bluuebunny/crossref_metadata_2025 huggingface dataset:
Endogenous TRAIL-R4 critically impacts apoptotic and non-apoptotic TRAIL-induced signaling in cancer cells
Authors: Rambow Anna-Christina , Aschenbach Insa , Hagelund Sofie , Tawfik Doaa , Gundlach Jan-Paul , Weiße Sebastian , Maass Nicolai , Trauzold Anna
Published: September 2022

Binding of TRAIL to its death domain-containing receptors TRAIL-R1 and TRAIL-R2 can induce cell death and/or pro-inflammatory signaling. The importance of TRAIL and TRAIL-R1/R2 in tumor immune surveillance and cancer biology has meanwhile been well documented. In addition, TRAIL has been shown to preferentially kill tumor cells, raising hope for the development of targeted anti-cancer therapies. Apart from death-inducing receptors, TRAIL also binds to TRAIL-R3 and TRAIL-R4. Whereas TRAIL-R3 is lacking an intracellular domain entirely, TRAIL-R4 contains a truncated death domain but still a signaling-competent intracellular part. It is assumed that these receptors have anti-apoptotic, yet still not well understood regulatory functions.

To analyze the significance of the endogenous levels of TRAIL-R4 for TRAIL-induced signaling in cancer cells, we stably knocked down this receptor in Colo357 and MDA-MB-231 cells and analyzed the activation of apoptotic and non-apoptotic pathways in response to treatment with TRAIL.

We found that TRAIL-R4 affects a plethora of signaling pathways, partly in an opposite way. While knockdown of TRAIL-R4 in Colo357 strongly increased apoptosis and reduced clonogenic survival, it inhibited cell death and improved clonogenic survival of MDA-MB-231 cells after TRAIL treatment. Furthermore, TRAIL-R4 turned out to be an important regulator of the expression of a variety of anti-apoptotic proteins in MDA-MB-231 cells since TRAIL-R4-KD reduced the cellular levels of FLIPs, XIAP and cIAP2 but upregulated the levels of Bcl-xL. By inhibiting Bcl-xL with Navitoclax, we could finally show that this protein mainly accounts for the acquired resistance of MDA-MB-231 TRAIL-R4-KD cells to TRAIL-induced apoptosis. Analyses of non-apoptotic signaling pathways revealed that in both cell lines TRAIL-R4-KD resulted in a constitutively increased activity of AKT and ERK, while it reduced AKT activity after TRAIL treatment. Furthermore, TRAIL-R4-KD potentiated TRAIL-induced activation of ERK and p38 in Colo357, and NF-κB in MDA-MB-231 cells. Importantly, in both cell lines the activity of AKT, ERK, p38 and NF-κB after TRAIL treatment was higher in TRAIL-R4-KD cells than in respective control cells.

Thus, our data provide evidence for the important regulatory functions of endogenous TRAIL-R4 in cancer cells and improve our understanding of the very complex human TRAIL/TRAIL-R system.
Electrochemical behavior of Mg electrode in sodium salt electrolyte system
Authors: Zhang Yu , Zhu Qingguang , Su Chang , Li Chao
Published: September 2022

A suitable electrolyte is crucial to enhancing the electrochemical performance of magnesium (Mg) batteries. Here, the influence of Na2SiO3 on the electrochemical behavior of AZ31B Mg alloy in the Na2SO4-NaNO3 composite electrolyte was investigated. The results revealed that the activation potential of the AZ31B Mg alloy first represented a negative shift and then a positive shift with the increase in Na2SiO3. The most negative activation potential (−1.51 V) and the lowest polarization (−3.20 V) were found when 6 mM of Na2SiO3 was added; no discharge hysteresis was observed, and the polarization resistance value (R1) was 3,806 Ω. After 24 h immersion in the composite electrolyte with Na2SiO3, more and wider cracks appeared on the alloy surface, where a thick, dense film was formed, showing excellent discharge performance and corrosion resistance.
Improved representativeness of simulated climate using natural units and monthly resolution
Authors: Huebener Heike , Gelhardt Ulrike , Lang Jürgen
Published: September 2022

There is a considerable discrepancy between the temporal and spatial resolution required by climate impact researchers, policy makers, and adaptation planners on the one hand and climate data providers on the other hand. While the spatial and temporal aggregation of climate data is necessary to increase the reliability and robustness of climate information, this often counteracts or even prohibits their use in adaptation planning. The problem is twofold (i.e., space and time) and needs to be approached accordingly. Climate impact research and adaptation planning are the domain of impact experts, politicians, and planners, rather than climate experts. Thus, besides the spatial and temporal resolution, information also needs to be provided on platforms and in data formats that are easily accessible, easy to handle, and easy to understand. We discuss possible steps toward bridging the gap using an example from the federal state Hesse (Germany) as illustration. We aggregate the climate data at a level of “natural units” and provide them as monthly data. We discuss the pros and cons of this kind of processed data for impact research and decision making. The spatial aggregation to “natural units” delivers suitable spatial aggregation, while maintaining physical geographic structures and their climatic characteristics. Within these “natural units,” single grid cell values are usable for climate impact analyses or decision making. The temporal resolution is monthly values, i.e., deviations of single month values for the scenario period from climatological monthly values in the (simulated) reference period. This resolution allows analyzing compound events or consecutive events on a monthly scale within a climatological (30-year) period.
Pre-suasive and persuasive strategies in the tweets of the Saudi Ministry of Health during the 2020 coronavirus pandemic: A corpus linguistic exploration
Authors: Ibrahim Wesam M. A. , Abaalalaa Hessah S. , Hardie Andrew
Published: September 2022

In this study, we assess the applicability and usefulness of a particular theoretical framework for qualitative analysis of communicative strategies in discourses from beyond the English language. The theory in question is Cialdini's model of persuasion (and the related concept of pre-suasion). We present an operationalisation of this framework in terms of concrete linguistic features, which is implemented using the computer-assisted methods of corpus linguistics. As a case study, we explore a particular type of Arabic-language online public discourse surrounding an issue of pressing contemporary concern, namely the COVID-19 Pandemic. Specifically, we use a large collection of texts produced by the Ministry of Health of Saudi Arabiaviathe medium of the Ministry's official Twitter account. The tweets in question were produced in the context of a campaign to persuade the public to modify their behavior to comply with policies on protective measures. While the use of corpus-assisted linguistic approaches to examine public discourses around socially or culturally prominent issues is well-developed in the Anglosphere, it remains much more rarely utilized in the Arab World context, and especially in application to discourses in the Arabic language itself. In addition to the contribution arising from the improvements generated in our understanding of the particular issue at hand, this paper aims to contribute to the broader field of Arabic linguistics by modeling a suitable approach—albeit one whose use we show to be subject to some complicating factors—to address other questions in the study of persuasive language in Arabic.
The privacy and control paradoxes in the context of smartphone apps
Authors: Ayres-Pereira Vanessa , Pirrone Angelo , Korbmacher Max , Tjostheim Ingvar , Böhm Gisela
Published: September 2022

This research examines how various factors, such as the degree of e-privacy concerns and control over data access permissions, can influence a user's intention to install a smartphone app. We conducted two survey-based experiments with 441 participants. In each experiment, we manipulated the degree of control over the number and type of data access permissions granted to different fictional apps. In Study 1, participants were informed about the set of permissions the apps required. In Study 2, participants indicated which individual permissions they were willing to grant to the apps. In both experiments, we assessed the level of e-privacy concerns, perceived app importance, and the intention to install the apps. The results suggest that the type of app plays a central role in determining both the perceived benefit of installing the app and the level of e-privacy concerns. The intention to install an app is more strongly associated with perceived app importance than with e-privacy concerns (especially when app importance is high, and users have explicit control over which specific data access permissions they want to grant). The implications of these results are discussed regarding psychological factors involved in app installation decision-making process and the importance of promoting data protection by design.
Long-term trends in elephant mortality and their causes in Kenya
Authors: Mukeka Joseph M. , Ogutu Joseph O. , Kanga Erustus , Piepho Hans-Peter , Røskaft Eivin
Published: September 2022

High mortality poses a serious threat to sustainable conservation of the African elephant (Loxodonta africana). Using detected carcass data collected by the Kenya Wildlife Service (KWS) during 1992-2017, we analyze temporal and spatial variation in elephant mortality in Kenya. We investigate the major mortality causes and means used to kill elephants, carcass category, tusk recovery status, variation in mortality with elephant age and sex classes, differences between inside and outside protected areas (PAs), the Proportion of Illegally Killed Elephants (PIKE) and the overall mortality rate (MR — the number of dead/number of live elephants in a given year). In total 9,182 elephant deaths were recorded during the 26 years. Elephant mortality increased over time and was attributed primarily to natural (33.1%) and human-related causes, particularly ivory poaching (31.5%) and human-elephant conflicts (19.9%). Elephant mortality varied across Kenya’s 47 counties in correspondence with variation in elephant population size and was the highest in the leading elephant range counties of Taita Taveta, Laikipia, Samburu and Meru. Mortality was higher for males and adults and outside the protected areas. Most elephant carcasses had tusks (75.1%) but a few did not (12.5%). Yearly PIKE values peaked in 2012, the year with the highest poaching levels in Kenya during 1992-2017. MR increased throughout 1992-2017. Temporal variation in elephant mortality probability was significantly influenced by human and livestock population densities, average annual maximum temperature and total annual rainfall and the strength of these influences varied across the seven leading elephant range counties of Kenya. Natural processes are increasingly contributing to elephant mortality likely due to climate change and the associated food and water stress, exacerbated by contracting range. Enhancing anti-poaching and strategies for mitigating climate change impacts and human-elephant conflict and reducing range contraction while sustaining habitat connectivity can help reduce mortality and promote elephant conservation. Strengthening enforcement of international wildlife laws can further reduce illegal trade in tusks and killing of elephants.
Simplification of ankle-brachial-index measurement using Doppler-waveform classification in symptomatic patients suspected of lower extremity artery disease
Authors: Métairie Antoine , Tollenaere Quentin , Lanéelle Damien , Le Faucheur Alexis , Le Pabic Estelle , Omarjee Loukman , Mahé Guillaume
Published: September 2022

Objectives

Ankle-brachial index (ABI) is commonly used for screening lower extremity peripheral artery disease (PAD) according to the international guidelines. Arterial Doppler waveform recordings is a tool to diagnose and assess PAD severity. We hypothesized that ABI measurement could be simplified by measuring only the pressure where the best arterial flow is recorded. The aim of this study was to evaluate the concordance between ABI performed according to the American Heart Association guidelines (AHA-ABI) and ABI measured according to best arterial waveform (FLOW-ABI).

Design

This was a monocentric cross-sectional study.

Methods

We included patients with exertional limb symptoms suspected of PAD. Arterial Doppler waveforms and ABI were acquired on both lower extremities at the pedis and tibial posterior arteries. Each arterial waveform was classified using the Saint-Bonnet classification. Concordances were analyzed with the kappa coefficient (confidence interval 95%). Exercise PAD study was registered n° NCT03186391.

Results

In total, one hundred and eighty-eight patients (62+/−12 years and 26.8+/−4.5 kg/m2) with exertional limb symptoms were included from May 2016 to June 2019. On each extremity, FLOW-ABI had excellent concordance for the diagnosis of PAD with the AHA-ABI with a kappa of 0.95 (95% CI: 0.90, 0.99) in the right extremity and 0.91 (95% CI: 0.86, 0.97) in the left extremity.

Conclusion

There is almost perfect concordance between AHA-ABI and FLOW-ABI. Thus, ABI can be simplified into five pressure measurements instead of seven in patient suspected of PAD with exertional limb symptoms. The question remains in patients with chronic limb ischemia.
Hemodynamic effects and tolerance of dobutamine for myocardial dysfunction during septic shock: An observational multicenter prospective echocardiographic study
Authors: Razazi Keyvan , Labbé Vincent , Laine Laurent , Bedet Alexandre , Carteaux Guillaume , de Prost Nicolas , Boissier Florence , Bagate Francois , Mekontso Dessap Armand
Published: September 2022

Background

The role of dobutamine during septic shock resuscitation is still controversial.

Methods

The aim of this prospective multicentre study was to comprehensively characterize the hemodynamic response of septic shock patients with systolic myocardial dysfunction to incremental doses of dobutamine (0, 5, 10, and 15 μg/kg/min).

Results

Thirty two patients were included in three centers. Dobutamine significantly increased contractility indices of both ventricles [crude and afterload-adjusted left ventricular (LV) ejection fraction, global LV longitudinal peak systolic strain, tissue Doppler peak systolic wave at mitral and tricuspid lateral annulus, and tricuspid annular plane excursion) as well as global function indices (stroke volume and cardiac index) and diastolic function (increased e' and decreased E/e' ratio at lateral mitral annulus). Dobutamine also induced a significant decrease in arterial pressure and cardiac afterload indices (effective arterial elastance, systemic vascular resistance and diastolic shock index). Oxygen transport, oxygen consumption and carbon dioxide production all increased with dobutamine, without change in the respiratory quotient or lactate. Dobutamine was discontinued for poor tolerance in a majority of patients (n = 21, 66%) at any dose and half of patients (n = 15, 47%) at low-dose (5 μg/kg/min). Poor tolerance to low-dose dobutamine was more frequent in case of acidosis, was associated with lower vasopressor-free days and survival at day-14.

Conclusion

In patients with septic myocardial dysfunction, dobutamine induced an overall improvement of echocardiographic parameters of diastolic and systolic function, but was poorly tolerated in nearly two thirds of patients, with worsening vasoplegia. Patients with severe acidosis seemed to have a worse response to dobutamine.
Effect of itraconazole on the safety and pharmacokinetics of antitumor SHR6390
Authors: Lv Xiaozhi , Wu Junyan , Yao Herui , Ye Suiwen , Zhang Nan
Published: September 2022

The experimental drug SHR6390 has anti-tumor activity as a cyclin dependent kinase 4/6 inhibitor and is metabolized primarily by the cytochrome P450 3A4 enzyme. Therefore, The purpose of this trial was to evaluate the safety and pharmacokinetics of SHR6390, a potent cytochrome P450 3A4 inhibitor, in healthy Chinese subjects. In this trial study, 18 subjects received a single oral dose of SHR6390 50 mg on day 1, multiple doses of 200 mg itraconazole on days 12–24 for 13 days, and a single oral dose of SHR6390 50 mg on day 15. After coadministration with itraconazole, the maximum plasma concentration (Cmax) of SHR6390 increased by 70.7% (from 14.3 ng/ml to 24.5 ng/ml), and the area under the time curve from 0 to T (AUC0-T) increased by 110.8% from 468 h∙ng/mL to 988 h∙ng/mL. The area under the concentration-time curve extrapolated to ∞(AUC0-∞) increases from 509 H∙ng/mL to 1,040 h∙ng/mL, an increase of 105.1%. Oral gap (CL/F) decreased (47.9 L/h and 98.3 L/h) and apparent volume of distribution (Vz/F) decreased (4190 L and 5890 L). According to common terminology criteria, 15 32 adverse events were reported in 18 subjects (AEs) (27 SHR6390-related AEs and 15 Itraconazole-related AEs), AEs were all Class 1 adverse events. Overall, co-administration of Itraconazole increased the plasma exposure of SHR6390 in healthy subjects. Both SHR6390 alone and co-administration of Itraconazole showed acceptable safety profiles, which warrants further investigation. The experimental drug SHR-6390 of this clinical trial has been applied for registration, which is classified as Chemical drugs Class 1. The study drug SHR6390 registration number:ClinicalTrials.gov Identifier: NCT04423601 (https://clinicaltrials.gov/)
Natural gas accumulation conditions and exploration prospects of the Middle Permian Qixia Formation in the Sichuan Basin
Authors: Zhang Ya , Chen Shuangling , Wen Long , Zhang Benjian , Wang Hua , Xiao Di , Xie Chen , Zhang Xiaoli , Quan Li , Liu Ran , Qiao Yanping , Wang Guangwei
Published: September 2022

Exploration of natural gases in the Middle Permian Qixia Formation has achieved a breakthrough in the central and western Sichuan Basin since 2010. This study discusses the quality of dolomite reservoirs and source rocks, trap types and hydrocarbon charging history and proposes that good accumulation conditions are the basis for the large-scale enrichment of natural gas in the Qixia Formation. The high-quality reservoirs in the Qixia Formation are dolomites that primarily occur along platform margins and in the inner-platform shoals surrounding the Caledonian palaeo-uplifts. The Qixia gases originated mainly from the Cambrian and Permian mudstone source rocks. The overlaying Permian source rocks and the underlying Cambrian source rocks are both widely distributed and could provide sufficient gases for dolomite reservoirs. Additionally, the structural or structural-lithologic traps formed by an overlap of the Qixia dolomites and structurally high are favourable for oil and gas accumulation. The Qixia Formation had experienced four episodes of oil and gas charging from the middle-late Triassic to the Early Cretaceous, and traps located in structural-high zones are most favourable for hydrocarbon accumulation. Thus, the Qixia Formation has excellent accumulation conditions for the formation of large-scale gas fields. The concealed structural belts in the footwall of fault No. 1, the Longmenshan–Daxingchang structural belts and the periphery Gaomo–Shehong palaeo-uplift are the key zones for large-scale gas exploration in the Qixia Formation. The Qixia Formation is an important strategic replacement field for natural gas exploration in the Sichuan Basin following the Ediacaran Dengying Formation and the Cambrian Longwangmiao Formation.
The inflow performance relationship in fractured, vertical, and dewatered coalbed-methane wells
Authors: Dou Xiangji , Lu Jiahao , Li Jingxuan , Wu Xiaojun , Zhai Yu , Wu Bo , Qian Kun
Published: September 2022

Although not greatly studied, the inflow performance relationship (IPR) in dewatered and vertical coalbed methane (CBM) wells is essential in the development of a CBM reservoir. The dynamics of the stress sensitivity effect (SSE) and the matrix shrinkage effect (MSE), as well as the hydraulic fracture propagation, have all been neglected, especially for the exterior region, which is larger than the drainage radius. A novel IPR model has now been built that integrates dynamic SSE–MSE and hydraulic fracture propagation into the skin factor, and is validated with real production data from the Qinshui Basin, China. The absolute open flow rate given the SSE–MSE is 60.5% larger than without SSE–MSE. If the positive effect of the SSE–MSE on the permeability in the exterior region is neglected, the absolute open flow rate is reduced by 21%. The MSE has a greater effect on the fracturing skin factor than the SSE and tends to lower the fracturing skin factor, benefitting the production of CBM. Moreover, in light of the SSE or MSE, the non-Darcy flow effect is weaker due to restraints on the velocity of flow or the permeability. Useful and essential theoretical guidance for real CBM production can thus be gleaned from this novel IPR model.
The principal's role in improving the quality: A concepts framework to developing school culture
Authors: Sumiran Sumiran , Waston Waston , Zamroni Zamroni , Mahmudah Fitri Nur
Published: September 2022

This study aims to explore the role of principals in school culture so as to produce an ideal conceptual framework for principals in improving school quality. The method used in this research is qualitative with a case study approach. The research was conducted in MAN 2, Sragen, and MAN 2, Boyolali, Indonesia. The data analysis procedure used is Miles and Huberman with four procedures. Data analysis was carried out with the help of ATLAS.ti software version 8. Validity was carried out using data triangulation. The results of this study illustrate that the principal's role in school culture to improve school quality consists of role sets, attitudes and actions, personality characteristics, and control. The recommendations from this study are meant for principals at primary and secondary levels to help them improve the quality of their schools and create certain characteristics that are unique and superior compared to other schools.
Antihypertensive treatment improves glycemic control in patients with newly diagnosed type 2 diabetes mellitus: A prospective cohort study
Authors: Li Jung-Chi , Cheng Po-Chung , Huang Chien-Nin , Jian Li-Fen , Wu Ying-Syuan , Lin Chih-Li
Published: September 2022

Background

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder involving progressive pancreatic dysfunction. A substantial proportion of patients with T2DM cannot achieve euglycemia despite pharmacologic therapy. Preceding clinical studies have shown that hypertension contributes to glucose dysregulation, and investigators in this study hypothesized that antihypertensive treatment may improve glycemic control in patients with T2DM.

Methods

This prospective cohort study investigates the effect of adding the antihypertensive drug Amlodipine to standard diabetes therapy on serum glycosylated hemoglobin A1c (HbA1c) and lipid profile in patients with newly diagnosed T2DM. The study enrolled a total of 168 participants with newly diagnosed T2DM.

Results

Recipients of additional antihypertensive drug Amlodipine demonstrated significantly lower serum HbA1c (6.62% vs. 7.01%, P = 0.01), systolic blood pressure (132 mm Hg vs. 143 mm Hg, P < 0.001), and diastolic blood pressure (78.9 mm Hg vs. 86.0 mm Hg, P <0.001) compared to recipients of standard diabetes therapy after 24 weeks.

Conclusion

Antihypertensive treatment with Amlodipine in addition to standard diabetes therapy improves glycemic control in patients with T2DM and may be an appropriate option in people with diabetes and concomitant hypertension to help maintain euglycemia.
Ovarian tissue bank for fertility preservation and anti-menopause hormone replacement
Authors: Chen Jing , Han Yan , Shi Wenjie , Yan Xiaohong , Shi Yingying , Yang Ye , Gao Hong , Li Youzhu
Published: September 2022

Traditional fertility preservation methods such as embryo or oocyte cryopreservation cannot meet the needs of a cancer patient or for personal reasons. The cryopreservation of ovarian tissue can be an alternative and has become a hot spot to preserve fertility or hormone replacement. The freezing of ovarian tissue can be carried out at any time without ovarian hyperstimulation to retrieve follicles. It is an ideal strategy to preserve reproductive function in children, adolescent cancer patients, and patients who are in urgent need of cancer treatment. With the increasing demands of women with premature ovarian failure or in menopause, ovarian tissue transplantation is also an alternative for hormone replacement that can provide physiological doses of hormone levels, which can avoid a series of risks such as thrombosis, breast cancer, or other hormone-dependent tumors, caused by oral hormone replacement. Hence, ovarian tissue banking can be regarded as a mainstream strategy for fertility preservation and anti-menopause hormone replacement in further clinical investigation.
Case report: Successful combination therapy with double-filtration plasmapheresis and rituximab under the condition of the use of a sensor-augmented pump for type B insulin resistance syndrome
Authors: Osanami Arata , Kanda Masatoshi , Sato Tatsuya , Akazawa Chikako , Baba Shuhei , Komatsu Hiroaki , Murase Kazuyuki , Yamashita Tomohisa , Yano Toshiyuki
Published: September 2022

Type B insulin resistance syndrome (TBIR) is a rare disease characterized by refractory diabetes due to severe insulin resistance caused by anti-insulin receptor autoantibodies, and a standard treatment regimen for TBIR has not been established, leading to therapeutic difficulties and high mortality. Since TBIR is known to be associated with autoimmune diseases such as systemic lupus erythematosus (SLE), glucocorticoids are often used as key immunosuppressive agents. However, glucocorticoids have the potential to exacerbate the pathophysiology of TBIR by worsening insulin sensitivity, which leads to hyperglycemia and muscle wasting. Here, we report a case history of a 66-year-old man who was diagnosed as having TBIR in combination with SLE and Sjögren’s syndrome with marked hyperglycemia, ketosis, and muscle wasting. He was successfully treated with combination therapy of double-filtration plasmapheresis (DFPP) and administration of the anti-CD20 monoclonal antibody rituximab without induction of glucocorticoid therapy while using a sensor-augmented insulin pump (SAP) to prevent hypoglycemia. Remission of diabetes was achieved without severe hypoglycemic events and his circulating insulin receptor antibodies became negative after seven months of initiation of these treatments. Based on the successful clinical courses of this case, our report suggests the possibility of an effective therapeutic regimen with DFPP and rituximab under the condition of the use of an SAP for a patient with TBIR without induction of glucocorticoids.
Catchment properties as predictors of greenhouse gas concentrations across a gradient of boreal lakes
Authors: Valiente Nicolas , Eiler Alexander , Allesson Lina , Andersen Tom , Clayer François , Crapart Camille , Dörsch Peter , Fontaine Laurent , Heuschele Jan , Vogt Rolf D. , Wei Jing , de Wit Heleen A. , Hessen Dag O.
Published: September 2022

Boreal lakes are the most abundant lakes on Earth. Changes in acid rain deposition, climate, and catchment land use have increased lateral fluxes of terrestrial dissolved organic matter (DOM), resulting in a widespread browning of boreal freshwaters. This browning affects the aqueous communities and ecosystem processes, and boost emissions of the greenhouse gases (GHG) CH4, CO2, and N2O. In this study, we predicted biotic saturation of GHGs in boreal lakes by using a set of chemical, hydrological, climate, and land use parameters. For this purpose, concentrations of GHGs and nutrients (organic C, -P, and -N) were determined in surface water samples from 73 lakes in south-eastern Norway covering wide ranges in DOM and nutrient concentrations, as well as catchment properties and land use. The spatial variation in saturation of each GHG is related to explanatory variables. Catchment characteristics (hydrological and climate parameters) such as lake size and summer precipitation, as well as NDVI, were key determinants when fitting GAM models for CH4 and CO2 saturation (explaining 71 and 54%, respectively), while summer precipitation and land use data were the best predictors for the N2O saturation, explaining almost 50% of deviance. Our results suggest that lake size, precipitation, and terrestrial primary production in the watershed control the saturation of GHG in boreal lakes. These predictions based on the 73-lake dataset was validated against an independent dataset from 46 lakes in the same region. Together, this provides an improved understanding of drivers and spatial variation in GHG saturation in boreal lakes across wide gradients of lake and catchment properties. The assessment highlights the need to incorporate multiple explanatory parameters in prediction models of GHGs for extrapolation across the boreal biome.
MJDs family members: Potential prognostic targets and immune-associated biomarkers in hepatocellular carcinoma
Authors: Zhou Lei , Chen Guojie , Liu Tao , Liu Xinyuan , Yang Chengxiao , Jiang Jianxin
Published: September 2022

Hepatocellular carcinoma (HCC) is one of the most common gastrointestinal malignancies. It is not easy to be diagnosed in the early stage and is prone to relapse, with a very poor prognosis. And immune cell infiltration and tumor microenvironment play important roles in predicting therapeutic response and prognosis of HCC. Machado-Joseph domain-containing proteases (MJDs), as a gene family extensively involved in tumor progression, has pro-cancer and anti-cancer effects. However, the relationship between MJDs family members and immune cell infiltration and tumor microenvironment in HCC remains unclear. Therefore, cBio Cancer Genomics Portal (cBioPortal), The Cancer Genome Atlas (TCGA), UALCAN, Human Protein Atlas (HPA), MethSurv, and Tumor Immune Estimation Resource (TIMER) databases were performed to investigate the mRNA expression, DNA methylation, clinicopathologic features, immune cell infiltration and other related functions of MJDs family members in HCC. The results indicated that the expression of ATXN3, JOSD1, and JOSD2 was dramatically increased in HCC tissues and cell lines, and was correlated with histological grade, specimen type, TP53 mutation, lymph node metastatic, gender, and age of patients with HCC. Meanwhile, these genes also showed clinical value in improving the overall survival (OS), disease-specific survival (DSS), progression free survival (PFS), and relapse-free survival (RFS) in patients with HCC. The prognostic model indicated that the worse survival was associated with overall high expression of MJDs members. Next, the results suggested that promotor methylation levels of the MJDs family were closely related to these family mRNA expression levels, clinicopathologic features, and prognostic values in HCC. Moreover, the MJDs family were significantly correlated with CD4+ T cells, CD8+ T cells, B cells, neutrophils, macrophages, and DCs. And MJDs family members’ expression were substantially associated with the levels of several lymphocytes, immunomoinhibitors, immunomostimulators, chemokine ligands, and chemokine receptors. In addition, the expression levels of MJDs family were significantly correlated with cancer-related signaling pathways. Taken together, our results indicated that the aberrant expression of MJDs family in HCC played a critical role in clinical feature, prognosis, tumor microenvironment, immune-related molecules, mutation, gene copy number, and promoter methylation level. And MJDs family may be effective immunotherapeutic targets for patients with HCC and have the potential to be prognostic biomarkers.
Living birth following preimplantation genetic testing for monogenic disorders to prevent low-level germline mosaicism related Nicolaides–Baraitser syndrome
Authors: Pan Jiexue , Li Jie , Chen Songchang , Xu Chenming , Huang Hefeng , Jin Li
Published: September 2022

Objective: Paternal sperm mosaicism has few consequences for fathers for mutations being restricted to sperm. However, it could potentially underlie severe sporadic disease in their offspring. Here, we present a live birth of a female infant from a father with low-level sperm DNA mosaicism achieved via preimplantation genetic testing for monogenic disorders (PGT-M).

Methods: A couple with the father carrying sperm DNA mosaicism received standard in vitro fertilization treatment, with intracytoplasmic sperm injection, embryo biopsy, polymerase chain reaction, and DNA analysis. Only one unaffected embryo was transferred to the uterine cavity. Amniocentesis was performed at the 16th week of gestation by copy-number variation-sequencing, karyotyping, and Sanger sequencing.

Results: Eight surviving embryos were biopsied during the blastocyst stage. Karyomapping and Sanger sequencing were applied to detect the euploidy and paternal mutation. After performing PGT-M, followed by successful pregnancy, the prenatal genetic diagnoses revealed that the fetus was unaffected, and one healthy girl was born.

Conclusion: This is the first reported live birth with unaffected children achieved via PGT for a low-level germline mosaicism father. It not only opens the possibility of preventing the recurrent monogenic disease of children among gonadal mosaicism families but also alerts clinicians to consider gonadal mosaicism as the source of DMNs.
Intrahepatic activated leukocyte cell adhesion molecule induces CD6highCD4+ T cell infiltration in autoimmune hepatitis
Authors: Qian Qiwei , Cui Nana , Huang Bingyuan , Zhao Yudong , Liu Qiaoyan , Hu Mingli , Li Bo , Wang Qixia , Miao Qi , You Zhengrui , Ma Xiong , Tang Ruqi
Published: September 2022

Background and objectives

Autoimmune hepatitis (AIH) is characterized by the expansion and accumulation of pathogenic T cells in liver. Although CD6 and its ligand activated leukocyte cell adhesion molecule (ALCAM) are involved in the evolution of multiple inflammatory diseases, their roles in the pathogenesis of AIH remain unknown. Herein, we aimed to investigate ALCAM-CD6 axis in AIH development.

Methods

Immunohistochemistry was performed to examine hepatic expression of CD6 and ALCAM. The concentration of serum ALCAM was evaluated by ELISA. The phenotypes of liver infiltrating T cells were determined by flow cytometry. Primary human CD4+T cells were used for functional studies.

Results

Our data showed that patients with AIH exhibited significantly higher expression of CD6 in the liver as compared to primary biliary cholangitis (PBC), chronic hepatitis B (CHB), non-alcoholic liver disease (NAFLD), and healthy controls (HC). In addition, hepatic CD6 expression was strongly correlated with disease severity of AIH. CD6 was mainly expressed on CD4+T cells in the liver and intrahepatic CD6highCD4+T cells demonstrated stronger proinflammatory response and proliferation features than CD6lowcounterparts in both AIH and HC. ALCAM, the ligand of CD6, was highly expressed in the hepatocytes of AIH and serum ALCAM was strongly associated with clinical indices of AIH. Interestingly, close spatial location between CD6+CD4+T cells and ALCAM+hepatocytes was observed. Finally, we found that CD6highCD4+T cells showed enhanced capacity of trans-endothelial migrationin vitro, which could be promoted by recombinant ALCAM.

Conclusions

Our study found that ALCAM-CD6 axis was upregulated in the AIH liver, suggesting a potential target for alleviating AIH.
Unveiling the molecular features, relevant immune and clinical characteristics of SIGLEC15 in thyroid cancer
Authors: Hou Xiaofeng , Chen Chao , Lan Xiabin , He Xiaodong
Published: September 2022

The groundbreaking research work about SIGLEC15 has raised it as a potential promising target in cancer immunotherapy. Unfortunately, the role of SIGLEC15 in thyroid carcinoma (THCA) remains obscure. Public and home multi-omics data were collected to investigate the role of SIGLEC15 in THCA in our study. SIGLEC15 was upregulated in THCA tumor tissue compared to nontumor tissue in both mRNA and protein levels; gene set enrichment analysis (GSEA) results showed that high SIGLEC15 mRNA expression was positively correlated to many immune pathways. Results of the examination of immunological landscape characteristics displayed high SIGLEC15 mRNA expression that mainly positively correlated with a large number of cancer immunity immunomodulators and pathways. In addition, upregulation of SIGLEC15 was positively correlated with an enhanced immune score, stromal score, and estimate score. However, higher SIGLEC15 mRNA also met high immune exhausted status. The majority of CpG methylation sites negatively correlated with SIGLEC15 mRNA expression. Analysis of clinical characteristics supported increased SIGLEC15 expression that was positively correlated with more extrathyroid extension and lymph node metastasis. We observed different single nucleotide variant (SNV) and copy number variation (CNV) patterns in high and low SIGLEC15 mRNA expression subgroups; some vital DNA damage repair deficiency scores addressed a negative correlation with SIGLEC15 mRNA expression. We also found that some commonly used chemotherapy drugs might be suitable for different SIGLEC15 mRNA expression subgroups. This study highlighted the vital role of SIGLEC15 in THCA. Targeting SIGLEC15 may offer a potential novel therapeutic opportunity for THCA patients. However, the detailed exact cellular mechanisms of SIGLEC15 in THCA still needed to be elucidated by further studies.
SNAI1-dependent upregulation of CD73 increases extracellular adenosine release to mediate immune suppression in TNBC
Authors: Hasmim Meriem , Xiao Malina , Van Moer Kris , Kumar Akinchan , Oniga Alexandra , Mittelbronn Michel , Duhem Caroline , Chammout Anwar , Berchem Guy , Thiery Jean Paul , Volpert Marianna , Hollier Brett , Noman Muhammad Zaeem , Janji Bassam
Published: September 2022

Triple-negative subtype of breast cancer (TNBC) is hallmarked by frequent disease relapse and shows highest mortality rate. Although PD-1/PD-L1 immune checkpoint blockades have recently shown promising clinical benefits, the overall response rate remains largely insufficient. Hence, alternative therapeutic approaches are warranted. Given the immunosuppressive properties of CD73-mediated adenosine release, CD73 blocking approaches are emerging as attractive strategies in cancer immunotherapy. Understanding the precise mechanism regulating the expression of CD73 is required to develop effective anti-CD73-based therapy. Our previous observations demonstrate that the transcription factors driving epithelial-to-mesenchymal transition (EMT-TF) can regulate the expression of several inhibitory immune checkpoints. Here we analyzed the role of the EMT-TF SNAI1 in the regulation of CD73 in TNBC cells. We found that doxycycline-driven SNAI1 expression in the epithelial -like TNBC cell line MDA-MB-468 results in CD73 upregulation by direct binding to the CD73 proximal promoter. SNAI1-dependent upregulation of CD73 leads to increased production and release of extracellular adenosine by TNBC cells and contributes to the enhancement of TNBC immunosuppressive properties. Our data are validated in TNBC samples by showing a positive correlation between the mRNA expression of CD73 and SNAI1. Overall, our results reveal a new CD73 regulation mechanism in TNBC that participates in TNBC-mediated immunosuppression and paves the way for developing new treatment opportunities for CD73-positive TNBC.
Effect of Angelica polysaccharide on mouse myeloid-derived suppressor cells
Authors: Shen Jie , Zhang Mengyu , Zhang Ke , Qin Yahan , Liu Meifang , Liang Shujuan , Chen Daquan , Peng Meiyu
Published: September 2022

Angelica polysaccharide (APS) is a polysaccharide extracted from Angelica sinensis and it is one of the main active components of Angelica sinensis. Many studies have demonstrated that APS can promote the activation and function of a variety of immune cells and is recognized as an immune enhancer, but the regulatory effect of APS on myeloid-derived suppressor cells (MDSC) is still unclear. In this study, we investigated the effects of APS on MDSC proliferation, differentiation and function through in vivo and in vitro experiments. In vitro, our results showed that APS promoted the proliferation, differentiation and immunosuppressive function of MDSC through STAT1 and STAT3 signaling pathways, and positively correlated with the expression level of Mannose receptor (MR, also known as CD206) and in a concentration-dependent manner on APS. In vivo, APS up-regulated T cells, γδT cells, CD8+T cells, natural killer cells, monocytes/macrophages, and granulocytes in the peripheral blood and spleen of mice to varying degrees and was accompanied by the same degree of increase in the proportion of MDSC. That reminds to the clinician that when applying APS as treatment they should pay attention to its possible side effects of increasing the quantity and function of MDSC, in order to increase its efficacy.
Increased DMSP availability during thermal stress influences DMSP-degrading bacteria in coral mucus
Authors: Gardner Stephanie G. , Nitschke Matthew R. , O’Brien James , Motti Cherie A. , Seymour Justin R. , Ralph Peter J. , Petrou Katherina , Raina Jean-Baptiste
Published: September 2022

Reef-building corals are among the largest producers of dimethylsulfoniopropionate (DMSP), an essential compound in marine biogeochemical cycles. DMSP can be catabolised in coral mucus by a wide diversity of coral-associated bacteria, where it can either be demethylated, leading to the incorporation of sulfur and carbon into bacterial biomass – or cleaved by lyases, releasing the climatically-active gas dimethyl sulfide (DMS). It has been demonstrated that thermal stress increases DMSP concentrations in many coral species, however the effect of increased DMSP availability on coral-associated bacteria has not been explored. Here we performed thermal stress experiments to examine how changes in DMSP availability impact bacterial degradation pathways in the mucus of Acropora millepora. DMSP concentrations increased with temperature, reaching a maximum of 177.3 μM after 10 days of heat stress, which represents the highest concentration of DMSP recorded in any environment to date. Bacterial communities in coral mucus were significantly different from the surrounding seawater, yet they did not vary significantly between temperature or time. However, during thermal stress, when DMSP concentrations increased, a significant increase in the abundance of both the demethylation gene dmdA and the cleavage gene dddP were recorded. Importantly, our results show that for the highest DMSP concentrations recorded (above 30 μM), the cleavage pathway became more abundant than the demethylation pathway. This suggests that under high DMSP concentrations characteristic of heat stress, a larger fraction of the DMSP pool in the coral mucus is likely catabolised through the DMS-producing cleavage pathway.
Trauma of bone and soft tissues in South American mummies—New cases provide further insight into violence and lethal outcome
Authors: Begerock Anna-Maria , Loynes Robert , Peschel Oliver K. , Verano John , Bianucci Raffaella , Martinez Armijo Isabel , González Mercedes , Nerlich Andreas G.
Published: September 2022

There exist numerous reports on violence in South American populations which shed a particular light on life and living conditions in those historic communities. Most studies have been performed on collections of isolated skulls. Whole-body investigations especially on well-preserved mummified human remains are rare. In the present study we investigated three South American mummies predating the Colonial Spanish period. The “Marburg” man lived between 996 and 1147 CE and was buried in typical burial bundle. The analysis of the textiles, ceramics and fishing tools associated with his naturally mummified body suggests that he most likely originated from the Arica region in Northern Chile and was possibly part of a fishing community. The “Delémont” natural mummies belong to an adult male and an adult female, respectively. The mummies, the textiles and grave goods were investigated. The ceramics suggest a provenance from the Arequipa region, supposing that all the artifacts were originally associated with the two mummies. The Delémont male mummy is 14C dated between 902 and 994 CE and the “Delémont” female mummy 14C dated between 1224 and 1282 CE. All mummies underwent Multidetector Computed Tomography which showed evidence of trauma, some of which were interpreted as evidence of interpersonal violence. An interdisciplinary approach was applied with the particular intention to identify trauma sequels and to evaluate their paleo-forensic potential. Evidence of violence was identified in the two male individuals. Our study provides evidence that the interdisciplinary investigation of well-preserved human remains may detect much more frequent traces of intentional trauma than previously thought. Particularly, trauma against the body may not be identified in studies on skulls alone, and trauma residues of internal organs/soft tissues will only be seen in mummies. We therefore add further evidence of two cases of (lethal) trauma in pre-colonial South-American male individuals.
Critical reflection on required service to the community propels prospective medical students toward higher empathy, compassion, and bias mitigation but are these gains sustainable?
Authors: Van Winkle Lon J. , Thornock Bradley O. , Schwartz Brian D. , Horst Alexis , Fisher Jensen A. , Michels Nicole
Published: September 2022

Purpose

We observed increased cognitive empathy and reflective capacity scores when prospective medical students wrote critical reflections on mandatory team service-learning in a Medical Humanities course, but these findings did not include a control group. Here we compare these survey results in similar courses with and without required service-learning.

Methods

Forty-three prospective medical students completed a Medical Humanities course requiring critical reflection on team service-learning. In comparison, 32 students finished a similar course in which service to the community was not mandatory. Before starting the courses, students completed reliable surveys of their cognitive empathy and reflective capacity, and more than 93% of the students completed the same surveys after finishing the courses.

Results

Students' cognitive empathy and reflective capacity scores increased significantly when service-learning was required, but the scores did not increase significantly when service to the community was not required. The effect size for the empathy increase was of crucial practical importance (r = 0.50), whereas it was of moderate practical importance for the increase in reflective capacity (r = 0.34).

Conclusions

These and prior findings strongly support the conclusion that students' critical reflection on mandatory team service-learning fosters development of their cognitive empathy and reflective capacity. We present a model program to incorporate critical reflection on service to the community throughout the curricula of all healthcare professions trainees.