bluuebunny/crossref_metadata_2025 huggingface dataset:
Coordinated regulation of gene expression and microRNA changes in adipose tissue and circulating extracellular vesicles in response to pioglitazone treatment in humans with type 2 diabetes
Authors: Nunez Lopez Yury O. , Casu Anna , Kovacova Zuzana , Petrilli Alejandra M. , Sideleva Olga , Tharp William G. , Pratley Richard E.
Published: August 2022

Pioglitazone, a PPARγ agonist, is used to treat type 2 diabetes (T2D). PPARγ is highly expressed in adipose tissue (AT), however the effects of pioglitazone to improve insulin sensitivity are also evident in other tissues and PPARγ agonism has been shown to alter cancer derived extracellular vesicle (EV)-miRNAs. We hypothesized that pioglitazone modifies the cargo of circulating AT-derived EVs to alter interorgan crosstalk in people with diabetes. We tested our hypothesis in a 3-month trial in which 24 subjects with T2D were randomized to treatment with either pioglitazone 45 mg/day or placebo (NCT00656864). Levels of 42 adipocyte-derived EV-miRNAs were measured in plasma EVs using low density TaqMan arrays. Levels of differentially expressed EV-miRNAs and their most relevant target genes were also measure in adipose tissue from the same participants, using individual TaqMan assays. Levels of 5 miRNAs (i.e., miR-7-5p, miR-20a-5p, miR-92a-3p, miR-195-5p, and miR-374b-5p) were significantly downregulated in EVs in response to pioglitazone treatment relative to placebo. The opposite occurred for miR-195-5p in subcutaneous AT. Changes in miRNA expression in EVs and AT correlated with changes in suppression of lipolysis and improved insulin sensitivity, among others. DICER was downregulated and exosomal miRNA sorting-related genes YBX1 and hnRNPA2B1 displayed a downregulation trend in AT. Furthermore, analysis of EV-miRNA targeted genes identified a network of transcripts that changed in a coordinated manner in AT. Collectively, our results suggest that some beneficial pharmacologic effects of pioglitazone are mediated by adipose-specific miRNA regulation and exosomal/EV trafficking.

Clinical Trial Registration

ClinicalTrials.gov, identifier NCT00656864.
Causal relationships between rheumatism and dyslipidemia: A two-sample Mendelian randomization study
Authors: Zhang Guangyang , Cai Yuanqing , Liang Jialin , Zhang Jianan , Jing Zhaopu , Lv Leifeng , Zhang Rupeng , Song Jidong , Dang Xiaoqian , Song Qichun
Published: August 2022

Background

Dyslipidemia is often observed in rheumatic diseases, such as ankylosing spondylitis (AS), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE), yet it remains to be detected whether rheumatic diseases have a causal effect on dyslipidemia.

Methods

Significant (P < 5 × 10-8) and independent (r2 < 0.1) single-nucleotide polymorphisms in genome-wide association studies were selected as instrumental variables to conduct Mendelian randomization (MR) analysis. Inverse variance weighted, weighted median, and MR–Egger regression were adopted for the causal inference. Subsequently, sensitivity analysis was conducted to assess the stability and reliability of MR.

Results

The MR results revealed positive causal relationships of AS with total cholesterol (TC) (β = 0.089, 95% CI = 0.050 to 0.128, P = 6.07 × 10-6), low-density lipoprotein (LDL) (β = 0.087, 95% CI = 0.047 to 0.127, P = 1.91 × 10-5), and high-density lipoprotein (HDL) (β = 0.043, 95% CI = 0.001 to 0.074, P = 0.009). There was no causal effect of RA on TC (β = 0.008, 95% CI = 4.86 × 10-4 to 0.017, P = 0.064), LDL (β = 6.4 × 10-4, 95% CI = -0.008 to 0.007, P = 0.871), or HDL (β = 0.005, 95% CI = -0.003 to 0.013, P = 0.200). Additionally, SLE had negative causal links for TC (β = -0.025, 95% CI = -0.036 to -0.015, P = 4.42 × 10-6), LDL (β = -0.015, 95% CI = -0.025 to -0.005, P = 0.003), and HDL (β = -0.013, 95% CI = -0.021 to -0.004, P = 0.004). The results were stable and reliable.

Conclusion

This study suggested positive causal effects of AS on TC, LDL, and HDL and negative causal effects of SLE on these cholesterol levels, which could provide much help for the pathogenesis and treatment of rheumatic disease patients with dyslipidemia.
Association of thyroid peroxidase antibodies with the rate of first-trimester miscarriage in euthyroid women with unexplained recurrent spontaneous abortion
Authors: Liu Meilan , Wang Dongyan , Zhu Liqiong , Yin Jianlan , Ji Xiaohui , Zhong Yilei , Gao Yuan , Zhang Jianping , Liu Yukun , Zhang Rui , Chen Hui
Published: August 2022

Background

Unexplained recurrent spontaneous abortion is a serious reproductive problem of unknown etiology. Thyroid peroxidase antibodies (TPO-Ab) may be associated with pregnancy outcomes in unexplained recurrent spontaneous abortion with normal thyroid function.

Objective

This study aimed to investigate the relationship between TPO-Ab and the first trimester miscarriage rate/live birth rate in women of unexplained recurrent spontaneous abortion with normal thyroid function.

Methods

We retrospectively analyzed the clinical data of 297 women who met our strict inclusion criteria, comparing the first trimester miscarriage rate/live birth rate between the TPO-Ab positive and TPO-Ab negative groups. For the same purpose, we also performed subgroup analysis.

Results

Of the included women, 76 (25.6%) were TPO-Ab positive, and 221 (74.4%) were negative. First trimester miscarriage rate differed between the two groups (36.8% vs 24.0%, RR = 1.54, 95% CI: 1.05–2.24, P = 0.030). In the younger subgroup (<35 years) and the primary RSA subgroup, First trimester miscarriage rate was also higher in the TPO-Ab positive group (33.3% vs 19.0%, RR = 1.75, 95% CI: 1.07–2.87, P = 0.030; 36.5% vs 21.7%, RR = 1.69, 95% CI: 1.10–2.58, P = 0.020). While the live birth rate was lower in women with TPO-Ab positive, the difference did not reach statistical significance, even in the subgroup analysis.

Conclusion

Our results suggest that TPO-Ab is associated with first trimester miscarriage rate in euthyroid women with unexplained recurrent spontaneous abortion.
Body composition of the upper limb associated with hypertension, hypercholesterolemia, and diabetes
Authors: Qi Qianjin , Sun Kui , Rong Ying , Li Zhaoping , Wu Yixia , Zhang Di , Song Shuaihua , Wang Haoran , Feng Li
Published: August 2022

The associations between segmental body composition and metabolic diseases remain equivocal. This study aimed to investigate this association using the example of U.S. adults. This cross-sectional study included 12,148 participants from the National Health and Nutrition Examination Survey (NHANES) (2011-2018). Multivariable logistic regression models were used to estimate associations between segmental body composition quartiles of hypertension, hypercholesterolemia, and diabetes. Among 12,148 participants, 3,569, 5,683, and 1,212 had hypertension, hypercholesterolemia, and diabetes, respectively. After adjusting for potential confounders, increased percent upper limb lean body mass was associated with a lower risk of hypertension (OR= 0.88, 95%CI: 0.84, 0.92, P trend<0.001), hypercholesterolemia (OR= 0.93, 95%CI: 0.89, 0.96, P trend<0.001), and diabetes (OR= 0.96, 95%CI: 0.95, 0.98, P trend<0.001). Increased upper limb fat mass is associated with an increased risk of hypertension (OR= 1.11, 95%CI: 1.07, 1.15, P trend<0.001), hypercholesterolemia (OR= 1.05, 95%CI: 1.01, 1.09, P trend=0.07), and diabetes (OR= 1.03, 95%CI: 1.01, 1.05, P trend=0.014). The same correlations were found in the torso and whole-body composition parameters. We observed that for women, lean body mass has a better protective effect on metabolic diseases [hypertension (OR= 0.88, 95%CI: 0.82, 0.93), hypercholesteremia (OR =0.86, 95%CI: 0.81, 0.92), diabetes (OR= 0.97, 95%CI: 0.85, 0.99)]; for men, increased body fat is associated with greater risk of metabolic disease[hypertension (OR= 1.24, 95%CI: 1.15, 1.33), hypercholesteremia (OR =1.09, 95%CI: 1.01, 1.18), diabetes (OR= 1.06, 95%CI: 1.01, 1.10)]. There were significant differences between different gender. These findings suggested that upper limb and torso adiposity should be considered when assessing chronic metabolic disease risk using body composition.
Blood immune indexes can predict lateral lymph node metastasis of thyroid papillary carcinoma
Authors: Zhao Lingqian , Zhou Tianhan , Zhang Wenhao , Wu Fan , Jiang Kecheng , Lin Bei , Zhan Siqi , Hu Tao , Tang Tian , Zhang Yu , Luo Dingcun
Published: August 2022

Objective

To explore the clinical significance of blood immune indexes in predicting lateral lymph node metastasis (LLNM) of thyroid papillary carcinoma (PTC).

Methods

The pathological data and preoperative blood samples of 713 patients that underwent thyroid surgery at affiliated Hangzhou First People’s Hospital Zhejiang University School of Medicine from January 2013 to June 2021 were collected as the model group. The pathological data and preoperative blood samples of 177 patients that underwent thyroid surgery in the same hospital from July 2021 to October 2021 were collected as the external validation group. Univariate and multivariate logistic regression analyses were used to determine the independent risk factors of LLNM in PTC patients. A predictive model for assessing LLNM in PTC patients was established and externally validated using the external data.

Results

According to univariate and multivariate logistic regression analyses, tumor diameter (P < 0.001, odds ratios (OR): 1.205, 95% confidence interval (CI): 1.162–1.249) and the preoperative systemic immune-inflammation index (SII) (P = 0.032, OR: 1.001, 95% CI: 1.000–1.002) were independent risk factors for distinguishing LLNM in PTC patients. When the Youden index was the highest, the area under the curve (AUC) was 0.860 (P < 0.001, 95% CI: 0.821–0.898). The externally validated AUC was 0.827 (P < 0.001, 95% CI: 0.724–0.929), the specificity was 86.4%, and the sensitivity was 69.6%. The calibration curve and the decision curve indicated that the model had good diagnostic value.

Conclusion

Blood immune indexes can reflect the occurrence of LLNM and the biological behavior of PTC. The predictive model established in combination with SII and tumor diameter can effectively predict the occurrence of LLNM in PTC patients.
Caprock self-sealing effect due to CO2 leakage from geologic carbon sequestration reservoirs: a case study at Ping’an, China
Authors: Fu Lei , Diao Yujie , Zheng Changyuan , Ma Xin , Zhang Chenglong , Liu Ting , Jin Xiaolin , Shao Wei
Published: August 2022

As a bottom technology for CO2 reduction, geological CO2 storage has attracted great attention from geologists, but there are few reports on the research of the caprock self-sealing effect due to CO2 leakage. Ping’an is a natural CO2 leakage site, which can be compared to the leakage scenarios of geological CO2 storage. Based on the water quality test results and geological observation data, the numerical simulation of geochemistry is carried out. The results show that: First, gypsum dissolves and calcite precipitates during the migration of CO2-rich water to the surface. This process presents a self-sealing effect, and the closer to the surface, the more obvious the self-sealing; Second, the self-sealing effect is formed rapidly. For a 30 cm wide fissure, it only takes a few hundred days to achieve self-sealing; Third, the CO2 leakage was estimated, about 140,813.3 m3, or about 251.28 tons for 1 m long fissure.
Research on the output coordinated strategy of a DPFC considering device fault probability
Authors: Chen Xiaogang , Tang Aihong , Xiong Binyu , Zhou Wei
Published: August 2022

A distributed power flow controller (DPFC) can control the line power flow in a flexible and fast way to meet the requirements of a new power system. However, the output of DPFC sub-units is generally distributed by the even distribution method or proportional distribution method at present. The internal health status and output capacity of the device are not taken into account, which affects the efficiency and service life of the device. In this article, a reliability description method of DPFC based on fault probability is proposed. The coordination strategy of output voltage capability and the number of input sub-units is proposed, and the process of the proposed coordinated strategy for device output is presented. The simulation results show that the proposed coordinated output strategy can address the issue of rapid reliability decline caused by the long-term work of some sub-units and improve the overall reliability of the DPFC.
A feasibility study of SMART reactor power performance optimizations-part 2: Reflector material selection
Authors: Zhong Yiming , Norman Paul , Wu Wenbin
Published: August 2022

The neutron reflector is a general component in the nuclear reactor design. The original SMART reactor design used light water as a reflector surrounding the fission zone. However, this design has low uranium utilization rates in the outermost fuel assemblies, so poor fuel economy. In this study, six potential reflector materials, i.e., heavy water, graphite, beryllium metal and its oxide, steel, and tungsten carbide has been investigated as the neutron reflector for SMART. Firstly, the materials’ cross-sections of neutron scattering and (n, 2n) reactions have been cited from ENDF data libraries and analyzed. This analysis found for the neutrons with energy lower than 1 eV, the 9Be atom has six barn elastic scattering cross-sections, and the 9Be(n, 2n)8Be reaction can compensate for neutron leakage. Then, OpenMC is employed to simulate the effect of these reflector materials on power distribution and depletion. Compared with the original design, the beryllium oxide can improve the initial keff from 1.22906 to 1.27446, flat the radial direction power distribution. The analysis on both scales agrees that the beryllium oxide is an efficient neutron reflector choice with good material properties.
Winter warming effects on soil nitrate leaching under cover crops: A field study using high-frequency weighing lysimeters
Authors: Lapierre Jared , Machado Pedro Vitor Ferrari , Debruyn Zachary , Brown Shannon E. , Jordan Sean , Berg Aaron , Biswas Asim , Henry Hugh A. L. , Wagner-Riddle Claudia
Published: August 2022

Leaching of nitrate (NO3−)—a reactive nitrogen form with impacts on ecosystem health—increases during the non-growing season (NGS) of agricultural soils under cold climates. Cover crops are effective at reducing NGS NO3− leaching, but this benefit may be altered with less snow cover inducing more soil freezing under warmer winters. Our objective was to quantify the effect of winter warming on NO3− leaching from cover crops for a loamy sand (LS) and a silt loam (SIL) soil. This research was conducted over 2 years in Ontario, Canada, using 18 high-precision weighing lysimeters designed to study ecosystem services from agricultural soils. Infra-red heaters were used to simulate warming in lysimeters under a wheat-corn-soybean rotation planted with a cover crop mixture with (+H) and without heating (-H). Nitrate leaching determination used NO3− concentration at 90 cm (discrete sampling) and high temporal resolution drainage volume measurements. Data were analyzed for fall, overwinter, spring-thaw, post-planting, and total period (i.e., November 1 to June 30 of 2017/2018 and 2018/2019). Warming significantly affected soil temperature and soil water content—an effect that was similar for both years. As expected, experimental units under + H presented warmer soils at 5 and 10 cm, along with higher soil water content in liquid form than –H lysimeters, which translated into higher drainage values for + H than –H, especially during the overwinter period. NO3− concentrations at 90 cm were only affected by winter heating for the LS soil. The drainage and NO3− concentrations exhibited high spatial variation, which likely reduced the sensitivity to detect significant differences. Thus, although absolute differences in NO3− leaching between LS vs. SIL and +H (LS) vs. –H (LS) were large, only a trend occurred for higher leaching in LS in 2018/2019. Our research demonstrated that soil heating can influence overwinter drainage (for LS and SIL soils) and NO3− concentration at 90 cm in the LS soil—important NO3− leaching controlling factors. However, contrary to our initial hypothesis, the heating regime adopted in our study did not promote colder soils during the winter. We suggest different heating regimes such as intermittent heating to simulate extreme weather freeze/thaw events as a future research topic.
Heavy metal pollution characteristics and potential ecological risk assessment of soils around three typical antimony mining areas and watersheds in China
Authors: Qi Yanting , Wei Xiangdong , Zhao MengJie , Pan Weisong , Jiang Chao , Wu Jinbiao , Li WaiChin
Published: August 2022

China is the largest antimony resource globally. The mining and smelting of antimony will inevitably have a significant impact on the surrounding and downstream farmlands of the mining area, Therefore, it is necessary to understand the pollution characteristics of antimony and evaluate its potential environmental risks. In this paper, three typical antimony mining areas were used as research districts to analyze the contents of heavy metals in soils of the mining areas and watersheds. The single-factor pollution index method, Nemerow comprehensive pollution index method, geo-accumulation index method, and potential ecological risk index method were used to comprehensively evaluate the pollution status and ecological risk of heavy metals in soils around the mining areas. The soil around the Lengshuijiang tin mine was polluted by As, Cd, Zn, and Sb, it was a heavily polluted soil and at a high ecological risk level. The arable soil around the Nandan tea mountain antimony mine was polluted by As, Cd, Cu, Pb, Sb, and Zn, and it was a heavily polluted soil with very high ecological risk level. The soil around the Xunyang antimony mine was mainly polluted by Sb and it was a moderately polluted soil with moderate ecological risk level. The results revealed that the overall soil heavy metal levels in the Lengshuijiang mining area and the Nandan mining area were in a high-risk state, most likely due to the mining and smelting of metal ores and the weathering of mineralised rocks. showing a high-potential ecological risk in these mining areas. We expect to provide a scientific basis for the safe utilization of farmland and pollution control around the antimony mining areas and watersheds in China.
Source Apportionment of Elemental Carbon in Different Seasons in Hebei, China
Authors: Hou Dongli , Zhang Xiang , Zhao Jiangwei , Qiang Jie , Wang Jianguo , Wang Peng , An Qingxian , Wang Yang , Wang Liwei , Yuan Shihui , Zhang Feng
Published: August 2022

Black carbon (BC), also termed elemental carbon (EC), is a strong light-absorbing substance. It can disturb the radiation balance between the earth and atmosphere resulting in changing regional and global climate conditions. This study conducted a thorough analysis of EC in Hebei during different seasons and provided comprehensive EC emission data in the Beijing–Tianjin–Hebei (BTH) region for future policy making connected with air pollution mitigation and control. The results showed that the concentration of EC during the sampling period varied from 0.01 to 18.4 μg/m3 with a mean value of 2.6 ± 2.8 μg/m3. The EC source apportionment exercise identified four regular emission sources for all seasons, including traffic-related emissions, coal combustion, biomass burning, and mineral dust. Annually, traffic-related emissions were the primary EC contributor with an annual average contribution of 38%, followed by biomass burning (30%) and coal combustion (25%). In addition, the EC mass concentration at Shijiazhuang was also influenced by diverse pollutants from upwind regions. This study shows that traffic emissions are a major contributor to EC mass concentration in Shangjiazhuang and highlights that regional joint control of air pollution is important to local air quality.
The relationship between environmental scanning and organizational resilience: Roles of process innovation and environmental uncertainty
Authors: YahiaMarzouk Yasmine , Jin Jiafei
Published: August 2022

Due to increased global environment volatility and uncertainty, organizations are constantly faced with unexpected events such as the COVID-19 pandemic, which has brought large international disruptions for several firms. Organizational resilience is a potential notion for describing how firms might stay alive and thrive in such a volatile environment. Therefore, this study aimed to examine how SMEs can foster their resilience through investigating the roles of environmental scanning and process innovation while testing the moderating role of environmental uncertainty. To achieve this aim, we tested a structural model through an empirical investigation with partial least squares structural equation modelling (PLS-SEM) using a sample of 249 Egyptian SMEs. The results reveal that process innovation is a necessary condition for environmental scanning to affect organizational resilience. Furthermore, the results do not support the moderating role of environmental uncertainty the indirect relationship between environmental scanning and organizational resilience. Our findings contribute to innovation and resilience literature by proving that process innovation is a necessary mechanism to translate environmental scanning information to enhance resilience. This research is the first to highlight the role of process innovation in linking environmental scanning to organizational resilience. Our results provide insights about how Egyptian SMEs could remain resilient amidst the COVID-19 through scanning their environments to improve internal processes. We discuss related theoretical and managerial implications.
Integration of landscape-level remote sensing and tree-level ecophysiology reveals drought refugia for a rare endemic, bigcone Douglas-fir
Authors: Post-Leon Annapurna C. , Dryak Mahalia , Zhu Edward , De Guzman Mark E. , Salladay Ryan , Moritz Max A. , Parkinson Anne-Marie L. , Ramirez Aaron R.
Published: August 2022

For forest species, areas buffered from the rapidly increasing climate stressors and patterns of disturbance — i.e., climate change refugia — are important targets for conservation and protection. Here, we present a novel field survey and remote sensing approach to identification of fine-scalefunctional drought refugiafor bigcone Douglas-fir (Pseudotsuga macrocarpa)-dominated forests. This rare species has been exposed to climate change-exacerbated drought conditions over the past two decades; yet, little is known about its responses to recent drought and how these drought responses vary across local environmental gradients and interact with recent record wildfire seasons. We combined a remote sensing analysis of vegetation condition with field surveys and physiological measurements to better understand bigcone Douglas-fir responses to recent climate trends. We also identified 444 stands exhibiting relatively low response and high resilience to drought — i.e., potential drought refugia. We found that low elevation stands and those in south-facing aspects generally experienced greater levels of seasonal and interannual drought stress. This trend was more pronounced for stands that experienced fire (2007 Zaca Fire) prior to the drought, suggesting that wildfire can increase the importance of topographic mediation of climate conditions in bigcone Douglas-fir forests. Elevation and aspect also interacted to affect physiological acclimation to seasonal drought conditions, with low elevation north-facing sites in particular experiencing a favorable combination of greater climate buffering and greater drought resilience, suggesting that these sites may be important refugia for bigcone Douglas-fir at low elevations. Furthermore, we found that the relationships between topography and drought response were weaker in more coastal sites, possibly due to maritime climate buffering in these sites. Altogether, these results illustrate how topographic mediation of regional drought conditions is critical for the persistence of this rare species in drought and fire-prone landscapes, and offer important insights for the conservation and restoration of this iconic species.
Non-native tree regeneration indicates regional and national risks from current invasions
Authors: Potter Kevin M. , Riitters Kurt H. , Guo Qinfeng
Published: August 2022

Non-native (introduced, exotic, and alien) species alter forest ecosystem processes, cause landscape change, interfere with services provided by native trees, and contribute to biotic homogenization. To quantify the degree of invasion by non-native trees in the United States, we combined two broad-scale datasets: (1) tree species occurrence data from the national Forest Inventory and Analysis (FIA) plot network and (2) ecoregions characterized by relatively homogeneous environmental conditions. Using the FIA statistical design, we created an indicator of non-native tree regeneration success by estimating the proportion of small trees (seedlings and saplings) relative to all trees for non-native species in the conterminous United States and southeast Alaska, Hawaii, and Puerto Rico. Species with at least 75 percent of their stems consisting of smaller stems were classified as highly invasive while those with 60 percent to 75 percent of smaller stems were classified as moderately invasive. Above these thresholds, non-native species are of ecological concern because they are established and reproducing successfully and therefore likely to continue to spread in the future. For the conterminous United States and southeast Alaska, we identified 16 highly invasive and four moderately invasive non-native tree species. Widespread highly invasive and relatively well-established species included Ailanthus altissima, Triadica sebifera, and Ulmus pumila. The richness of highly invasive species was the highest in parts of the Midwest and Mid-Atlantic States, followed by much of the Southeast. In Hawaii, we identified seven highly invasive and three moderately invasive non-native tree species. The most widespread highly invasive and well-established tree species in the archipelago were Psidium cattleyanum, Psidium guajava, Ardisia elliptica, and Syzygium cumini. The largest numbers of highly invasive species were inventoried in the lowland/leeward dry and mesic forests of O’ahu and the lowland wet and mesic forests of Hawai’i Island. Puerto Rico had 17 highly invasive and two moderately invasive tree species. The most widespread and well-established non-native species were Leucaena leucocephala, Spathodea campanulata, Coffea arabica, Syzygium jambos, and Melicoccus bijugatus. The results of this assessment offer insights into which species are most likely to alter forest ecosystems and which forests may be effectively managed to control invasive trees.
Case report: Analysis of novel compound heterozygous TPP1 variants in a Chinese patient with neuronal ceroid lipofuscinosis type 2
Authors: Miao Sui-Bing , Guo Hui , Kong De-Xian , Zhao Yuan-Yuan , Pan Shu-Hong , Jiang Yan , Gao Xing , Wu Xiao-Hua
Published: August 2022

Neuronal ceroid lipofuscinosis type 2 (CLN2) is an autosomal recessive neurodegenerative disease caused by variants in the TPP1 gene that lead to the deficiency of the lysosomal enzyme tripeptidyl peptidase I (TPP1) activity. Herein, we report a rare case of CLN2 caused by two novel variants of TPP1. The patient presented with seizures at onset, followed by progressive cognitive impairment, motor decline, and vision loss. Novel compound heterozygous variants, c.544_545del and c.230-3C>G, in TPP1 were identified by whole-exome sequencing. The variant assessment showed that the c.544_545del is a frameshift variant mediating mRNA decay and that c.230-3C>G is a splice variant generating aberrantly spliced TPP1 mRNA, as confirmed by a Splicing Reporter Minigene assay. In conclusion, clinical history, variant assessment, and molecular analyses demonstrate that the novel compound heterozygous variants are responsible for CLN2 disease in this patient. This study expands the mutation spectrum of TPP1.
The experiences of endometriosis patients with diagnosis and treatment in New Zealand
Authors: Ellis Katherine , Munro Deborah , Wood Rachael
Published: August 2022

Endometriosis is a chronically painful, invasive, inflammatory disease, with limited treatment options and long delays to diagnosis, which impacts 10% of females in New Zealand.

Introduction

As part of a larger group discussion study, this paper covers three themes associated with endometriosis patient experiences: intensity of pain, diagnostic tool shortcomings and perspectives of treatment options.

Materials and methods

The goal of this research was the inclusion of patient voices to guide research priorities. In early 2022, 50 New Zealand endometriosis patients participated in anonymous, asynchronous, text-based group discussions on the VisionsLive platform. The patients ranged in age from 18–48. The patients answered 50 questions, 23 text-based and 27 quantitative, and then took part in online group discussions.

Results and discussion

The average age of symptom onset was 15.3 years, while the average delay from symptom onset to a working or surgically confirmed diagnosis was 7.91 years. The top five reported symptoms within the cohort were pain-based, and the participants discussed the many impacts of this pain on their work and education. The four main diagnostic tools employed on this cohort were abdominal ultrasound (72%), transvaginal ultrasound (68%), laparoscopy (82%) and sharing their symptom history with a medical practitioner (88%). The most common emotions patients experienced following receiving a diagnosis of endometriosis were relief (86%), feeling overwhelmed (54%), and anger (32%). The main treatments offered to this cohort were pain relief (96%), laparoscopic surgery (84%) and the combined oral contraceptive pill (80%). Of these three treatments, only laparoscopic surgery was viewed positively by the majority of users, with 67% considering laparoscopy an effective treatment, compared to 46% of users for pain relief, and 25% of users for the combined oral contraceptive pill.

Conclusions

Gathering the voice of patients revealed that long delays to diagnosis and dismissal by medical practitioners frequently manifests as a reaction of relief by patients once diagnosed. Results also showed treatment options such as pain relief and hormonal medications were often considered ineffective, but were routinely offered as the first, or only, options for patients. It is therefore important that both quicker routes to diagnosis and more effective treatment options be developed.
Migrant visibility: Digitization and heritage policies
Authors: Faassen Marijke van , Hoekstra Rik
Published: August 2022

Digitization and digital methods have had a big impact on migration history and history in general. The dispersed and fragmented nature of migration heritage that involves at least two countries and many cultural heritage institutions make it clear that migration history can be much improved by using digital means to connect collections. This makes it possible to overcome the biases that policy have introduced in private and public collections alike by selection and perspective. Digital methods are not immune to these biases and may even introduce new distortions because they often change heritage contextualizations. In this article, Van Faassen and Hoekstra argue that therefore they should be embedded in source criticism methodology. They use the example of post-world War II Dutch-Australian emigration to show how a migrant registration system can be used as a structural device to connect migrant heritage. They use methods from computer vision to assess the information distribution of the registration system. Together, connecting collections and information assessments give an encompassing view of the migrant visibility and invisibility in the heritage collections and perspectives for scholars to become aware of heritage biases.
Challenges and dilemmas of social cohesion between the Rohingya and host communities in Bangladesh
Authors: Siddiqi Bulbul
Published: August 2022

Social Cohesion is an important issue for refugees and their host communities. Much attention on social cohesion in the literature has been focused on situations in the Middle East. This paper will bring attention to the Rohingya crisis in Bangladesh. With the influx of nearly one million Rohingya into Bangladesh in 2017, social cohesion between the Rohingya and their host communities has become more complex than ever. Although ensuring social cohesion is very important for Bangladesh, it has not been easy to implement under the present legislative framework of refugee management in Bangladesh. The sympathetic attitude of the host community toward the Rohingya has significantly declined during the past 4 years. In this context, qualitative research was undertaken to understand the challenges and dilemmas of social cohesion from both the host and Rohingya perspectives. Based on 50 key informant interviews, observations, and several informal group discussions, this paper argues that a negative perception among the neighboring host communities toward the Rohingya has increased, contributing to social tension. A pragmatic and sustainable approach has to be taken to ensure a cohesive and peaceful coexistence of the host communities and the Rohingya until dignified repatriation of the Rohingya is possible.
Alpha-D-glucan-based vaccine adjuvants: Current status and future perspectives
Authors: Patil Veerupaxagouda , Hernandez-Franco Juan F. , HogenEsch Harm , Renukaradhya Gourapura J.
Published: August 2022

Nanoparticles (NPs) are increasingly used as efficient vaccine antigen-delivery platforms and vaccine adjuvants. Alpha (α)-D-glucans are polysaccharide polymers found in plants, animals, and microbes. Phytoglycogen (PG) is a densely branched dendrimer-like α-D-glucan that forms nanoparticle structures. Two simple chemical modifications of corn-derived PG create positively charged, amphiphilic nanoparticles, known as Nano-11, that stimulate immune responses when used as vaccine adjuvant in a variety of species. Nano-11 is a versatile adjuvant that can be used for alternative routes of vaccination and in combination with other immunostimulatory molecules. This review discusses our current understanding of the mechanism of action of Nano-11 and its future potential applications in animal vaccines.
MS4A6A is a new prognostic biomarker produced by macrophages in glioma patients
Authors: Zhang Chunyu , Liu Haitao , Tan Yinqiu , Xu Yang , Li Yuntao , Tong Shiao , Qiu Sheng , Chen Qianxue , Su Zhongzhou , Tian Daofeng , Zhou Wei , Zhong Chunlong
Published: August 2022

MS4A6A has been recognized as being associated with aging and the onset of neurodegenerative disease. However, the mechanisms of MS4A6A in glioma biology and prognosis are ill-defined. Here, we show that MS4A6A is upregulated in glioma tissues, resulting in unfavorable clinical outcomes and poor responses to adjuvant chemotherapy. Multivariate Cox regression analysis suggested that MS4A6A expression can act as a strong and independent predictor for glioma outcomes (CGGA1: HR: 1.765, p < 0.001; CGGA2: HR: 2.626, p < 0.001; TCGA: HR: 1.415, p < 0.001; Rembrandt: HR: 1.809, p < 0.001; Gravendeel: HR: 1.613, p < 0.001). A protein–protein interaction (PPI) network revealed that MS4A6A might be coexpressed with CD68, CD163, and macrophage-specific signatures. Enrichment analysis showed the innate immune response and inflammatory response to be markedly enriched in the high MS4A6A expression group. Additionally, single-cell RNA sequencing (scRNA-seq) analysis revealed distinctive expression features for MS4A6A in macrophages in the glioma immune microenvironment (GIME). Immunofluorescence staining confirmed colocalization of CD68/MS4A6A and CD163/MS4A6A in macrophages. Correlation analysis revealed that MS4A6A expression is positively related to the tumor mutation burden (TMB) of glioma, displaying the high potential of applying MS4A6A to evaluate responsiveness to immunotherapy. Altogether, our research indicates that MS4A6A upregulation may be used as a promising and effective indicator for adjuvant therapy and prognosis assessment.
Serum soluble Fas ligand is a severity and mortality prognostic marker for COVID-19 patients
Authors: Saleki Kiarash , Shirzad Moein , Javanian Mostafa , Mohammadkhani Sheyda , Alijani Mohammad Hossein , Miri Niloufarsadat , Oladnabi Morteza , Azadmehr Abbas
Published: August 2022

Finding cytokine storm initiator factors associated with uncontrolled inflammatory immune response is necessary in COVID-19 patients. The aim was the identification of Fas/Fas Ligand (FasL) role in lung involvement and mortality of COVID-19 patients. In this case-control study, mild (outpatient), moderate (hospitalized), and severe (ICU) COVID-19 patients and healthy subjects were investigated. RNA isolated from PBMCs for cDNA synthesis and expression of mFas/mFasL mRNA was evaluated by RT-PCR. Serum sFas/sFasL protein by ELISA and severity of lung involvement by CT-scan were evaluated. Also, we docked Fas and FasL via Bioinformatics software (in silico) to predict the best-fit Fas/FasL complex and performed molecular dynamics simulation (MDS) in hyponatremia and fever (COVID-19 patients), and healthy conditions. mFasL expression was increased in moderate and severe COVID-19 patients compared to the control group. Moreover, mFas expression showed an inverse correlation with myalgia symptom in COVID-19 patients. Elevation of sFasL protein in serum was associated with reduced lung injury and mortality. Bioinformatics analysis confirmed that blood profile alterations of COVID-19 patients, such as fever and hyponatremia could affect Fas/FasL complex interactions. Our translational findings showed that decreased sFasL is associated with lung involvement; severity and mortality in COVID-19 patients. We think that sFasL is a mediator of neutrophilia and lymphopenia in COVID-19. However, additional investigation is suggested. This is the first report describing that the serum sFasL protein is a severity and mortality prognostic marker for the clinical management of COVID-19 patients.
The intersection molecule MDA5 in Cancer and COVID-19
Authors: Jin Renjing , Cao Xiaoqing , Lu Mingjun , Gao Qing , Ma Teng
Published: August 2022

The connections between pattern recognition receptors (PRRs) and pathogen-associated molecular patterns (PAMPs) constitutes the crucial signaling pathways in the innate immune system. Cytoplasmic nucleic acid sensor melanoma differentiation-associated gene 5 (MDA5) serves as an important pattern recognition receptor in the innate immune system by recognizing viral RNA. MDA5 also plays a role in identifying the cytoplasmic RNA from damaged, dead cancer cells or autoimmune diseases. MDA5’s recognition of RNA triggers innate immune responses, induces interferon (IFN) response and a series of subsequent signaling pathways to produce immunomodulatory factors and inflammatory cytokines. Here we review the latest progress of MDA5 functions in triggering anti-tumor immunity by sensing cytoplasmic dsRNA, and recognizing SARS-CoV-2 virus infection for antiviral response, in which the virus utilizes multiple ways to evade the host defense mechanism.
New insights on the role of human leukocyte antigen complex in primary biliary cholangitis
Authors: Mulinacci Giacomo , Palermo Andrea , Gerussi Alessio , Asselta Rosanna , Gershwin Merrill Eric , Invernizzi Pietro
Published: August 2022

Primary Biliary Cholangitis (PBC) is a rare autoimmune cholangiopathy. Genetic studies have shown that the strongest statistical association with PBC has been mapped in the human leukocyte antigen (HLA) locus, a highly polymorphic area that mostly contribute to the genetic variance of the disease. Furthermore, PBC presents high variability throughout different population groups, which may explain the different geoepidemiology of the disease. A major role in defining HLA genetic contribution has been given by genome-wide association studies (GWAS) studies; more recently, new technologies have been developed to allow a deeper understanding. The study of the altered peptides transcribed by genetic alterations also allowed the development of novel therapeutic strategies in the context of immunotolerance. This review summarizes what is known about the immunogenetics of PBC with a focus on the HLA locus, the different distribution of HLA alleles worldwide, and how HLA modifications are associated with the pathogenesis of PBC. Novel therapeutic strategies are also outlined.
Discovering common pathogenetic processes between COVID-19 and sepsis by bioinformatics and system biology approach
Authors: Lu Lu , Liu Le-Ping , Gui Rong , Dong Hang , Su Yan-Rong , Zhou Xiong-Hui , Liu Feng-Xia
Published: August 2022

Corona Virus Disease 2019 (COVID-19), an acute respiratory infectious disease caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has spread rapidly worldwide, resulting in a pandemic with a high mortality rate. In clinical practice, we have noted that many critically ill or critically ill patients with COVID-19 present with typical sepsis-related clinical manifestations, including multiple organ dysfunction syndrome, coagulopathy, and septic shock. In addition, it has been demonstrated that severe COVID-19 has some pathological similarities with sepsis, such as cytokine storm, hypercoagulable state after blood balance is disrupted and neutrophil dysfunction. Considering the parallels between COVID-19 and non-SARS-CoV-2 induced sepsis (hereafter referred to as sepsis), the aim of this study was to analyze the underlying molecular mechanisms between these two diseases by bioinformatics and a systems biology approach, providing new insights into the pathogenesis of COVID-19 and the development of new treatments. Specifically, the gene expression profiles of COVID-19 and sepsis patients were obtained from the Gene Expression Omnibus (GEO) database and compared to extract common differentially expressed genes (DEGs). Subsequently, common DEGs were used to investigate the genetic links between COVID-19 and sepsis. Based on enrichment analysis of common DEGs, many pathways closely related to inflammatory response were observed, such as Cytokine-cytokine receptor interaction pathway and NF-kappa B signaling pathway. In addition, protein-protein interaction networks and gene regulatory networks of common DEGs were constructed, and the analysis results showed that ITGAM may be a potential key biomarker base on regulatory analysis. Furthermore, a disease diagnostic model and risk prediction nomogram for COVID-19 were constructed using machine learning methods. Finally, potential therapeutic agents, including progesterone and emetine, were screened through drug-protein interaction networks and molecular docking simulations. We hope to provide new strategies for future research and treatment related to COVID-19 by elucidating the pathogenesis and genetic mechanisms between COVID-19 and sepsis.
Immune response in ofatumumab treated multiple sclerosis patients after SARS-CoV-2 vaccination
Authors: Faissner Simon , Heitmann Neele , Plaza-Sirvent Carlos , Trendelenburg Paulina , Ceylan Ulas , Motte Jeremias , Bessen Clara , Urlaub Doris , Watzl Carsten , Overheu Oliver , Reinacher-Schick Anke , Hellwig Kerstin , Pfaender Stephanie , Schmitz Ingo , Gold Ralf
Published: August 2022

Objective

The pandemic induced by SARS-CoV-2 has huge implications for patients with immunosuppression that is caused by disorders or specific treatments. Especially approaches targeting B cells via anti-CD20 therapy are associated with impaired humoral immune response but sustained cellular immunity. Ofatumumab is a human anti-CD20 directed antibody applied in low dosages subcutaneously, recently licensed for Multiple Sclerosis (MS). Effects of early ofatumumab treatment on alterations of immune cell composition and immune response towards SARS-CoV-2 are incompletely understood.

Methods

We here investigated immune cell alterations in early ofatumumab (Ofa) treated patients and effects on humoral (titer, neutralization capacity against wild type, Delta and Omicron) and cellular immune responses in Ofa treated MS patients following a third vaccination against SARS-CoV-2 compared to healthy controls.

Results

We show that a mean treatment duration of three months in the Ofa group led to near complete B cell depletion in line with altered composition of certain CD4+ T cell subpopulations such as enhanced frequencies of naive and a decrease of non-suppressive regulatory T cells (Tregs). Titer and neutralization capacity against SARS-CoV-2 variants was impaired while cellular immune response was sustained, characterized by a strong T helper 1 profile (Th1).

Interpretation

In summary, low dosage ofatumumab treatment elicits sustained depletion of B cells in line with alterations of immune cells, mainly Tregs. This is associated with impaired humoral immune response towards SARS-CoV-2 vaccination but preserved, Th1 driven cellular immunity adding crucial information regarding early effects of low dosage anti-CD20 therapy on humoral and cellular immunity.
Extracellular matrix metalloproteinase inducer in brain ischemia and intracerebral hemorrhage
Authors: Liu Yang , Mu Yanling , Li Zhe , Yong Voon Wee , Xue Mengzhou
Published: August 2022

Increasing evidence from preclinical and clinical studies link neuroinflammation to secondary brain injury after stroke, which includes brain ischemia and intracerebral hemorrhage (ICH). Extracellular matrix metalloproteinase inducer (EMMPRIN), a cell surface transmembrane protein, is a key factor in neuroinflammation. It is widely elevated in several cell types after stroke. The increased EMMPRIN appears to regulate the expression of matrix metalloproteinases (MMPs) and exacerbate the pathology of stroke-induced blood-brain barrier dysfunction, microvascular thrombosis and neuroinflammation. In light of the neurological effects of EMMPRIN, we present in this review the complex network of roles that EMMPRIN has in brain ischemia and ICH. We first introduce the structural features and biological roles of EMMPRIN, followed by a description of the increased expression of EMMPRIN in brain ischemia and ICH. Next, we discuss the pathophysiological roles of EMMPRIN in brain ischemia and ICH. In addition, we summarize several important treatments for stroke that target the EMMPRIN signaling pathway. Finally, we suggest that EMMPRIN may have prospects as a biomarker of stroke injury. Overall, this review collates experimental and clinical evidence of the role of EMMPRIN in stroke and provides insights into its pathological mechanisms.