bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary Evaluation of Rapid Visual Identification of Burkholderia pseudomallei Using a Newly Developed Lateral Flow Strip-Based Recombinase Polymerase Amplification (LF-RPA) System
Authors: Li Jin , Zhong Qiu , Shang Mei-Yun , Li Min , Jiang Yuan-Su , Zou Jia-Jun , Ma Shan-Shan , Huang Qing , Lu Wei-Ping
Published: January 2022

Burkholderia pseudomallei is an important infectious disease pathogen that can cause melioidosis. Melioidosis is mainly prevalent in Thailand, northern Australia and southern China and has become a global public health problem. Early identification of B. pseudomallei is of great significance for the diagnosis and prognosis of melioidosis. In this study, a simple and visual device combined with lateral flow strip-based recombinase polymerase amplification (LF-RPA) was developed, and the utility of the LF-RPA assay for identifying B. pseudomallei was evaluated. In order to screen out the optimal primer probe, a total of 16 pairs of specific primers targeting the orf2 gene of B. pseudomallei type III secretion system (T3SS) cluster genes were designed for screening, and F1/R3 was selected as an optimal set of primers for the identification of B. pseudomallei, and parameters for LF-RPA were optimized. The LF-RPA can be amplified at 30-45°C and complete the entire reaction in 5-30 min. This reaction does not cross-amplify the DNA of other non-B. pseudomallei species. The limit of detection (LOD) of this assay for B. pseudomallei genomic DNA was as low as 30 femtograms (fg), which was comparable to the results of real-time PCR. Moreover, 21 clinical B. pseudomallei isolates identified by 16S rRNA gene sequencing were retrospectively confirmed by the newly developed LF-RPA system. Our results showed that the newly developed LF-RPA system has a simple and short time of operation and has good application prospect in the identification of B. pseudomallei.
Experimental Periodontitis Deteriorated Atherosclerosis Associated With Trimethylamine N-Oxide Metabolism in Mice
Authors: Xiao Lingling , Huang Lingyan , Zhou Xin , Zhao Dan , Wang Yan , Min Haiyan , Song Shiyu , Sun Weibin , Gao Qian , Hu Qingang , Xie Sijing
Published: January 2022

Background

Periodontitis is considered a risk factor for atherosclerosis, but the mechanism is not clear. It was reported that oral administration of Porphyromonas gingivalis altered the gut microbiota in mice. Gut dysbiosis and the intestinal metabolite trimethylamine N-oxide (TMAO) were verified to be associated with atherosclerosis. Therefore, the possible TMAO-related mechanism between periodontitis and atherosclerosis needs to be explored.

Methods

Experimental periodontitis was established by oral administration of P. gingivalis for 2 months in ApoE−/− mice. Mouse hemi-mandibles were scanned using Micro-CT. Quantification of TMAO was performed using liquid chromatography–tandem mass spectrometry. Mouse feces were collected and the bacterial DNA was extracted, then the gut microbiota was analyzed using 16S rRNA genes. Atherosclerotic lesion areas were quantified. Livers, small intestines, and large intestines were analyzed for gene expression.

Results

Aggravated atherosclerosis plaques were found in experimental periodontitis mice. Plasma TMAO, a pathogenic factor of atherosclerosis, was initially found to be increased in periodontitis mice. Changes in the composition and abundance of the intestinal microflora of periodontitis mice were found. Flavin monooxygenase 3 (FMO3), the catalyzing enzyme of TMAO in the liver, was significantly increased, accompanied by an increase of IL-6 in liver, the abnormal intestinal integrity and enhanced plasma LPS. The IL-6 and LPS were verified to be able to increase FMO3 in HepG2 cells.

Conclusion

Our research discovered that experimental periodontitis in ApoE−/− mice induced gut dysbiosis and an increase in TMAO. These results suggest a possible mechanism by which periodontitis may accelerate atherosclerosis by influencing the intestinal microbes and the metabolism, which were triggered by inflammation of the liver and intestine.
Using a Modeling Approach to Inform Progress Towards Stoat Eradication From the Orkney Islands
Authors: Zub Karol , García-Díaz Pablo , Sankey Sarah , Eisler Robert , Lambin Xavier
Published: January 2022

Invasive non-native species eradication attempts are typically large and expensive projects that benefit from the support of quantitative tools, such as population models, to be completed within the scheduled and funded time. Managed ecosystems are constantly changing due to population and ecosystem dynamics. Accordingly, any model predictions need to be updated, using different sources of data, to inform the project about the progress toward eradication. The stoat Mustela erminea was introduced to the hitherto predatory land mammal free Orkney archipelago around 2010. In 2016, a project aiming to eradicate stoats to preserve ecologically and economically important native wildlife was designed and implemented. It entailed a “knockdown” phase followed by a “mopping-up” phase to remove stoats that escaped capture. We used data from this project to iteratively predict the progress toward eradication. We applied spatially explicit individual-based models to estimate the proportion of stoats being exposed to capture, and then compared these simulation-based predictions with removal data, allowing us to estimate changes in the population size through time. We also used sighting data from members of the public to refine eradication probability. We were also able to demonstrate how the initially wide uncertainty gradually diminished as more evidence accumulated. The information derived from different types of data and quantitative models allowed us to track the effectiveness of current trapping approaches and to help to inform project managers about when the project achieved the knockdown phase milestone. Our analyses confirmed that the expected magnitude of the initial knockdown phase has been achieved in some areas, but also revealed spatial and temporal heterogeneity in the distribution of captures, most likely caused by the sequential trapping and stoat movement and trap shy stoats exposed to capture but not caught. This heterogeneity calls for additional data sources (e.g., from camera traps or detection dogs) to estimate the proportion of trap-shy individuals and the size of the untrapped population, and ultimately the feasibility of eradication.
Is Partially Thrombosed False Lumen Really a Predictor for Adverse Events in Uncomplicated Type B Aortic Dissection: A Systematic Review and Meta-Analysis?
Authors: Wu Jinlin , Song Jian , Li Xin , Yang Jue , Yu Changjiang , Zhou Chenyu , Sun Tucheng , Fan Ruixin
Published: January 2022

Objective:

This meta-analysis and systematic review investigated whether partial thrombosed false lumen was a predictor for adverse events in uncomplicated Type B aortic dissection (TBAD).

Methods:

We performed the current systematic review of the medical literature according to the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The Newcastle-Ottawa Scale was used to evaluate the quality of individual studies. Search terms based on the MEDLINE database included “type B aortic dissection,” “false lumen” and “thrombosis.” The primary outcomes included mortality, intervention, and aortic growth.

Results:

Six studies were included in this systematic review, with a total number of 692 patients, including 197 patency (28.5%), 214 partial thrombosis (30.9%), and 281 complete thrombosis (40.6%). Due to the insufficient data for quantitative analysis, we only conducted a scoping review for mortality and intervention. For aortic growth, we conducted a meta-analysis based on Standardized Mean Difference (SMD). The SMD of PT vs. P by random effect model was −0.05 (random effect model) [95% confidence interval (CI), −0.39 to 0.29]. The 95% CI crossed with the null line of 0, indicating no significant difference. The SMD was 0.37 (fixed effects model) (95% CI, 0.03–0.71) and 0.70 (fixed effects model) (95% CI, 0.37–1.04) for PT vs. CT, and P vs. CT, respectively.

Conclusions:

Current researches on partial thrombosis of TBAD are inconsistent. Partial thrombosis is not associated with a faster aortic growth rate. Until more solid evidence is available, we do not recommend partial thrombosis as a surgical indication or high-risk profile for TBAD.

Systematic Review Registration: Unique Identifier: CRD42019121912.
A Clinical Approach to Multimodality Imaging in Pulmonary Hypertension
Authors: Farrell Christine , Balasubramanian Aparna , Hays Allison G. , Hsu Steven , Rowe Steven , Zimmerman Stefan L. , Hassoun Paul M. , Mathai Stephen C. , Mukherjee Monica
Published: January 2022

Pulmonary hypertension (PH) is a clinical condition characterized by progressive elevations in mean pulmonary artery pressures and right ventricular dysfunction, associated with significant morbidity and mortality. For resting PH to develop, ~50–70% of the pulmonary vasculature must be affected, suggesting that even mild hemodynamic abnormalities are representative of advanced pulmonary vascular disease. The definitive diagnosis of PH is based upon hemodynamics measured by right heart catheterization; however this is an invasive and resource intense study. Early identification of pulmonary vascular disease offers the opportunity to improve outcomes by instituting therapies that slow, reverse, or potentially prevent this devastating disease. Multimodality imaging, including non-invasive modalities such as echocardiography, computed tomography, ventilation perfusion scans, and cardiac magnetic resonance imaging, has emerged as an integral tool for screening, classifying, prognosticating, and monitoring response to therapy in PH. Additionally, novel imaging modalities such as echocardiographic strain imaging, 3D echocardiography, dual energy CT, FDG-PET, and 4D flow MRI are actively being investigated to assess the severity of right ventricular dysfunction in PH. In this review, we will describe the utility and clinical application of multimodality imaging techniques across PH subtypes as it pertains to screening and monitoring of PH.
Mitochondria in Pathological Cardiac Hypertrophy Research and Therapy
Authors: Yang Dan , Liu Han-Qing , Liu Fang-Yuan , Guo Zhen , An Peng , Wang Ming-Yu , Yang Zheng , Fan Di , Tang Qi-Zhu
Published: January 2022

Cardiac hypertrophy, a stereotypic cardiac response to increased workload, ultimately progresses to severe contractile dysfunction and uncompensated heart failure without appropriate intervention. Sustained cardiac overload inevitably results in high energy consumption, thus breaking the balance between mitochondrial energy supply and cardiac energy demand. In recent years, accumulating evidence has indicated that mitochondrial dysfunction is implicated in pathological cardiac hypertrophy. The significant alterations in mitochondrial energetics and mitochondrial proteome composition, as well as the altered expression of transcripts that have an impact on mitochondrial structure and function, may contribute to the initiation and progression of cardiac hypertrophy. This article presents a summary review of the morphological and functional changes of mitochondria during the hypertrophic response, followed by an overview of the latest research progress on the significant modulatory roles of mitochondria in cardiac hypertrophy. Our article is also to summarize the strategies of mitochondria-targeting as therapeutic targets to treat cardiac hypertrophy.
Daily Variations in pCO2 and fCO2 in a Subtropical Urbanizing Lake
Authors: Yang Rongjie , Chen Yingying , Du Jie , Pei Xiangjun , Li Jinghua , Zou Zan , Song Huixing
Published: January 2022

The transfer of CO2 from lakes to the atmosphere is a component of the global carbon equilibrium, while the quantification of the CO2 partial pressure (pCO2) is critical for exploring the contribution of freshwater CO2 emissions in the regional/global carbon budget. To investigate the daily variability of pCO2 and CO2 fluxes (fCO2), we conducted in situ biweekly pCO2 detection at 7:00, 10:00, 14:00, and 17:00 China Standard Time (CST) from Jan. to Sept. 2020 in the subtropical urbanizing Qinglonghu Lake in Chengdu, Sichuan, China. The pCO2 during the daytime varied greatly from 8.3 to 1,061.3 μatm, with an average of 137.7 μatm, while the average pCO2 (n = 11) clearly gradually decreased from 7:00 CST (204.9 ± 295.7 μatm) to 17:00 CST (93.5 ± 105.5 μatm). Similarly, the average fCO2 values were −19.3 (±27.5), −24.8 (±20.7), −29.2 (±9.1) and −30.4 (±10.7) mmol m2 h−1 at 7:00–17:00 CST, respectively. Further, we observed a negative correlation between pCO2 and water temperature and dissolved oxygen, but a positive correlation between pCO2 and total organic carbon and chlorophyll a. By a systematic overview of previously published data, we also discussed the differences and uncertainties in pCO2 and fCO2 estimates at regional and global scales. We therefore speculate that uncertainties may exist in the contributions of CO2 balance on lake surface in regional/global carbon budgets due to this daily pCO2 variation.
Phenolic Bioactives From Plant-Based Foods for Glycemic Control
Authors: Sarkar Dipayan , Christopher Ashish , Shetty Kalidas
Published: January 2022

Plant-based foods containing phenolic bioactives have human health protective functions relevant for combating diet and lifestyle-influenced chronic diseases, including type 2 diabetes (T2D). The molecular structural features of dietary phenolic bioactives allow antioxidant functions relevant for countering chronic oxidative stress-induced metabolic breakdown commonly associated with T2D. In addition to antioxidant properties, phenolic bioactives of diverse plant foods have therapeutic functional activities such as improving insulin sensitivity, reducing hepatic glucose output, inhibiting activity of key carbohydrate digestive enzymes, and modulating absorption of glucose in the bloodstream, thereby subsequently improving post-prandial glycemic control. These therapeutic functional properties have direct implications and benefits in the dietary management of T2D. Therefore, plant-based foods that are rich in phenolic bioactives are excellent dietary sources of therapeutic targets to improve overall glycemic control by managing chronic hyperglycemia and chronic oxidative stress, which are major contributing factors to T2D pathogenesis. However, in studies with diverse array of plant-based foods, concentration and composition of phenolic bioactives and their glycemic control relevant bioactivity can vary widely between different plant species, plant parts, and among different varieties/genotypes due to the different environmental and growing conditions, post-harvest storage, and food processing steps. This has allowed advances in innovative strategies to screen and optimize whole and processed plant derived foods and their ingredients based on their phenolic bioactive linked antioxidant and anti-hyperglycemic properties for their effective integration into T2D focused dietary solutions. In this review, different pre-harvest and post-harvest strategies and factors that influence phenolic bioactive-linked antioxidant and anti-hyperglycemic properties in diverse plant derived foods and derivation of extracts with therapeutic potential are highlighted and discussed. Additionally, novel bioprocessing strategies to enhance bioavailability and bioactivity of phenolics in plant-derived foods targeting optimum glycemic control and associated T2D therapeutic benefits are also advanced.
hsa_circ_0111707 Is Associated With Risk of Stress-Related Type 2 Diabetes via Sponging miR-144-3p
Authors: Yan Yu-Xiang , Xiao Huan-Bo , Lu Ya-Ke , Sun Yue , Wang Shuo , Dong Jing , Wu Li-Juan
Published: January 2022

Introduction

Chronic stress plays an important role in the development of type 2 diabetes (T2D). Circular RNAs (circRNAs) play significant roles in regulating the pathogenesis of diseases by regulating gene expression. The aim of the present study was to identify the association between hsa_circ_0111707 and stress-related T2D.

Methods

The present study was performed based on a three-part design. The association between hsa_circ_0111707 in peripheral blood mononuclear cells (PBMCs) and T2D and stress-related variables were assessed in a cross-sectional study. The causal relationship of hsa_circ_0111707 on T2D was further investigated in a nested case-control study. miR-144-3p as the miRNA target of hsa_circ_0111707 was verified by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay.

Results

The relative expression of hsa_circ_0111707 was significantly lower in the T2D and impaired fasting glucose (IFG) cases in comparison with controls. The hsa_circ_0111707 expression was significantly negatively correlated with miR-144-3p expression and plasma cortisol concentration and positively correlated with NR3C1 expression. In addition, hsa_circ_0111707 expression was negatively correlated with scores of “demands at work” and “insecurity at work” of Copenhagen Psychosocial Questionnaire (COPSOQ). Decreased hsa_circ_0111707 expression was associated with increased risk of T2D development. Functional analysis demonstrated that hsa_circ_0111707 functions as a sponge for miR-144-3p.

Conclusion

hsa_circ_0111707 is associated with risk of T2D development via sponging miR-144-3p. hsa_circ_0111707 in PBMCs can be considered a potential biomarker of stress-related T2D.
Acromegaly: The Research and Practical Value of Noninvasive Hemodynamic Assessments via Impedance Cardiography
Authors: Jurek Agnieszka , Krzesiński Paweł , Gielerak Grzegorz , Witek Przemysław , Zieliński Grzegorz , Kazimierczak Anna , Wierzbowski Robert , Banak Małgorzata , Uziębło-Życzkowska Beata
Published: January 2022

Background

Arterial hypertension (AH) that accompanies acromegaly (AC) may lead to cardiovascular dysfunction. Such consequences may be detected with impedance cardiography (ICG), which is a noninvasive method of hemodynamic assessment. Early detection of subclinical hemodynamic alterations in AC patients may be crucial for optimizing treatment and preventing cardiovascular remodeling. The purpose of this study was to identify the hemodynamic parameters of the cardiovascular system that differentiate patients with AC from those in the control group (CG), with a particular emphasis on potential targets for medical therapy.

Methods

This observational, prospective, clinical study involved a comparative analysis of 33 AC patients with no significant comorbidities and the controls selected via propensity score matching based on a set of baseline characteristics (age, sex, body mass index, mean blood pressure [MBP]), with comparable proportions of AH patients. The assessed hemodynamic parameters included the stroke volume index (SI), cardiac index, systemic vascular resistance index, velocity index (VI), acceleration index, Heather index (HI), and thoracic fluid content (TFC).

Results

Both the AC group and the CG had well-controlled AH (mean blood pressure of 121/77 mmHg and 119/76 mmHg, respectively). In terms of baseline characteristics, the AC group was characterized by a higher hear rate and lower creatinine levels than the CG (76.2 bpm vs. 66.8 bpm [p = 0.001] and 0.755 mg/dL vs. 0.850 mg/dL [p = 0.035], respectively). ICG assessment of AC patients and CG patients showed the former to have higher heart rates (73.5 bpm vs. 65.2 bpm; p = 0.003), lower SI (43.8 mL/m2 vs. 53.4 mL/m2; p = 0.0001), lower VI (42.1 1/1000/s vs. 49.3 1/1000/s; p = 0.037), lower HI (8.49 Ohm/s2 vs. 13.4 Ohm/s2, p ≤ 0.0001), and higher thoracic fluid content (TFC) (38.4 1/kOhm vs. 28.1 1/kOhm; p ≤ 0.0001), respectively.

Conclusions

Even with well-controlled hypertension, AC is associated with a high TFC, increased heart rate, and decreased indices of cardiac contractility. Hemodynamic changes in AC patients may be detected with the modern, noninvasive diagnostic tool, ICG.
Association Between Red Blood Cell Distribution Width and Thyroid Function
Authors: Zhou Guowei , Ai Yueqin , Guo Song , Chen Quan , Feng Xiao , Xu Kun , Wang Gaoyuan , Ma Chaoqun
Published: January 2022

Aim

Red blood cell distribution width (RDW) is an important parameter with broad biological implications. However, the study investigating the association between RDW and thyroid function remains sparse and inconsistent. We aimed to investigate the association between RDW and thyroid function in the US population.

Methods

A cross-sectional analysis was performed using the data from the National Health and Nutrition Examination Survey (NHANES) conducted from 2007 to 2010. The thyroid parameters investigated were mainly free triiodothyronine (fT3), free thyroxine (fT4), thyroid-stimulating hormone (TSH), antithyroglobulin antibody (TgAb), and antithyroperoxidase antibody (TPOAb). In the 6,895 adults aged 18 years or older, logistic regression modeling was applied to estimate the association between RDW quartiles and thyroid parameters. Smooth curve fittings and generalized additive models were then performed to address the nonlinear relationship.

Results

The association between RDW and TSH followed a J-shaped curve, and a significant positive relationship existed in the 12.5%–17.5% range of RDW (β  = 0.350, 95% confidence interval (CI): 0.225 to 0.474), which was prominent in females. We further demonstrated a negative association (β = −0.018, 95% CI: −0.030 to −0.005) between RDW and fT3. Moreover, elevated RDW was more likely to be subclinical hypothyroidism. However, there was no obvious association between RDW and fT4.

Conclusion

This study confirmed a significant association between RDW and TSH, and future studies are needed to elucidate the underlying mechanisms of the peculiar RDW-fT3 relationship. RDW may be a significant clinical marker of subclinical hypothyroidism.
Biogeographical Importance of the Livingstone Mountains in Southern Tanzania: Comparative Genetic Structure of Small Non-volant Mammals
Authors: Cuypers Laura N. , Sabuni Christopher , Šumbera Radim , Aghová Tatiana , Lišková Edita , Leirs Herwig , Baird Stuart J. E. , Goüy de Bellocq Joëlle , Bryja Josef
Published: January 2022

The Livingstone Mountains (LM; also known as the Kipengere Range) found in south-western Tanzania at the northern end of Lake Nyasa are an important region for understanding the biogeography of Eastern Africa. The two branches of the East African Rift Valley meet here and the mountains might represent stepping stones for colonization and migration between different parts of the Eastern Afromontane Biodiversity Hotspot (especially the link between the Eastern Arc Mountains, EAM, and the Southern Rift Mountains, SRM), as well as an efficient barrier to gene flow for taxa living in drier savannahs in lower elevations. Here we combine new mitochondrial sequence data from 610 recently sampled rodents and shrews with available georeferenced genetic data (3538 specimens) from southern Tanzania, northern Malawi/Zambia and northern Mozambique and compare the spatial genetic structure among different taxa. There is no universal phylogeographic pattern in taxa preferring humid montane habitats. For some of them, the Makambako Gap acts as a barrier between the SRM and the EAM, but other taxa can bridge this gap. Barriers within the EAM (frequently) and within the SRM (sometimes) appear more important. The Rukwa rift between the SRM and the ARM is an important barrier that perhaps can only be crossed by taxa that are not that strictly tied to humid montane environments. For mammals living in lower-elevation savannah-like habitats, the LM can act as a strict barrier to gene flow, and together with the Ufipa Plateau, Lake Nyasa and the EAM create a very similar phylogeographic pattern with three recognizable genetic groups in most savannah-dwellers. The Livingstone Mountains thus appear to be one of the most important biogeographic crossroads in Eastern Africa.
Identifying Ecological Security Patterns Based on Ecosystem Services Is a Significative Practice for Sustainable Development in Southwest China
Authors: Su Xukun , Shen Yu , Xiao Yi , Liu Yuqing , Cheng Hao , Wan Lingfan , Zhou Su , Yang Murong , Wang Qiusheng , Liu Guohua
Published: January 2022

Southwest China, which is rich in biodiversity and a wide range of ecosystem services (ESs), is a strong support for local human wellbeing. This area is also one of the key components of the ecological security shelter (ESS) for national ecological security and biodiversity conservation. Due to the combination of man-made and natural factors, Southwest China has suffered serious ecological degradation that directly threatens ecological security which refers to the health status of ecosystems and ESs functions. Mapping ESs-based ecological security patterns (ESPs) is essential for designing conservation strategies that suitably combine regional environment conservation with sustainable utilization. We used the InVEST (Integrated Valuation of Ecosystem Services and Tradeoffs Tool) model to identify ecological conservation priority areas which integrated ecological sensitivity (soil erosion sensitivity, rock desertification sensitivity, landslide sensitivity, debris flow sensitivity, and freezing-thawing erosion sensitivity), ecological risk (drought risk, natural disaster risk, and socio-economic risk), and ecological conservation importance (soil conservation, water conservation, and biodiversity conservation importance). In this research, we summarized a new designing framework of ESs-based ESPs. We divided the study area into two zones and four belts including: (A) the alpine steppe and wetland zone, (B) Hengduan Mountain zone, (C) northern shelter belt (Daba-Micang Mountain), (D) central shelter belt (Wumeng-Wuling Mountain), (E) southern shelter belt (southern border of China), and (F) southwestern shelter belt (eastern Himalayas Mountain). Identifying distributions of the ESs-based ESPs has practical significance to improve local human wellbeing and to maintain sustainable development of natural-social ecosystems in Southwest China. Furthermore, ESs-based ESPs are necessary for local administrations to create rationalizing plans on balancing conservation and utilization of natural resources, so that policy-makers can put into place targeted prevention and control measures to limit the development of excessive consumption of natural resources and ecological damages, which is worth promoting.
Case Report and Literature Review: Diagnosis, Tailored Genetic Counseling and Cancer Prevention for a Locally Advanced dMMR/MSI-H/TMB-H Lung Cancer Patient With Concurrent Lynch Syndrome Mediated by a Rare PMS2 Splicing Variant (c.1144+1G>A)
Authors: Han Quanli , Liu Si , Cui Zhi , Wang Qi , Ma Tonghui , Jiang Liwen , Li Xiaomo , Dai Guanghai
Published: January 2022

Lynch syndrome (LS) is a cancer-predisposing genetic disease mediated by pathogenic mutations in DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, and PMS2. Accumulating evidence demonstrates that there is significant biological heterogeneity across MMR genes. Compared to MLH1 and MSH2, PMS2 variant carriers have a much lower risk for LS-related cancers. Tumors in MLH1 and MSH2 variant carriers often display MMR deficiency (dMMR) and/or high microsatellite instability (MSI-H), two predictive biomarkers for immunotherapy efficacy. However, tumors in PMS2 variant carriers are largely microsatellite stable (MSS) instead of MSI. Therefore, the optimal management of cancer patients with LS requires the integration of disease stage, MMR gene penetrance, dMMR/MSI status, and tumor mutational burden (TMB). In this work, we presented a locally advanced lung cancer patient with dMMR/MSI-H/TMB-H tumor and selective loss of PMS2 by immunohistochemistry. Germline testing revealed a rare PMS2 splicing variant (c.1144+1G>A) in the proband and his healthy daughter. The diagnosis of LS was made based on genetic analysis of this variant and literature review. Given the incomplete penetrance of PMS2, the proband and the carrier received tailored genetic counseling. To reduce cancer risk, the proband received four cycles of nivolumab plus chemotherapy and achieved a disease-free survival of sixteen months.
Identifying Balanced Chromosomal Translocations in Human Embryos by Oxford Nanopore Sequencing and Breakpoints Region Analysis
Authors: Pei Zhenle , Deng Ke , Lei Caixai , Du Danfeng , Yu Guoliang , Sun Xiaoxi , Xu Congjian , Zhang Shuo
Published: January 2022

Background: Balanced chromosomal aberrations, especially balanced translocations, can cause infertility, recurrent miscarriage or having chromosomally defective offspring. Preimplantation genetic testing for structural rearrangement (PGT-SR) has been widely implemented to improve the clinical outcomes by selecting euploid embryos for transfer, whereas embryos with balanced translocation karyotype were difficult to be distinguished by routine genetic techniques from those with a normal karyotype.

Method: In this present study, we developed a clinically applicable method for reciprocal translocation carriers to reduce the risk of pregnancy loss. In the preclinical phase, we identified reciprocal translocation breakpoints in blood of translocation carriers by long-read Oxford Nanopore sequencing, followed by junction-spanning polymerase chain reaction (PCR) and Sanger sequencing. In the clinical phase of embryo diagnosis, aneuploidies and unbalanced translocations were screened by comprehensive chromosomal screening (CCS) with single nucleotide polymorphism (SNP) microarray, carrier embryos were diagnosed by junction-spanning PCR and family haplotype linkage analysis of the breakpoints region. Amniocentesis and cytogenetic analysis of fetuses in the second trimester were performed after embryo transfer to conform the results diagnosed by the presented method.

Results: All the accurate reciprocal translocation breakpoints were effectively identified by Nanopore sequencing and confirmed by Sanger sequencing. Twelve embryos were biopsied and detected, the results of junction-spanning PCR and haplotype linkage analysis were consistent. In total, 12 biopsied blastocysts diagnosed to be euploid, in which 6 were aneuploid or unbalanced, three blastocysts were identified to be balanced translocation carriers and three to be normal karyotypes. Two euploid embryos were subsequently transferred back to patients and late prenatal karyotype analysis of amniotic fluid cells was performed. The outcomes diagnosed by the current approach were totally consistent with the fetal karyotypes.

Conclusions: In summary, these investigations in our study illustrated that chromosomal reciprocal translocations in embryos can be accurately diagnosed. Long-read Nanopore sequencing and breakpoint analysis contributes to precisely evaluate the genetic risk of disrupted genes, and provides a way of selecting embryos with normal karyotype, especially for couples those without a reference.
CD8+ T-Cell Epitope Variations Suggest a Potential Antigen HLA-A2 Binding Deficiency for Spike Protein of SARS-CoV-2
Authors: Qiu Congling , Xiao Chanchan , Wang Zhigang , Zhu Guodong , Mao Lipeng , Chen Xiongfei , Gao Lijuan , Deng Jieping , Su Jun , Su Huanxing , Fang Evandro Fei , Zhang Zhang-Jin , Zhang Jikai , Xie Caojun , Yuan Jun , Luo Oscar Junhong , Huang Li`an , Wang Pengcheng , Chen Guobing
Published: January 2022

We identified SARS-CoV-2 specific antigen epitopes by HLA-A2 binding affinity analysis and characterized their ability to activate T cells. As the pandemic continues, variations in SARS-CoV-2 virus strains have been found in many countries. In this study, we directly assess the immune response to SARS-CoV-2 epitope variants. We first predicted potential HLA-A*02:01-restricted CD8+ T-cell epitopes of SARS-CoV-2. Using the T2 cell model, HLA-A*02:01-restricted T-cell epitopes were screened for their binding affinity and ability to activate T cells. Subsequently, we examined the identified epitope variations and analyzed their impact on immune response. Here, we identified specific HLA-A2-restricted T-cell epitopes in the spike protein of SARS-CoV-2. Seven epitope peptides were confirmed to bind with HLA-A*02:01 and potentially be presented by antigen-presenting cells to induce host immune responses. Tetramers containing these peptides could interact with specific CD8+ T cells from convalescent COVID-19 patients, and one dominant epitope (n-Sp1) was defined. These epitopes could activate and generate epitope-specific T cells in vitro, and those activated T cells showed cytolytic activity toward target cells. Meanwhile, n-Sp1 epitope variant 5L>F significantly decreased the proportion of specific T-cell activation; n-Sp1 epitope 8L>V variant showed significantly reduced binding to HLA-A*02:01 and decreased proportion of n-Sp1-specific CD8+ T cell, which potentially contributes to the immune escape of SARS-CoV-2. Our data indicate that the variation of a dominant epitope will cause the deficiency of HLA-A*02:01 binding and T-cell activation, which subsequently requires the formation of a new CD8+ T-cell immune response in COVID-19 patients.
Melatonin Mitigates Oxazolone-Induced Colitis in Microbiota-Dependent Manner
Authors: Zhao Zi-xiao , Yuan Xi , Cui Yan-yan , Liu Jun , Shen Jing , Jin Bi-ying , Feng Bing-cheng , Zhai Yun-jiao , Zheng Meng-qi , Kou Guan-jun , Zhou Ru-chen , Li Li-xiang , Zuo Xiu-li , Li Shi-yang , Li Yan-qing
Published: January 2022

Levels of type 2 cytokines are elevated in the blood and intestinal tissues of ulcerative colitis (UC) patients in the active phase; this phenomenon indicates the participation of type 2 immune response in UC progression. The beneficial effects of melatonin in dextran sodium sulfate (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) colitis models have been illustrated, but its role in the oxazolone (Oxa)-induced colitis model (driven by type 2 immune response) remains relatively unknown. We investigated the relationship between melatonin concentration and the severity of UC, revealing a significantly negative correlation. Subsequently, we investigated the effects of melatonin in Oxa-induced colitis mice and the potential underlying mechanisms. Administration of melatonin significantly counteracted body weight loss, colon shortening, and neutrophil infiltration in Oxa-induced colitis mice. Melatonin treatment mitigated Oxa-induced colitis by suppressing type 2 immune response. In addition, melatonin attenuated intestinal permeability by enhancing the expression of ZO-1 and occludin in colitis mice. Interestingly, the protective effect of melatonin was abolished when the mice were co-housed, indicating that the regulation of gut microbiota by melatonin was critical in alleviating Oxa-induced colitis. Subsequently, 16S rRNA sequencing was performed to explore the microbiota composition. Decreased richness and diversity of intestinal microbiota at the operational taxonomic unit (OTU) level resulted from melatonin treatment. Melatonin also elevated the abundance of Bifidobacterium, a well-known probiotic, and reduced proportions of several harmful bacterial genera, such as Desulfovibrio, Peptococcaceae, and Lachnospiraceae. Fecal microbiota transplantation (FMT) was used to explore the role of microbiota in the function of melatonin in Oxa-induced colitis. Microbiota transplantation from melatonin-treated mice alleviated Oxa-induced colitis, suggesting that the microbiome participates in the relief of Oxa-induced colitis by melatonin. Our findings demonstrate that melatonin ameliorates Oxa-induced colitis in a microbiota-dependent manner, suggesting the therapeutic potential of melatonin in treating type 2 immunity-associated UC.
Case Report: Cytomegalovirus Reactivation and Pericarditis Following ChAdOx1 nCoV-19 Vaccination Against SARS-CoV-2
Authors: Plüß Marlene , Mese Kemal , Kowallick Johannes T. , Schuster Andreas , Tampe Désirée , Tampe Björn
Published: January 2022

As the coronavirus disease 2019 (COVID-19) pandemic is ongoing and new variants of severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) are emerging, there is an urgent need for vaccines to protect individuals at high risk for complications and to potentially control disease outbreaks by herd immunity. Surveillance of rare safety issues related to these vaccines is progressing, since more granular data emerge about adverse events of SARS-CoV-2 vaccines during post-marketing surveillance. Varicella zoster virus (VZV), Epstein-Barr virus (EBV) and cytomegalovirus (CMV) reactivation has already been reported in COVID-19 patients. In addition, adverse events after SARS-CoV-2 mRNA vaccination have also been in the context of varicella zoster virus (VZV) reactivation and directly associated with the mRNA vaccine. We present the first case of CMV reactivation and pericarditis in temporal association with SARS-CoV-2 vaccination, particularly adenovirus-based DNA vector vaccine ChAdOx1 nCoV-19 against SARS-CoV-2. After initiation of antiviral therapy with oral valganciclovir, CMV viremia disappeared and clinical symptoms rapidly improved. Since huge vaccination programs are ongoing worldwide, post-marketing surveillance systems must be in place to assess vaccine safety that is important for the detection of any events. In the context of the hundreds of millions of individuals to be vaccinated against SARS-CoV-2, a potential causal association with CMV reactivation may result in a considerable number of cases with potentially severe complications.
Single-Cell Transcriptome Profiling Reveals Neutrophil Heterogeneity and Functional Multiplicity in the Early Stage of Severe Burn Patients
Authors: Huang Jiamin , Zhu Zhechen , Ji Dongdong , Sun Ran , Yang Yunxi , Liu Lu , Shao Yiming , Chen Yi , Li Linbin , Sun Binwei
Published: January 2022

The pathophysiological mechanisms, especially the roles of immune cells, underlying early stages of severe burn injury have not yet been fully clarified. Here, we analyzed circulating neutrophils (PMNs) in healthy donors and early burned patients by single-cell RNA sequencing to provide a comprehensive transcriptional landscape of PMNs in heterogeneity and functional multiplicity. Circulating PMNs in the healthy donors and burned groups were divided into five subgroups (G3, G4, G5a, G5b, G5c) with different functions. The dominant subsets of PMNs in homeostasis and burn injury significantly differed between groups. In addition, cells in the same subpopulation had the same core identity markers but performed different functions in healthy and burned states. Under burned conditions, PMN activation was very evident and accompanied by clear degranulation and metabolic abnormalities. Interestingly, was found that PMN activation, degranulation, chemotaxis, phagocytosis and reactive oxygen species (ROS) production in burned patients significantly differed between day 1 and days 2 or 3, thus providing a theoretical basis for PMN interventions in early burn stages. Significantly, previously undescribed transcription factors were also identified, including ZNF-787, ZNF-467, ZNF-189, ZNF-770, ZNF-262. In conclusion, this study conducted for the first time a detailed analysis of the heterogeneity and functional multiplicity of PMNs in early stages of severe burn injuries. Our findings attempted to clarify the influence of PMN heterogeneity on the pathophysiology and related mechanisms of burn injuries, which can provide new ideas for further research in burn intervention.
CD300a Receptor Blocking Enhances Early Clearance of Leishmania donovani From Its Mammalian Host Through Modulation of Effector Functions of Phagocytic and Antigen Experienced T Cells
Authors: Singh Rajan , Anand Anshul , Rawat Arun K. , Saini Shashi , Mahapatra Baishakhi , Singh Naveen K. , Mishra Alok K. , Singh Samer , Singh Nisha , Kishore Dhiraj , Kumar Vinod , Das Pradeep , Singh Rakesh K.
Published: January 2022

The parasites of the genusLeishmaniasurvive and proliferate in the host phagocytic cells by taking control over their microbicidal functions. The parasite also promotes differentiation of antigen-specific anti-inflammatory cytokines producing effector T cells, which eventually results in disease pathogenesis. The mechanisms that parasites employ to dominate host adaptive immunity are largely unknown. For the first time, we report thatL. donovani, which causes visceral leishmaniasis in the Indian subcontinent, upregulates the expression of an immune inhibitory receptor i.e., CD300a on antigen presenting and phagocytic cells to dampen their effector functions. The blocking of CD300a signals in leishmania antigens activated macrophages and dendritic cells enhanced the production of nitric oxide, pro-inflammatory cytokines along with MHCI/II genes expression, and reduced parasitic uptake. Further, the abrogation of CD300a signals inLeishmaniainfected mice benefited antigen-experienced, i.e., CD4+CD44+and CD8+CD44+T cells to acquire more pro-inflammatory cytokines producing phenotypes and helped in the early clearance of parasites from their visceral organs. The CD300a receptor blocking also enhanced the conversion of CD4+T effectors cells to their memory phenotypes i.e., CCR7highCD62Lhighup to 1.6 and 1.9 fold after 14 and 21 days post-infection, respectively. These findings implicate that CD300a is an important determinant of host phagocytic cells functions and T cells differentiation againstLeishmaniaantigens.
Identification of Inflammation-Related Biomarker Pro-ADM for Male Patients With Gout by Comprehensive Analysis
Authors: Qiu Kangli , Zeng Tianshu , Liao Yunfei , Min Jie , Zhang Nan , Peng Miaomiao , Kong Wen , Chen Lu-lu
Published: January 2022

Objective

Gout is a local inflammatory disease caused by the deposition of monosodium urate (MSU) crystals in joints or adjacent tissues. When some gout occurs without hyperuricemia, or its clinical symptoms and signs are not typical, the diagnosis of gout will be delayed, so there is an urgent need to find a new biomarker to predict and diagnose of gout flare. Our research attempts to find the key genes and potential molecular mechanisms of gout through bioinformatics analysis, and collected general data and blood biochemical samples of patients with gout and healthy, then analyzed and compared the expression of factors regulated by key genes.

Method

GSE160170 were downloaded from GEO database for analysis. The data were normalized to identify the differentially expressed genes (DEGs), then GO and KEGG enrichment analysis were applied. Protein-protein interaction (PPI) networks and hub genes between DEGs were identified. Then collect general information and blood samples from male patients with acute gout, hyperuricemia and healthy. ELISA method was used to detect pro-ADM levels of different groups, and the data was input into SPSS statistical software for analysis.

Result

We identified 266 DEGs (179 up-regulated and 87 down-regulated) between gout patients and healthy controls. GO analysis results show that DEGs are mostly enriched in inflammatory response, growth factor activity, cytokine activity, chemokine activity, S100 protein binding and CXCR chemokine receptor binding. KEGG pathway analysis showed that DEGs are mainly related to Chemokine signaling pathway and Cytokine-cytokine receptor interaction. ADM, CXCR1, CXCR6, CXCL3, CCL3, CCL18, CCL3L3, CCL4L1, CD69, CD83, AREG, EREG, B7RP1, HBEGF, NAMPT and S100B are the most important hub genes in the PPI network. We found that the expression of pro-ADM in the gout group and hyperuricemia group was higher than that in the healthy group, and the difference was statistically significant.

Conclusion

In this study, a series of bioinformatics analyses were performed on DEGs to identify key genes and pathways related to gout. Through clinical verification, we found that pro-ADM can be used as an inflammation-related biomarker for acute attacks of gout, providing new ideas for the diagnosis and treatment of gout.
Polymorphonuclear Myeloid-Derived Suppressor Cells Are Abundant in Peripheral Blood of Cancer Patients and Suppress Natural Killer Cell Anti-Tumor Activity
Authors: Tumino Nicola , Besi Francesca , Martini Stefania , Di Pace Anna Laura , Munari Enrico , Quatrini Linda , Pelosi Andrea , Fiore Piera Filomena , Fiscon Giulia , Paci Paola , Scordamaglia Francesca , Covesnon Maria Grazia , Bogina Giuseppe , Mingari Maria Cristina , Moretta Lorenzo , Vacca Paola
Published: January 2022

Tumor microenvironment (TME) includes a wide variety of cell types and soluble factors capable of suppressing immune-responses. While the role of NK cells in TME has been analyzed, limited information is available on the presence and the effect of polymorphonuclear (PMN) myeloid-derived suppressor cells, (MDSC). Among the immunomodulatory cells present in TME, MDSC are potentially efficient in counteracting the anti-tumor activity of several effector cells. We show that PMN-MDSC are present in high numbers in the PB of patients with primary or metastatic lung tumor. Their frequency correlated with the overall survival of patients. In addition, it inversely correlated with low frequencies of NK cells both in the PB and in tumor lesions. Moreover, such NK cells displayed an impaired anti-tumor activity, even those isolated from PB. The compromised function of NK cells was consequent to their interaction with PMN-MDSC. Indeed, we show that the expression of major activating NK receptors, the NK cytolytic activity and the cytokine production were inhibited upon co-culture with PMN-MDSC through both cell-to-cell contact and soluble factors. In this context, we show that exosomes derived from PMN-MDSC are responsible of a significant immunosuppressive effect on NK cell-mediated anti-tumor activity. Our data may provide a novel useful tool to implement the tumor immunoscore. Indeed, the detection of PMN-MDSC in the PB may be of prognostic value, providing clues on the presence and extension of both adult and pediatric tumors and information on the efficacy not only of immune response but also of immunotherapy and, possibly, on the clinical outcome.
Interleukin-27 in Tuberculosis: A Sheep in Wolf’s Clothing?
Authors: Ritter Kristina , Rousseau Jasmin , Hölscher Christoph
Published: January 2022

In tuberculosis (TB), protective inflammatory immune responses and the pathological sequelae of chronic inflammation significantly depend on a timely balance of cytokine expression. In contrast to other anti-inflammatory cytokines, interleukin (IL)-27 has fundamental effects in experimentalMycobacterium tuberculosis(Mtb) infection: the absence of IL-27-mediated signalling promotes a better control of mycobacterial growth on the one hand side but also leads to a chronic hyperinflammation and immunopathology later during infection. Hence, in the context of novel host-directed therapeutic approaches and vaccination strategies for the management of TB, the timely restricted blockade of IL-27 signalling may represent an advanced treatment option. In contrast, administration of IL-27 itself may allow to treat the immunopathological consequences of chronic TB. In both cases, a better knowledge of the cell type-specific and kinetic effects of IL-27 after Mtb infection is essential. This review summarizes IL-27-mediated mechanisms affecting protection and immunopathology in TB and discusses possible therapeutic applications.