bluuebunny/crossref_metadata_2025 huggingface dataset:
Postnatal Smad3 Inactivation in Murine Smooth Muscle Cells Elicits a Temporally and Regionally Distinct Transcriptional Response
Authors: Bramel Emily E. , Creamer Tyler J. , Saqib Muzna , Camejo Nunez Wendy A. , Bagirzadeh Rustam , Roker LaToya Ann , Goff Loyal A. , MacFarlane Elena Gallo
Published: April 2022

Heterozygous, loss of function mutations in positive regulators of the Transforming Growth Factor-β (TGF-β) pathway cause hereditary forms of thoracic aortic aneurysm. It is unclear whether and how the initial signaling deficiency triggers secondary signaling upregulation in the remaining functional branches of the pathway, and if this contributes to maladaptive vascular remodeling. To examine this process in a mouse model in which time-controlled, partial interference with postnatal TGF-β signaling in vascular smooth muscle cells (VSMCs) could be assessed, we used a VSMC-specific tamoxifen-inducible system, and a conditional allele, to inactivate Smad3 at 6 weeks of age, after completion of perinatal aortic development. This intervention induced dilation and histological abnormalities in the aortic root, with minor involvement of the ascending aorta. To analyze early and late events associated with disease progression, we performed a comparative single cell transcriptomic analysis at 10- and 18-weeks post-deletion, when aortic dilation is undetectable and moderate, respectively. At the early time-point, Smad3-inactivation resulted in a broad reduction in the expression of extracellular matrix components and critical components of focal adhesions, including integrins and anchoring proteins, which was reflected histologically by loss of connections between VSMCs and elastic lamellae. At the later time point, however, expression of several transcripts belonging to the same functional categories was normalized or even upregulated; this occurred in association with upregulation of transcripts coding for TGF-β ligands, and persistent downregulation of negative regulators of the pathway. To interrogate how VSMC heterogeneity may influence this transition, we examined transcriptional changes in each of the four VSMC subclusters identified, regardless of genotype, as partly reflecting the proximal-to-distal anatomic location based on in situ RNA hybridization. The response to Smad3-deficiency varied depending on subset, and VSMC subsets over-represented in the aortic root, the site most vulnerable to dilation, most prominently upregulated TGF-β ligands and pro-pathogenic factors such as thrombospondin-1, angiotensin converting enzyme, and pro-inflammatory mediators. These data suggest that Smad3 is required for maintenance of focal adhesions, and that loss of contacts with the extracellular matrix has consequences specific to each VSMC subset, possibly contributing to the regional susceptibility to dilation in the aorta.
Machine Learning Analyzed Weather Conditions as an Effective Means in the Predicting of Acute Coronary Syndrome Prevalence
Authors: Wlodarczyk Aleksandra , Molek Patrycja , Bochenek Bogdan , Wypych Agnieszka , Nessler Jadwiga , Zalewski Jaroslaw
Published: April 2022

Background

The prediction of the number of acute coronary syndromes (ACSs) based on the weather conditions in the individual climate zones is not effective. We sought to investigate whether an artificial intelligence system might be useful in this prediction.

Methods

Between 2008 and 2018, a total of 105,934 patients with ACS were hospitalized in Lesser Poland Province, one covered by two meteorological stations. The predicted daily number of ACS has been estimated with the Random Forest machine learning system based on air temperature (°C), air pressure (hPa), dew point temperature (Td) (°C), relative humidity (RH) (%), wind speed (m/s), and precipitation (mm) and their daily extremes and ranges derived from the day of ACS and from 6 days before ACS.

Results

Of 840 pairwise comparisons between individual weather parameters and the number of ACS, 128 (15.2%) were significant but weak with the correlation coefficients ranged from −0.16 to 0.16. None of weather parameters correlated with the number of ACS in all the seasons and stations. The number of ACS was higher in warm front days vs. days without any front [40 (29–50) vs. 38 (27–48), respectively, P < 0.05]. The correlation between the predicted and observed daily number of ACS derived from machine learning was 0.82 with 95% CI of 0.80–0.84 (P < 0.001). The greatest importance for machine learning (range 0–1.0) among the parameters reached Td daily range with 1.00, pressure daily range with 0.875, pressure maximum daily range with 0.864, and RH maximum daily range with 0.853, whereas among the clinical parameters reached hypertension daily range with 1.00 and diabetes mellitus daily range with 0.28. For individual seasons and meteorological stations, the correlations between the predicted and observed number of ACS have ranged for spring from 0.73 to 0.77 (95% CI 0.68–0.82), for summer from 0.72 to 0.76 (95% CI 0.66–0.81), for autumn from 0.72 to 0.83 (95% CI 0.67–0.87), and for winter from 0.76 to 0.79 (95% CI 0.71–0.83) (P < 0.001 for each).

Conclusion

The weather parameters have proven useful in predicting the prevalence of ACS in a temperate climate zone for all the seasons, if analyzed with an artificial intelligence system. Simultaneously, the analysis of individual weather parameters or frontal scenarios has provided only weak univariate relationships. These findings will require validation in other climatic zones.
A Novel Missense Variant in Actin Binding Domain of MYH7 Is Associated With Left Ventricular Noncompaction
Authors: Hesaraki Mahdi , Bora Ugur , Pahlavan Sara , Salehi Najmeh , Mousavi Seyed Ahmad , Barekat Maryam , Rasouli Seyed Javad , Baharvand Hossein , Ozhan Gunes , Totonchi Mehdi
Published: April 2022

Cardiomyopathies are a group of common heart disorders that affect numerous people worldwide. Left ventricular non-compaction (LVNC) is a structural disorder of the ventricular wall, categorized as a type of cardiomyopathy that mostly caused by genetic disorders. Genetic variations are underlying causes of developmental deformation of the heart wall and the resultant contractile insufficiency. Here, we investigated a family with several affected members exhibiting LVNC phenotype. By whole-exome sequencing (WES) of three affected members, we identified a novel heterozygous missense variant (c.1963C>A:p.Leu655Met) in the gene encoding myosin heavy chain 7 (MYH7). This gene is evolutionary conserved among different organisms. We identified MYH7 as a highly enriched myosin, compared to other types of myosin heavy chains, in skeletal and cardiac muscles. Furthermore, MYH7 was among a few classes of MYH in mouse heart that highly expresses from early embryonic to adult stages. In silico predictions showed an altered actin-myosin binding, resulting in weaker binding energy that can cause LVNC. Moreover, CRISPR/Cas9 mediated MYH7 knockout in zebrafish caused impaired cardiovascular development. Altogether, these findings provide the first evidence for involvement of p.Leu655Met missense variant in the incidence of LVNC, most probably through actin-myosin binding defects during ventricular wall morphogenesis.
Irisin Suppresses Nicotine-Mediated Atherosclerosis by Attenuating Endothelial Cell Migration, Proliferation, Cell Cycle Arrest, and Cell Senescence
Authors: Chen Junye , Li Kang , Shao Jiang , Lai Zhichao , Gao Ran , Wang Chaonan , Song Xitao , Guo Wenjun , Yu Xiaoxi , Du Fenghe , Zhu Zhan , Wang Jiaxian , Ma Jiangyu , Xu Leyin , Zhou Yan , Liu Jianghao , Shu Keqiang , Zhao Hongmei , Wang Jing , Liu Bao
Published: April 2022

Atherosclerotic disease has become the major cause of death worldwide. Smoking, as a widespread independent risk factor, further strengthens the health burden of atherosclerosis. Irisin is a cytokine that increases after physical activity and shows an atheroprotective effect, while its specific mechanism in the process of atherosclerosis is little known. The reversal effect of irisin on intimal thickening induced by smoking-mediated atherosclerosis was identified in Apoe–/– mice through the integrin αVβ5 receptor. Endothelial cells treated with nicotine and irisin were further subjected to RNA-seq for further illustrating the potential mechanism of irisin in atherosclerosis, as well as the wound healing assays, CCK-8 assays, β-gal staining and cell cycle determination to confirm phenotypic alterations. Endothelial differential expressed gene enrichment showed focal adhesion for migration and proliferation, as well as the P53 signaling pathway for cell senescence and cell cycle control. Irisin exerts antagonistic effects on nicotine-mediated migration and proliferation via the integrin αVβ5/PI3K pathway. In addition, irisin inhibits nicotine-mediated endothelial senescence and cell cycle arrest in G0/G1 phase via P53/P21 pathway. This study further illustrates the molecular mechanism of irisin in atherosclerosis and stresses its potential as an anti-atherosclerotic therapy.
Palliative Care in Children With Advanced Heart Disease in a Tertiary Care Environment: A Mini Review
Authors: Bergsträsser Eva , Lukose Saumya , Zimmermann Karin , Oxenius Angela
Published: April 2022

Palliative care for children continues to evolve. More recently, this has also been true in the field of pediatric cardiology, particularly for children with advanced heart disease. In these children, similarly to children with cancer, treatment successes are offset by the risks of long-term morbidities, including premature death. This mini review aims to provide an overview of current knowledge on children suffering from advanced heart disease, their medical care during various phases of illness (including the palliative and end-of-life phase), symptom burden, experiences of parents, prognostic understanding of parents and physicians, and current status of the involvement of pediatric palliative care. In conclusion, the suffering of these children at the end of their young lives is pronounced and many parents feel prepared neither for medical problems nor for the child’s death. An effective and mutually trusting partnership between pediatric cardiology and pediatric palliative care would appear to be a prerequisite for the timely involvement of palliative care in further supporting these children and their families.
Flow Path of the Carbonate Geothermal Water in Xiong’an New Area, North China: Constraints From 14C Dating and H-O Isotopes
Authors: Zhang Baojian , Wang Siqi , Kang Fengxin , Li Yanyan , Zhuo Linyang , Gao Jun , Yuan Wenzhen , Xing Yifei
Published: April 2022

Studying the flow path of geothermal water in geothermal fields is an important basis for the scientific development and management of geothermal resources. However, due to the influence of engineering volume, economic benefits and demand, it is very difficult to fully grasp the flow path of deep geothermal water in large areas. The use of hydrogeochemical tracers to determine the flow path of geothermal water is a scientific and effective research method. In order to accurately describe the flow path of carbonate geothermal water in the Xiong’an New Area and its surrounding areas, this study systematically analyzed the 14C, 18O, and 2H data of carbonate and Cenozoic sandstone geothermal water, Quaternary groundwater, as well as mountain spring water of the study area. Based on these results, we can conclude that 1) The 14C, d, and 18O values are favourable clues for indicating the circulating runoff conditions and runoff paths of geothermal water. 2) The salinity of the Xushui-Wenan and Lilan transfer zone are <3 g/l, the 14C values are lower than 25000 years, the d value is higher, and the phenomenon of “18O drift” is weak, all these indicating the dominant flow path of carbonate geothermal water, featured by relative lower temperature. 3) The salinity of karst geothermal water in the southwest of Gaoyang low uplift, Rongcheng uplift and Niutuozhen uplift is > 3 g/l, the 14C values are higher than 40,000 years, the d value is lower, and the phenomenon of “18O drift” is obvious, all these indicating that the tectonic sites are the convergence areas of regional karst geothermal water, featured by relative high temperature. 4) The hydrochemical indicators combined with previous carbonate groundwater flow field indicate that the recharge of carbonate geothermal water in the Xiong’an New Area may not only drive from the western Taihang Mountains, but also along the Xushui-Wenan transfer zone and the Lilan fault, with the recharge of carbonate groundwater from the Cangxian uplift from east to west. By further identifying and defining the dominant flow path and supply direction of carbonate geothermal water in the Xiong’an New Area and surrounding areas, it provides strong support for the scientific development of regional carbonate geothermal water.
Detecting Geothermal Resources in a Plateau Area: Constraints From Land Surface Temperature Characteristics Using Landsat 8 Data
Authors: Dong Ben , Dong Shuyi , Wang Yingchun , Wen Fayang , Yu Chunmei , Zhou Jinlin , Song Rongcai
Published: April 2022

Geothermal energy is a kind of clean energy, which attracts more attention. The detection of geothermal resources is inseparable from regional geothermal prospects. Land surface temperature (LST) is an indispensable parameter for geothermal exploration, but the retrieval accuracy of LST for complex and remote areas is currently a major challenge. In this article, based on Landsat 8 remote sensing data, the characteristics of surface temperature retrieval methods are systematically reviewed, and the differences among these three algorithms are researched by using them to detect the surface temperature in the study area, which is Kangding County, Sichuan Province, China. Then the experimental results of the three algorithms are verified by using long-time (more than 1 year) measured data from the two monitoring sites, and the monitoring sites are situated in Zhonggu and Lao Yulin area of Kangding County. The results show that the radiative transfer equation (RTE) has the highest accuracy, and the mean error is 0.372°C; mono-window algorithm (MW) has a mean error of −0.606°C; and the split-window (SW) algorithm has the lowest accuracy, with a mean error of −2.07°C. The experimental results were used to select an algorithm with relatively high accuracy and low sensitivity. At the same time, a time series was used to perform temperature retrieval for this study area from November 2016 to December 2017 to evaluate the applicability of the method. The result shows that the RTE has the highest accuracy in mid-winter and a relatively low accuracy in summer in Kangding County. The purpose of this article is to establish a suitable method for high-precision surface temperature retrieval in plateau areas and to provide technical support for exploring geothermal resources or evaluating geothermal potential in these areas.
Quantifying the Relationship Between Human Activities Intensity and Thawing Hazards of the Frozen Ground on the Qinghai–Tibet Plateau
Authors: Ni Jie , Wu Tonghua , Zhu Xiaofan , Chen Jie , Wu Xiaodong , Hu Guojie , Zou Defu , Li Ren , Du Yizhen
Published: April 2022

Climate warming could accelerate frozen ground degradation on the Qinghai–Tibet Plateau (QTP). Quantitative analysis of the impacts of thaw-induced hazards of the frozen ground on human activities in cold regions has become one of the most important issues in current research. To identify adverse impacts of these thawing hazards on human activities, this study explores a spatially explicit, temporally consistent and quantitative method to map human activity intensity (HAI). Four categories of variables are selected to represent some of the most important human activities on the QTP, including land use, road distribution, population density, and grazing density. By improving the human footprint index method, HAI maps of the QTP in 1995, 2005, and 2015 are created, and then quantitative analysis of the HAI under different thawing hazard levels in the frozen ground of QTP is done. The results show that, for the above three periods, the mean HAI values on the QTP are 0.10, 0.11, and 0.12, respectively. Moreover, during 1995–2015, the intensity and extent of human activities increase by 15.35% and 40.64%, respectively. The superposition results of the HAI and frozen ground thawing hazard maps show that a seasonally frozen ground region has relatively larger HAI, and its mean value is more than twice that of the permafrost region. For permafrost regions, the medium-hazard area has the highest HAI (0.09), which possibly has great impacts on the linear infrastructure. The establishment of a thawing disaster warning map can effectively shield high thaw settlement hazard areas without human activities and thus can present a more accurate early warning. These results can provide important scientific references for the disaster prevention and mitigation work in frozen ground regions, including risk assessment and infrastructure maintenance.
Research on Reservoir Characteristics and Main Controlling Factors of Longwangmiao Formation of Cambrian in Sichuan Basin
Authors: Wang Qiang , Wang Xingzhi , Zeng Xinyao
Published: April 2022

Based on the 4 measured profiles, 17 observation profiles, and 13 drilling core macroscopic and microscopic characteristics of the Cambrian Longwangmiao Formation in the Sichuan Basin, combined with analysis and testing, and reservoir logging interpretation, the reservoir characteristics and main controlling factors of the Longwangmiao Formation are analyzed. The marginal bank of the underwater paleo-uplift of the restricted platform and the point bank facies within the platform belong to the sedimentary facies belts that are most conducive to the formation and evolution of the reservoir. However, the later transformation of dolomitization and dissolution played decisive roles in the formation of the reservoir. The Caledonian epigenetic karstification is the main reason for the lack of the overlying stratum of the Cambrian in the Sichuan Basin, and it is also the most important factor for the formation of large-scale dissolved cavities in the Longwangmiao Formation in the Sichuan Basin.
An Analytical Framework on Utilizing Natural Resources and Promoting Urban–Rural Development for Increasing Farmers’ Income Through Industrial Development in Rural China
Authors: Deng Xiangzheng , Wang Guofeng , Song Wei , Chen Mingxin , Liu Yujie , Sun Zhigang , Dong Jinwei , Yue Tianxiang , Shi Wenjiao
Published: April 2022

Lucid waters and lush mountains are invaluable assets. The countryside is an important carrier of these assets, and rural revitalization is a national strategy to meet the needs of the people. This study constructs the framework system for improving the efficiency of resource utilization, refining the effect of urban–rural integration, and optimizing the efficiency of industrial development for increasing farmers’ income. The challenges facing rural revitalization are clarified, especially including limited space for the growth of cultivated land quantity and significant challenges for quality improvement, insufficient effective supply of labor resources, uneven spatial distribution of water resources, low utilization efficiency of agricultural water resources, and so on. Finally, it puts forward the possible direction of future policies for rural revitalization, which is mainly reflected in the transformation of resource utilization efficiency improvement from single element to multi-element, the development of an urban–rural integration effect from extensive to lean, and the optimization of the industrial enrichment efficiency from management to comprehensive service. The analytical framework of resource utilization, urban–rural integration development, and industrial enrichment will provide regulatory policies and theoretical support for the flow of urban–rural factors.
Economic Evaluation and Systematic Review of Salt Marsh Restoration Projects at a Global Scale
Authors: Wang Jiang-Jing , Li Xiu-Zhen , Lin Shi-Wei , Ma Yu-Xi
Published: April 2022

Restoring degraded and damaged salt marshes has become an important initiative in the coastal wetlands management around the world. Evaluating the economic output of salt marsh restoration is of great significance for identifying the current state of knowledge gaps related to conservation activities and economic benefits. To address this question, we conducted an overview of global salt marsh restoration projects, and their financial expenses and restoration benefits in the past 40 years. The results showed that most of the saltmarsh restoration projects are near megacities and larger rivers, and restoration techniques of different regions depend on the types of disturbance factors such as climate change, extreme weather events, and land use change. With limited resources, fund allocation between protected areas and unprotected areas in middle-income countries is often unbalanced, indicating a mismatch between conservation efforts and regional needs. Although restoration projects are expensive, the evidence in this article implies that most salt marsh restoration projects could recover their financial expense in the finite time, especially for large-scale restoration activities. Besides, the great carbon sequestration potential would make salt marsh restoration projects more profitable under current efforts to promote carbon sequestration for combating global warming.
Genetic Engineering of the Rock Inhabitant Knufia petricola Provides Insight Into the Biology of Extremotolerant Black Fungi
Authors: Erdmann Eileen A. , Nitsche Sarah , Gorbushina Anna A. , Schumacher Julia
Published: April 2022

Black microcolonial fungi (Ascomycetes from Arthonio-, Dothideo-, and Eurotiomycetes) are stress-tolerant and persistent dwellers of natural and anthropogenic extreme habitats. They exhibit slow yeast-like or meristematic growth, do not form specialized reproduction structures and accumulate the black pigment 1,8-dihydroxynaphthalene (DHN) melanin in the multilayered cell walls. To understand how black fungi live, survive, colonize mineral substrates, and interact with phototrophs genetic methods are needed to test these functions and interactions. We chose the rock inhabitant Knufia petricola of the Chaetothyriales as a model for developing methods for genetic manipulation. Here, we report on the expansion of the genetic toolkit by more efficient multiplex CRISPR/Cas9 using a plasmid-based system for expression of Cas9 and multiple sgRNAs and the implementation of the three resistance selection markers genR (geneticin/nptII), baR (glufosinate/bar), and suR (chlorimuron ethyl/sur). The targeted integration of expression constructs by replacement of essential genes for pigment synthesis allows for an additional color screening of the transformants. The black-pink screening due to the elimination of pks1 (melanin) was applied for promoter studies using GFP fluorescence as reporter. The black-white screening due to the concurrent elimination of pks1 and phs1 (carotenoids) allows to identify transformants that contain the two expression constructs for co-localization or bimolecular fluorescence complementation (BiFC) studies. The co-localization and interaction of the two K. petricola White Collar orthologs were demonstrated. Two intergenic regions (igr1, igr2) were identified in which expression constructs can be inserted without causing obvious phenotypes. Plasmids of the pNXR-XXX series and new compatible entry plasmids were used for fast and easy generation of expression constructs and are suitable for a broad implementation in other fungi. This variety of genetic tools is opening a completely new perspective for mechanistic and very detailed study of expression, functioning and regulation of the genes/proteins encoded by the genomes of black fungi.
Prevalence of Clinically Relevant Germline BRCA Variants in a Large Unselected South African Breast and Ovarian Cancer Cohort: A Public Sector Experience
Authors: Van der Merwe Nerina C. , Combrink Herkulaas MvE , Ntaita Kholiwe S. , Oosthuizen Jaco
Published: April 2022

Breast cancer is a multifaceted disease that currently represents a leading cause of death in women worldwide. Over the past two decades (1998–2020), the National Health Laboratory Service’s Human Genetics Laboratory in central South Africa screened more than 2,974 breast and/or ovarian cancer patients for abnormalities characteristic of the widely known familial breast cancer genes, Breast Cancer gene 1 (BRCA1) and Breast Cancer gene 2 (BRCA2). Patients were stratified according to the presence of family history, age at onset, stage of the disease, ethnicity and mutation status relative to BRCA1/2. Collectively, 481 actionable (likely-to pathogenic) variants were detected in this cohort among the different ethnic/racial groups. A combination of old (pre-2014) and new (post-2014) laboratory techniques was used to identify these variants. Additionally, targeted genotyping was performed as translational research revealed the first three recurrent South African pathogenic variants, namely BRCA1 c.1374del (legacy name 1493delC), BRCA1 c.2641G>T (legacy name E881X) and BRCA2 c.7934del (legacy name 8162delG). This initial flagship study resulted in a cost-effective diagnostic test that enabled screening of a particular ethnic group for these variants. Since then, various non-Afrikaner frequent variants were identified that were proven to represent recurrent variants. These include BRCA2 c.5771_5774del (legacy name 5999del4) and BRCA2 c.582G>A, both Black African founder mutations. By performing innovative translational research, medical science in South Africa can adopt first-world technologies into its healthcare context as a developing country. Over the past two decades, the progress made in the public sector enabled a pivotal shift away from population-directed genetic testing to the screening of potentially all breast and ovarian cancer patients, irrespective of ethnicity, family history or immunohistochemical status. The modifications over the years complied with international standards and guidelines aimed at universal healthcare for all. This article shares all the cohort stratifications and the likely-to pathogenic variants detected.
Genetic Diagnosis of Rubinstein–Taybi Syndrome With Multiplex Ligation-Dependent Probe Amplification (MLPA) and Whole-Exome Sequencing (WES): Case Series With a Novel CREBBP Variant
Authors: Lee Yu-Rong , Lin Yu-Chen , Chang Yi-Han , Huang Hsin-Yu , Hong Yi-Kai , Aala Wilson Jr F. , Tu Wei-Ting , Tsai Meng-Che , Chou Yen-Yin , Hsu Chao-Kai
Published: April 2022

Rubinstein–Taybi Syndrome (RSTS) is a rare congenital disease with distinctive facial features, broadening of the thumbs and halluces, and developmental delay. RSTS is caused by de novo genetic alterations in CREBBP and the homologous EP300 genes. In this study, we established a genetic diagnostic protocol by integrating multiplex ligation-dependent probe amplification (MLPA) and whole-exome sequencing (WES). Five patients clinically diagnosed with RSTS were enrolled for genetic testing. Germline DNA was extracted from the peripheral blood of the patients and their families. One patient (case 1) was identified as harboring a large heterozygous deletion in the 16p13.3 region, spanning the CREBBP gene. Three patients (Cases 2–4) harbored different CREBBP variants (c.2608C>T:p.Gln870Ter,c.4404_4405del:p.Thr1468fs,c.3649C>T:p.Gln1217Ter). No causative variants were identified for the fifth RSTS patient (case 5). Here, we propose a molecular diagnostic protocol that identified causative genetic alterations in 4/5 of the patients, yielding a molecular diagnostic rate of 80%. Given the rarity of RSTS, more research is needed to explore its pathogenesis and mechanism.
The Development of Education of Public Health Nurses for Applying Genomics in Preventive Health Care
Authors: Laaksonen Mari , Airikkala Elisa , Halkoaho Arja
Published: April 2022

Genetics and genomics have become one of the most important development areas in healthcare. For this reason, it is essential that nursing professionals take their role to offer their skills in implementing genomics in health promotion. The education of public health nurses is taking vital steps in training the health promoters who are able to take the genome-based knowledge into account in precision healthcare. Tampere University of Applied Sciences managed to integrate genomics into the studies of public health nursing. This article describes the process of development and lays emphasis on the importance of genomic education of public health nurses.
Genomic Surveillance of COVID-19 Variants With Language Models and Machine Learning
Authors: Nagpal Sargun , Pal Ridam , Ashima  , Tyagi Ananya , Tripathi Sadhana , Nagori Aditya , Ahmad Saad , Mishra Hara Prasad , Malhotra Rishabh , Kutum Rintu , Sethi Tavpritesh
Published: April 2022

The global efforts to control COVID-19 are threatened by the rapid emergence of novel SARS-CoV-2 variants that may display undesirable characteristics such as immune escape, increased transmissibility or pathogenicity. Early prediction for emergence of new strains with these features is critical for pandemic preparedness. We present Strainflow, a supervised and causally predictive model using unsupervised latent space features of SARS-CoV-2 genome sequences. Strainflow was trained and validated on 0.9 million sequences for the period December, 2019 to June, 2021 and the frozen model was prospectively validated from July, 2021 to December, 2021. Strainflow captured the rise in cases 2 months ahead of the Delta and Omicron surges in most countries including the prediction of a surge in India as early as beginning of November, 2021. Entropy analysis of Strainflow unsupervised embeddings clearly reveals the explore-exploit cycles in genomic feature-space, thus adding interpretability to the deep learning based model. We also conducted codon-level analysis of our model for interpretability and biological validity of our unsupervised features. Strainflow application is openly available as an interactive web-application for prospective genomic surveillance of COVID-19 across the globe.
The Proliferation of Glioblastoma Is Contributed to Kinesin Family Member 18A and Medical Data Analysis of GBM
Authors: Wang Lei-Bo , Zhang Xue-Bin , Liu Jun , Liu Qing-Jun
Published: April 2022

Background: Glioblastoma (GBM) is widely known as a classical kind of malignant tumor originating in the brain with high morbidity and mortality. Targeted therapy has shown great promise in treating glioblastoma, but more promising targets, including effective therapeutic targets, remain to be identified. 18A (KIF18A) is a microtubule-based motor protein that is dysregulated and involved in the progression of multiple human cancers. However, the possible effects of KIF18A on GBM progression are still unclear.

Methods: We performed DEG analysis, medical data analysis, and network analysis to identify critical genes affecting glioma progression. We also performed immunohistochemical analysis of the KIF18A levels in 94 patients with glioblastoma and the associated surrounding tissues. Patients were divided into two groups according to the high and low expression. Using a clinical analysis, we showed the potential associations between KIF18A expression and clinical characteristics of 94 GBM patients. We then investigated the effects of KIF18A on GBM cell proliferation by colony establishment, MTT, and immune blogging. The possible effect of KIF18A on GBM tumor growth was determined in mice.

Results: We identified KIF18A as a potential gene affecting GBM progression. We further demonstrated that GBM tissues expressed KIF18A much higher, and its presentation was associated with recurrence in glioblastoma patients. We believe KIF18A promotes GBM cell proliferation.

Conclusion: We demonstrated that KIF18A could be a promising target in treating GBM.
Effects of Inflammatory Response Genes on the Immune Microenvironment in Colorectal Cancer
Authors: Wang YaChen , Zhang Luping , Shi Guanghuan , Liu Mingqing , Zhao Weidan , Zhang Yingli , Wang Ying , Zhang Nan
Published: April 2022

Background: The close relationship between colorectal cancer and inflammation has been widely reported. However, the relationship between colorectal cancer and inflammation at the genetic level is not fully understood.

Method: From a genetic perspective, this study explored the relationship between inflammation-related genes and the immune microenvironment in colorectal cancer. We identified prognostic genes, namely CX3CL1, CCL22, SERPINE1, LTB4R, XCL1, GAL, TIMP1, ADIPOQ, and CRH, by using univariate and multivariate regression analyses. A risk scoring model for inflammatory response was established, and patients in The Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database were divided into two groups: high risk group and low risk group.

Results: The analysis showed that the prognosis of the two groups was significantly different, and the low-risk group had a higher survival rate and longer survival time. Pathways related to apoptosis, inflammatory response, and hypoxia were significantly enriched as shown via Gene Set Enrichment Analysis (GSEA). Activated dendritic cell infiltration was found in both the TCGA and GEO databases, and the CCL21 gene played a significant role in the process of activated dendritic cell infiltration. CCL21 gene was also positively correlated with inflammatory response, and the gene expression and risk score were significantly different between the two groups.

Conclusion: In summary, inflammatory response has a direct impact on patients with colorectal cancer in the prognosis and immune infiltration and further research studies on the inflammatory response can help in advancing the development of immunotherapy for colorectal cancer.
Rituximab in Systemic Lupus Erythematosus: Transient Effects on Autoimmunity Associated Lymphocyte Phenotypes and Implications for Immunogenicity
Authors: Faustini Francesca , Sippl Natalie , Stålesen Ragnhild , Chemin Karine , Dunn Nicky , Fogdell-Hahn Anna , Gunnarsson Iva , Malmström Vivianne
Published: April 2022

B cell abnormalities are common in systemic lupus erythematosus (SLE), and include expansion of double negative (DN) and age-associated-like B cells (ABC-like). We aimed to investigate rituximab (RTX) effects on DN and ABC-like B-cell subsets and, when possible, also secondary effects on T cells. Fifteen SLE patients, fulfilling the ACR 1982 criteria, starting RTX and followed longitudinally up to two years, were analyzed for B- and T- lymphocyte subsets using multicolor flow cytometry. DN were defined as IgD-CD27- and ABC-like as CD11c+CD21- within the DN gate. Additional phenotyping was performed adding CXCR5 in the B-cell panel. Cellular changes were further analyzed in the context of the generation of anti-drug antibodies (ADA) against RTX and clinical information. The SLE patients were mainly females (86.6%), of median age 36.7 (29.8-49.4) years and disease duration of 6.1 (1.6-11.8) years. Within the DN subset, ABC-like (IgD-CD27-CD11c+CD21-) B cell frequency reduced from baseline median level of 20.4% to 11.3% (p=0.03), at early follow-up. The DN B cells were further subdivided based on CXCR5 expression. Significant shifts were observed at the early follow-up in the DN2 sub-cluster (CD11c+CXCR5-), which reduced significantly (-15.4 percentage points, p=0.02) and in the recently described DN3 (CD11c-CXCR5-) which increased (+13 percentage points, p=0.03). SLE patients treated with RTX are at high risk of developing ADA. In our cohort, the presence of ADA at 6 months was associated with lower frequencies of DN cells and to a more pronounced expansion of plasmablasts at early follow-up. The frequency of follicular helper T cells (TFH, CD4+PD-1+CXCR5+) and of peripheral helper T cells (TPH, CD4+PD-1+CXCR5-) did not change after RTX. A sub-cluster of PD-1highCD4+ T cells showed a significant decrease at later follow-up compared to early follow-up (p=0.0039). It is well appreciated that RTX transiently influences B cells. Here, we extend these observations to cell phenotypes which are believed to directly contribute to autoimmunity in SLE. We show early transient effects of RTX on ABC-like memory B cells, later effects on PD-1high CD4+ cells, and possible implications for RTX immunogenicity. Further insight in such effects and their monitoring may be of clinical relevance.
Co-Expression of the B-Cell Key Transcription Factors Blimp-1 and IRF4 Identifies Plasma Cells in the Pig
Authors: Villanueva-Hernández Sonia , Adib Razavi Mahsa , van Dongen Katinka A. , Stadler Maria , de Luca Karelle , Beyersdorf Niklas , Saalmüller Armin , Gerner Wilhelm , Mair Kerstin H.
Published: April 2022

Antibody-secreting plasma cells (PCs) have remained largely uncharacterized for years in the field of porcine immunology. For an in-depth study of porcine PCs, we identified cross-reactive antibodies against three key transcription factors: PR domain zinc finger protein-1 (Blimp-1), interferon regulatory factor 4 (IRF4), and paired box 5 (Pax5). A distinct Blimp-1+IRF4+ cell population was found in cells isolated from blood, spleen, lymph nodes, bone marrow, and lung of healthy pigs. These cells showed a downregulation of Pax5 compared to other B cells. Within Blimp-1+IRF4+ B cells, IgM-, IgG-, and IgA-expressing cells were identified and immunoglobulin-class distribution was clearly different between the anatomical locations, with IgA+ PCs dominating in lung tissue and IgM+ PCs dominating in the spleen. Expression patterns of Ki-67, MHC-II, CD9, and CD28 were investigated in the different organs. A high expression of Ki-67 was observed in blood, suggesting a plasmablast stage. Blimp-1+IRF4+ cells showed an overall lower expression of MHC-II compared to regular B cells, confirming a progressive loss in B-cell differentiation toward the PC stage. CD28 showed slightly elevated expression levels in Blimp-1+IRF4+ cells in most organs, a phenotype that is also described for PCs in mice and humans. This was not seen for CD9. We further developed a FACS-sorting strategy for live porcine PCs for functional assays. CD3-CD16-CD172a– sorted cells with a CD49dhighFSC-Ahigh phenotype contained Blimp-1+IRF4+ cells and were capable of spontaneous IgG production, thus confirming PC identity. These results reveal fundamental phenotypes of porcine PCs and will facilitate the study of this specific B-cell subset in the future.
CD39 and CD326 Are Bona Fide Markers of Murine and Human Plasma Cells and Identify a Bone Marrow Specific Plasma Cell Subpopulation in Lupus
Authors: Dang Van Duc , Mohr Elodie , Szelinski Franziska , Le Tuan Anh , Ritter Jacob , Hinnenthal Timo , Stefanski Ana-Luisa , Schrezenmeier Eva , Ocvirk Soeren , Hipfl Christian , Hardt Sebastian , Cheng Qingyu , Hiepe Falk , Löhning Max , Dörner Thomas , Lino Andreia C.
Published: April 2022

Antibody-secreting cells (ASCs) contribute to immunity through production of antibodies and cytokines. Identification of specific markers of ASC would allow selective targeting of these cells in several disease contexts. Here, we performed an unbiased, large-scale protein screening, and identified twelve new molecules that are specifically expressed by murine ASCs. Expression of these markers, particularly CD39, CD81, CD130, and CD326, is stable and offers an improved resolution for ASC identification. We accessed their expression in germ-free conditions and in T cell deficient mice, showing that at least in part their expression is controlled by microbial- and T cell-derived signals. Further analysis of lupus mice revealed the presence of a subpopulation of LAG-3–plasma cells, co-expressing high amounts of CD39 and CD326 in the bone marrow. This population was IgM+and correlated with IgM anti-dsDNA autoantibodies in sera. Importantly, we found that CD39, CD81, CD130, and CD326 are also expressed by human peripheral blood and bone marrow ASCs. Our data provide innovative insights into ASC biology and function in mice and human, and identify an intriguing BM specific CD39++CD326++ASC subpopulation in autoimmunity.
Vaccine Can Induce CD4-Mediated Responses to Homocitrullinated Peptides via Multiple HLA-Types and Confer Anti-Tumor Immunity
Authors: Cook Katherine , Xue Wei , Atabani Suha , Symonds Peter , Al Omari Abdullah , Daniels Ian , Shah Sabaria , Choudhury Ruhul Hasan , Weston Daisy , Metheringham Rachael , Brentville Victoria , Durrant Lindy
Published: April 2022

Homocitrullination is the post translation modification (PTM) of the amino acid lysine to homocitrulline also referred to as carbamylation. This PTM has mainly been studied in relation to autoimmune diseases including rheumatoid arthritis. Homocitrullination of lysines alters their charge which can lead to generation of neoepitopes that are differentially presented by MHC-II and induce modification-specific immune responses. Homocitrullination is often considered a process which triggers autoimmune disease by bypassing self-tolerance however, we suggest that homocitrullination may also have an alternative role in immune responses including protection against cancer. Here we demonstrate that immune responses to homocitrullinated peptides from three different proteins can be induced via multiple HLA-types. Immunization of Balb/c or HLA-transgenic DR4 and DR1 mice can induce modification-specific CD4 mediated IFNγ responses. Healthy human donors show a clear repertoire for the homocitrullinated Vimentin peptide (Vim116-135Hcit), with modification-specific and oligoclonal responses. Importantly, in vivo homocitrulline specific Vim116-135Hcit,Cyk8 371-388Hcit and Aldo 140-157Hcit responses are able to confer an anti-tumor effect in the murine B16 melanoma model. The Vim116-135Hcit anti-tumor response was dependent upon tumor expression of MHC-II suggesting the direct recognition of PTMs on tumor is an important anti-tumor mechanism. Cancer patients also have a CD4 repertoire for Vim116-135Hcit. Together these results suggest that homocitrulline-specific immune responses can be generated in healthy mice and detected in human donors through a variety of HLA-restrictions. Immunization can induce responses to Vim116-135Hcit,Aldolase 140-157Hcit and Cyk8 371-388Hcit which provide anti-tumor therapy across several HLA-types. Our results advance our understanding of homocitrulline-specific immune responses, with implications for a number of fields beyond autoimmunity, including tumor immune surveillance.
Differences in SARS-CoV-2 Vaccine Response Dynamics Between Class-I- and Class-II-Specific T-Cell Receptors in Inflammatory Bowel Disease
Authors: Xu Alexander M. , Li Dalin , Ebinger Joseph E. , Mengesha Emebet , Elyanow Rebecca , Gittelman Rachel M. , Chapman Heidi , Joung Sandy , Botwin Gregory J. , Pozdnyakova Valeriya , Debbas Philip , Mujukian Angela , Prostko John C. , Frias Edwin C. , Stewart James L. , Horizon Arash A. , Merin Noah , Sobhani Kimia , Figueiredo Jane C. , Cheng Susan , Kaplan Ian M. , McGovern Dermot P. B. , Merchant Akil , Melmed Gil Y. , Braun Jonathan
Published: April 2022

T-cells specifically bind antigens to induce adaptive immune responses using highly specific molecular recognition, and a diverse T-cell repertoire with expansion of antigen-specific clones can indicate robust immune responses after infection or vaccination. For patients with inflammatory bowel disease (IBD), a spectrum of chronic intestinal inflammatory diseases usually requiring immunomodulatory treatment, the T-cell response has not been well characterized. Understanding the patient factors that result in strong vaccination responses is critical to guiding vaccination schedules and identifying mechanisms of T-cell responses in IBD and other immune-mediated conditions. Here we used T-cell receptor sequencing to show that T-cell responses in an IBD cohort were influenced by demographic and immune factors, relative to a control cohort of health care workers (HCWs). Subjects were sampled at the time of SARS-CoV-2 vaccination, and longitudinally afterwards; TCR Vβ gene repertoires were sequenced and analyzed for COVID-19-specific clones. We observed significant differences in the overall strength of the T-cell response by age and vaccine type. We further stratified the T-cell response into Class-I- and Class-II-specific responses, showing that Ad26.COV2.S vector vaccine induced Class-I-biased T-cell responses, whereas mRNA vaccine types led to different responses, with mRNA-1273 vaccine inducing a more Class-I-deficient T-cell response compared to BNT162b2. Finally, we showed that these T-cell patterns were consistent with antibody levels from the same patients. Our results account for the surprising success of vaccination in nominally immuno-compromised IBD patients, while suggesting that a subset of IBD patients prone to deficiencies in T-cell response may warrant enhanced booster protocols.
Integrated Metabolomics and Transcriptome Revealed the Effect of Fermented Lycium barbarum Residue Promoting Ovis aries Immunity
Authors: Zhang Yajun , Guo Yansheng , Luo Yulong , Du Min , Yin Xin , Xu Xiaochun , Zhang Guijie
Published: April 2022

Lycium barbarum residue contains abundant bioactive nutrients which can be used as feed supplement. The fermentation treatment of plant residue can promote the utilization of nutrients, rumen digestion, and the growth and immunity of animals. Based on ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) metabolomics and in-depth transcriptome analysis, the study tested the mechanisms of Lycium barbarum residue (RW) and fermented Lycium barbarum residue (RFW) on meat quality and immunity of sheep. Fifty-four Tan sheep were randomly divided into control, RFW or RW treatments. Data showed that RFW and RW increased the carcass weight, fat content, ash content and reduced the cooking loss of lamb. RFW performed more significant effects on activating immune-related genes than those of RW. The expression of chemokines and immune-related pathways, such as signaling pathways of interleukin-17 signaling pathway and NOD-like receptor signaling pathway, were elevated in sheep fed RFW. RW increased the diversity in rumen metabolites, especially compositions of lipids, organic acids and organ heterocyclic compounds. RFW affected numerous compounds which are closely correlated with the activation of immune genes. In conclusion, RFW could represent a valuable strategy to improve growth performance and immunity of sheep.
DNA Barcoding Reveals High Hidden Species Diversity of Chinese Waters in the Cephalopoda
Authors: Xu Ran , Lü Yuhan , Tang Yan , Chen Zhiwei , Xu Chenxi , Zhang Xiaoying , Zheng Xiaodong
Published: April 2022

Species delimitation by traditional morphological methods is challenging in cephalopods due to their flexible bodies, changeable pigment traits, and sometimes high morphological homoplasy. Molecular information provides important assistance for taxonomic decision. In this study, we applied three species delimitation methods on 132 cephalopods from 7 families along Chinese waters, and we found anunderestimated species diversity in these taxa. A maximum of 56 molecular operational taxonomic units was detected, and possible cryptic diversities were revealed in Loliolus beka, Uroteuthis edulis, Octopus minor, Amphioctopus fangsiao, and Hapalochlaena lunulate. This study provides molecular evidence for the hidden species diversity along Chinese waters, and it provides insight into further taxonomic research on these morphologically variable taxa.