bluuebunny/crossref_metadata_2025 huggingface dataset:
Research advancements for impact chain based climate risk and vulnerability assessments
Authors: Petutschnig Linda , Rome Erich , Lückerath Daniel , Milde Katharina , Gerger Swartling Åsa , Aall Carlo , Meyer Mark , Jordá Gabriel , Gobert Julie , Englund Mathilda , André Karin , Bour Muriel , Attoh Emmanuel M. N. A. N. , Dale Brigt , Renner Kathrin , Cauchy Adeline , Reuschel Saskia , Rudolf Florence , Agulles Miguel , Melo-Aguilar Camilo , Zebisch Marc , Kienberger Stefan
Published: May 2023

As the climate crisis continues to worsen, there is an increasing demand for scientific evidence from Climate Risk and Vulnerability Assessments (CRVA). We present 12 methodological advancements to the Impact Chain-based CRVA (IC-based CRVA) framework, which combines participatory and data-driven approaches to identify and measure climate risks in complex socio-ecological systems. The advancements improve the framework along five axes, including the existing workflow, stakeholder engagement, uncertainty management, socio-economic scenario modeling, and transboundary climate risk examination. Eleven case studies were conducted and evaluated to produce these advancements. Our paper addresses two key research questions: (a) How can the IC-based CRVA framework be methodologically advanced to produce more accurate and insightful results? and (b) How effectively can the framework be applied in research and policy domains that it was not initially designed for? We propose methodological advancements to capture dynamics between risk factors, to resolve contradictory worldviews, and to maintain consistency between Impact Chains across policy scales. We suggest using scenario-planning techniques and integrating uncertainties via Probability Density Functions and Reverse Geometric Aggregation. Our research examines the applicability of IC-based CRVAs to address transboundary climate risks and integrating macro-economic models to reflect possible future socio-economic exposure. Our findings demonstrate that the modular structure of IC-based CRVA allows for the integration of various methodological advancements, and further advancements are possible to better assess complex climate risks and improve adaptation decision-making.
Recovery and genotyping ancient Sicilian monumental olive trees
Authors: Marchese A. , Bonanno F. , Marra F. P. , Trippa D. A. , Zelasco S. , Rizzo S. , Giovino A. , Imperiale V. , Ioppolo A. , Sala G. , Granata I. , Caruso T.
Published: May 2023

The long-lived and evergreen olive tree dominates the Mediterranean landscape, representing an agroecological and cultural symbol and a genetic heritage of inestimable value. Sicily, for historical, geographical, and cultural reasons, has a very rich and distinctive olive germplasm. In this work, a large survey was conducted to discover, collect, and characterize the genetic diversity of centennial monumental olive trees from historical sites, such as the Greek Temple Valley (Agrigento), ancient gardens, or farmland present in the western part of the island. Trees were chosen based on their height, trunk, stump size, and presumed age; particularly, only olive trees with an age estimated at more than 400 years old were taken into consideration. For the morphological characterization, the leaf, fruit, and endocarp traits were analyzed. For the molecular characterization, 11 polymorphic microsatellite markers largely used for fingerprinting analysis were used. Reference cultivars were included in the analysis for comparison. Nuclear DNA was extracted from different parts of the plant (young leaves of shoots taken from the canopy and young leaves taken from suckers, which arose from the basal part of the tree) to check if the trees were grafted and to explore their diversity. Most of the monumental trees have been grafted at least one time during their long life, and some genotypes showed unique genetic profiles combined with peculiar phenotypic traits. Suckers (rootstock of the trees) showed a strict genetic relationship with an ancient monumental oleaster tree, also included in the study. “Patriarch” (original mother plants) trees of local cultivars were also identified. This research revealed a high level of the still unexplored genetic diversity of the Sicilian olive germplasm and highlighted its importance as a gene reservoir, which could support new breeding programs for the evaluation and possible selection of traits linked to putative resilience to abiotic and biotic stresses (particularly Xylella fastidiosa subsp. pauca ST53 or soil- borne diseases or insects). The results will be useful for improving the conservation process, enriching existing collections of olive genetic resources, and supporting on-farm conservation projects.
The prognostic value of deep earlobe creases in patients with acute ischemic stroke
Authors: Xu Jiaping , Wang Lixuan , Zhang Chunqing , Wang Jiayun , Zheng Danni , Huang Yaqian , Zhang Xia , You Shoujiang , Cao Yongjun , Liu Chun-Feng
Published: May 2023

Background and purpose

Data on earlobe crease (ELC) among patients with acute ischemic stroke (AIS) are limited. Here, we determined the frequency and characteristics of ELC and the prognostic effect of ELC among AIS patients.

Methods

A total of 936 patients with acute AIS were enrolled during the period between December 2018 and December 2019. The patients were divided into those without and with ELC, unilateral and bilateral ELC, and shallow and deep ELC, according to the photographs taken of the bilateral ears. Logistic regression models were used to estimate the effect of ELC, bilateral ELC, and deep ELC on poor functional outcomes at 90 days (a modified Rankin Scale score ≥2) in AIS patients.

Results

Among the 936 AIS patients, there were 746 (79.7%) patients with ELC. Among patients with ELC, there were 156 (20.9%) patients with unilateral ELC and 590 (79.1%) with bilateral ELC and 476 (63.8%) patients with shallow ELC and 270 (36.2%) with deep ELC. After adjusting for age, sex, baseline NIHSS score, and other potential covariates, patients with deep ELC were associated with a 1.87-fold [odds ratio (OR) 1.87; 95% confidence interval (CI), 1.13–3.09] and 1.63-fold (OR 1.63; 95%CI, 1.14–2.34) increase in the risk of poor functional outcome at 90 days in comparison with those without ELC or shallow ELC.

Conclusion

ELC was a common phenomenon, and eight out of ten AIS patients had ELC. Most patients had bilateral ELC, and more than one-third had deep ELC. Deep ELC was independently associated with an increased risk of poor functional outcome at 90 days.
Rapid environmental changes in the Lake Qinghai basin during the late Holocene
Authors: Wang Chen , Qiu Yahui , Fan Fenglei , Li Baosheng , Niu Dongfeng , Shu Peixian
Published: May 2023

The Lake Qinghai Basin is sensitive to global and regional climate change because of its unique geographical location. It is the hotspot for paleoclimate research in East Asia. In this study, we reconstructed the environmental evolution of the Lake Qinghai since ∼9 ka by using a high-resolution peat and fluvial-lacustrine record (Laoyinggou profile) obtained at the foot of Nanshan Mountain. Based on 8 AMS14C dates and lithology, loss on ignition (LOI), total organic matter (TOC), X-ray fluorescence (XRF) core-scanning measurements, ratio of total organic carbon to nitrogen (TOC/TN), and sediment particle sorting coefficients, we show that during the Middle Holocene (∼9–4.4 ka BP) this region was primarily dominated by the Asian summer monsoon, with a consistent, warm, and humid environment. By contrast, during the late Holocene (4.4 ka to present), the climatic context in this area fluctuated dramatically at the millennial scales. The low TOC content, lower TOC/TN ration and strong hydroclimatic indicate six rapid climate change events, which occurred at ∼4.0 ka, ∼3.6 ka, ∼3.2 ka, ∼2.8 ka, ∼2.1 ka, and ∼1.4 ka, all of which coincided to cold episodes in the North Atlantic Ocean.
Strain fields of Ms >6.0 earthquakes in Menyuan, Qinghai, China
Authors: Luo Guofu , Ding Fenghe , Xu Yingcai , Luo Hengzhi , Li Wenjun
Published: May 2023

In predicting earthquakes, it is a major challenge to capture the time factor and spatial isoline anomalies, and understand their physical processes, of the seismic strain field before a strong earthquake. In this study, the seismic strain field was used as representative of seismic activity. The natural orthogonal function expansion method was used to calculate the seismic strain field before the Menyuan Ms 6.4 earthquakes in 1986 and 2016, and the Ms 6.9 earthquake in 2022. Time factor and spatial isoline anomaly of the strain field before each earthquake was extracted. We also compared the evolution of the strain field with numerical simulation results under the tectonic stress system at the source. The results showed that the time factor before the earthquakes had high or low value anomalies, exceeding the mean square error of the stable background. The anomalies were concentrated in the first four typical fields of the strain field, which has multiple components. The abnormal contribution rate of the first typical field is the largest (accounting for 42%–49% of the total field). The long- and medium-term anomalies appear 3-4, and 1-2 years before the earthquake, respectively. There were no short or immediate-term anomalies within 3 months of the earthquake. In addition, during the evolution of the strain field, the abnormal area of the spatial isoline changed with the change in time. Usually, the intersection area of the two isoseismic lines of strain accumulation and strain release becomes a potential location for strong earthquakes. Finally, we found that the high strain field values of the 1986 and 2016 Ms 6.4 earthquakes were equivalent to the numerical simulation results, while the high strain field values of the 2022 Menyuan Ms 6.9 earthquakes were slightly different, but within the accepted error range. These results indicate that the two methods are consistent. We have shown that the natural orgthagonal method can be used to obtain the spatiotemporal anomaly information of strain field preceding strong earthquakes.
Study on the improvement of the open TBM system and supporting equipment based on the Gaojiapu Coal Mine
Authors: Liu Yexian , Ren Dengjun , Zhou Changkuan , Qiu Huafu , Ding Ziwei , Liang Chao
Published: May 2023

In order to cope with multi-dimensional mine disasters in deep mines, enhance the adaptability of the open tunnel-boring machine (TBM) to the actual mine working face environment, and improve the excavation speed of the open TBM, based on the excavation project of Gaojiapu Coal Mine in Zhengtong Coal Industry, Shaanxi Province, this paper comprehensively considers the difficulties encountered by the TBM in the excavation process and improves the open TBM system and its supporting equipment. The research shows that removing the redundant system and supporting equipment of the open TBM can effectively solve the difficulties of the TBM entering the mine, such as loading and unloading, and turning; optimizing the open TBM shield, shortening the main beam, and setting the support platform and jumbolter system on the main beam can deal with the problem that the TBM support is not timely and easy to jam. Opening circular holes and installing slag cleaning guide plates on the main beam of the open TBM can timely clean up the waste slag on the main beam and protect the main beam from deformation. Installing a slag cleaning bucket wheel machine between the main beam of the open TBM and the trailer can reduce the accumulation of waste slag on the road ahead. Compared with ordinary excavation construction technology, the monthly average footage level of the open TBM after technical improvement is 300.88 m, which is 3.8 times that of the rock roadway general excavation and 1.6 times that of the rock roadway comprehensive excavation.
The impact of effective study strategy use in an introductory anatomy and physiology class
Authors: Firetto Carla M. , Starrett Emily , Montalbano Amy Collins , Yan Lin , Penkrot Tonya A. , Kingsbury Jeffrey S. , Hyatt Jon-Philippe K.
Published: May 2023

Introductory courses in biology often act as a gateway for students seeking careers in healthcare and science-related fields. As such, they provide a prime entry point for innovations seeking to enhance students’ learning of foundational content. Extant innovations and interventions have been found to positively impact students’ study strategy use with concomitant impacts on course exams and grades. These innovations, however, often have associated time and other costs, which may ultimately limit more widespread use. Our study builds on prior findings by exploring the extent to which students evidence increased use of effective study strategies after engaging in a brief (i.e., 15-min), online module requiring no financial cost for students or time commitment from instructors, and whether changes in students’ use of effective study strategies are associated with changes in exam performance. The present study employed a brief, online module designed to support undergraduate students’ (n = 98) use of effective study strategies in an introductory human anatomy and physiology course. Through a pretest-posttest design, students described the strategies they used to study and completed four cognitive and metacognitive subscales before and after engaging in a brief, online module designed to teach them about effective study strategies. Results were somewhat mixed: students evidenced a modest, statistically significant increase in the number of strategies used and changes in strategy use were associated with changes in exam score only for some measures. Notably, this relationship was not moderated by GPA, suggesting that the strength of the relationship between changes in strategy use and changes in exam scores were not different depending on students’ levels of prior academic performance. Taken together, the innovation was associated with increases in students’ exam scores, irrespective of GPA, but future research should explore the refinement and extension of the innovation to explore ways that increase efficacy and impact while still balancing sustainable implementation to account for challenges associated with instructor supervision and training, financial costs, and students’ time.
Identifying and analyzing the key genes shared by papillary thyroid carcinoma and Hashimoto’s thyroiditis using bioinformatics methods
Authors: Liu Ting-ting , Yin De-tao , Wang Nan , Li Na , Dong Gang , Peng Meng-fan
Published: May 2023

Background

Hashimoto’s thyroiditis (HT) is a chronic autoimmune disease that poses a risk factor for papillary thyroid carcinoma (PTC). The present study aimed to identify the key genes shared by HT and PTC for advancing the current understanding of their shared pathogenesis and molecular mechanisms.

Methods

HT- and PTC-related datasets (GSE138198 and GSE33630, respectively) were retrieved from the Gene Expression Omnibus (GEO) database. Genes significantly related to the PTC phenotype were identified using weighted gene co-expression network analysis (WGCNA). Differentially expressed genes (DEGs) were identified between PTC and healthy samples from GSE33630, and between HT and normal samples from GSE138198. Subsequently, functional enrichment analysis was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). Transcription factors and miRNAs regulating the common genes in PTC and HT were forecasted using the Harmonizome and miRWalk databases, respectively, and drugs targeting these genes were investigated using the Drug-Gene Interaction Database (DGIdb). The key genes in both GSE138198 and GSE33630 were further identified via Receiver Operating Characteristic (ROC) analysis. The expression of key genes was verified in external validation set and clinical samples using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC).

Results

In total, 690 and 1945 DEGs were associated with PTC and HT, respectively; of these, 56 were shared and exhibited excellent predictive accuracy in the GSE138198 and GSE33630 cohorts. Notably, four genes, Alcohol Dehydrogenase 1B (ADH1B), Active BCR-related (ABR), alpha-1 antitrypsin (SERPINA1), and lysophosphatidic acid receptor 5 (LPAR5) were recognized as key genes shared by HT and PTC. Subsequently, EGR1 was identified as a common transcription factor regulating ABR, SERPINA1, and LPAR5 expression. These findings were confirmed using qRT-PCR and immunohistochemical analysis.

Conclusion

Four (ADH1B, ABR, SERPINA1, and LPAR5) out of 56 common genes exhibited diagnostic potential in HT and PTC. Notably, this study, for the first time, defined the close relationship between ABR and HT/PTC progression. Overall, this study provides a basis for understanding the shared pathogenesis and underlying molecular mechanisms of HT and PTC, which might help improve patient diagnosis and prognosis.
Preservation of parathyroid glands during thyroid and neck surgery
Authors: Rao Smitha S. , Rao Himagirish , Moinuddin Zia , Rozario Anthony P. , Augustine Titus
Published: May 2023

The parathyroid glands are situated in close proximity to the thyroid gland. They have an important endocrine function maintaining calcium and phosphate homeostasis in the body by the secretion of parathormone (PTH), which is responsible for this function. The parathyroid glands are commonly damaged during thyroid surgeries. This could lead to transient or permanent hypoparathyroidism in 30% of cases. Preservation of the parathyroid glands, is an important and integral part of thyroidectomy and other surgical interventions in the neck. The main principle underlying this is a thorough understanding of parathyroid anatomy in relation to the thyroid gland and other important structures in the area. There can also be significant variation in the anatomical location of the glands. Various techniques and methods have been described for parathyroid preservation. They include intraoperative identification utilizing indocyanine green (ICG) fluorescence, carbon nanoparticles, loupes, and microscopes. The techniques of surgery (meticulous capsular dissection), expertise, central compartment neck dissection, preoperative vitamin D deficiency, extent and type of thyroidectomy are the risk factors associated with damaged thyroids, inadvertent parathyroidectomy and subsequent hypoparathyroidism. Parathyroid Autotransplantation is a treatment option for inadvertent parathyroidectomy. Ultimately, the best way to assure normal parathyroid function is to preserve them in situ intraoperatively undamaged.
Postoperative hypoparathyroidism after thyroid operation and exploration of permanent hypoparathyroidism evaluation
Authors: Wang Xi , Wang Shun-lan , Cao Yang , Li Chun-qiao , He Weiping , Guo Zhu-ming
Published: May 2023

Background

To investigate the risk factors for hypoparathyroidism, discuss the prevention of postoperative hypoparathyroidism, and explore permanent postoperative hypoparathyroidism evaluation (PPHE).

Methods

A total of 2,903 patients with thyroid nodules were treated between October 2012 and August 2015. Serum calcium and intact parathyroid hormone (iPTH) levels were measured at 1 day, 1 month, and 6 months postoperatively. The incidence and management of hypoparathyroidism were analyzed. The PPHE was established based on the risk factors and clinical practice.

Results

A total of 637 (21.94%) patients developed hypoparathyroidism, and 92.15% of them had malignant nodules. The incidence rates of transient and permanent hypoparathyroidism were 11.47% and 10.47%, respectively. The iPTH level was lower in patients with malignant nodules who underwent total thyroidectomy (TT) and central-compartment neck dissection (CND). These factors were independently associated with the recovery rate of parathyroid function. The formula for PPHE is as follows: {iPTH} + {sCa} + {surgical procedure} + {reoperation} + {pathologic type}. A scoring system was developed, and we scored low, middle, and high risk of permanent postoperative hypoparathyroidism as 4–6, 7–9, and 10–13, respectively. The differences in the recovery rates of parathyroid function in several risk groups were statistically significant (p < 0.001).

Conclusion

Simultaneous TT and CND is a risk factor for hypoparathyroidism. The reoperation is not associated with hypoparathyroidism. Identification of parathyroid glands in situ and preservation of their vascular pedicles are key factors in managing hypoparathyroidism. PPHE can forecast the risk of permanent postoperative hypoparathyroidism well.
Metabolic syndrome as risk factor for left ventricular hypertrophy in children with chronic kidney disease
Authors: Drożdż Monika , Moczulska Anna , Rudziński Andrzej , Drożdż Dorota
Published: May 2023

Background

The metabolic syndrome (MS), a cluster of clinical and biochemical abnormalities including insulin resistance, dyslipidemia and hypertension, is often diagnosed in chronic kidney disease (CKD) children. Left ventricular hypertrophy (LVH) is a major target organ damage in hypertension and an important cardiovascular risk factor in CKD patients. We aimed to identify the most significant risk factors of LVH in children with CKD.

Methods

Children with CKD stage 1-5 were enrolled in the study. MS was diagnosed according to De Ferranti (DF) as ≥3 from 5 criteria. Ambulatory blood pressure measurements (ABPM) and echocardiographic evaluation were performed. LVH was defined as ≥95th percentile of LV mass index related to height and age. Clinical and laboratory parameters included: serum albumin, Ca, HCT, cystatin C, creatinine, estimated glomerular filtration rate (eGFR) based on Schwartz formula, triglycerides, high-density lipoprotein (HDL), proteinuria, BMI standard deviation score (SDS), height SDS, waist circumference, ABPM data.

Results

71 children (28 girls/43 boys) with median age 14.05 (25%-75%:10.03-16.30) years and median eGFR 66.75 (32.76-92.32) ml/min/1.73m2 were evaluated. CKD stage 5 was diagnosed in 11 pts (15.5%). MS (DF) was diagnosed in 20 pts (28.2%). Glucose ≥ 110 mg/dL was present in 3 pts (4.2%); waist circumference ≥75th pc in 16 pts (22.5%); triglycerides ≥ 100 mg/dL in 35 pts (49.3%); HDL < 50mg/dL in 31 pts (43.7%) and BP ≥ 90th pc in 29 pts (40.8%), respectively. LVH was detected in 21 (29.6%) children. In univariate regression the strongest risk factor for LVH was CKD stage 5 (OR 4.9, p=0.0019) and low height SDS (OR 0.43,p=0.0009). In stepwise multiple logistic regression analysis (logit model) of the most important risk factors for LVH in CKD children, only three were statistically significant predictors: 1)MS diagnosis based on DF criteria (OR=24.11; 95%CI 1.1-528.7; p=0.043; Chi2 = 8.38,p=0.0038); 2), high mean arterial pressure (MAP SDS) in ABPM (OR=2.812; 95%CI 1.057-7.48; p=0.038;Chi2 = 5.91, p=0.015) and 3) low height SDS (OR=0.078; 95%CI 0.013-0.486;p=0.006; Chi2 = 25.01, p<0.001).

Conclusions

In children with chronic kidney disease LVH is associated with the cluster of multiple factors, among them the components of MS, hypertension, stage 5 CKD and growth deficit were the most significant.
Research progress of aqueous Zn–CO2 battery: design principle and development strategy of a multifunctional catalyst
Authors: Guo Wenqi , Wang Yukun , Yi Qun , Devid Edwin , Li Xuelian , Lei Puying , Shan Wenlan , Qi Kai , Shi Lijuan , Gao Lili
Published: May 2023

Aqueous Zn–CO2 battery possesses a large theoretical capacity of 820 mAh g-1 (5855 mAh cm-3) and high safety, showing a unique position in carbon neutrality and/or reduction and energy conversion and storage, which has developed rapidly in recent years. However, obstacles such as low value-added products, low current density, high overvoltage, and finite cycles impede its practical application. Cathode catalysts, as a key component, have a significant influence on gas cell performance. Despite many updated papers on cathode materials for aqueous Zn–CO2 batteries, a systematic summary has rarely been reported, and even less is mentioned about the design principle and development strategy for efficient catalysts. Relying on the structure and mechanism of the Zn–CO2 battery, this review discusses the research progress and existing challenges, and, more importantly, the design strategies and preparation methods of the efficient cathode are proposed, centering on material structure, charge distribution, and coordination environment. Finally, in this review, the opportunities for the development of a high-performance Zn–CO2 battery are highlighted, which enables enlightening the future exploration of next-generation energy storage systems.
Wildfire-related smoke inhalation worsens cardiovascular risk in sleep disrupted rats
Authors: Martin W. Kyle , Schladweiler M. C. , Oshiro W. , Smoot J. , Fisher A. , Williams W. , Valdez M. , Miller C. N. , Jackson T. W. , Freeborn D. , Kim Y. H. , Davies D. , Gilmour M. Ian , Kodavanti U. , Kodavanti P. , Hazari M. S. , Farraj A. K.
Published: May 2023

Introduction

As a lifestyle factor, poor sleep status is associated with increased cardiovascular morbidity and mortality and may be influenced by environmental stressors, including air pollution.

Methods

To determine whether exposure to air pollution modified cardiovascular effects of sleep disruption, we evaluated the effects of single or repeated (twice/wk for 4 wks) inhalation exposure to eucalyptus wood smoke (ES; 964 µg/m3 for 1 h), a key wildland fire air pollution source, on mild sleep loss in the form of gentle handling in rats. Blood pressure (BP) radiotelemetry and echocardiography were evaluated along with assessments of lung and systemic inflammation, cardiac and hypothalamic gene expression, and heart rate variability (HRV), a measure of cardiac autonomic tone.

Results and Discussion

GH alone disrupted sleep, as evidenced by active period-like locomotor activity, and increases in BP, heart rate (HR), and hypothalamic expression of the circadian gene Per2. A single bout of sleep disruption and ES, but neither alone, increased HR and BP as rats transitioned into their active period, a period aligned with a critical early morning window for stroke risk in humans. These responses were immediately preceded by reduced HRV, indicating increased cardiac sympathetic tone. In addition, only sleep disrupted rats exposed to ES had increased HR and BP during the final sleep disruption period. These rats also had increased cardiac output and cardiac expression of genes related to adrenergic function, and regulation of vasoconstriction and systemic blood pressure one day after final ES exposure. There was little evidence of lung or systemic inflammation, except for increases in serum LDL cholesterol and alanine aminotransferase. These results suggest that inhaled air pollution increases sleep perturbation-related cardiovascular risk, potentially in part by increased sympathetic activity.
Non-oral manifestations in adults with a clinical and molecularly confirmed diagnosis of periodontal Ehlers-Danlos syndrome
Authors: Angwin C. , Zschocke J. , Kammin T. , Björck E. , Bowen J. , Brady A. F. , Burns H. , Cummings C. , Gardner R. , Ghali N. , Gröbner R. , Harris J. , Higgins M. , Johnson D. , Lepperdinger U. , Milnes D. , Pope F. M. , Sehra R. , Kapferer-Seebacher I. , Sobey G. , Van Dijk F. S.
Published: May 2023

Introduction: Periodontal Ehlers-Danlos Syndrome (pEDS) is a rare autosomal dominant type of EDS characterised by severe early-onset periodontitis, lack of attached gingiva, pretibial plaques, joint hypermobility and skin hyperextensibility as per the 2017 International EDS Classification. In 2016, deleterious pathogenic heterozygous variants were identified in C1R and C1S, which encode components of the complement system.

Materials and Methods: Individuals with a clinical suspicion of pEDS were clinically and molecularly assessed through the National EDS Service in London and Sheffield and in genetic services in Austria, Sweden and Australia. Transmission electron microscopy and fibroblast studies were performed in a small subset of patients.

Results: A total of 21 adults from 12 families were clinically and molecularly diagnosed with pEDS, with C1R variants in all families. The age at molecular diagnosis ranged from 21–73 years (mean 45 years), male: female ratio 5:16. Features of easy bruising (90%), pretibial plaques (81%), skin fragility (71%), joint hypermobility (24%) and vocal changes (38%) were identified as well as leukodystrophy in 89% of those imaged.

Discussion: This cohort highlights the clinical features of pEDS in adults and contributes several important additional clinical features as well as novel deleterious variants to current knowledge. Hypothetical pathogenic mechanisms which may help to progress understanding and management of pEDS are also discussed.
A partitioned 88-loci psoriasis genetic risk score reveals HLA and non-HLA contributions to clinical phenotypes in a Newfoundland psoriasis cohort
Authors: Bui Audrey , Kumar Sugandh , Liu Jared , Orcales Faye , Gulliver Susanne , Tsoi Lam C. , Gulliver Wayne , Liao Wilson
Published: May 2023

Psoriasis is an immune-mediated inflammatory skin disease typically characterized by erythematous and scaly plaques. It affects 3% of the Newfoundland population while only affecting 1.7% of the general Canadian population. Recent genome-wide association studies (GWAS) in psoriasis have identified more than 63 genetic susceptibility loci that individually have modest effects. Prior studies have shown that a genetic risk score (GRS) combining multiple loci can improve psoriasis disease prediction. However, these prior GRS studies have not fully explored the association of GRS with patient clinical characteristics. In this study, we calculated three types of GRS: one using all known GWAS SNPs (GRS-ALL), one using a subset of SNPs from the HLA region (GRS-HLA), and the last using non-HLA SNPs (GRS-noHLA). We examined the relationship between these GRS and a number of psoriasis features within a well characterized Newfoundland psoriasis cohort. We found that both GRS-ALL and GRS-HLA were significantly associated with early age of psoriasis onset, psoriasis severity, first presentation of psoriasis at the elbow or knee, and the total number of body locations affected, while only GRS-ALL was associated with a positive family history of psoriasis. GRS-noHLA was uniquely associated with genital psoriasis. These findings clarify the relationship of the HLA and non-HLA components of GRS with important clinical features of psoriasis.
The same heterozygous Col4A4 mutation triggered different renal pathological changes in Chinese family members
Authors: Zhu Fengming , Li Yueqiang , Wang Yuxi , Yao Ying , Zeng Rui
Published: May 2023

Background: Mutations in the collagen components of the glomerular basement membrane (GBM) often lead to hereditary glomerulonephritis. Previous studies have identified that autosomal dominant mutations of Col4A3, Col4A4 or Col4A5 are associated with thin basement membrane nephropathy (TBMN), Alport syndrome and other hereditary kidney diseases. However, the genetic mutations underlying other glomerulonephritis types have not been elucidated.

Methods: In this study, we investigated a Chinese family with hereditary nephritis using the methods of genetic sequencing and renal biopsy. Genomic DNA was extracted from peripheral blood of the proband and her sister, and subsequently was performed genetic sequencing. They were found to have the similar mutation sites. Other family members were then validated using Sanger sequencing. The proband and her sister underwent renal puncture biopsies, and experienced pathologists performed PAS, Masson, immunofluorescence, and immunoelectron microscopic staining of the kidney tissue sections.

Results: Through genetic sequencing analysis, we detected a novel heterozygous frameshift mutation c.1826delC in the COL4A4 (NM_000092.4) gene coding region, and 1 hybrid missense variation c.86G>A (p. R29Q) was also detected in the TNXB (NM_019105.6) gene coding region in several members of this Chinese family. Interestingly, we found that the same mutations caused different clinical features and distinct pathological changes in individual family members, which confirmed that pathological and genetic testing are crucial for the diagnosis and treatment of hereditary kidney diseases.

Conclusion: In this study, we found a novel heterozygous mutation in Col4A4 and co-mutations of the TNXB gene in this Chinese family. Our study indicated that the same Col4A4 mutated variants produced different pathological and clinical changes in different family members. This discovery may provide novel insights into the study of hereditary kidney disease. In addition, new genetic biology techniques and renal biopsy of individual family members are essential.
A novel anoikis-related gene prognostic signature and its correlation with the immune microenvironment in colorectal cancer
Authors: Xiao Yu , Zhou Han , Chen Yiran , Liu Libin , Wu Qian , Li Hui , Lin Peicheng , Li Jinluan , Wu Junxin , Tang Lirui
Published: May 2023

Background: Anoikis is a type of apoptosis associated with cell detachment. Resistance to anoikis is a focal point of tumor metastasis. This study aimed to explore the relationship among anoikis-related genes (ARGs), immune infiltration, and prognosis in colorectal cancer (CRC).

Methods: The transcriptome profile and clinical data on patients with CRC were retrieved from The Cancer Genome Atlas and Gene Expression Omnibus databases. Patients were divided into two clusters based on the expression of ARGs. Differences between the two ARG molecular subtypes were analyzed in terms of prognosis, functional enrichment, gene mutation frequency, and immune cell infiltration. An ARG-related prognostic signature for predicting overall survival in patients with CRC was developed and validated using absolute value convergence and selection operator (LASSO) regression analysis. The correlation between the signature risk score and clinicopathological features, immune cell infiltration, immune typing, and immunotherapy response was analyzed. The risk score combined with clinicopathological characteristics was used to construct a nomogram to assess CRC patients’ prognosis.

Results: Overall, 151 ARGs were differentially expressed in CRC. Two ARG subtypes, namely, ARG-high and ARG-low groups, were identified and correlated with CRC prognosis. The gene mutation frequency and immune, stromal, and ESTIMATE scores of the ARG-high group were higher than those of the ARG-low group. Moreover, CD8, natural killer cells, M1 macrophages, human leukocyte antigen (HLA), and immune checkpoint-related genes were significantly increased in the ARG-high group. An optimized 25-gene CRC prognostic signature was successfully constructed, and its prognostic predictive ability was validated. The high-risk score was correlated with T, N, M, and TNM stages. Risk scores were negatively correlated with dendritic cells, eosinophils, and CD4 cells, and significantly positively correlated with regulatory T cells. Patients in the high-risk group were more likely to exhibit immune unresponsiveness. Finally, the nomogram model was constructed and showed good prognostic predictive power.

Conclusion: ARGs are associated with clinicopathological features and the prognosis of CRC, and play important roles in the immune microenvironment. Herein, we underpinned the usefulness of ARGs in CRC to develop more effective immunotherapy techniques.
Incidence and Distinct Features of Immune Checkpoint Inhibitor-Related Myositis From Idiopathic Inflammatory Myositis: A Single-Center Experience With Systematic Literature Review and Meta-Analysis
Authors: Hamada Naoki , Maeda Ayaka , Takase-Minegishi Kaoru , Kirino Yohei , Sugiyama Yumiko , Namkoong Ho , Horita Nobuyuki , Yoshimi Ryusuke , Nakajima Hideaki ,   YCU irAE Working Group
Published: May 2023

Immune checkpoint inhibitor (ICI)-related myositis is a rare, potentially fatal condition that warrants further studies. Its incidence, clinical features, and prognosis remain poorly understood. To address these gaps, we conducted a systematic review and meta-analysis to evaluate the risk of myositis associated with ICI for solid tumors by analyzing phase III randomized controlled trials of anti-programmed death-1/ligand-1 (PD-1/PD-L1) and anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4). To complement this analysis with clinical data, we evaluated published ICI case reports along with cases from our institutional registry. This registry comprised 422 patients treated with ICIs alone or in combination from September 2014 to June 2021. The analysis revealed an incidence of ICI-related myositis in 6,838 patients in 18 randomized controlled trials of 0.38% (odds ratio 1.96; 95% confidence interval 1.02–3.75) for patients receiving ICIs compared with controls. Detailed analysis of 88 cases from the literature search and our registry showed that myositis induced by PD-1 inhibitors was more frequent than that induced by anti-CTLA-4 agents, revealing a clinically diverse trend including myasthenia gravis and myocarditis. Importantly, having ptosis at the time of onset was significantly associated with the development of concomitant myocarditis (odds ratio 3.81; 95% CI 1.48–9.83), which is associated with poor prognosis. Regarding treatment, most patients received glucocorticoids, and some received immunosuppressants. Our study revealed the incidence of ICI-mediated myositis and the clinical features of myocarditis, highlighting the need for recognition and early intervention.
In-stent restenosis is associated with proliferative skin healing and specific immune and endothelial cell profiles: results from the RACHEL trial
Authors: Lozano Íñigo , Bangueses Roi , Rodríguez Isabel , Pevida Marta , Rodríguez-Aguilar Raúl , Rodríguez Diana , Espasandín-Arias Martina , Llames Sara , Meana Álvaro , Suárez Ana , Rodríguez-Carrio Javier
Published: May 2023

Introduction

In-stent restenosis (ISR) is a major challenge in interventional cardiology. Both ISR and excessive skin healing are aberrant hyperplasic responses, which may be functionally related. However, the cellular component underlying ISR remains unclear, especially regarding vascular homeostasis. Recent evidence suggest that novel immune cell populations may be involved in vascular repair and damage, but their role in ISR has not been explored. The aims of this study is to analyze (i) the association between ISR and skin healing outcomes, and (ii) the alterations in vascular homeostasis mediators in ISR in univariate and integrative analyses.

Methods

30 patients with ≥1 previous stent implantation with restenosis and 30 patients with ≥1 stent without restenosis both confirmed in a second angiogram were recruited. Cellular mediators were quantified in peripheral blood by flow cytometry. Skin healing outcomes were analyzed after two consecutive biopsies.

Results

Hypertrophic skin healing was more frequent in ISR patients (36.7%) compared to those ISR-free (16.7%). Patients with ISR were more likely to develop hypertrophic skin healing patterns (OR 4.334 [95% CI 1.044–18.073], p=0.033), even after correcting for confounders. ISR was associated with decreased circulating angiogenic T-cells (p=0.005) and endothelial progenitor cells (p<0.001), whereas CD4+CD28null and detached endothelial cells counts were higher (p<0.0001 and p=0.006, respectively) compared to their ISR-free counterparts. No differences in the frequency of monocyte subsets were found, although Angiotensin-Converting Enzyme expression was increased (non-classical: p<0.001; and intermediate: p<0.0001) in ISR. Despite no differences were noted in Low-Density Granulocytes, a relative increase in the CD16- compartment was observed in ISR (p=0.004). An unsupervised cluster analysis revealed the presence of three profiles with different clinical severity, unrelated to stent types or traditional risk factors.

Conclusion

ISR is linked to excessive skin healing and profound alterations in cellular populations related to vascular repair and endothelial damage. Distinct cellular profiles can be distinguished within ISR, suggesting that different alterations may uncover different ISR clinical phenotypes.
Development of innate immune memory by non-immune cells during Staphylococcus aureus infection depends on reactive oxygen species
Authors: Chaumond Emmanuel , Peron Sandrine , Daniel Nathalie , Le Gouar Yann , Guédon Éric , Williams David L. , Le Loir Yves , Jan Gwénaël , Berkova Nadia
Published: May 2023

Introduction

The mechanisms underlying innate immune memory (trained immunity) comprise epigenetic reprogramming of transcriptional pathways associated with alterations of intracellular metabolism. While the mechanisms of innate immune memory carried out by immune cells are well characterized, such processes in non-immune cells, are poorly understood. The opportunistic pathogen, Staphylococcus aureus, is responsible for a multitude of human diseases, including pneumonia, endocarditis and osteomyelitis, as well as animal infections, including chronic cattle mastitis that are extremely difficult to treat. An induction of innate immune memory may be considered as a therapeutic alternative to fight S. aureus infection.

Methods

In the current work, we demonstrated the development of innate immune memory in non-immune cells during S. aureus infection employing a combination of techniques including Enzyme-linked immunosorbent assay (ELISA), microscopic analysis, and cytometry.

Results

We observed that training of human osteoblast-like MG-63 cells and lung epithelial A549 cells with β-glucan increased IL-6 and IL-8 production upon a stimulation with S. aureus, concomitant with histones modifications. IL-6 and IL-8 production was positively correlated with an acetylation of histone 3 at lysine 27 (H3K27), thus suggesting epigenetic reprogramming in these cells. An addition of the ROS scavenger N-Acetylcysteine, NAC, prior to β-glucan pretreatment followed by an exposure to S. aureus, resulted in decreased IL-6 and IL-8 production, thereby supporting the involvement of ROS in the induction of innate immune memory. Exposure of cells to Lactococcus lactis resulted in increased IL-6 and IL-8 production by MG-63 and A549 cells upon a stimulation with S. aureus that was correlated with H3K27 acetylation, suggesting the ability of this beneficial bacterium to induce innate immune memory.

Discussion

This work improves our understanding of innate immune memory in non-immune cells in the context of S. aureus infection. In addition to known inducers, probiotics may represent good candidates for the induction of innate immune memory. Our findings may help the development of alternative therapeutic approaches for the prevention of S. aureus infection.
Interferon beta treatment is a potent and targeted epigenetic modifier in multiple sclerosis
Authors: Xavier Alexandre , Campagna Maria Pia , Maltby Vicki E. , Kilpatrick Trevor , Taylor Bruce V. , Butzkueven Helmut , Ponsonby Anne-Louise , Scott Rodney J. , Jokubaitis Vilija G. , Lea Rodney A. , Lechner-Scott Jeannette
Published: May 2023

Introduction

Multiple Sclerosis (MS) has a complex pathophysiology that involves genetic and environmental factors. DNA methylation (DNAm) is one epigenetic mechanism that can reversibly modulate gene expression. Cell specific DNAm changes have been associated with MS, and some MS therapies such as dimethyl fumarate can influence DNAm. Interferon Beta (IFNβ), was one of the first disease modifying therapies in multiple sclerosis (MS). However, how IFNβ reduces disease burden in MS is not fully understood and little is known about the precise effect of IFNβ treatment on methylation.

Methods

The objective of this study was to determine the changes in DNAm associated with INFβ use, using methylation arrays and statistical deconvolutions on two separate datasets (total ntreated = 64, nuntreated = 285).

Results

We show that IFNβ treatment in people with MS modifies the methylation profile of interferon response genes in a strong, targeted, and reproducible manner. Using these identified methylation differences, we constructed a methylation treatment score (MTS) that is an accurate discriminator between untreated and treated patients (Area under the curve = 0.83). This MTS is time-sensitive and in consistent with previously identified IFNβ treatment therapeutic lag. This suggests that methylation changes are required for treatment efficacy. Overrepresentation analysis found that IFNβ treatment recruits the endogenous anti-viral molecular machinery. Finally, statistical deconvolution revealed that dendritic cells and regulatory CD4+ T cells were most affected by IFNβ induced methylation changes.

Discussion

In conclusion, our study shows that IFNβ treatment is a potent and targeted epigenetic modifier in multiple sclerosis.
HIV-1 activates oxidative phosphorylation in infected CD4 T cells in a human tonsil explant model
Authors: Freeman Tracey L. , Zhao Connie , Schrode Nadine , Fortune Trinisia , Shroff Sanjana , Tweel Benjamin , Beaumont Kristin G. , Swartz Talia H.
Published: May 2023

Introduction

Human immunodeficiency virus type 1 (HIV-1) causes a chronic, incurable infection leading to immune activation and chronic inflammation in people with HIV-1 (PWH), even with virologic suppression on antiretroviral therapy (ART). The role of lymphoid structures as reservoirs for viral latency and immune activation has been implicated in chronic inflammation mechanisms. Still, the specific transcriptomic changes induced by HIV-1 infection in different cell types within lymphoid tissue remain unexplored.

Methods

In this study, we utilized human tonsil explants from healthy human donors and infected them with HIV-1 ex vivo. We performed single-cell RNA sequencing (scRNA-seq) to analyze the cell types represented in the tissue and to investigate the impact of infection on gene expression profiles and inflammatory signaling pathways.

Results

Our analysis revealed that infected CD4+ T cells exhibited upregulation of genes associated with oxidative phosphorylation. Furthermore, macrophages exposed to the virus but uninfected showed increased expression of genes associated with the NLRP3 inflammasome pathway.

Discussion

These findings provide valuable insights into the specific transcriptomic changes induced by HIV-1 infection in different cell types within lymphoid tissue. The activation of oxidative phosphorylation in infected CD4+ T cells and the proinflammatory response in macrophages may contribute to the chronic inflammation observed in PWH despite ART. Understanding these mechanisms is crucial for developing targeted therapeutic strategies to eradicate HIV-1 infection in PWH.