bluuebunny/crossref_metadata_2025 huggingface dataset:
Att bygga relationer mellan lärare, student och naturvetenskapligt innehåll i digitala miljöer
Authors: Högström Per , Rundberg Mattias
Published: March 2021

Att bygga relationer är en viktig del av lärande och undervisning. Det handlar såväl om relationer mellan individer som mellan individer och ämnesinnehåll. Dessutom skapar relationer mellan teknik, pedagogik och ämneskunskap fundament för lärarprofessionen i ett allt mer digitaliserat samhälle. Den snabba övergång till undervisning på distans på grund av COVID-19 som många lärare vid universitet och skolor har gjort innebär nya utmaningar för byggandet av dessa relationer. Men även om det är svårare att skapa relationer på distans är det fortfarande möjligt. På Högskolan i Halmstad har undervisningen i lärarutbildningens kurser med naturvetenskapligt innehåll gett erfarenheter och anpassningar som är intressanta att dela med sig av. I vårt arbete som lärare innebar onlineläget att flera komplexa tekniska och professionella utmaningar har kunnat uppmärksammas och lösas. Syftet med den här texten är att beskriva hur vi tagit oss an de utmaningar som detta inneburit och att reflektera över de kompetenser som vi utvecklat under anpassningen av olika processer i vår undervisning till den rådande situationen.
Characterization of Innate Immune Responses to House Dust Mite Allergens: Pitfalls and Limitations
Authors: Jacquet Alain
Published: March 2021

Whereas house dust mite (HDM) allergy results from a dysregulated Th2-biased adaptive immune response, activation of innate immune signaling pathways is a critical prerequisite for the initiation of HDM sensitizations. Such innate sensing is mainly controlled by the airway epithelium and the skin. The resulting release of epithelial-derived proinflammatory cytokines and innate alarmins such as GM-CSF, IL-25, IL-33 and TSLP mediates the activation of ILC2 cells and cDCs to promote Th2-biased inflammation. Significant progress in the elucidation of HDM innate immune activation has been made in the past decade and highlighted key roles of the LPS/TLR4 axis, chitin-dependent pathways together with HDM protease allergens. However, the precise mechanisms by which HDM allergens are sensed by the innate immune system remain largely unknown. Such investigations are made difficult for several reasons. Among these are (1) the natural association of HDM allergens with immunostimulators from the mite exoskeleton as well as from environmental microorganisms/pollutants or endosymbiotic bacteria; (2) the purification of individual HDM allergens from extracts in sufficient amounts and devoid of any microbial and protein impurities; (3) the production of correctly folded recombinant HDM allergens which could display the same biological activity than their natural counterparts; (4) the accessibility to human epithelial samples with cellular heterogeneities and inter-donor variations; (5) the translation of experimental data from mouse models to humans is almost missing. The goal of the present mini-review is to emphasize some important limitations and pitfalls in the elucidation of innate immunostimulatory properties of HDM allergens.
Balance Impairments as Differential Markers of Dementia Disease Subtype
Authors: Mc Ardle Ríona , Pratt Stephanie , Buckley Christopher , Del Din Silvia , Galna Brook , Thomas Alan , Rochester Lynn , Alcock Lisa
Published: March 2021

Background

Accurately differentiating dementia subtypes, such as Alzheimer’s disease (AD) and Lewy body disease [including dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD)] is important to ensure appropriate management and treatment of the disease. Similarities in clinical presentation create difficulties for differential diagnosis. Simple supportive markers, such as balance assessments, may be useful to the diagnostic toolkit. This study aimed to identify differences in balance impairments between different dementia disease subtypes and normal aging using a single triaxial accelerometer.

Methods

Ninety-seven participants were recruited, forming four groups: cognitive impairment due to Alzheimer’s disease (AD group; n = 31), dementia with Lewy bodies (DLB group; n = 26), Parkinson’s disease dementia (PDD group; n = 13), and normal aging controls (n = 27). Participants were asked to stand still for 2 minutes in a standardized position with their eyes open while wearing a single triaxial accelerometer on their lower back. Seven balance characteristics were derived, including jerk (combined, mediolateral, and anterior–posterior), root mean square (RMS; combined, mediolateral, and anterior–posterior), and ellipsis. Mann–Whitney U tests identified the balance differences between groups. Receiver operating characteristics and area under the curve (AUC) determined the overall accuracy of the selected balance characteristics.

Results

The PDD group demonstrated higher RMS [combined (p = 0.001), mediolateral (p = 0.005), and anterior–posterior (p = 0.001)] and ellipsis scores (p < 0.002) than the AD group (AUC = 0.71–0.82). The PDD group also demonstrated significantly impaired balance across all characteristics (p ≤ 0.001) compared to the controls (AUC = 0.79–0.83). Balance differences were not significant between PDD and DLB (AUC = 0.69–0.74), DLB and AD (AUC = 0.50–0.65), DLB and controls (AUC = 0.62–0.68), or AD and controls (AUC = 0.55–0.67) following Bonferroni correction.

Discussion

Although feasible and quick to conduct, key findings suggest that an accelerometer-based balance during quiet standing does not differentiate dementia disease subtypes accurately. Assessments that challenge balance more, such as gait or standing with eyes closed, may prove more effective to support differential diagnosis.
The Interaction Efficiency of XPD-p44 With Bulky DNA Damages Depends on the Structure of the Damage
Authors: Petruseva Irina , Naumenko Natalia , Kuper Jochen , Anarbaev Rashid , Kappenberger Jeannette , Kisker Caroline , Lavrik Olga
Published: March 2021

The successful elimination of bulky DNA damages via the nucleotide excision repair (NER) system is largely determined by the damage recognition step. This step consists of primary recognition and verification of the damage. The TFIIH helicase XPD plays a key role in the verification step during NER. To date, the mechanism of damage verification is not sufficiently understood and requires further detailed research. This study is a systematic investigation of the interaction of ctXPD (Chaetomium thermophilum) as well as ctXPD-ctp44 with model DNAs, which contain structurally different bulky lesions with previously estimated NER repair efficiencies. We have used ATPase and DNA binding studies to assess the interaction of ctXPD with damaged DNA. The result of the analysis of ctXPD-ctp44 binding to DNA containing fluorescent and photoactivatable lesions demonstrates the relationship between the affinity of XPD for DNAs containing bulky damages and the ability of the NER system to eliminate the damage. Photo-cross-linking of ctXPD with DNA probes containing repairable and unrepairable photoactivatable damages reveals differences in the DNA interaction efficiency in the presence and absence of ctp44. In general, the results obtained indicate the ability of ctXPD-ctp44 to interact with a damage and suggest a significant role for ctp44 subunit in the verification process.
Telomere Length in Valve Tissue Is Shorter in Individuals With Aortic Stenosis and in Calcified Valve Areas
Authors: Saraieva Ilona , Benetos Athanase , Labat Carlos , Franco-Cereceda Anders , Bäck Magnus , Toupance Simon
Published: March 2021

Background

Short telomere length (TL) is associated with age-related diseases, in particular cardiovascular diseases. However, whether the onset and course of aortic stenosis (AS) is linked to TL in aortic valves remains unknown.

Objectives

To assess telomere dynamics (TL and telomerase activity) in aortic valves and the possible implication of TL in onset and course of AS.

Methods

DNA was extracted from aortic valves obtained from 55 patients (78.2% men; age, 37–79 years), who had undergone replacement surgery due to AS (AS group, n = 32), aortic valve regurgitation and aortic dilation (Non-AS group, n = 23). TL was measured by telomere restriction fragment analysis (TRF) in calcified and non-calcified aortic valve areas. Telomerase activity was evaluated using telomerase repeat amplification protocol (TRAP) in protein extracts from non-calcified and calcified areas of valves obtained from 4 additional patients (50% men; age, 27–70 years).

Results

TL was shorter in calcified aortic valve areas in comparison to non-calcified areas (n = 31, 8.58 ± 0.73 kb vs. 8.12 ± 0.75 kb, p < 0.0001), whereas telomerase activity was not detected in any of those areas. Moreover, patients from AS group displayed shorter telomeres in non-calcified areas than those from the Non-AS group (8.40 ± 0.64 kb vs. 8.85 ± 0.65, p = 0.01).

Conclusions

Short telomeres in aortic valves may participate in the development of AS, while concurrently the calcification process seems to promote further local decrease of TL in calcified areas of valves.
Nucleophosmin Protein Dephosphorylation by DUSP3 Is a Fine-Tuning Regulator of p53 Signaling to Maintain Genomic Stability
Authors: Russo Lilian C. , Ferruzo Pault Y. M. , Forti Fabio L.
Published: March 2021

The dual-specificity phosphatase 3 (DUSP3), an atypical protein tyrosine phosphatase (PTP), regulates cell cycle checkpoints and DNA repair pathways under conditions of genotoxic stress. DUSP3 interacts with the nucleophosmin protein (NPM) in the cell nucleus after UV-radiation, implying a potential role for this interaction in mechanisms of genomic stability. Here, we show a high-affinity binding between DUSP3-NPM and NPM tyrosine phosphorylation after UV stress, which is increased in DUSP3 knockdown cells. Specific antibodies designed to the four phosphorylated NPM’s tyrosines revealed that DUSP3 dephosphorylates Y29, Y67, and Y271 after UV-radiation. DUSP3 knockdown causes early nucleolus exit of NPM and ARF proteins allowing them to disrupt the HDM2-p53 interaction in the nucleoplasm after UV-stress. The anticipated p53 release from proteasome degradation increased p53-Ser15 phosphorylation, prolonged p53 half-life, and enhanced p53 transcriptional activity. The regular dephosphorylation of NPM’s tyrosines by DUSP3 balances the p53 functioning and favors the repair of UV-promoted DNA lesions needed for the maintenance of genomic stability.
Macrophages and Their Organ Locations Shape Each Other in Development and Homeostasis – A Drosophila Perspective
Authors: Mase Anjeli , Augsburger Jordan , Brückner Katja
Published: March 2021

Across the animal kingdom, macrophages are known for their functions in innate immunity, but they also play key roles in development and homeostasis. Recent insights from single cell profiling and other approaches in the invertebrate model organismDrosophila melanogasterreveal substantial diversity amongDrosophilamacrophages (plasmatocytes). Together with vertebrate studies that show genuine expression signatures of macrophages based on their organ microenvironments, it is expected thatDrosophilamacrophage functional diversity is shaped by their anatomical locations and systemic conditions.In vivoevidence for diverse macrophage functions has already been well established byDrosophilagenetics:Drosophilamacrophages play key roles in various aspects of development and organogenesis, including embryogenesis and development of the nervous, digestive, and reproductive systems. Macrophages further maintain homeostasis in various organ systems and promote regeneration following organ damage and injury. The interdependence and interplay of tissues and their local macrophage populations inDrosophilahave implications for understanding principles of organ development and homeostasis in a wide range of species.
Cerebral Ischemia-Reperfusion Is Associated With Upregulation of Cofilin-1 in the Motor Cortex
Authors: Xu Ming-Shu , Yin Lei-Miao , Cheng Ai-Fang , Zhang Ying-Jie , Zhang Di , Tao Miao-Miao , Deng Yun-Yi , Ge Lin-Bao , Shan Chun-Lei
Published: March 2021

Cerebral ischemia is one of the leading causes of death. Reperfusion is a critical stage after thrombolysis or thrombectomy, accompanied by oxidative stress, excitotoxicity, neuroinflammation, and defects in synapse structure. The process is closely related to the dephosphorylation of actin-binding proteins (e.g., cofilin-1) by specific phosphatases. Although studies of the molecular mechanisms of the actin cytoskeleton have been ongoing for decades, limited studies have directly investigated reperfusion-induced reorganization of actin-binding protein, and little is known about the gene expression of actin-binding proteins. The exact mechanism is still uncertain. The motor cortex is very important to save nerve function; therefore, we chose the penumbra to study the relationship between cerebral ischemia-reperfusion and actin-binding protein. After transient middle cerebral artery occlusion (MCAO) and reperfusion, we confirmed reperfusion and motor function deficit by cerebral blood flow and gait analysis. PCR was used to screen the high expression mRNAs in penumbra of the motor cortex. The high expression of cofilin in this region was confirmed by immunohistochemistry (IHC) and Western blot (WB). The change in cofilin-1 expression appears at the same time as gait imbalance, especially maximum variation and left front swing. It is suggested that cofilin-1 may partially affect motor cortex function. This result provides a potential mechanism for understanding cerebral ischemia-reperfusion.
Protective Effects of Dexmedetomidine on the Vascular Endothelial Barrier Function by Inhibiting Mitochondrial Fission via ER/Mitochondria Contact
Authors: She Han , Zhu Yu , Deng Haoyue , Kuang Lei , Fang He , Zhang Zisen , Duan Chenyang , Ye Jiaqing , Zhang Jie , Liu Liangming , Hu Yi , Li Tao
Published: March 2021

The damage of vascular endothelial barrier function induced by sepsis is critical in causing multiple organ dysfunctions. Previous studies showed that dexmedetomidine (Dex) played a vital role in protecting organ functions. However, whether Dex participates in protecting vascular leakage of sepsis and the associated underlying mechanism remains unknown yet. We used cecal ligation and puncture induced septic rats and lipopolysaccharide stimulated vascular endothelial cells (VECs) to establish models in vivo and in vitro, then the protective effects of Dex on the vascular endothelial barrier function of sepsis were observed, meanwhile, related mechanisms on regulating mitochondrial fission were further studied. The results showed that Dex could significantly reduce the permeability of pulmonary veins and mesenteric vessels, increase the expression of intercellular junction proteins, enhance the transendothelial electrical resistance and decrease the transmittance of VECs, accordingly protected organ functions and prolonged survival time in septic rats. Besides, the mitochondria of VECs were excessive division after sepsis, while Dex could significantly inhibit the mitochondrial fission and protect mitochondrial function by restoring mitochondrial morphology of VECs. Furthermore, the results showed that ER-MITO contact sites of VECs were notably increased after sepsis. Nevertheless, Dex reduced ER-MITO contact sites by regulating the polymerization of actin via α2 receptors. The results also found that Dex could induce the phosphorylation of the dynamin-related protein 1 through down-regulating extracellular signal-regulated kinase1/2, thus playing a role in the regulation of mitochondrial division. In conclusion, Dex has a protective effect on the vascular endothelial barrier function of septic rats. The mechanism is mainly related to the regulation of Drp1 phosphorylation of VECs, inhibition of mitochondrial division by ER-MITO contacts, and protection of mitochondrial function.
Three-Dimensional Architecture of Glomerular Endothelial Cells Revealed by FIB-SEM Tomography
Authors: Kawasaki Yuto , Hosoyamada Yasue , Miyaki Takayuki , Yamaguchi Junji , Kakuta Soichiro , Sakai Tatsuo , Ichimura Koichiro
Published: March 2021

Focused-ion beam-scanning electron microscopic (FIB-SEM) tomography enables easier acquisition of a series of ultrastructural, sectional images directly from resin-embedded biological samples. In this study, to clarify the three-dimensional (3D) architecture of glomerular endothelial cells (GEnCs) in adult rats, we manually extracted GEnCs from serial FIB-SEM images and reconstructed them on an Amira reconstruction software. The luminal and basal surface structures were clearly visualized in the reconstructed GEnCs, although only the luminal surface structures could be observed by conventional SEM. The luminal surface visualized via the reconstructed GEnCs was quite similar to that observed through conventional SEM, indicating that 3D reconstruction could be performed with high accuracy. Thus, we successfully described the 3D architecture of normal GEnCs in adult rats more clearly and precisely than ever before. The GEnCs were found to consist of three major subcellular compartments, namely, the cell body, cytoplasmic ridges, and sieve plates, in addition to two associated subcellular compartments, namely, the globular protrusions and reticular porous structures. Furthermore, most individual GEnCs made up a “seamless” tubular shape, and some of them formed an autocellular junction to make up a tubular shape. FIB-SEM tomography with reconstruction is a powerful approach to better understand the 3D architecture of GEnCs. Moreover, the morphological information revealed in this study will be valuable for the 3D pathologic evaluation of GEnCs in animal and human glomerular diseases and the structural analysis of developmental processes in the glomerular capillary system.
Thrombolysis Combined Therapy Using CuS@SiO2-PEG/uPA Nanoparticles
Authors: Fu Dapeng , Fang Qingbo , Yuan Fukang , Liu Junle , Ding Heyi , Chen Xuan , Cui Chaoyi , Ding Jinhui
Published: March 2021

Massive hemorrhage caused by the uncontrolled release of thrombolysis drugs is a key issue of thrombolysis therapy in clinical practice. In this study, we report a near-infrared (NIR) light-triggered drug delivery system, i.e., CuS@mSiO2-PEG (CSP) nanoparticles, for the loading of a thrombolytic drug (urokinase plasminogen activators, uPA). CSP nanoparticles with the CuS nanoparticles as photothermal agents and mesoporous SiO2 for the loading of uPA were synthesized using a facile hydrothermal method. The CSP core-shell nanoparticles were demonstrated to possess excellent photothermal performance, exhibiting a photothermal conversion efficiency of up to 52.8%. Due to the mesoporous SiO2 coating, the CSP core-shell nanoparticles exhibited appropriate pore size, high pore volume, and large surface area; thus, they showed great potential to be used as drug carriers. Importantly, the release of uPA from CuS@mSiO2-PEG/uPA (CSPA) carriers can be promoted by the NIR laser irradiation. The drug loading content of uPA for the as-prepared NIR-triggered drug delivery system was calculated to be 8.2%, and the loading efficiency can be determined to be as high as 89.6%. Due to the excellent photothermal effect of CSP nanocarriers, the NIR-triggered drug delivery system can be used for infrared thermal imaging in vivo. The in vivo thrombolysis assessment demonstrated that the NIR-triggered drug delivery system showed excellent thrombolytic ability under the irradiation of an 808 nm laser, showing the combined therapy for thrombolysis. As far as we know, the CSPA core-shell nanoparticles used as NIR-triggered drug delivery systems for thrombolysis have not been reported.
Novel Virulence Role of Pneumococcal NanA in Host Inflammation and Cell Death Through the Activation of Inflammasome and the Caspase Pathway
Authors: Tseng Yu-Wen , Chang Chun-Chi , Chang Yung-Chi
Published: March 2021

Streptococcus pneumoniaeis one of most deadly Gram-positive bacterium that causes significant mortality and morbidity worldwide. Intense inflammation and cytotoxicity is a hallmark of invasive pneumococcal disease. Pneumococcal NanA has been shown to exaggerate the production of inflammatory cytokines via unmasking of inhibitory Siglec-5 from its sialylcis-ligands. To further investigate the mechanistic role of NanA and Siglec-5 in pneumococccal diseases, we systemically analyzed genes and signaling pathways differentially regulated in macrophages infected with wild type and NanA-deficient pneumococcus. We found that NanA-mediated desialylation impairs the Siglec-5-TLR-2 interaction and reduces the recruitment of phosphatase SHP-1 to Siglec-5. This dysregulated crosstalk between TLR-2 and inhibitory Siglec-5 exaggerated multiple inflammatory and death signaling pathways and consequently caused excessive inflammation and cytotoxicity in the infected macrophage. Collectively, our results reveal a novel virulence role of NanA in pneumococcal pathogenesis and suggest that targeting NanA activity may ameliorate the pneumococcus-mediated inflammation and cytotoxicity in severe invasive pneumococcal diseases.
Assessing L. donovani Skin Parasite Load: A Proof of Concept Study of a Microbiopsy Device in an Indian Setting
Authors: Cloots Kristien , Singh Om Prakash , Singh Abhishek Kumar , Van der Auwera Gert , Kumar Prashant , Gedda Mallikarjuna Rao , Rai Tulika Kumari , Hasker Epco , Sundar Shyam , Boelaert Marleen
Published: March 2021

Background

In the endgame of the elimination initiative of visceral leishmaniasis (VL) on the Indian subcontinent, one of the main questions remaining is whether asymptomatically infected individuals also contribute to transmission. We piloted a minimally invasive microbiopsy device that could help answer this question. While the potential of this device has been previously illustrated in Ethiopia, no such information is available for the setting of the Indian subcontinent. In this proof of concept study we aimed to assess 1) to what extent skin parasite load obtained with the new microbiopsy device correlates with disease status, 2) to what extent skin parasite load correlates with blood parasite load in the same subject, and 3) to what extent the skin parasite load obtained from different sampling sites on the body correlates with one another.

Methods

We performed a pilot study in Bihar, India, including 29 VL patients, 28 PKDL patients, 94 asymptomatically infected individuals, 22 endemic controls (EC), and 28 non-endemic controls (NEC). Presence of infection with L. donovani in the blood was assessed using Direct Agglutination Test, rK39 ELISA, Whole Blood Analysis measuring IFN-γ and qPCR. A skin sample was collected with the microbiopsy device on two different locations on the body. PKDL patients provided a third skin sample from the edge of a PKDL lesion. Parasite load in the skin was measured by qPCR.

Findings

We found a clear correlation between the skin parasite load obtained with the microbiopsy device and disease status, with both higher skin parasite loads and higher proportions of positive skin samples in VL and PKDL patients compared to asymptomatics, EC, and NEC. No clear correlation between skin parasite load and blood parasite load was found, but a moderate correlation was present between the skin parasite load in arm and neck samples. In addition, we found four positive skin samples among asymptomatic individuals, and 85% of PKDL lesions tested positive using this microbiopsy device.

Conclusions

In line with previous pilot studies, our results from an Indian setting suggest that the microbiopsy device provides a promising tool to measure skin parasite load, and – if validated by xenodiagnosis studies – could facilitate much needed larger scale studies on infectiousness of human subgroups. In addition, we advocate further evaluation of this device as a diagnostic tool for PKDL.
Guiding Myocardial Revascularization by Algorithmic Interpretation of FFR Pullback Curves: A Proof of Concept Study
Authors: Argacha Jean-François , Decamp Jean , Vandeloo Bert , Babin Danilo , Lochy Stijn , Van den Bussche Karen , de Hemptinne Quentin , Xaplanteris Panagiotis , Magne Julien , Segers Patrick , Cosyns Bernard
Published: March 2021

Background: Coronary artery disease distribution along the vessel is a main determinant of FFR improvement after PCI. Identifying focal from diffuse disease from visual inspections of coronary angiogram (CA) and FFR pullback (FFR-PB) are operator-dependent. Computer science may standardize interpretations of such curves.

Methods: A virtual stenting algorithm (VSA) was developed to perform an automated FFR-PB curve analysis. A survey analysis of the evaluations of 39 vessels with intermediate disease on CA and a distal FFR <0.8, rated by 5 interventional cardiologists, was performed. Vessel disease distribution and PCI strategy were successively rated based on CA and distal FFR (CA); CA and FFR-PB curve (CA/FFR-PB); and CA and VSA (CA/VSA). Inter-rater reliability was assessed using Fleiss kappa and an agreement analysis of CA/VSA rating with both algorithmic and human evaluation (operator) was performed. We hypothesize that VSA would increase rater agreement in interpretation of epicardial disease distribution and subsequent evaluation of PCI eligibility.

Results: Inter-rater reliability in vessel disease assessment by CA, CA/FFR-PB, and CA/VSA were respectively, 0.32 (95% CI: 0.17–0.47), 0.38 (95% CI: 0.23–0.53), and 0.4 (95% CI: 0.25–0.55). The raters' overall agreement in vessel disease distribution and PCI eligibility was higher with the VSA than with the operator (respectively, 67 vs. 42%, and 80 vs. 70%, both p < 0.05). Compared to CA/FFR-PB, CA/VSA induced more reclassification toward a focal disease (92 vs. 56.2%, p < 0.01) with a trend toward more reclassification as eligible for PCI (70.6 vs. 33%, p = 0.06). Change in PCI strategy did not differ between CA/FFR-PB and CA/VSA (23.6 vs. 28.5%, p = 0.38).

Conclusions: VSA is a new program to facilitate and standardize the FFR pullback curves analysis. When expert reviewers integrate VSA data, their assessments are less variable which might help to standardize PCI eligibility and strategy evaluations.

Clinical Trial Registration:https://www.clinicaltrials.gov/ct2/show/NCT03824600.
Elevated Plasma Big Endothelin-1 at Admission Is Associated With Poor Short-Term Outcomes in Patients With Acute Decompensated Heart Failure
Authors: Mo Ran , Yang Yan-min , Yu Li-tian , Tan Hui-qiong , Zhu Jun
Published: March 2021

Objective: We aimed to evaluate the association between plasma big endothelin-1 (ET-1) at admission and short-term outcomes in acute decompensated heart failure (ADHF) patients.

Methods: In this single-center, retrospective study, a total of 746 ADHF patients were enrolled and divided into three groups according to baseline plasma big ET-1 levels: tertile 1 (<0.43 pmol/L, n = 250), tertile 2 (between 0.43 and 0.97 pmol/L, n = 252), and tertile 3 (>0.97 pmol/L, n = 244). The primary outcomes were all-cause death, cardiac arrest, or utilization of mechanical support devices during hospitalization. Logistic regression analysis and net reclassification improvement approach were applied to assess the predictive power of big ET-1 on short-term outcomes.

Results: During hospitalization, 92 (12.3%) adverse events occurred. Etiology, arterial pH, lactic acid, total bilirubin, serum creatine, serum uric acid, presence of atrial fibrillation and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels were positively correlated with plasma big ET-1 level, whereas systolic blood pressure, serum sodium, hemoglobin, albumin, and estimated glomerular filtration rate were negatively correlated. In multivariate logistic regression, tertile 3 compared with tertile 1 had a 3.68-fold increased risk of adverse outcomes [odds ratio (OR) = 3.681, 95% confidence interval (CI) 1.410–9.606, p = 0.008]. However, such adverse effect did not exist between tertile 2 and tertile 1 (OR = 0.953, 95% CI 0.314–2.986, p = 0.932). As a continuous variable, big ET-1 level was significantly associated with primary outcome (OR = 1.756, 95% CI 1.413–2.183, p < 0.001). The C statistic of baseline big ET-1 was 0.66 (95% CI 0.601–0.720, p < 0.001). Net reclassification index (NRI) analysis showed that big ET-1 provided additional predictive power when combining it to NT-proBNP (NRI = 0.593, p < 0.001).

Conclusion: Elevated baseline big ET-1 is an independent predictor of short-term adverse events in ADHF patients and may provide valuable information for risk stratification.
Bisphenol A and Bisphenol S Induce Endocrine and Chromosomal Alterations in Brown Trout
Authors: Frenzilli Giada , Martorell-Ribera Joan , Bernardeschi Margherita , Scarcelli Vittoria , Jönsson Elisabeth , Diano Nadia , Moggio Martina , Guidi Patrizia , Sturve Joachim , Asker Noomi
Published: March 2021

Bisphenol A is a widely used compound found in large amount of consumer products. As concerns have been raised about its toxicological and public health effect, the use of alternatives to bisphenol A are now increasing. Bisphenol S is one of the analogues being used as a replacement for bisphenol A despite the fact that little is known about the effects of bisphenol S on living organisms. In this study, we investigated the potential endocrine and genotoxic effects of bisphenol A and bisphenol S in juvenile brown trout (Salmo trutta). The fish were exposed to the compounds for either 2 weeks or 8 weeks via sustained-release cholesterol implants containing doses of 2 mg/kg fish or 20 mg/kg fish of the substances. The effects on the thyroid hormone levels and the estrogenic disrupting marker vitellogenin were evaluated, along with the genotoxic markers micronucleated cells and erythrocyte nuclear abnormalities. An increase in plasma vitellogenin was observed in fish exposed to the high dose of bisphenol A for 2 weeks. At this experimental time the level of the thyroid hormone triiodothyronine (T3) in plasma was elevated after bisphenol S exposure at the high concentration, and paralleled by an increase of micronucleated cells. Moreover, bisphenol A induced an increase of micronuclei frequency in fish erythrocytes after the exposure at the lowest dose tested. Taken together the results indicate that both bisphenol A and its alternative bisphenol S cause endocrine disrupting and genotoxic effects in brown trout, although suggesting two different mechanisms of damage underlying bisphenol A and bisphenol S activity.
Adapting Research, Management, and Governance to Confront Socioecological Uncertainties in Novel Ecosystems
Authors: McKelvey Kevin S. , Block William M. , Jain Theresa B. , Luce Charles H. , Page-Dumroese Deborah S. , Richardson Bryce A. , Saab Victoria A. , Schoettle Anna W. , Sieg Carolyn H. , Williams Daniel R.
Published: March 2021

Wildland research, management, and policy in western democracies have long relied on concepts of equilibrium: succession, sustained yield, stable age or species compositions, fire return intervals, and historical range of variability critically depend on equilibrium assumptions. Not surprisingly, these largely static concepts form the basis for societal expectations, dominant management paradigms, and environmental legislation. Knowledge generation has also assumed high levels of stasis, concentrating on correlational patterns with the expectation that these patterns would be reliably transferrable. Changes in climate, the introduction of large numbers of exotic organisms, and anthropogenic land conversion are leading to unprecedented changes in disturbance regimes and landscape composition. Importantly, these changes are largely non-reversable; once introduced exotic species are seldom eradicated, climates will continue to warm for the foreseeable future, and many types of land conversion cannot be easily undone. Due to their effects on extant infrastructure and expectations for ecosystem services, these changes are, and will be, viewed by western societies as overwhelmingly negative. The continued acceleration of change will generate increasingly novel systems for which the transferability of correlational relationships will prove unreliable. Our abilities to predict system trajectories will therefore necessarily decrease. In this environment, top-down, expert dominated approaches to environmental decision making are unlikely to produce results that meet broader societal expectations. To be successful we need to embrace a more inclusive paradigm of collaborative governance and multiple forms of knowledge for adapting to constant change, including indigenous epistemological systems. By increasing public and stakeholder participation, we can encourage collaborative social learning allowing all parties to more fully understand the complexities and tradeoffs associated with wildland management and the technical limits of models that seek to quantify those tradeoffs. System novelty will necessarily make forecasting more dependent on predictive modeling and will require better models. Data collection should therefore be strongly influenced by model input requirements and validation; research will need to focus on fundamental and causal relationships to a much greater degree than is done currently.
Following Guidelines for Drug-Resistant Tuberculosis: “Yes, it’s a challenge”
Authors: Gray Adam T. , Wood Caroline E. , Boyles Tom , Luedtke Susanne , Birjovanu Georgiana , Hughes Jennifer , Kostkova Patty , Esmail Hanif
Published: March 2021

Background

Drug-resistant tuberculosis (DR-TB) is a major contributor to antimicrobial resistance (AMR) globally and is projected to be responsible for up to a quarter of AMR-associated deaths in the future. Management of DR-TB is increasingly decentralised to primary healthcare settings, and simultaneously becoming more complex due to a growing range of treatment options (e.g. novel agents, shorter regimens). This is reflected in the numerous recent updates to international guidelines and as such understanding the barriers and enablers to how healthcare workers access and use guidelines is vital.

Materials and Methods

We used an established psychological framework – the theoretical domains framework (TDF) – to construct and analyse an online survey and focus groups to explore healthcare workers current use of DR-TB guidelines in South Africa. We aimed to identify barriers and enablers with which to direct future attempts at improving guideline use.

Results

There were 19 responses to the online survey and 14 participants in two focus groups. 28% used the most up-to-date national guidelines, 79% accessed guidelines primarily on electronic devices. The TDF domains of ‘Social Influences’ (mean Likert score = 4.3) and ‘Beliefs about Consequences’ (4.2) were key enablers, with healthcare workers encouraged to use guidelines and also recognising the value in doing so. ‘Environmental Resources’ (3.7) and ‘Knowledge’ (3.3) were key barriers with limited, or variable access to guidelines and lack of confidence using them being notable issues. This was most noted for certain subgroups: children, HIV co-infected, pregnant women (2.7).

Discussion

Current use of DR-TB guidelines in South Africa is suboptimal. Planned interventions should focus on overcoming the identified key barriers and might include an increased use of digital tools.
Environmental and Anthropogenic Factors Shape Major Bacterial Community Types Across the Complex Mountain Landscape of Switzerland
Authors: Mayerhofer Johanna , Wächter Daniel , Calanca Pierluigi , Kohli Lukas , Roth Tobias , Meuli Reto Giulio , Widmer Franco
Published: March 2021

Mountain areas harbor large climatic and geographic gradients and form numerous habitats that promote high overall biodiversity. Compared to macroorganisms, knowledge about drivers of biodiversity and distribution of soil bacteria in mountain regions is still scarce but a prerequisite for conservation of bacterial functions in soils. An important question is, whether soil bacterial communities with similar structures share environmental preferences. Using metabarcoding of the 16S rRNA gene marker, we assessed soil bacterial communities at 255 sites of a regular grid covering the mountainous landscape of Switzerland, which is characterized by close location of biogeographic regions that harbor different land-use types. Distribution of bacterial communities was mainly shaped by environmental selection, as revealed by 47.9% variance explained by environmental factors, with pH (29%) being most important. Little additional variance was explained by biogeographic regions (2.8%) and land-use types (3.3%). Cluster analysis of bacterial community structures revealed six bacterial community types (BCTs), which were associated to several biogeographic regions and land-use types but overall differed mainly in their preference for soil pH. BCT I and II occurred at neutral pH, showed distinct preferences for biogeographic regions mainly differing in elevation and nutrient availability. BCT III and IV differed only in their preferred soil pH. BCT VI occurred in most acidic soils (pH 3.6) and almost exclusively at forest sites. BCT V occurred in soils with a mean pH of 4 and differed from BCT VI in preference for lower values of organic C, total nitrogen and their ratio. Indicator species and bipartite network analyses revealed 3,998 OTUs associating to different levels of environmental factors and BCTs. Taxonomic classification revealed opposing associations of taxa deriving from the same phyla. The results revealed that pH, land-use type, biogeographic region, and nutrient availability were the main factors shaping bacterial communities across Switzerland. Indicator species and bipartite network analyses revealed environmental preferences of bacterial taxa. Combining information of environmental factors and BCTs yielded increased resolution of the factors shaping soil bacterial communities and provided an improved biodiversity framework. OTUs exclusively associated to BCTs provide a novel resource to identify unassessed environmental drivers.
Soluble Epoxide Hydrolase Inhibition Prevents Experimental Type 4 Cardiorenal Syndrome
Authors: Hamzaoui Mouad , Roche Clothilde , Coquerel David , Duflot Thomas , Brunel Valery , Mulder Paul , Richard Vincent , Bellien Jérémy , Guerrot Dominique
Published: March 2021

Objectives: Cardiovascular diseases (CVD) remain the leading cause of morbimortality in patients with chronic kidney disease (CKD). The aim of this study was to assess the cardiovascular impact of the pharmacological inhibition of soluble epoxide hydrolase (sEH), which metabolizes the endothelium-derived vasodilatory and anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatrienoic acid (DHETs), in the 5/6 nephrectomy (Nx) mouse model.

Methods and Results: Compared to sham-operated mice, there was decrease in EET-to-DHET ratio 3 months after surgery in vehicle-treated Nx mice but not in mice treated with the sEH inhibitor t-AUCB. Nx induced an increase in plasma creatinine and in urine albumin-to-creatinine ratio as well as the development of kidney histological lesions, all of which were not modified by t-AUCB. In addition, t-AUCB did not oppose Nx-induced blood pressure increase. However, t-AUCB prevented the development of cardiac hypertrophy and fibrosis induced by Nx, as well as normalized the echocardiographic indices of diastolic and systolic function. Moreover, the reduction in endothelium-dependent flow-mediated dilatation of isolated mesenteric arteries induced by Nx was blunted by t-AUCB without change in endothelium-independent dilatation to sodium nitroprusside.

Conclusion: Inhibition of sEH reduces the cardiac remodelling, and the diastolic and systolic dysfunctions associated with CKD. These beneficial effects may be mediated by the prevention of endothelial dysfunction, independent from kidney preservation and antihypertensor effect. Thus, inhibition of sEH holds a therapeutic potential in preventing type 4 cardiorenal syndrome.
Individual Differences in Working Memory and the N2pc
Authors: Couperus Jane W. , Lydic Kirsten O. , Hollis Juniper E. , Roy Jessica L. , Lowe Amy R. , Bukach Cindy M. , Reed Catherine L.
Published: March 2021

The lateralized ERP N2pc component has been shown to be an effective marker of attentional object selection when elicited in a visual search task, specifically reflecting the selection of a target item among distractors. Moreover, when targets are known in advance, the visual search process is guided by representations of target features held in working memory at the time of search, thus guiding attention to objects with target-matching features. Previous studies have shown that manipulating working memory availability via concurrent tasks or within task manipulations influences visual search performance and the N2pc. Other studies have indicated that visual (non-spatial) vs. spatial working memory manipulations have differential contributions to visual search. To investigate this the current study assesses participants' visual and spatial working memory ability independent of the visual search task to determine whether such individual differences in working memory affect task performance and the N2pc. Participants (n = 205) completed a visual search task to elicit the N2pc and separate visual working memory (VWM) and spatial working memory (SPWM) assessments. Greater SPWM, but not VWM, ability is correlated with and predicts higher visual search accuracy and greater N2pc amplitudes. Neither VWM nor SPWM was related to N2pc latency. These results provide additional support to prior behavioral and neural visual search findings that spatial WM availability, whether as an ability of the participant's processing system or based on task demands, plays an important role in efficient visual search.
Serum Metabolic Profiling Analysis of Chronic Gastritis and Gastric Cancer by Untargeted Metabolomics
Authors: Yu Lin , Lai Qinhuai , Feng Qian , Li Yuanmeng , Feng Jiafu , Xu Bei
Published: March 2021

Purpose

Gastric cancer is a common tumor of the digestive system. Identification of potential molecules associated with gastric cancer progression and validation of potential biomarkers for gastric cancer diagnosis are very important. Thus, the aim of our study was to determine the serum metabolic characteristics of the serum of patients with chronic gastritis (CG) or gastric cancer (GC) and validate candidate biomarkers for disease diagnosis.

Experimental Design

A total of 123 human serum samples from patients with CG or GC were collected for untargeted metabolomic analysis via UHPLC-Q-TOF/MS to determine characteristics of the serum. Principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and heat map were used for multivariate analysis. In addition, commercial databases were used to identify the pathways of metabolites. Differential metabolites were identified based on a heat map with a t-test threshold (p < 0.05), fold-change threshold (FC > 1.5 or FC < 2/3) and variable importance in the projection (VIP >1). Then, differential metabolites were analyzed by receiver operating characteristic (ROC) curve to determine candidate biomarkers. All samples were analyzed for fasting lipid profiles.

Results

Analysis of serum metabolomic profiles indicated that most of the altered metabolic pathways in the three groups were associated with lipid metabolism (p < 0.05) and lipids and lipid-like molecules were the predominating metabolites within the top 100 differential metabolites (p < 0.05, FC > 1.5 or FC < 2/3, and VIP >1). Moreover, differential metabolites, including hexadecasphinganine, linoleamide, and N-Hydroxy arachidonoyl amine had high diagnostic performance according to PLS-DA. In addition, fasting lipid profile analysis showed the serum levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A1 (Apo-A1) were decreased concomitant to the progression of the progression of the disease compared with those in the control group (p < 0.05).

Conclusions

Thus, this study demonstrated that lipid metabolism may influence the development of CG to GC. Hexadecasphinganine, linoleamide, and N-Hydroxy arachidonoyl amine were selected as candidate diagnostic markers for CG and GC.
Dynamic PET/CT Imaging of 68Ga-FAPI-04 in Chinese Subjects
Authors: Wang Shuailiang , Zhou Xin , Xu Xiaoxia , Ding Jin , Liu Teli , Jiang Jinquan , Li Nan , Zhu Hua , Yang Zhi
Published: March 2021

This study aims to further explore dynamic 68Ga-FAPI-04 PET/CT imaging of healthy Chinese subjects and lung cancer patients. Moreover, the variability of 68Ga-FAPI-04 uptake in normal organs was measured to provide a basis for analyzing its biological distribution, interpreting auxiliary images, determining the reliability of image quantification, and monitoring treatment. Six patients (3 subjects without tumors and 3 lung cancer patients) separately underwent 68Ga-FAPI-04 and 2-[18F]FDG PET/CT imaging within 1 week. The biodistribution and internal radiation dosimetry were reported and compared with data previously obtained from Caucasian patients. Moreover, the mean SUV (standardized uptake value) was normalized to body mass or to lean body mass (SUL), and the coefficients of variation (CVs) were calculated and compared for each volume of interest. The average whole-body effective dose was calculated to be 1.27E-02 mSv/MBq, which was comparable with previously reported results of 68Ga-FAPI-04 probes. Furthermore, the SUVmean was slightly higher than the SULmean in most organs; however, the CV of the SULmean for most organs was higher than that of the SUVmean at later time points. In the liver, the CV of the SUVmean was lower (12.7%) than that of the SULmean and was similar to the CV for corresponding 2-[18F]FDG PET/CT value (11.8%). In addition, 68Ga-FAPI-04 PET/CT showed good efficacy for diagnosing lung cancer patients in this study. A comparison of the radiation dosimetry obtained before from a Caucasian population demonstrated no clinically significant differences between these two populations after 68Ga-FAPI-04 injection. The variability in most organs was slightly lower for SUVmean than for SULmean, suggesting that SUVmean may be the preferable parameter for quantifying images obtained with 68Ga-FAPI-04. In addition, 68Ga-FAPI-04 PET/CT imaging is expected to be a promising tool for diagnosing lung cancer.
The Advantages of Connectivity Map Applied in Traditional Chinese Medicine
Authors: Jiang Huimin , Hu Cheng , Chen Meijuan
Published: March 2021

Amid the establishment and optimization of Connectivity Map (CMAP), the functional relationships among drugs, genes, and diseases are further explored. This biological database has been widely used to identify drugs with common mechanisms, repurpose existing drugs, discover the molecular mechanisms of unknown drugs, and find potential drugs for some diseases. Research on traditional Chinese medicine (TCM) has entered a new era in the wake of the development of bioinformatics and other subjects including network pharmacology, proteomics, metabolomics, herbgenomics, and so on. TCM gradually conforms to modern science, but there is still a torrent of limitations. In recent years, CMAP has shown its distinct advantages in the study of the components of TCM and the synergetic mechanism of TCM formulas; hence, the combination of them is inevitable.