Clair Seth B. , St. Clair Elijah A. , St. Clair Samuel B.
Published: January 2022

Eastern Joshua tree (Yucca jaegeriana) plays a central role in the ecology of the Mojave Desert ecosystem. However, the emergence of invasive grass fire-cycles in the last several decades brings into question Joshua trees’ tolerance and resilience to changing fire regimes. This study’s objective was to examine the effects of wildfires on the structure and regeneration potential of Joshua trees forests. We examined the density, size class structure, and regeneration response of Joshua tree populations on a network of one kilometer transects along the boundaries of four independent wildfires and the interior of the largest fire that occurred 15 years ago (2005) in the northeast Mojave Desert. Burned edge and burned interior transects had 23- and 4.1-fold lower Joshua tree stand densities than unburned transects. The more robust recovery of stand density along burned interior transects compared to burned edge transects appears to be primarily driven by more prolific vegetative sprouting. Our data show that Joshua trees can sprout vegetatively following fire, but it is not a strong or consistent post-fire resprouter. Limiting the spread of invasive annual grasses and novel fire regimes will be critical to maintaining healthy Joshua tree populations into the future, particularly on the edge of its ecological range.
Combined Transcriptome and Metabolome Analysis of Musa nana Laur. Peel Treated With UV-C Reveals the Involvement of Key Metabolic Pathways
Authors: Chen Ming-zhong , Zhong Xu-Mei , Lin Hai-Sheng , Qin Xiao-Ming
Published: January 2022

An increasing attention is being given to treat fruits with ultraviolet C (UV-C) irradiation to extend shelf-life, senescence, and protection from different diseases during storage. However, the detailed understanding of the pathways and key changes in gene expression and metabolite accumulation related to UV-C treatments are yet to be explored. This study is a first attempt to understand such changes in banana peel irradiated with UV-C. We treatedMusa nanaLaur. with 0.02 KJ/m2UV-C irradiation for 0, 4, 8, 12, 15, and 18 days and studied the physiological and quality indicators. We found that UV-C treatment reduces weight loss and decay rate, while increased the accumulation of total phenols and flavonoids. Similarly, our results demonstrated that UV-C treatment increases the activity of defense and antioxidant system related enzymes. We observed that UV-C treatment for 8 days is beneficial forM. nanapeels. The peels ofM. nanatreated with UV-C for 8 days were then subjected to combined transcriptome and metabolome analysis. In total, there were 425 and 38 differentially expressed genes and accumulated metabolites, respectively. We found that UV-C treatment increased the expression of genes in secondary metabolite biosynthesis related pathways. Concomitant changes in the metabolite accumulation were observed. Key pathways that were responsive to UV-C irradiation include flavonoid biosynthesis, phenylpropanoid bios6ynthesis, plant-pathogen interaction, MAPK signaling (plant), and plant hormone signal transduction pathway. We concluded that UV-C treatment imparts beneficial effects on banana peels by triggering defense responses against disease, inducing expression of flavonoid and alkaloid biosynthesis genes, and activating phytohormone and MAPK signaling pathways.
Molecular Characterization of Two Known SRD5A2 Gene Variants in Mexican Patients With Disorder of Sexual Development
Authors: María Guadalupe Ortiz-López , Katy Sánchez-Pozos , Charmina Aguirre-Alvarado , Vihko Pirkko , Marta Menjivar
Published: January 2022

Background: The 5α-reductase type 2 deficiency (5α-RD2) is a specific form of disorder of sexual development (DSD). Pathogenic variants in the SRD5A2 gene, which encodes this enzyme, are responsible for 46,XY DSD.

Objective: The objective of the study was to investigate the genetic etiology of 46,XY DSD in two Mexican families with affected children.

Materials and methods: The SRD5A2 gene of the parents and affected children was screened in both families via polymerase chain reaction amplification and DNA direct sequencing. The role of genetic variants in enzymatic activity was tested by site-directed mutagenesis.

Results: Subject 1 presented two variants: p.Glu197Asp and p.Pro212Arg. Subject 2 was homozygous for the variant p.Glu197Asp. The two variants were reported in early studies. The directed mutagenesis study showed that the p.Glu197Asp and p.Pro212Arg variants lead to a total loss of enzymatic activity and, consequently, abnormal genitalia development in the patients.

Conclusion: These results suggest that p.Glu197Asp and p.Pro212Arg are pathogenic variants that lead to the phenotypic expression of DSD. 5α-RD2 is of extreme importance not only because of its frequency (it is rare) but also because of its significance in understanding the mechanism of androgen action, the process of sexual differentiation, and the factors that influence normal sexual behavior.
The Peopling and Migration History of the Natives in Peninsular Malaysia and Borneo: A Glimpse on the Studies Over the Past 100 years
Authors: Hoh Boon-Peng , Deng Lian , Xu Shuhua
Published: January 2022

Southeast Asia (SEA) has one of the longest records of modern human habitation out-of-Africa. Located at the crossroad of the mainland and islands of SEA, Peninsular Malaysia is an important piece of puzzle to the map of peopling and migration history in Asia, a question that is of interest to many anthropologists, archeologists, and population geneticists. This review aims to revisit our understanding to the population genetics of the natives from Peninsular Malaysia and Borneo over the past century based on the chronology of the technology advancement: 1) Anthropological and Physical Characterization; 2) Blood Group Markers; 3) Protein Markers; 4) Mitochondrial and Autosomal DNA Markers; and 5) Whole Genome Analysis. Subsequently some missing gaps of the study are identified. In the later part of this review, challenges of studying the population genetics of natives will be elaborated. Finally, we conclude our review by reiterating the importance of unveiling migration history and genetic diversity of the indigenous populations as a steppingstone towards comprehending disease evolution and etiology.
Rare Variants and Polymorphisms of FBN1 Gene May Increase the Risk of Non-Syndromic Aortic Dissection
Authors: Pan Meichen , Li Lianjie , Li Zehao , Chen Shu , Li Zongzhe , Wang Yuning , He Henghui , Lin Lihua , Wang Haihao , Liu Qian
Published: January 2022

Aortic dissection (AD) is a cardiovascular disease characterized by high mortality and poor prognosis. Although FBN1 is associated with syndromic AD, its association with non-syndromic AD remains unclear. In this study, DNA samples from 90 Chinese individuals with non-syndromic AD (60 Stanford A, 30 Stanford B types) were analyzed to determine the relationship between diverse genotypes of the FBN1 gene and non-syndromic AD. Eleven pathogenic/likely pathogenic variants (1 novel) were identified in 12.2% of patients with non-syndromic AD. Patients with positive variants suffered from AD at a younger age than those in the negative variant group. Among the six positive missense mutations associated with cysteine residue hosts, four (66.7%) were Stanford A AD, whereas two (33.3%) were Stanford B AD. Three (100%) positive splicing/truncation variant hosts were Stanford A AD. The splicing/truncation variants and missense variants involving cysteine residues in the FBN1 gene increased the risk of Stanford A AD. Ten common SNPs that increased susceptibility to AD were identified. In particular, five SNPs were detected significantly in Stanford A AD, whereas another four SNPs were significantly detected in Stanford B AD. These significant variants can function as biomarkers for the identification of patients at risk for AD. Our findings have the potential to broaden the database of positive mutations and common SNPs of FBN1 in non-syndromic AD among the Chinese population.
The Validation of a Single Multiplex Typing System With 45 Y-STR Markers for Familial Searching and Database Construction
Authors: Zeng Ying , Chen Ling , Wang Mengge , Yang Chengliang , Liu Hong , Xiao Cheng , Liu ChangHui , Li Yue , Xu Quyi , Du Weian , Liu Chao
Published: January 2022

The Y-chromosomal short tandem repeat (Y-STR) is an effective forensic tool in familial searches and patrilineal relationship evaluation. However, currently available Y-STR panels often lack sufficient discriminatory power to resolve genetic relationships between distant relatives or within patrilocal populations. This study aims to establish a novel Y-STR amplification system for forensic casework analysis and database construction, which contains 44 slowly and moderately mutating and one rapidly mutating Y-STR. The validation of the assay was conducted following the recommendations of SWGDAM developmental validation guidelines. Different types of casework samples were tested and reliable profiles were obtained. Furthermore, we genotyped and analyzed 141 unrelated Han Chinese male samples. The results showed that this Y45 kit could improve the performance of identifying male individuals, higher haplotype diversity, and discrimination capacity when compared to the previous widely used Yfiler Plus kit. In general, the validation study demonstrated that the newly developed Y45 kit possesses high sensitivity, inhibitor tolerance, male specificity in a mixture, species specificity, and precision and is capable of forensic casework analysis and database construction.
IBD-Associated Atg16L1T300A Polymorphism Regulates Commensal Microbiota of the Intestine
Authors: Liu Hongtao , Gao Ping , Jia Baoqian , Lu Na , Zhu Baoli , Zhang Fuping
Published: January 2022

The development of inflammatory bowel disease (IBD) is driven by the interaction among host genetics, microbiota, and the immune system of the entire digestive tract. Atg16L1T300A polymorphism is a genetic factor that confers increased risk for the pathogenesis of Crohn’s disease. However, the exact contributions of Atg16L1T300A to intestinal mucosal homeostasis are not well understood. Here we show that Atg16L1T300A polymorphism impacts commensal bacterial flora in the intestine under a steady state. Analysis of intestinal bacteria from Atg16L1T300A/T300A mice showed that they harbored an altered microbiota in both the terminal ileum and colon compared to cohoused WT mice. Interestingly, Atg16L1T300A/T300A mice harbored a significant increase in the abundance of Tyzzerella, Mucispirillum, Ruminococcaceae, and Cyanobacteria which were known associated with IBD. Moreover, Akkermansia, a bacterium that is mucin-associated, was reduced greatly in Atg16L1T300A/T300A mice. Further analysis indicated that goblet cells of Atg16L1T300A/T300A mice had diminished mucin secretion that resulted from defective autophagy. Finally, Atg16L1T300A/T300A mice developed more severe inflammation in the DSS colitis model than in WT mice. These results indicate that the altered microbiota in Atg16L1T300A/T300A mice might be an important factor that contributed to the risk of Atg16L1T300A carriers to Crohn’s disease and supports a multi-hit disease model involving specific gene–microbe interactions.
Conserved and Unique Functions of Blimp1 in Immune Cells
Authors: Nadeau Samantha , Martins Gislâine A.
Published: January 2022

B-lymphocyte-induced maturation protein-1 (Blimp1), is an evolutionarily conserved transcriptional regulator originally described as a repressor of gene transcription. Blimp1 crucially regulates embryonic development and terminal differentiation in numerous cell lineages, including immune cells. Initial investigations of Blimp1’s role in immunity established its non-redundant role in lymphocytic terminal effector differentiation and function. In B cells, Blimp1 drives plasmablast formation and antibody secretion, whereas in T cells, Blimp1 regulates functional differentiation, including cytokine gene expression. These studies established Blimp1 as an essential transcriptional regulator that promotes efficient and controlled adaptive immunity. Recent studies have also demonstrated important roles for Blimp1 in innate immune cells, specifically myeloid cells, and Blimp1 has been established as an intrinsic regulator of dendritic cell maturation and T cell priming. Emerging studies have determined both conserved and unique functions of Blimp1 in different immune cell subsets, including the unique direct activation of the igh gene transcription in B cells and a conserved antagonism with BCL6 in B cells, T cells, and myeloid cells. Moreover, polymorphisms associated with the gene encoding Blimp1 (PRDM1) have been linked to numerous chronic inflammatory conditions in humans. Blimp1 has been shown to regulate target gene expression by either competing with other transcription factors for binding to the target loci, and/or by recruiting various chromatin-modifying co-factors that promote suppressive chromatin structure, such as histone de-acetylases and methyl-transferases. Further, Blimp1 function has been shown to be essentially dose and context-dependent, which adds to Blimp1’s versatility as a regulator of gene expression. Here, we review Blimp1’s complex roles in immunity and highlight specific gaps in the understanding of the biology of this transcriptional regulator, with a major focus on aspects that could foster the description and understanding of novel pathways regulated by Blimp1 in the immune system.
PiggyBac Transposon-Mediated CD19 Chimeric Antigen Receptor-T Cells Derived From CD45RA-Positive Peripheral Blood Mononuclear Cells Possess Potent and Sustained Antileukemic Function
Authors: Suematsu Masaya , Yagyu Shigeki , Nagao Nobuyoshi , Kubota Susumu , Shimizu Yuto , Tanaka Miyuki , Nakazawa Yozo , Imamura Toshihiko
Published: January 2022

The quality of chimeric antigen receptor (CAR)-T cell products, namely, memory and exhaustion markers, affects the long-term functionality of CAR-T cells. We previously reported that piggyBac (PB) transposon-mediated CD19 CAR-T cells exhibit a memory-rich phenotype that is characterized by the high proportion of CD45RA+/C-C chemokine receptor type 7 (CCR7)+ T-cell fraction. To further investigate the favorable phenotype of PB-CD19 CAR-T cells, we generated PB-CD19 CAR-T cells from CD45RA+ and CD45RA− peripheral blood mononuclear cells (PBMCs) (RA+ CAR and RA− CAR, respectively), and compared their phenotypes and antitumor activity. RA+ CAR-T cells showed better transient gene transfer efficiency 24 h after transduction and superior expansion capacity after 14 days of culture than those shown by RA− CAR-T cells. RA+ CAR-T cells exhibited dominant CD8 expression, decreased expression of the exhaustion marker programmed cell death protein-1 (PD-1) and T-cell senescence marker CD57, and enriched naïve/stem cell memory fraction, which are associated with the longevity of CAR-T cells. Transcriptome analysis showed that canonical exhaustion markers were downregulated in RA+ CAR-T, even after antigen stimulation. Although antigen stimulation could increase CAR expression, leading to tonic CAR signaling and exhaustion, the expression of CAR molecules on cell surface after antigen stimulation in RA+ CAR-T cells was controlled at a relatively lower level than that in RA− CAR-T cells. In the in vivo stress test, RA+ CAR-T cells achieved prolonged tumor control with expansion of CAR-T cells compared with RA− CAR-T cells. CAR-T cells were not detected in the control or RA− CAR-T cells but RA+ CAR-T cells were expanded even after 50 days of treatment, as confirmed by sequential bone marrow aspiration. Our results suggest that PB-mediated RA+ CAR-T cells exhibit a memory-rich phenotype and superior antitumor function, thus CD45RA+ PBMCs might be considered an efficient starting material for PB-CAR-T cell manufacturing. This novel approach will be beneficial for effective treatment of B cell malignancies.
CD36 is Associated With the Development of Coronary Artery Lesions in Patients With Kawasaki Disease
Authors: Guo Mindy Ming-Huey , Huang Ying-Hsien , Wang Feng-Sheng , Chang Ling-Sai , Chen Kuang-Den , Kuo Ho-Chang
Published: January 2022

Kawasaki disease (KD) is an autoimmune-like vasculitis of childhood involving the coronary arteries. Macrophages require scavenger receptors such as CD36 to effectively clear cellular debris and induce self-tolerance. In this study, we hypothesized that CD36 plays an important role in the immunopathogenesis of KD, by aiding in the clearance of plasma mitochondrial DNA, and by amplifying the immune response by activating the inflammasome pathway via AIM2. Fifty-two healthy controls, 52 febrile controls, and 102 KD patients were recruited for RT-PCR of target mRNA expression and plasma mitochondrial DNA. Blood samples were obtained 24 hours prior and 21 days after the administration of intravenous immunoglobulin (IVIG) therapy. Patients with acute KD had higher plasma levels of cell-free mitochondrial DNA (ND1, ND4, and COX1), and higher mRNA expressions of CD36 and AIM2 when compared to both healthy and febrile controls. A greater decrease in both CD36 and AIM2 mRNA expression after IVIG therapy was associated with the development of coronary artery lesions. Coronary artery lesions were associated with a larger decrease of CD36 expression following IVIG therapy, which may indicate that prolonged expression of the scavenger receptor may have a protective effect against the development of coronary artery lesions in KD.
Transcriptional Analysis of Total CD8+ T Cells and CD8+CD45RA- Memory T Cells From Young and Old Healthy Blood Donors
Authors: Toma Georgiana , Lemnian Ioana Maria , Karapetian Eliza , Grosse Ivo , Seliger Barbara
Published: January 2022

Memory CD8+ T cells accumulate with aging, while the naïve T cell compartment decreases, leading to an increased susceptibility to infections and a decreased vaccine efficiency. To get deeper insights into the underlying mechanisms, this study aims to determine the age-dependent expression profile of total versus memory CD8+ T cells from young and old donors. Total CD8+ and CD8+CD45RA- memory T cells isolated from young (<30 years) and old (>60 years) donors were stimulated with anti-CD3 and anti-CD28 antibodies for 48h before analyzing the cytokine secretion and activation markers by flow cytometry and changes in the expression profiles using RNA sequencing. Gene ontology (GO) term enrichment analyses were performed for up-regulated and uniquely expressed transcripts identified in the T cell populations of both age groups. Total and memory CD8+ T cells from old donors expressed significantly higher CD25 levels and have an increased cytokine secretion. While approximately 1,500 up-regulated transcripts were identified in all groups, CD8+CD45RA- memory T cells of old donors had approximately 500 more uniquely expressed transcripts. Four GO terms related to the JAK-STAT pathway were identified for up-regulated transcripts in the total CD8+ T cells of old donors, whereas CD8+CD45RA- memory T cells GO terms related to adjacent pathways, like JNK and MAPK/ERK, were found. Additionally, the unique transcripts of CD8+CD45RA- memory T cells of old donors were related to the JNK, MAPK and IL-12 pathways. For both T cell populations of the old donors, cytokine and JAK-STAT pathway transcripts were up-regulated. Thus, an age-dependent effect was observed on the transcriptomes of total and memory CD8+ T cells. The CD8+ CD45RA- memory T cells from old donors maintained the increased cytokine secretion of the total CD8+ T cell population and the increased JAK-STAT pathway transcripts, which have an impact on inflammation and senescence.
Revealing Clonal Responses of Tumor-Reactive T-Cells Through T Cell Receptor Repertoire Analysis
Authors: Aoki Hiroyasu , Shichino Shigeyuki , Matsushima Kouji , Ueha Satoshi
Published: January 2022

CD8+ T cells are the key effector cells that contribute to the antitumor immune response. They comprise various T-cell clones with diverse antigen-specific T-cell receptors (TCRs). Thus, elucidating the overall antitumor responses of diverse T-cell clones is an emerging challenge in tumor immunology. With the recent advancement in next-generation DNA sequencers, comprehensive analysis of the collection of TCR genes (TCR repertoire analysis) is feasible and has been used to investigate the clonal responses of antitumor T cells. However, the immunopathological significance of TCR repertoire indices is still undefined. In this review, we introduce two approaches that facilitate an immunological interpretation of the TCR repertoire data: inter-organ clone tracking analysis and single-cell TCR sequencing. These approaches for TCR repertoire analysis will provide a more accurate understanding of the response of tumor-specific T cells in the tumor microenvironment.
Roles of the Exosomes Derived From Myeloid-Derived Suppressor Cells in Tumor Immunity and Cancer Progression
Authors: Chen Zhuang , Yuan Rui , Hu Shengyun , Yuan Weitang , Sun Zhenqiang
Published: January 2022

Tumor immunity is involved in malignant tumor progression. Myeloid-derived suppressor cells (MDSCs) play an irreplaceable role in tumor immunity. MDSCs are composed of immature myeloid cells and exhibit obvious immunomodulatory functions. Exosomes released by MDSCs (MDSCs-Exos) have similar effects to parental MDSCs in regulating tumor immunity. In this review, we provided a comprehensive description of the characteristics, functions and mechanisms of exosomes. We analyzed the immunosuppressive, angiogenesis and metastatic effects of MDSCs-Exos in different tumors through multiple perspectives. Immunotherapy targeting MDSCs-Exos has demonstrated great potential in cancers and non-cancerous diseases.
Heterologous Immunity Between SARS-CoV-2 and Pathogenic Bacteria
Authors: Eggenhuizen Peter J. , Ng Boaz H. , Chang Janet , Cheong Rachel M.Y. , Yellapragada Anusha , Wong Wey Y. , Ting Yi Tian , Monk Julie A. , Gan Poh-Yi , Holdsworth Stephen R. , Ooi Joshua D.
Published: January 2022

Heterologous immunity, when the memory T cell response elicited by one pathogen recognizes another pathogen, has been offered as a contributing factor for the high variability in coronavirus disease 2019 (COVID-19) severity outcomes. Here we demonstrate that sensitization with bacterial peptides can induce heterologous immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) derived peptides and that vaccination with the SARS-CoV-2 spike protein can induce heterologous immunity to bacterial peptides. Using in silico prediction methods, we identified 6 bacterial peptides with sequence homology to either the spike protein or non-structural protein 3 (NSP3) of SARS-CoV-2. Notwithstanding the effects of bystander activation, in vitro co-cultures showed that all individuals tested (n=18) developed heterologous immunity to SARS-CoV-2 peptides when sensitized with the identified bacterial peptides. T cell recall responses measured included cytokine production (IFN-γ, TNF, IL-2), activation (CD69) and proliferation (CellTrace). As an extension of the principle of heterologous immunity between bacterial pathogens and COVID-19, we tracked donor responses before and after SARS-CoV-2 vaccination and measured the cross-reactive T cell responses to bacterial peptides with similar sequence homology to the spike protein. We found that SARS-CoV-2 vaccination could induce heterologous immunity to bacterial peptides. These findings provide a mechanism for heterologous T cell immunity between common bacterial pathogens and SARS-CoV-2, which may explain the high variance in COVID-19 outcomes from asymptomatic to severe. We also demonstrate proof-of-concept that SARS-CoV-2 vaccination can induce heterologous immunity to pathogenic bacteria derived peptides.
SARS-CoV-2 Variants of Concern and Variants of Interest Receptor Binding Domain Mutations and Virus Infectivity
Authors: Liu Haolin , Wei Pengcheng , Kappler John W. , Marrack Philippa , Zhang Gongyi
Published: January 2022

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has lasted more than 2 years with over 260 million infections and 5 million deaths worldwide as of November 2021. To combat the virus, monoclonal antibodies blocking the virus binding to human receptor, the angiotensin converting enzyme 2 (ACE2), have been approved to treat the infected patients. Inactivated whole virus or the full-length virus spike encoding adenovirus or mRNA vaccines are being used to immunize the public. However, SARS-CoV-2 variants are emerging. These, to some extent, escape neutralization by the therapeutic antibodies and vaccine-induced immunity. Thus, breakthrough infections by SARS-CoV-2 variants have been reported in previously virus-infected or fully vaccinated individuals. The receptor binding domain (RBD) of the virus spike protein reacts with host ACE2, leading to the entry of the virus into the cell. It is also the major antigenic site of the virus, with more than 90% of broadly neutralizing antibodies from either infected patients or vaccinated individuals targeting the spike RBD. Therefore, mutations in the RBD region are effective ways for SARS-CoV-2 variants to gain infectivity and escape the immunity built up by the original vaccines or infections. In this review, we focus on the impact of RBD mutations in SARS-CoV-2 variants of concern (VOC) and variants of interest (VOI) on ACE2 binding affinity and escape of serum antibody neutralization. We also provide protein structure models to show how the VOC and VOI RBD mutations affect ACE2 binding and allow escape of the virus from the therapeutic antibody, bamlanivimab.