bluuebunny/crossref_metadata_2025 huggingface dataset:
What does the public think about artificial intelligence?—A criticality map to understand bias in the public perception of AI
Authors: Brauner Philipp , Hick Alexander , Philipsen Ralf , Ziefle Martina
Published: March 2023

Introduction

Artificial Intelligence (AI) has become ubiquitous in medicine, business, manufacturing and transportation, and is entering our personal lives. Public perceptions of AI are often shaped either by admiration for its benefits and possibilities, or by uncertainties, potential threats and fears about this opaque and perceived as mysterious technology. Understanding the public perception of AI, as well as its requirements and attributions, is essential for responsible research and innovation and enables aligning the development and governance of future AI systems with individual and societal needs.

Methods

To contribute to this understanding, we asked 122 participants in Germany how they perceived 38 statements about artificial intelligence in different contexts (personal, economic, industrial, social, cultural, health). We assessed their personal evaluation and the perceived likelihood of these aspects becoming reality.

Results

We visualized the responses in a criticality map that allows the identification of issues that require particular attention from research and policy-making. The results show that the perceived evaluation and the perceived expectations differ considerably between the domains. The aspect perceived as most critical is the fear of cybersecurity threats, which is seen as highly likely and least liked.

Discussion

The diversity of users influenced the evaluation: People with lower trust rated the impact of AI as more positive but less likely. Compared to people with higher trust, they consider certain features and consequences of AI to be more desirable, but they think the impact of AI will be smaller. We conclude that AI is still a “black box” for many. Neither the opportunities nor the risks can yet be adequately assessed, which can lead to biased and irrational control beliefs in the public perception of AI. The article concludes with guidelines for promoting AI literacy to facilitate informed decision-making.
Correlations between serum laminin level and severity of heart failure in patients with chronic heart failure
Authors: Xie Ling , Zhou Zhen , Chen Hai-Xiao , Yan Xiao-Yun , Ye Jia-Qi , Jiang Ying , Zhou Lei , Zhang Qing
Published: March 2023

Objective

This study aimed to investigate the correlation between serum laminin (LN) levels and clinical stages of heart failure in patients with chronic heart failure.

Methods

A total of 277 patients with chronic heart failure were selected from September 2019 to June 2020 in the Department of Cardiology, Second Affiliated Hospital of Nantong University. Based on stages of heart failure, the patients were divided into four groups: stage A, stage B, stage C, and stage D, with 55, 54, 77, and 91 cases, respectively. At the same time, 70 healthy people in this period were selected as the control group. Baseline data were recorded and serum Laminin (LN) levels were measured. The research compared, the differences in baseline data among the four groups of HF and normal controls, and analyzed the correlation between N-terminal pro-brain natriuretic peptide (NT-proBNP) and left ventricular ejection fraction (LVEF). The receiver operating characteristic (ROC) curve was used to evaluate the predictive value of LN in the C-D stage of heart failure. Logistic multivariate ordered analysis was applied to screen the independent related factors of clinical stages of heart failure.

Results

Serum LN levels in patients with chronic heart failure were significantly higher than those in healthy people, which were 33.2 (21.38, 101.9) ng/ml and 20.45 (15.53, 23.04) ng/ml, respectively. With the progression of clinical stages of HF, serum LN and NT-proBNP levels increased, while LVEF gradually decreased (P < 0.05). Correlation analysis showed that LN was positively correlated with NT-proBNP (r = 0.744, P = 0.000) and negatively correlated with LVEF (r = −0.568, P = 0.000). The area under the ROC curve of LN for predicting C and D stages of heart failure was 0.913, 95% confidence interval was 0.882–0.945, P = 0.000, specificity 94.97%, and sensitivity 77.38%. Multivariate Logistic analysis showed that LN, Total bilirubin, NT-proBNP and HA were all independent correlates of heart failure staging.

Conclusion

Serum LN levels in patients with chronic heart failure are significantly increased and are independently correlated with the clinical stages of heart failure. It could potentially be an early warning index of the progression and severity of heart failure.
Age, sex and angiographic type-related phenotypic differences in inpatients with Takayasu arteritis: A 13-year retrospective study at a national referral center in China
Authors: Zhou Jingya , Li Jing , Wang Yi , Yang Yunjiao , Zhao Jiuliang , Li Mengtao , Pang Haiyu , Wang Tingyu , Chen Yuexin , Tian Xinping , Zeng Xiaofeng , Zheng Yuehong
Published: March 2023

Backgrounds

We aimed to investigate the demographic characteristics, vascular involvement, angiographic patterns, complications, and associations of these variables in a large sample of TAK patients at a national referral center in China.

Methods

The medical records of TAK patients discharged from 2008 to 2020 were retrieved from the hospital discharge database using ICD-10 codes. Demographic data, vascular lesions, Numano classifications and complications were collected and analyzed.

Results

The median age at onset was 25 years in 852 TAK patients (670 female, 182 male). Compared with the females, the male patients were more likely to have type IV and were more likely to have iliac (24.7% vs. 10.0%) and renal artery (62.7% vs. 53.9%) involvement. They also had a higher prevalence of systemic hypertension (62.1% vs. 42.4%), renal dysfunction (12.6% vs. 7.8%) and aortic aneurysm (AA) (8.2% vs. 3.6%). The childhood-onset group was more likely to have involvement of the abdominal aorta (68.4% vs. 52.1%), renal artery (69.0% vs. 51.8%) and superior mesenteric artery (41.5% vs. 28.5%), and they were more likely to have type IV, V and hypertension than the adult-onset group. After adjusting for sex and age at onset, the patients with type II were associated with an increased risk of cardiac dysfunction (II vs. I: OR = 5.42; II vs. IV: OR = 2.63) and pulmonary hypertension (II vs. I: OR = 4.78; II vs. IV: OR = 3.95) compared with those with types I and IV. Valvular abnormalities (61.0%) were observed to be most prevalent in patients with type IIa. The patients with Type III were associated with a higher risk of aortic aneurysm (23.3%) than the patients with types IV (OR = 11.00) and V (OR = 5.98). The patients with types III and IV were more commonly complicated with systemic hypertension than the patients with types I, II and V. P < 0.05 in all of the above comparisons.

Conclusion

Sex, adult/childhood presentation and Numano angiographic type were significantly associated with differences in phenotypic manifestations, especially cardiopulmonary abnormalities, systemic hypertension, renal dysfunction and aortic aneurysm.
Comparing the effectiveness and safety of dual antiplatelet with ticagrelor or clopidogrel in elderly Asian patients with acute myocardial infraction
Authors: Yeh Jong-Shiuan , Chen Wan-Ting , Tomlinson Brian , Tam Weng-Chio , Chien Li-Nien
Published: March 2023

Background

Current guidelines recommend potent P2Y12 inhibitors for patients after acute coronary syndrome. However, the data on the efficacy and safety of potent P2Y12 inhibitors in elderly Asian populations was limited. We aimed to investigate the major adverse cardiovascular events (MACE), bleeding events, and net adverse clinical events (NACE) with ticagrelor and clopidogrel in Taiwanese patients aged 65 and older after acute myocardial infarction (AMI).

Methods

This retrospective population-based cohort study was conducted using data from the National Health Insurance Research Database. The AMI patients aged ≥65 years who underwent percutaneous coronary intervention (PCI) and survived after 1 month were included. The patients were separated into 2 cohorts depending on the type of dual antiplatelet therapy (DAPT) they received: ticagrelor plus aspirin (T + A) or clopidogrel plus aspirin (C + A). We used inverse probability of treatment weighting to balance the difference between these 2 study groups. The outcome included all-cause mortality, MACE (cardiovascular death, nonfatal ischemic stroke, and nonfatal myocardial infarction), intracerebral hemorrhage, major bleeding, and NACE which is composed of cardiovascular death, ischemic and hemorrhagic events. The follow-up period was up to 12 months.

Results

From 2013 to 2017, a total of 14,715 patients who met the eligibility criteria were separated into 2 groups: 5,051 for T + A and 9,664 for C + A. Compared to patients with C + A, patients who received T + A had a lower risk of cardiovascular death and all-cause death, with an adjusted HR of 0.57 [95% confidence interval (CI), 0.38–0.85, p = 0.006] and 0.58 (95% CI 0.45–0.74, p < 0.001), respectively. No differences were found in MACE, intracranial and major bleeding between the 2 groups. In addition, the patients with T + A had a lower risk of NACE with an adjusted HR of 0.86 (95% CI 0.74–1.00, p = 0.045)

Conclusion

Among elderly AMI patients receiving DAPT after successful PCI, ticagrelor was a more favorable P2Y12 inhibitor than clopidogrel because of lowering the risk of death and NACE without increasing the risk of severe bleeding. Ticagrelor is an effective and safe P2Y12 inhibitor in Asian elderly survivors after PCI.
The immune checkpoint molecule, VTCN1/B7-H4, guides differentiation and suppresses proinflammatory responses and MHC class I expression in an embryonic stem cell-derived model of human trophoblast
Authors: Zhou Jie , Tian Yuchen , Qu Ying , Williams Madyson , Yuan Ye , Karvas Rowan M. , Sheridan Megan A. , Schulz Laura C. , Ezashi Toshihiko , Roberts Michael R. , Schust Danny J.
Published: March 2023

The placenta acts as a protective barrier to pathogens and other harmful substances present in the maternal circulation throughout pregnancy. Disruption of placental development can lead to complications of pregnancy such as preeclampsia, intrauterine growth retardation and preterm birth. In previous work, we have shown that expression of the immune checkpoint regulator, B7-H4/VTCN1, is increased upon differentiation of human embryonic stem cells (hESC) to an in vitro model of primitive trophoblast (TB), that VTCN1/B7-H4 is expressed in first trimester but not term human placenta and that primitive trophoblast may be uniquely susceptible to certain pathogens. Here we report on the role of VTCN1 in trophoblast lineage development and anti-viral responses and the effects of changes in these processes on major histocompatibility complex (MHC) class I expression and peripheral NK cell phenotypes.
Quality and cost of healthcare services in patients with diabetes in Iran: Results of a nationwide short-term longitudinal survey
Authors: Abbasi-Kangevari Mohsen , Mohebi Farnam , Ghamari Seyyed-Hadi , Modirian Mitra , Shahbal Nazila , Ahmadi Naser , Farzi Yosef , Azmin Mehrdad , Roshani Shahin , Zokaei Hossein , Khezrian Maryam , Seyfi Shahedeh , Keykhaei Mohammad , Gorgani Fatemeh , Rahimi Saral , Rezaei Negar , Khatibzadeh Shahab , Shahraz Saeid
Published: March 2023

Aims

To investigate the journey of patients with diabetes in the healthcare system using nationally-representative patient-reported data.

Methods

Participants were recruited using a machine-learning-based sampling method based on healthcare structures and medical outcome data and were followed up for three months. We assessed the resource utilization, direct/indirect costs, and quality of healthcare services.

Results

One hundred fifty-eight patients with diabetes participated. The most utilized services were medication purchases (276 times monthly) and outpatient visits (231 times monthly). During the previous year, 90% of respondents had a laboratory fasting blood glucose assessment; however, less than 70% reported a quarterly follow-up physician visit. Only 43% had been asked about any hypoglycemia episodes by their physician. Less than 45% of respondents had been trained for hypoglycemia self-management. The annual average health-related direct cost of a patient with diabetes was 769 USD. The average out-of-pocket share of direct costs was 601 USD (78.15%). Medication purchases, inpatient services, and outpatient services summed up 79.77% of direct costs with a mean of 613 USD.

Conclusion

Healthcare services focused solely on glycemic control and the continuity of services for diabetes control was insufficient. Medication purchases, and inpatient and outpatient services imposed the most out-of-pocket costs.
The association between maternal HbA1c and adverse outcomes in gestational diabetes
Authors: Muhuza Marie Parfaite Uwimana , Zhang Lixia , Wu Qi , Qi Lu , Chen Danqing , Liang Zhaoxia
Published: March 2023

Background

The role of HbA1c in women with gestational diabetes mellitus (GDM) is still unclear, particularly in the Asian population.

Aim

To investigate the association between HbA1c levels and adverse outcomes considering maternal age, pre-pregnancy body mass index (BMI), and gestational weight gain (GWG) in women with GDM.

Method

A retrospective study included 2048 women with GDM and singleton live births. Using logistic regression, the associations between HbA1c and adverse pregnancy outcomes were assessed.

Result

Compared to women with HbA1c ≤ 5.0%, HbA1c was significantly associated with macrosomia (aOR 2.63,95%CI1.61,4.31), pregnancy-induced hypertension (PIH, aOR 2.56,95%CI1.57,4.19), preterm birth (aOR 1.64,95%CI 1.05,2.55), and primary Cesarean section (primary C-section, aOR1.49,95%CI1.09,2.03) in GDM women with HbA1c ≥5.5% while significantly associated with PIH (aOR 1.91,95%CI1.24,2.94) in women with HbA1c 5.1-5.4%. The associations between HbA1c and adverse outcomes varied with maternal age, pre-pregnancy BMI, and GWG. In women aged ≤29 years, there’s significant association between HbA1c and primary C-section when HbA1c was 5.1-5.4% and ≥5.5%. In women aged 29-34 years and HbA1c ≥5.5%, HbA1c was significantly associated with macrosomia. In women aged ≥35 years, there’s significant association between HbA1c and preterm birth when HbA1c was 5.1-5.4% and macrosomia and PIH when HbA1c ≥5.5%. In pre-pregnant normal-weight women, HbA1c was significantly associated with macrosomia, preterm birth, primary C-section, and PIH when HbA1c ≥5.5% while HbA1c was significantly associated with PIH when HbA1c was 5.1-5.4% . In pre-pregnant underweight women with HbA1c 5.1-5.4%, HbA1c was significantly associated with primary C-section. HbA1c was significantly associated with macrosomia among women with inadequate GWG or excess GWG and HbA1c≥5.5%. In women with adequate GWG, there’s significant association between HbA1c and PIH when HbA1c was 5.1-5.4% and ≥5.5% .

Conclusion

Conclusively, HbA1c at the time of diagnosis is significantly associated with macrosomia, preterm birth, PIH, and primary C-section in Chinese women with GDM.
Clinicopathological features and prognosis of idiopathic membranous nephropathy with thyroid dysfunction
Authors: Wang Peiheng , Wang Shulei , Huang Bo , Liu Yiming , Liu Yingchun , Chen Huiming , Zhang Junjun
Published: March 2023

Background

Thyroid dysfunction is common in patients with kidney disease. However, the relationship between thyroid dysfunction and idiopathic membranous nephropathy (IMN) remains unclear. This retrospective study aimed to investigate the clinicopathological characteristics and prognosis of patients with IMN and thyroid dysfunction compared to patients with IMN and without thyroid dysfunction.

Methods

A total of 1052 patients with IMN diagnosed by renal biopsy were enrolled in this study, including 736 (70%) with normal thyroid function and 316 (30%) with abnormal thyroid function. We analyzed the clinicopathological features and prognostic data between the two groups, using propensity score matching (PSM) to reduce the bias. Logistic regression analysis was performed to investigate the risk factors for IMN combined with thyroid dysfunction. Kaplan-Meier curves and Cox regression analysis were used to evaluate the association between thyroid dysfunction and IMN.

Results

Patients with IMN and thyroid dysfunction exhibited more severe clinical features. Female sex, lower albumin level, higher D-dimer level, severe proteinuria, and decreased estimated glomerular filtration rate were predictors of thyroid dysfunction in patients with IMN. After PSM, 282 pairs were successfully matched. Results from the Kaplan-Meier curves indicated that the thyroid dysfunction group had a lower complete remission rate (P = 0.044), higher relapse rate (P < 0.001), and lower renal survival rate (P = 0.004). The multivariate Cox regression analysis revealed that thyroid dysfunction was an independent risk factor for complete remission [hazard ratio (HR) = 0.810, P = 0.045], relapse (HR = 1.721, P = 0.001), and composite endpoint event (HR = 2.113, P = 0.014) in IMN.

Conclusions

Thyroid dysfunction is relatively common in patients with IMN, and the clinical indicators are more severe in these patients. Thyroid dysfunction is an independent risk factor for poor prognosis in patients with IMN. More attention should be paid to thyroid function in patients with IMN.
EpiCRISPR targeted methylation of Arx gene initiates transient switch of mouse pancreatic alpha to insulin-producing cells
Authors: Đorđević Marija , Stepper Peter , Feuerstein-Akgoz Clarissa , Gerhauser Clarissa , Paunović Verica , Tolić Anja , Rajić Jovana , Dinić Svetlana , Uskoković Aleksandra , Grdović Nevena , Mihailović Mirjana , Jurkowska Renata Z. , Jurkowski Tomasz P. , Jovanović Jelena Arambašić , Vidaković Melita
Published: March 2023

Introduction

Beta cell dysfunction by loss of beta cell identity, dedifferentiation, and the presence of polyhormonal cells are main characteristics of diabetes. The straightforward strategy for curing diabetes implies reestablishment of pancreatic beta cell function by beta cell replacement therapy. Aristaless-related homeobox (Arx) gene encodes protein which plays an important role in the development of pancreatic alpha cells and is a main target for changing alpha cell identity.

Results

In this study we used CRISPR/dCas9-based epigenetic tools for targeted hypermethylation of Arx gene promoter and its subsequent suppression in mouse pancreatic αTC1-6 cell line. Bisulfite sequencing and methylation profiling revealed that the dCas9-Dnmt3a3L-KRAB single chain fusion constructs (EpiCRISPR) was the most efficient. Epigenetic silencing of Arx expression was accompanied by an increase in transcription of the insulin gene (Ins2) mRNA on 5th and 7th post-transfection day, quantified by both RT-qPCR and RNA-seq. Insulin production and secretion was determined by immunocytochemistry and ELISA assay, respectively. Eventually, we were able to induce switch of approximately 1% of transiently transfected cells which were able to produce 35% more insulin than Mock transfected alpha cells.

Conclusion

In conclusion, we successfully triggered a direct, transient switch of pancreatic alpha to insulin-producing cells opening a future research on promising therapeutic avenue for diabetes management.
Serum creatinine levels, traditional cardiovascular risk factors and 10-year cardiovascular risk in Chinese patients with hypertension
Authors: Chen Xin , Jin Hang , Wang Dan , Liu Jiali , Qin Yu , Zhang Yongqing , Zhang Yuqing , Xiang Quanyong
Published: March 2023

Background

Serum creatinine is associated with cardiovascular risk and cardiovascular events, however, the relationship between serum creatinine levels and cardiovascular risk is not well established in hypertensive population in Jiangsu Province. We aimed to evaluate the association of serum creatinine levels with traditional cardiovascular risk factors and 10-year cardiovascular risk in a Chinese hypertensive population.

Methods

Participants were patients with hypertension registered and enrolled in health service centers in 5 counties or districts from January 2019 to May 2020 in Jiangsu Province of China followed strict inclusion and exclusion criteria, demographics as well as clinical indicators and disease history and lifestyle were collected. Participants were divided into four groups according to quartiles of serum creatinine levels, then the China-PAR model was used to calculate 10-year cardiovascular risk for each individual.

Results

A total of 9978 participants were enrolled in this study, 4173(41.82%) were males. The blood pressure level and prevalence of dyslipidemia, elderly, current smokers and drinking as well as obesity were higher in the Q4 group than the Q1 group (all P < 0.05). Multivariable logistic regression showed that serum creatinine in the Q4 group compared with that in the Q1 group was positively associated with overweight and obesity (OR=1.432, 95% CI 1.237-1.658, P<0.001), while negatively associated with physical activity (OR=0.189, 95%CI 0.165-0.217, P<0.001), and so on. Multiple linear regression showed 10-year cardiovascular risk is positively associated with serum creatinine levels after adjusting for multiple risk factors (β=0.432, P< 0.001).

Conclusion

Serum creatinine was associated with several traditional cardiovascular risk factors and the 10-year cardiovascular risk in hypertensive patients. Creatinine-reduction and kidney-sparing therapy are essential for patients with hypertension to optimize control of cardiovascular risk.
Prognostic implication of heterogeneity and trajectory progression induced by enzalutamide in prostate cancer
Authors: Feng Yuanfa , Deng Yulin , Tang Zhenfeng , Cai Shanghua , Li Jinchuang , Liu Ren , Wan Jiaming , He Huichan , Zeng Guohua , Ye Jianheng , Han Zhaodong , Zhong Weide
Published: March 2023

Background

Enzalutamide, as a second-generation endocrine therapy drug for prostate cancer (PCa), is prominent representative among the synthetic androgen receptor antagonists. Currently, there is lack of enzalutamide-induced signature (ENZ-sig) for predicting progression and relapse-free survival (RFS) in PCa.

Methods

Enzalutamide-induced candidate markers were derived from single-cell RNA sequencing analysis integrating three enzalutamide-stimulated models (0-, 48-, and 168-h enzalutamide stimulation). ENZ-sig was constructed on the basis of candidate genes that were associated with RFS in The Cancer Genome Atlas leveraging least absolute shrinkage and selection operator method. The ENZ-sig was further validated in GSE70768, GSE94767, E-MTAB-6128, DFKZ, GSE21034, and GSE70769 datasets. Biological enrichment analysis was used to discover the underlying mechanism between high ENZ-sig and low ENZ-sig in single-cell RNA sequencing and bulk RNA sequencing.

Results

We identified a heterogenous subgroup that induced by enzalutamide stimulation and found 53 enzalutamide-induced candidate markers that are related to trajectory progression and enzalutamide-stimulated. The candidate genes were further narrowed down into 10 genes that are related to RFS in PCa. A 10-gene prognostic model (ENZ-sig)—IFRD1, COL5A2, TUBA1A, CFAP69, TMEM388, ACPP, MANEA, FOSB, SH3BGRL, and ST7—was constructed for the prediction of RFS in PCa. The effective and robust predictability of ENZ-sig was verified in six independent datasets. Biological enrichment analysis revealed that differentially expressed genes in high ENZ-sig were more activated in cell cycle–related pathway. High–ENZ-sig patients were more sensitive to cell cycle–targeted drugs (MK-1775, AZD7762, and MK-8776) than low–ENZ-sig patients in PCa.

Conclusions

Our results provided evidence and insight on the potential utility of ENZ-sig in PCa prognosis and combination therapy strategy of enzalutamide and cell cycle–targeted compounds in treating PCa.
Present and future distribution of Faidherbia albida in Cabo Verde as revealed by climatic modelling and LULC analysis
Authors: Varela Danilson , Romeiras Maria M. , Silva Luís
Published: March 2023

Climate change poses one of the most significant challenges to conserve biodiversity, especially in tropical dry islands, as is the case of Cabo Verde (northeast Atlantic Ocean). This archipelago has a low percentage of forest cover and hosts only seven native tree species, among them, Faidherbia albida (Delile) A.Chev. (Fabaceae). Therefore, protective afforestation is extremely important in Cabo Verde, one of the most vulnerable West African countries to climate change. With this work, we aimed to estimate the current distribution and potential shifts in suitable areas for F. albida under climate change, using species distribution models (i.e., random forest, generalized linear and additive models), covering its distribution range in Cabo Verde and mainland Africa. The best model was then projected for the studied area, at two different slice times, using Representative Concentration Pathway (RCP) 4.5 and 8.5 scenarios. Based on current bioclimatic variables, we estimated that almost two thirds of Cabo Verde’s territory is highly suitable for F. albida, which contrasts with its current occurrence. By overlaying the present habitat suitability with land use and land cover data, we concluded that habitat availability and suitability could be constrained by that factor. On average, the predicted suitable habitat for future distributions gradually decreases by 2080 under both scenarios compared with the current, with a smaller effect of RCP4.5 than of RCP8.5. Local authorities can benefit from this research and develop actions to promote sustainable reforestation in Cabo Verde, which should include native tree species that are best adapted to the local climate and could thus contribute to mitigate the effects of climate change.
Deleterious mutation load in the admixed mice population
Authors: Ramasamy Umayal , Elizur Abigail , Subramanian Sankar
Published: March 2023

Deleterious mutation loads are known to correlate negatively with effective population size (Ne). Due to this reason, previous studies observed a higher proportion of harmful mutations in small populations than that in large populations. However, the mutational load in an admixed population that derived from introgression between individuals from two populations with vastly different Ne is not known. We investigated this using the whole genome data from two subspecies of the mouse (Mus musculus castaneus and Mus musculus musculus) with significantly different Ne. We used the ratio of diversities at nonsynonymous and synonymous sites (dN/dS) to measure the harmful mutation load. Our results showed that this ratio observed for the admixed population was intermediate between those of the parental populations. The dN/dS ratio of the hybrid population was significantly higher than that of M. m. castaneus but lower than that of M. m. musculus. Our analysis revealed a significant positive correlation between the proportion of M. m. musculus ancestry in admixed individuals and their dN/dS ratio. This suggests that the admixed individuals with high proportions of M. m. musculus ancestry have large dN/dS ratios. We also used the proportion of deleterious nonsynonymous SNVs as a proxy for deleterious mutation load, which also produced similar results. The observed results were in concordance with those expected by theory. We also show a shift in the distribution of fitness effects of nonsynonymous SNVs in the admixed genomes compared to the parental populations. These findings suggest that the deleterious mutation load of the admixed population is determined by the proportion of the ancestries of the subspecies. Therefore, it is important to consider the status and the level of genetic admixture of the populations whilst estimating the mutation loads.
The effect of systemic iron status on osteoarthritis: A mendelian randomization study
Authors: Ruan Guangfeng , Ying Yi , Lu Shilong , Zhu Zhaohua , Chen Shibo , Zeng Muhui , Lu Ming , Xue Song , Zhu Jianwei , Cao Peihua , Chen Tianyu , Wang Xiaoshuai , Li Shengfa , Li Jia , Liu Yu , Liu Yanqi , Zhang Yan , Ding Changhai
Published: March 2023

Objective: To assess the causal effect of systemic iron status by using four biomarkers (serum iron; transferrin saturation; ferritin; total iron-binding capacity) on knee osteoarthritis (OA), hip OA, total knee replacement, and total hip replacement using 2-sample Mendelian randomization (MR) design.

Methods: Three instrument sets were used to construct the genetic instruments for the iron status: Liberal instruments (variants associated with one of the iron biomarkers), sensitivity instruments (liberal instruments exclude variants associated with potential confounders), and conservative instruments (variants associated with all four iron biomarkers). Summary-level data for four OA phenotypes, including knee OA, hip OA, total knee replacement, and total hip replacement were obtained from the largest genome-wide meta-analysis with 826,690 individuals. Inverse-variance weighted based on the random-effect model as the main approach was conducted. Weighted median, MR-Egger, and Mendelian randomization pleiotropy residual sum and outlier methods were used as sensitivity MR approaches.

Results: Based on liberal instruments, genetically predicted serum iron and transferrin saturation were significantly associated with hip OA and total hip replacement, but not with knee OA and total knee replacement. Statistical evidence of heterogeneity across the MR estimates indicated that mutation rs1800562 was the SNP significantly associated with hip OA in serum iron (odds ratio, OR = 1.48), transferrin saturation (OR = 1.57), ferritin (OR = 2.24), and total-iron binding capacity (OR = 0.79), and hip replacement in serum iron (OR = 1.45), transferrin saturation (OR = 1.25), ferritin (OR = 1.37), and total-iron binding capacity (OR = 0.80).

Conclusion: Our study suggests that high iron status might be a causal factor of hip OA and total hip replacement where rs1800562 is the main contributor.
Identification of new co-diagnostic genes for sepsis and metabolic syndrome using single-cell data analysis and machine learning algorithms
Authors: Tao Linfeng , Zhu Yue , Liu Jun
Published: March 2023

Sepsis, a serious inflammatory response that can be fatal, has a poorly understood pathophysiology. The Metabolic syndrome (MetS), however, is associated with many cardiometabolic risk factors, many of which are highly prevalent in adults. It has been suggested that Sepsis may be associated with MetS in several studies. Therefore, this study investigated diagnostic genes and metabolic pathways associated with both diseases. In addition to microarray data for Sepsis, PBMC single cell RNA sequencing data for Sepsis and microarray data for MetS were downloaded from the GEO database. Limma differential analysis identified 122 upregulated genes and 90 downregulated genes in Sepsis and MetS. WGCNA identified brown co-expression modules as Sepsis and MetS core modules. Two machine learning algorithms, RF and LASSO, were used to screen seven candidate genes, namely, STOM, BATF, CASP4, MAP3K14, MT1F, CFLAR and UROD, all with an AUC greater than 0.9. XGBoost assessed the co-diagnostic efficacy of Hub genes in Sepsis and MetS. The immune infiltration results show that Hub genes were expressed at high levels in all immune cells. After performing Seurat analysis on PBMC from normal and Sepsis patients, six immune subpopulations were identified. The metabolic pathways of each cell were scored and visualized using ssGSEA, and the results show that CFLAR plays an important role in the glycolytic pathway. Our study identified seven Hub genes that serve as co-diagnostic markers for Sepsis and MetS and revealed that diagnostic genes play an important role in immune cell metabolic pathway.
Case report and discussion: Pre-implantation genetic diagnosis with surrogacy in vascular Ehlers–Danlos syndrome
Authors: Angwin Chloe , Ghali Neeti , Stephanie van Dijk Fleur
Published: March 2023

Introduction: Vascular Ehlers–Danlos syndrome (vEDS) is an autosomal dominant inherited connective tissue condition, characterized by generalized tissue fragility with an increased risk of arterial dissection and hollow organ rupture. In women with vEDS, pregnancy and childbirth carry significant risks of both morbidity and mortality. The Human Fertilisation and Embryology Authority has approved vEDS for pre-implantation genetic diagnosis (PGD), given the potential for life-limiting complications. PGD avoids implantation of embryos that are affected by specific disorders by carrying out genetic testing (either for a familial variant or whole gene) and selecting unaffected embryos prior to implantation.

Case: We present an essential clinical update to the only published clinical case of a woman with vEDS undergoing PGD with surrogacy, initially through stimulated in vitro fertilization (IVF) and in vitro maturation (IVM) and subsequently through natural IVF.

Discussion: In our experience, a subset of women with vEDS do wish to have biological, unaffected children through PGD despite being aware of the risks of pregnancy and delivery. Given the clinical heterogeneity in vEDS, these women could be considered on a case-by-case basis for PGD. Controlled studies with comprehensive patient monitoring evaluating the safety of PGD are essential to equitable healthcare provision.
Proof of concept for management of shoot blight and fire blight cankers on pear with preventive spray applications of giant knotweed extract
Authors: Borba Matheus C. , Meredith Christopher L. , Dhar Bidhan C. , Aćimović Srđan G.
Published: March 2023

With the goal to develop management tools to mitigate the severity of shoot blight on pear caused by Erwinia amylovora and prevent fire blight canker development from infected shoots on pear tree wood, we evaluated five preventive treatments in inoculated experiments over 2-years. We focused on foliar spray and trunk injection applications of extract of giant knotweed, Reynoutria sachalinensis (RSE), as a plant resistance activator candidate and on comparisons to antibiotics. Five foliar applications of RSE (2.24 L/ha) on 6-year-old trees of cultivar ‘Bartlett’ resulted in 100% control of shoot blight severity and canker incidence in both years of evaluation. The RSE trunk injection in fall of the first year did not control the disease allowing 75% of shoot severity and 38.5% of canker incidence. The opposite happened in the second year, when we injected RSE in spring, providing 85.7% control of shoot blight severity and 89.8% control of canker incidence. Antibiotics oxytetracycline (OTC) and streptomycin (STM) did not provide consistent control in the second year in comparison to the first year. In the first year, both antibiotics, OTC (trunk injection and foliar spray) and STM were effective, providing 94.8%, 100% and 86.3% control of shoot blight, respectively. They also provided 100, 91 and 84% control of canker incidence, respectively. However, in the second they were not effective allowing 69 – 96% of shoot blight severity and 70 – 92% of canker incidence. Regardless of the inconsistency in the effectiveness of antibiotics, which are not recommended for shoot blight control due to risks of promoting antibiotic resistance, five preventive spray applications of RSE could be used on pear trees to prevent shoot blight and canker development. Thus, the RSE spray program we developed could serve as a valuable control tool that could help prevent sudden outbreaks of shoot blight during summer and pear tree death from fire blight cankers with no risk for pathogen resistance.
Glacier tourism without ice: Envisioning future adaptations in a melting world
Authors: Salim Emmanuel
Published: March 2023

Climate change is causing profound changes in high mountain environments, including the rapid retreat of glaciers. The retreat and potential disappearance of Alpine glaciers during the twenty-first century raises questions about the future of glacier tourism sites. This perspective article reflects on these changes with a desk-based approach to suggest three possible ways glacier tourism can adapt to anticipated glacier loss. These three strategies include further developing geotourism, transforming last-chance tourism into “dark tourism,” and using virtual reality to “virtually” reconstruct disappearing glaciers. This paper draws on three cases to discuss the potential of these strategies. The first is the Aletsch Glacier, the largest in the Alps, which is listed as a UNESCO World Heritage Site. It has also been the subject of recent work on geotourism. The second case is Mer de Glace, the largest glacier at the Montenvers site in France. This glacier has been studied in the context of last-chance tourism. The final case is the Mortaretsch Glacier in Switzerland, which can be reached from Diavolezza and has not been the subject of many studies. However, this site is one of the first to incorporate virtual reality technology into the tourist experience of the glacier.
Diagnostic and vaccine potential of Zika virus envelope protein (E) derivates produced in bacterial and insect cells
Authors: Lunardelli Victória Alves Santos , Almeida Bianca da Silva , Apostolico Juliana de Souza , Rezende Thais , Yamamoto Marcio Massao , Pereira Samuel Santos , Bueno Maria Fernanda Campagnari , Pereira Lennon Ramos , Carvalho Karina Inacio , Slhessarenko Renata Dezengrini , de Souza Ferreira Luis Carlos , Boscardin Silvia Beatriz , Rosa Daniela Santoro
Published: March 2023

Introduction

In the present study we evaluated the features of different recombinant forms of Zika virus (ZIKV) proteins produced in either bacterial (Eschericha coli) or insect cells (Drosophila melanogaster). The ZIKV-envelope glycoprotein (EZIKV) is responsible for virus entry into host cells, is the main target of neutralizing antibodies and has been used as a target antigen either for serological tests or for the development of subunit vaccines. The EZIKV is composed of three structural and functional domains (EDI, EDII, and EDIII), which share extensive sequence conservation with the corresponding counterparts expressed by other flaviviruses, particularly the different dengue virus (DENV) subtypes.

Methods

In this study, we carried out a systematic comparison of the antigenicity and immunogenicity of recombinant EZIKV, EDI/IIZIKV and EDIIIZIKV produced in E. coli BL21 and Drosophila S2 cells. For the antigenicity analysis we collected 88 serum samples from ZIKV-infected participants and 57 serum samples from DENV-infected. For immunogenicity, C57BL/6 mice were immunized with two doses of EZIKV, EDI/IIZIKV and EDIIIZIKV produced in E. coli BL21 and Drosophila S2 cells to evaluate humoral and cellular immune response. In addition, AG129 mice were immunized with EZIKV and then challenge with ZIKV.

Results

Testing of samples collected from ZIKV-infected and DENV-infected participants demonstrated that the EZIKV and EDIIIZIKV produced in BL21 cells presented better sensitivity and specificity compared to proteins produced in S2 cells. In vivo analyses were carried out with C57BL/6 mice and the results indicated that, despite similar immunogenicity, antigens produced in S2 cells, particularly EZIKV and EDIIIZIKV, induced higher ZIKV-neutralizing antibody levels in vaccinated mice. In addition, immunization with EZIKV expressed in S2 cells delayed the onset of symptoms and increased survival rates in immunocompromised mice. All recombinant antigens, either produced in bacteria or insect cells, induced antigen-specific CD4+ and CD8+ T cell responses.

Conclusion

In conclusion, the present study highlights the differences in antigenicity and immunogenicity of recombinant ZIKV antigens produced in two heterologous protein expression systems.
Cannabinoid WIN55,212-2 reprograms monocytes and macrophages to inhibit LPS-induced inflammation
Authors: Pérez-Diego Mario , Angelina Alba , Martín-Cruz Leticia , de la Rocha-Muñoz Andrés , Maldonado Angel , Sevilla-Ortega Carmen , Palomares Oscar
Published: March 2023

Introduction

Chronic or uncontrolled activation of myeloid cells including monocytes, macrophages and dendritic cells (DCs) is a hallmark of immune-mediated inflammatory disorders. There is an urgent need for the development of novel drugs with the capacity to impair innate immune cell overactivation under inflammatory conditions. Compelling evidence pointed out cannabinoids as potential therapeutic tools with anti-inflammatory and immunomodulatory capacity. WIN55,212-2, a non-selective synthetic cannabinoid agonist, displays protective effects in several inflammatory conditions by mechanisms partially depending on the generation of tolerogenic DCs able to induce functional regulatory T cells (Tregs). However, its immunomodulatory capacity on other myeloid cells such as monocytes and macrophages remains incompletely understood.

Methods

Human monocyte-derived DCs (hmoDCs) were differentiated in the absence (conventional hmoDCs) or presence of WIN55,212-2 (WIN-hmoDCs). Cells were stimulated with LPS, cocultured with naive T lymphocytes and their cytokine production and ability to induce T cell responses were analysed by ELISA or flow cytometry. To evaluate the effect of WIN55,212-2 in macrophage polarization, human and murine macrophages were activated with LPS or LPS/IFNγ, in the presence or absence of the cannabinoid. Cytokine, costimulatory molecules and inflammasome markers were assayed. Metabolic and chromatin immunoprecipitation assays were also performed. Finally, the protective capacity of WIN55,212-2 was studied in vivo in BALB/c mice after intraperitoneal injection with LPS.

Results

We show for the first time that the differentiation of hmoDCs in the presence of WIN55,212-2 generates tolerogenic WIN-hmoDCs that are less responsive to LPS stimulation and able to prime Tregs. WIN55,212-2 also impairs the pro-inflammatory polarization of human macrophages by inhibiting cytokine production, inflammasome activation and rescuing macrophages from pyroptotic cell death. Mechanistically, WIN55,212-2 induced a metabolic and epigenetic shift in macrophages by decreasing LPS-induced mTORC1 signaling, commitment to glycolysis and active histone marks in pro-inflammatory cytokine promoters. We confirmed these data in ex vivo LPS-stimulated peritoneal macrophages (PMΦs), which were also supported by the in vivo anti-inflammatory capacity of WIN55,212-2 in a LPS-induced sepsis mouse model.

Conclusion

Overall, we shed light into the molecular mechanisms by which cannabinoids exert anti-inflammatory properties in myeloid cells, which might well contribute to the future rational design of novel therapeutic strategies for inflammatory disorders.
TR score: A noninvasive model to predict histological stages in patients with primary biliary cholangitis
Authors: Tu Zhixin , Wang Yao , Wang Yan , Huang Jianjie , Han Yujin , Ji Qijia , Cao Xiaoxuan , Wen Xiaoyu , Wang Yang , Jin Qinglong
Published: March 2023

Introduction

The aim of this study was to develop a noninvasive prediction model for histological stages in PBC that is simple, easy to implement, and highly accurate.

Methods

A total of 114 patients with PBC were included in this study. Demographic, laboratory data and histological assessments were collected. The independent predictors of histological stages were selected to establish a noninvasive serological model. The scores of 22 noninvasive models were calculated and compared with the established model.

Results

This study included 99 females (86.8%) and 15 males (13.2%). The number of patients in Scheuer’s stage 1, 2, 3 and 4 was 33 (29.0%), 34 (29.8%), 16 (14.0%), and 31 (27.2%), respectively. TBA and RDW are independent predictors of PBC histological stages. The above indexes were used to establish a noninvasive model-TR score. When predicting early histological change (S1) or liver fibrosis and cirrhosis (S3-S4), the AUROC of TR score were 0.887 (95% CI, 0.809-0.965) and 0.893 (95% CI, 0.816-0.969), higher than all of the other 22 models included in this study. When predicting cirrhosis (S4), its AUROC is still as high as 0.921 (95% CI, 0.837-1.000).

Conclusion

TR score is an easy, cheap and stable noninvasive model, without complex calculation formulas and tools, and shows good accuracy in diagnosing the histological stages of PBC.
Integrative analysis revealed that distinct cuprotosis patterns reshaped tumor microenvironment and responses to immunotherapy of colorectal cancer
Authors: Xu Ximo , Ding Chengsheng , Zhong Hao , Qin Wei , Shu Duohuo , Yu Mengqin , Abuduaini Naijipu , Zhang Sen , Yang Xiao , Feng Bo
Published: March 2023

Background

Cuprotosis is a novel form of programmed cell death that involves direct targeting of key enzymes in the tricarboxylic acid (TCA) cycle by excess copper and may result in mitochondrial metabolic dysfunction. However, whether cuprotosis may mediate the tumor microenvironment (TME) and immune regulation in colorectal cancer (CRC) remains unclear.

Methods

Ten cuprotosis-related genes were selected and unsupervised consensus clustering was performed to identify the cuprotosis patterns and the correlated TME characteristics. Using principal component analysis, a COPsig score was established to quantify cuprotosis patterns in individual patients. The top 9 most important cuprotosis signature genes were analyzed using single-cell transcriptome data.

Results

Three distinct cuprotosis patterns were identified. The TME cell infiltration characteristics of three patterns were associated with immune-excluded, immune-desert, and immune-inflamed phenotype, respectively. Based on individual cuprotosis patterns, patients were assigned into high and low COPsig score groups. Patients with a higher COPsig score were characterized by longer overall survival time, lower immune cell as well as stromal infiltration, and greater tumor mutational burden. Moreover, further analysis demonstrated that CRC patients with a higher COPsig score were more likely to respond to immune checkpoint inhibitors and 5-fluorouracil chemotherapy. Single-cell transcriptome analysis indicated that cuprotosis signature genes recruited tumor-associated macrophages to TME through the regulation of TCA and the metabolism of glutamine and fatty acid, thus influencing the prognosis of CRC patients.

Conclusion

This study indicated that distinct cuprotosis patterns laid a solid foundation to the explanation of heterogeneity and complexity of individual TME, thus guiding more effective immunotherapy as well as adjuvant chemotherapy strategies.