bluuebunny/crossref_metadata_2025 huggingface dataset:
Intracellular Cholesterol Synthesis and Transport
Authors: Shi Qingyang , Chen Jiahuan , Zou Xiaodong , Tang Xiaochun
Published: March 2022

Cholesterol homeostasis is related to multiple diseases in humans, including cardiovascular disease, cancer, and neurodegenerative and hepatic diseases. The cholesterol levels in cells are balanced dynamically by uptake, biosynthesis, transport, distribution, esterification, and export. In this review, we focus on de novo cholesterol synthesis, cholesterol synthesis regulation, and intracellular cholesterol trafficking. In addition, the progression of lipid transfer proteins (LTPs) at multiple contact sites between organelles is considered.
Subsidence Induced by Gas Extraction: A Data Assimilation Framework to Constrain the Driving Rock Compaction Process at Depth
Authors: Candela Thibault , Chitu A. G. , Peters E. , Pluymaekers M. , Hegen D. , Koster Kay , Fokker Peter A.
Published: March 2022

Surface movement can be induced by many human subsurface activities: production of natural gas, geothermal heat extraction, ground water extraction, phreatic groundwater level lowering, storage of natural gas and CO2. In this manuscript, we focus on subsidence caused by gas production. While geological interpretations, seismic campaigns and flow modeling often provide a relatively rich pre-existing knowledge, understanding of the driving mechanisms for production-induced subsidence is still poor and forecasts are often very uncertain. This is related to the multiple poorly constrained models that translate gas production to ground surface displacements. Currently, a biased constraint of these models is inferred by arbitrarily pre-selecting a subset of those. Here, we have devised and deployed an integrated approach of the entire chain of models from the flow simulations to the ground surface displacements which, for the first time, accounts for all our pre-existing knowledge in terms of processes and uncertainties attached to them. More specifically for the transfer between reservoir depletion to compacting volume at depth, four reservoir-rock compaction models are a-priori considered, ranging from linear elastic model to nonlinear time-dependent viscous-type model. After assimilation of the geodetic observations (i.e., the ground-surface displacements) with ensemble-smoother algorithms, we demonstrate that even when all the a-priori known complexities were present in all steps of the modelling chain, the model parameter uncertainties of each model could be reduced. Interestingly we demonstrate that one can discriminate which reservoir-rock compaction model driving subsidence is activated at depth. This identification of the activated compaction model at depth is crucial to build confidence in our subsidence forecasts. The predictive power of the integrated approach is demonstrated with an ensemble of synthetic but complex reservoir flow simulations mimicking all the characteristics and uncertainties representative for real gas fields in the north of the Netherlands.
An Improved Method for PWR Fuel Failure Detection Using Cascade-forward Neural Network With Decision Tree
Authors: Dong Bing , Yang Kang , Zhang Wei , Yin Junlian , Wang Dezhong
Published: March 2022

When a fuel rod is damaged, determining the degree of fuel failure makes sense. The operators can decide whether to continue operating the reactor or shut it down based on the severity of the fuel failure. The isotopic ratio of two radioactive fission products (FPs) is a typical technique for evaluating the degree of fuel failure, although this is not applicable in the case of little fuel failure but large tramp uranium mass. The feedforward neural network (FFNN) has been used to identify fuel failures in order to overcome the shortcomings of the isotopic ratio method, although there is still inadequacy in the ability to distinguish between an intact fuel rod and a defective fuel rod with a small defect. In this study, we propose a cascade-forward neural network with a decision tree for fuel failure detection that performs well at classifying the degree of fuel failure and, in particular, at differentiating between an intact fuel rod and a defective fuel rod with a small size defect. The input of the neural network is the specific activity of FPs measured in the coolant. The degree of fuel failure is determined by the neural network’s output, which is labeled using one-hot encoding. The training set is constructed using the Booth-type diffusion model and the first-order kinetic model. The performance of the improved neural network is demonstrated. It is shown that the improved method is more accurate and responsive than the previous neural network when recognizing the onset of fuel failure. Finally, the most important nuclides are determined through the sensitivity analysis, and the neural network is simplified according to the importance of nuclides and the limitation of the radioactive detector in practical application.
Bird Migration at the Edge – Geographic and Anthropogenic Factors but Not Habitat Properties Drive Season-Specific Spatial Stopover Distributions Near Wide Ecological Barriers
Authors: Schekler Inbal , Smolinsky Jaclyn A. , Troupin David , Buler Jeffrey J. , Sapir Nir
Published: March 2022

Stopping-over is critical for migrating birds. Yet, our knowledge of bird stopover distributions and their mechanisms near wide ecological barriers is limited. Using low elevation scans of three weather radars covering 81,343 km2, we quantified large-scale bird departure patterns during spring and autumn (2014–2018) in between two major ecological barriers, the Sahara Desert and Mediterranean Sea. Boosted Regression Tree models revealed that bird distributions differed between the seasons, with higher densities in the desert and its edge, as well as inland from the sea, during spring and a predominantly coastal distribution in the autumn. Bird distributions were primarily associated with broad-scale geographic and anthropogenic factors rather than individual fine-scale habitat types. Notably, artificial light at night strongly correlated with high densities of migrants, especially in the autumn. Autumn migrants also selected sites located close to water sources. Our findings substantially advance the understanding of bird migration ecology near ecological barriers and facilitate informed conservation efforts in a highly populated region by identifying a few high-priority stopover areas of migrating birds.
Characterization of Pyroptosis-Related Subtypes via RNA-Seq and ScRNA-Seq to Predict Chemo-Immunotherapy Response in Triple-Negative Breast Cancer
Authors: Li Chenlu , Pan Jingjing , Jiang Yinyan , Wu Yanzhi , Jin Zhenlin , Chen Xupeng
Published: March 2022

Triple-negative breast cancer (TNBC) is associated with poor prognosis and invalid therapeutical response to immunotherapy due to biological heterogeneity. There is an urgent need to screen for reliable indices, especially immunotherapy-associated biomarkers that can predict patient outcomes. Pyroptosis, as an inflammation-induced type of programmed cell death, is shown to create a tumor-suppressive environment and improve the chemotherapeutic response in multiple tumors. However, the specific therapeutic effect of pyroptosis in TNBC remains unclear. In this study, we present a consensus clustering by pyroptosis-related signatures of 119 patients with TNBC into two subtypes (clusterA and clusterB) with distinct immunological and prognostic characteristics. First, clusterB, associated with better outcomes, was characterized by a significantly higher pyroptosis-related signature expression, tumor microenvironment prognostic score, and upregulation of immunotherapy checkpoints. A total of 262 differentially expressed genes between the subtypes were further identified and the Ps-score was built using LASSO and COX regression analyses. The external GEO data set demonstrated that cohorts with low Ps-scores consistently had higher expression of pyroptosis-related signatures, immunocyte infiltration levels, and better prognosis. In addition, external immunotherapy and chemotherapy cohorts validated that patients with lower Ps-scores exhibited significant therapeutic response and clinical benefit. Combined with other clinical characteristics, we successfully constructed a nomogram to effectively predict the survival rate of patients with TNBC. Finally, using the scRNA-seq data sets, we validated the landscape of cellular subtypes of TNBC and successfully constructed an miRNA-Ps-score gene interaction network. These findings indicated that the systematic assessment of tumor pyroptosis and identification of Ps-scores has potential clinical implications and facilitates tailoring optimal immunotherapeutic strategies for TNBC.
Transcriptome Sequencing of the Pale Anemones (Exaiptasia diaphana) Revealed Functional Peptide Gene Resources of Sea Anemone
Authors: Fu Jinxing , He Yanbin , Peng Chao , Tang Tianle , Jin Aihua , Liao Yanling , Shi Qiong , Gao Bingmiao
Published: March 2022

Sea anemone venom is a marine drug resource library with pharmacological and biotechnology value, and it contains complex and diverse functional peptide neurotoxins. However, the venom components of only a limited number of sea anemone species have been globally evaluated by transcriptomics and proteomics. In this study, 533 putative protein as well as peptide toxin sequences were found on a large scale from dissimilar developmental stages of sea anemone Exaiptasia diaphana, which can be divided into 75 known superfamilies according to the predicted functions. Among them, the proportion of protein is 72.98%, and its main families are metalloproteases, chymotrypsinogen like, collagen, pancreatic lipase-associated protein like, and G-protein coupled receptor, while the proportion of peptides is 27.02%, and main families are ShK domain, thrombin, Kunitz-type, defensin, as well as insulin-like peptide. Finally, typical anemone peptide neurotoxins were screened, and the 3D structure and pharmacological activity of these anemone peptide neurotoxins were predicted by homology modeling. We elucidate on a valuable high-throughput approach for obtaining sea anemone proteins and peptides. Our findings form the basis for targeted studies on the diversity as well as pharmacological effects of sea anemone peptide neurotoxins.
Shelf Water Export at the Brazil-Malvinas Confluence Evidenced From Combined in situ and Satellite Observations
Authors: Manta Gaston , Speich Sabrina , Barreiro Marcelo , Trinchin Romina , de Mello Camila , Laxenaire Rémi , Piola Alberto R.
Published: March 2022

The Brazil-Malvinas Confluence (BMC) is the region where opposing and intense western boundary currents meet along the Southwestern Atlantic slope at about 38°S, generating one of the most energetic mesoscale regions of the global ocean. Based on shipborne observations acquired within the Uruguayan Economic Exclusive Zone (EEZ), combined with satellite data and an eddy tracking algorithm, we analyze the cross-shelf exchanges during May 2016, when the BMC was in an anomalous northern position. Two types of shelf water export were observed triggered by mesoscale dynamics: one was the export of shallow Rio de la Plata Plume waters driven off-shelf by the retroflection of the Brazil Current. This export formed a 70 km wide, 20 m deep filament that propagated offshore at 0.3 m s–1, with a transport of 0.42 Sv. It lasted about 10 days before being mixed with ambient Confluence waters by strong winds. An additional type of off-shelf transport consisted of a subsurface layer of Subantarctic Shelf Waters (SASW) about 60 m thick that subducted at the BMC reaching 130 m deep and transporting 0.91 ± 0.91 Sv. We show that geostrophic currents derived from satellite altimetry over the slope can be useful to track this subsurface off-shelf export as they are significantly correlated with absolute velocity measurements at this depth. Argo temperature and salinity profiles show evidence of these two types of shelf water export occurring between the BMC front and the separation of the Brazil Current from the shelf-break, suggesting this is a relatively frequent phenomenon, in agreement with previous observations.
Use of a Minimal Microbial Consortium to Determine the Origin of Kombucha Flavor
Authors: Tran Thierry , Billet Kevin , Torres-Cobos Berta , Vichi Stefania , Verdier François , Martin Antoine , Alexandre Hervé , Grandvalet Cosette , Tourdot-Maréchal Raphaëlle
Published: March 2022

Microbiological, chemical, and sensory analyses were coupled to understand the origins of kombucha organoleptic compounds and their implication in the flavor of the kombucha beverage. By isolating microorganisms from an original kombucha and comparing it to monocultures and cocultures of two yeasts (Brettanomyces bruxellensis and Hanseniaspora valbyensis) and an acetic acid bacterium (Acetobacter indonesiensis), interaction effects were investigated during the two phases of production. 32 volatile compounds identified and quantified by Headspace-Solid Phase-MicroExtraction-Gas Chromatography/Mass Spectrometry (HS-SPME-GC/MS) were classified according to their origin from tea or microorganisms. Many esters were associated to H. valbyensis, while alcohols were associated to both yeasts, acetic acid to A. indonesiensis, and saturated fatty acids to all microorganisms. Concentration of metabolites were dependent on microbial activity, yeast composition, and phase of production. Sensory analysis showed that tea type influenced the olfactive perception, although microbial composition remained the strongest factor. Association of B. bruxellensis and A. indonesiensis induced characteristic apple juice aroma.
The Antibody Response Against Neuraminidase in Human Influenza A (H3N2) Virus Infections During 2018/2019 Flu Season: Focusing on the Epitopes of 329-N-Glycosylation and E344 in N2
Authors: Ge Jing , Lin Xiaojing , Guo Jinlei , Liu Ling , Li Zi , Lan Yu , Liu Liqi , Guo Junfeng , Lu Jian , Huang Weijuan , Xin Li , Wang Dayan , Qin Kun , Xu Cuiling , Zhou Jianfang
Published: March 2022

Seasonal influenza A (H3N2) virus has been a concern since its first introduction in humans in 1968. Accumulating antigenic changes in viral hemagglutinin (HA), particularly recent cocirculations of multiple HA genetic clades, allow H3N2 virus evade into humans annually. From 2010, the binding of neuraminidase (NA) to sialic acid made the traditional assay for HA inhibition antibodies (Abs) unsuitable for antigenicity characterization. Here, we investigated the serum anti-NA response in a cohort with a seroconversion of microneutralizing (MN) Abs targeting the circulating strain, A/Singapore/INFIMH-16-0019/2016 (H3N2, 3C.2a1)-like, a virus during 2018/2019 flu seasons. We discovered that MN Ab titers show no difference between children and adults. Nevertheless, higher titers of Abs with NA activity inhibition (NI) activity of 129 and seroconversion rate of 68.42% are presented in children aged 7–17 years (n = 19) and 73.47 and 41.17% in adults aged 21–59 years (n = 17), respectively. The MN Abs generated in children display direct correlations with HA- and NA-binding Abs or NI Abs. The NI activity exhibited cross-reactivity to N2 of H3N2 viruses of 2007 and 2013, commonly with 329-N-glycosylation and E344 in N2, a characteristic of earlier 3C.2a H3N2 virus in 2014. The percentage of such viruses pronouncedly decreased and was even replaced by those dominant H3N2 viruses with E344K and 329 non-glycosylation, which have a significantly low activity to the tested antisera. Our findings suggest that NI assay is a testable assay applied in H3N2 infection in children, and the antigenic drift of current N2 should be considered for vaccine selection.
Impact of COVID-19 Pandemic on Treatment Management and Clinical Outcome of Aneurysmal Subarachnoid Hemorrhage – A Single-Center Experience
Authors: Kashefiolasl Sepide , Qasem Lina Elisabeth , Brawanski Nina , Funke Moritz , Keil Fee , Hattingen Elke , Foerch Christian , Seifert Volker , Prinz Vincent Matthias , Czabanka Marcus , Konczalla Juergen
Published: March 2022

Background

Previous studies reported decreased volumes of acute stroke admissions during the COVID-19 pandemic. We aimed to examine whether aneurysmal subarachnoid hemorrhage (aSAH) volumes demonstrated similar declines in our department. Furthermore, the impact of the pandemic on disease progression should be analyzed.

Methods

We conducted a retrospective study in the neurosurgical department of the university hospital Frankfurt including patients with the diagnosis of aSAH during the first year of the COVID pandemic. One year cumulative volume for aSAH hospitalization procedures was compared to the year before (03/2020 – 02/2021 vs. 03/2019 – 02/2020) and the last 5 pre-COVID-pandemic years (2015-2020). All relevant patient characteristics concerning family history, disease history, clinical condition at admission, active/past COVID-infection, treatment management, complications, and outcome were analyzed.

Results

Compared to the 84 hospital admissions during the pre-pandemic years, the number of aSAH hospitalizations (n = 56) declined during the pandemic without reaching significance. No significant difference in the analyzed patient characteristics including clinical condition at onset, treatment, complications, and outcome, between 56 patients with aSAH admitted during the COVID pandemic and the treated patients in the last 5 years in the pre-COVID period were found. In our multivariable analysis, we detected young age (p < 0.05; OR 4.2) and no existence of early hydrocephalus (p < 0.05; OR 0.13) as important factors for a favorable outcome (mRS ≤ 0–2) after aSAH during the COVID pandemic. A past COVID-infection was detected in young patients suffering from aSAH (Age <50years, p < 0.05; OR 10.5) with an increased rate of cerebral vasospasm after aSAH onset (p < 0.05; OR 26). Nevertheless, past COVID-infection did not reach significance as a high-risk factor for unfavorable outcomes.

Conclusion

There was a relative decrease in the number of patients with aSAH during the COVID-19 pandemic. Despite the extremely different conditions of hospitalization, there was no impairing significant effect on the treatment and outcome of admitted patients with aSAH. A past COVID infection seemed to be an irrelevant limiting factor concerning favorable outcomes.
Sex and Age Differences in Patient-Reported Acute Stroke Symptoms
Authors: Eddelien Heidi S. , Butt Jawad H. , Christensen Thomas , Danielsen Anne K. , Kruuse Christina
Published: March 2022

Background

Identification of sex- and age-related differences in the presentation of atypical symptoms at stroke onset may reduce prehospital delay and improve stroke treatment if acknowledged at first contact.

Aim

To explore sex- and age-related differences in patient-reported typical and atypical symptoms of a stroke.

Methods

We used data from a cross-sectional survey at two non-comprehensive stroke units in the Capital Region of Denmark. Patient-reported symptoms, stroke knowledge, and behavioral response were analyzed by the Chi-square test or a Fisher's exact test separated by sex. Multivariable logistic regression adjusted for covariates were used to explore sex- and age-related differences according to each patient-reported typical or atypical symptoms.

Results

In total, 479 patients with acute stroke were included (median age 74 years [25th to 75th percentile: 64–80], and 40.1% were women). Female sex was associated with higher odds of presenting with atypical symptoms, such as loss of consciousness (OR 2.12 [95% CI 1.08–4.18]) and nausea/vomiting (OR 2.33 [95% CI 1.24–4.37]), and lower odds of presenting with lower extremity paresis (OR 0.59 [95% CI 0.39–0.89). With each year of age, the odds decreased of presenting with sensory changes (OR 0.95 [95% CI 0.94–0.97]) and upper extremity paresis (OR 0.98 [95% CI 0.96–0.99]), whereas odds of presenting with dysphagia (OR 1.06 [95% CI 1.02–1.11]) increased.

Conclusions

Patients of female sex and younger age reported on admission more frequently atypical stroke symptoms. Attention should be drawn to this possible atypical first presentation to facilitate correct identification and early stroke revascularization treatment to improve the outcome for both sexes.
Practical Considerations for Continuous Time-Domain Cerebrovascular Reactivity Indices in Traumatic Brain Injury: Do Scaling Errors in Parent Signals Matter?
Authors: Froese Logan , Gomez Alwyn , Sainbhi Amanjyot Singh , Slack Trevor , Zeiler Frederick A.
Published: March 2022

Literature pertaining to traumatic brain injury care involves the mediation and control of secondary brain injury mechanisms, chief among these is cerebral autoregulation. Cerebral autoregulation is frequently assessed through surrogate measures of cerebrovascular reactivity. An important aspect to acknowledge when calculating cerebrovascular reactivity indices is the linearity within two-parent bio-signals or variables. We highlighted the concept of linearity in raw parent bio-signals used for the calculation of the cerebrovascular reactivity index and what potential implications linearity carries for index derivation. Key of which is that the initial differencing or location of the pressure probes does not influence linear methods of cerebral reactivity calculations so long as the slow-wave vasogenic changes are being recorded.
RNA-Seq Analysis Reveals the Potential Molecular Mechanisms of Puerarin on Intramuscular Fat Deposition in Heat-Stressed Beef Cattle
Authors: Chen Huan , Peng Tao , Shang Hanle , Shang Xianglong , Zhao Xianghui , Qu Mingren , Song Xiaozhen
Published: March 2022

To investigate the effect of Puerarin on intramuscular fat deposition in heat-stressed beef cattle and its underlying mechanism. Thirty-two healthy Jinjiang bulls were randomly divided into four groups and dietary with 0 (Control), 200 (Pue200), 400 (Pue400), and 800 (Pue800) mg/kg Puerarin in the feed concentrate. The results showed that Puerarin treatment enhanced the concentration of crude fat, fatty acid (C14:1 and C17:1), and the activity of fatty acid synthase in Longissimus thoracis (LT), but decreased the levels of blood leptin (P < 0.05). High-throughput sequencing of mRNA technology (RNA-Seq) was used and the analysis showed that 492 genes were down-regulated and 341 genes were up-regulated in LT, and these genes were significantly enriched to the pathways related to lipid metabolism. These results indicated that dietary supplemental with Puerarin enhanced intramuscular fat deposition by regulating lipid metabolism of heat-stressed beef cattle.
Protein Digestion Kinetics Influence Maternal Protein Loss, Litter Growth, and Nitrogen Utilization in Lactating Sows
Authors: Ye Hao , Langendijk Pieter , Jaworski Neil W. , Wu Yujun , Bai Yu , Lu Dongdong , Page Greg , Kemp Bas , Han Dandan , Soede Nicoline M. , Wang Junjun
Published: March 2022

Body protein losses in lactating sows have a negative impact on sow and litter performance. Improving dietary amino acid utilization may limit protein mobilization. The effects of dietary protein kinetics on sow body condition loss, blood plasma metabolites, and plasma insulin-like growth factor-1 (IGF-1), and also on litter gain during lactation, were investigated in this study. In total, 57 multiparous sows were fed one of three lactation diets with the same crude protein level: low level of slow protein diet (LSP) (8% slowly degradable protein of total protein), medium level of slow protein diet (MSP) (12% slowly degradable protein of total protein), or high level of slow protein diet (HSP) (16% slowly degradable protein of total protein) in a complete block design. Our results showed that HSP sows lost the least body weight compared to MSP and LSP sows (11.9 vs. 17.3 and 13.5 kg, respectively; p = 0.01), less body protein than MSP sows (1.0 vs. 2.1 kg; p = 0.01), and tended to lose less loin muscle thickness than LSP sows (1.7 vs. 4.9 mm; p = 0.09) between Day 2 to Day 21 post-farrowing. LSP sows had greatest plasma urea level on Day 6 than MSP and HSP sows (4.9 vs. 3.6 and 3.1 mmol/L, respectively; p < 0.01) and on Day 13 (5.6 vs. 4.1 and 3.7 mmol/L, respectively; p < 0.01). HSP sows had the lowest plasma urea level at Day 20 compared to LSP and MSP sows (4.0 vs. 5.5 and 4.9 mmol/L, respectively; p < 0.01). The average plasma urea level of Days 6, 13, and 20 post-farrowing was negatively correlated with slow protein intake (r = −0.49, p < 0.01). Litter gain, milk composition, and nitrogen output to the environment did not differ significantly among the treatment groups. Therefore, the dietary protein kinetics affected mobilization of maternal reserves in multiparous sows during lactation, with a high fraction of slow protein-sparing protein mobilization.
Breast Cancer Stem-Like Cells in Drug Resistance: A Review of Mechanisms and Novel Therapeutic Strategies to Overcome Drug Resistance
Authors: Saha Taniya , Lukong Kiven Erique
Published: March 2022

Breast cancer is the most frequent type of malignancy in women worldwide, and drug resistance to the available systemic therapies remains a major challenge. At the molecular level, breast cancer is heterogeneous, where the cancer-initiating stem-like cells (bCSCs) comprise a small yet distinct population of cells within the tumor microenvironment (TME) that can differentiate into cells of multiple lineages, displaying varying degrees of cellular differentiation, enhanced metastatic potential, invasiveness, and resistance to radio- and chemotherapy. Based on the expression of estrogen and progesterone hormone receptors, expression of human epidermal growth factor receptor 2 (HER2), and/or BRCA mutations, the breast cancer molecular subtypes are identified as TNBC, HER2 enriched, luminal A, and luminal B. Management of breast cancer primarily involves resection of the tumor, followed by radiotherapy, and systemic therapies including endocrine therapies for hormone-responsive breast cancers; HER2-targeted therapy for HER2-enriched breast cancers; chemotherapy and poly (ADP-ribose) polymerase inhibitors for TNBC, and the recent development of immunotherapy. However, the complex crosstalk between the malignant cells and stromal cells in the breast TME, rewiring of the many different signaling networks, and bCSC-mediated processes, all contribute to overall drug resistance in breast cancer. However, strategically targeting bCSCs to reverse chemoresistance and increase drug sensitivity is an underexplored stream in breast cancer research. The recent identification of dysregulated miRNAs/ncRNAs/mRNAs signatures in bCSCs and their crosstalk with many cellular signaling pathways has uncovered promising molecular leads to be used as potential therapeutic targets in drug-resistant situations. Moreover, therapies that can induce alternate forms of regulated cell death including ferroptosis, pyroptosis, and immunotherapy; drugs targeting bCSC metabolism; and nanoparticle therapy are the upcoming approaches to target the bCSCs overcome drug resistance. Thus, individualizing treatment strategies will eliminate the minimal residual disease, resulting in better pathological and complete response in drug-resistant scenarios. This review summarizes basic understanding of breast cancer subtypes, concept of bCSCs, molecular basis of drug resistance, dysregulated miRNAs/ncRNAs patterns in bCSCs, and future perspective of developing anticancer therapeutics to address breast cancer drug resistance.
Combined Effect of CYP2C19 Genetic Polymorphisms and C-Reactive Protein on Voriconazole Exposure and Dosing in Immunocompromised Children
Authors: Chen Juan , Wu Ying , He Yuelin , Feng Xiaoqin , Ren Yuqiong , Liu Shiting
Published: March 2022

Background

Pediatric patients have significant interindividual variability in voriconazole exposure. The aim of the study was to identify factors associated with voriconazole concentrations and dose requirements to achieve therapeutic concentrations in pediatric patients.

Methods

Medical records of pediatric patients were retrospectively reviewed. Covariates associated with voriconazole plasma concentrations and dose requirements were adjusted by using generalized linear mixed-effect models.

Results

A total of 682 voriconazole steady-state trough concentrations from 91 Chinese pediatric patients were included. Voriconazole exposure was lower in the CYP2C19 normal metabolizer (NM) group compared with the intermediate metabolizer (IM) group and the poor metabolizer (PM) group (p = 0.0016, p < 0.0001). The median daily dose of voriconazole required to achieve therapeutic range demonstrated a significant phenotypic dose effect: 20.8 mg/kg (range, 16.2–26.8 mg/kg) for the CYP2C19 NM group, 18.2 mg/kg (range, 13.3–21.8 mg/kg) for the CYP2C19 IM group, and 15.2 mg/kg (range, 10.7–19.1 mg/kg) for the CYP2C19 PM group, respectively. The extent of impact of C-reactive protein (CRP) levels on voriconazole trough concentrations and dose requirements varied between CYP2C19 phenotypes. Increases of 20, 120, 245, and 395 mg/L from 5 mg/L in CRP levels were associated with increases in voriconazole trough concentration by 22.22, 50, 64.81, and 75% respectively, in the NM group; by 39.26, 94.48, 123.93, and 146.63%, respectively, in the IM group; and by 17.17, 37.34, 46.78, and 53.65%, respectively, in the PM group. Meanwhile, increases of 20, 120, 245, and 395 mg/L from 5 mg/L in CRP levels were associated with increases in voriconazole dose requirements by 7.15, 14.23, 17.35, and 19.43%, respectively, in the PM group; with decreases in voriconazole dose requirements by 3.71, 7.38, 8.97, and 10.03%, respectively, in the NM group; and with decreases by 4, 9.10, 11.05, and 12.35%, respectively, in the IM group. In addition, age and presence of immunosuppressants had significant effects on voriconazole exposure.

Conclusions

Our study suggests that CYP2C19 phenotypes, CRP concentrations, age, and the presence of immunosuppressants were factors associated with the pharmacokinetic changes in voriconazole. There was heterogeneity in the effect of CRP on voriconazole plasma concentrations across different CYP2C19 genotypes. Combining relevant factors with dose adaptation strategies in therapeutic drug monitoring may help to reduce the incidence of subtherapeutic and supratherapeutic concentrations in clinical practice.
Positive Association Between Fluoroquinolone Exposure and Tendon Disorders: A Nationwide Population-Based Cohort Study in Taiwan
Authors: Chang Chun-Kai , Chien Wu-Chien , Hsu Wan-Fu , Chiao Hao-Yu , Chung Chi-Hsiang , Tzeng Yuan-Sheng , Huang Shao-Wei , Ou Kuang-Ling , Wang Chih-Chien , Chen Shyi-Jou , Wang Der-Shiun
Published: March 2022

Introduction: Fluoroquinolone exposure is reportedly associated with a higher risk of tendon disorders, tendonitis, or tendon rupture. However, studies in East Asian populations have not confirmed these risks in patients with comorbidities or concomitant medication use. This cohort study was designed to investigate the associations among fluoroquinolone exposure, comorbidities, medication use, and tendon disorders in Taiwan.

Materials and Methods: This population-based, nationwide, observational, cohort study used data from the National Health Insurance Research database in Taiwan, a nationwide claims database that covers more than 99% of the Taiwanese population. The study period was from January 2000 to December 2015, and the median follow-up time was 11.05 ± 10.91 years. Patients who were exposed to fluoroquinolones for more than three consecutive days were enrolled, and patients without fluoroquinolone exposure who were matched by age, sex, and index year were enrolled as controls. The associations of comorbidities and concomitant medication use with tendon disorder occurrence were analyzed using Cox regression models.

Results: The incidence of tendon disorders were 6.61 and 3.34 per 105 person-years in patients with and without fluoroquinolone exposure, respectively (adjusted hazard ratio, 1.423; 95% confidence interval [1.02,1.87]; p = 0.021). Sensitivity analyses yielded similar results. Patients under 18 and over 60 years with fluoroquinolone exposure; those with chronic kidney disease, diabetes, rheumatologic disease, cardiac disease, lipid disorder, or obesity; and those who concomitantly used statins, aromatase inhibitors, or glucocorticoids, had a significantly higher risk of tendon disorders.

Conclusion: The long-term risk of tendon disorders was higher in patients with fluoroquinolone exposure than in those without fluoroquinolone exposure. Clinicians should assess the benefits and risks of fluoroquinolone use in patients at high risk of tendon disorders who require fluoroquinolone administration.
Chronic Proinflammatory Signaling Accelerates the Rate of Degeneration in a Spontaneous Polygenic Model of Inherited Retinal Dystrophy
Authors: Hollingsworth T. J. , Wang Xiangdi , White William A. , Simpson Raven N. , Jablonski Monica M.
Published: March 2022

Collectively, retinal neurodegenerative diseases are comprised of numerous subtypes of disorders which result in loss of a varying cell types in the retina. These diseases can range from glaucoma, which results in retinal ganglion cell death, to age-related macular degeneration and retinitis pigmentosa, which result in cell death of the retinal pigment epithelium, photoreceptors, or both. Regardless of the disease, it’s been recently found that increased release of proinflammatory cytokines and proliferation of active microglia result in a remarkably proinflammatory microenvironment that assists in the pathogenesis of the disease; however, many of the details of these inflammatory events have yet to be elucidated. In an ongoing study, we have used systems genetics to identify possible models of spontaneous polygenic age-related macular degeneration by mining the BXD family of mice using single nucleotide polymorphism analyses of known genes associated with the human retinal disease. One BXD strain (BXD32) was removed from the study as the rate of degeneration observed in these animals was markedly increased with a resultant loss of most all photoreceptors by 6 months of age. Using functional and anatomical exams including optokinetic nystamography, funduscopy, fluorescein angiography, and optical coherence tomography, along with immunohistochemical analyses, we show that the BXD32 mouse strain exhibits a severe neurodegenerative phenotype accompanied by adverse effects on the retinal vasculature. We also expose the concurrent establishment of a chronic proinflammatory microenvironment including the TNFα secretion and activation of the NF-κB and JAK/STAT pathways with an associated increase in activated macrophages and phagoptosis. We conclude that the induced neuronal death and proinflammatory pathways work synergistically in the disease pathogenesis to enhance the rate of degeneration in this spontaneous polygenic model of inherited retinal dystrophy.
The Discovery of Novel PGK1 Activators as Apoptotic Inhibiting and Neuroprotective Agents
Authors: Qiang Shao-Jia , Shi Yu-Qi , Wu Tong-Yu , Wang Jing-Quan , Chen Xue-Lian , Su Jie , Chen Xin-Ping , Li Jia-Zhong , Chen Zhe-Sheng
Published: March 2022

Stroke is the second leading cause of death worldwide and the leading cause of long-term disability that seriously endangers health and quality of human life. Tissue-type fibrinogen activator is currently the only drug approved by FDA for the treatment of ischemic stroke. Neuroprotection is theoretically a common strategy for the treatment of both ischemic and hemorrhagic stroke; therefore, the development of neuroprotective agent has been the focus of research. However, no ideal neuroprotective drug is clinically available. Phosphoglycerate kinase-1 (PGK1) activator has the effect of inhibiting apoptosis and protecting tissue damage, and therefore could be a potential neuroprotective agent. To obtain effective PGK1 activators, we virtually screened a large chemical database and their evaluated the efficacy by the Drosophila oxidative stress model, PGK1 enzymatic activity assay, and oxygen-glucose stripping reperfusion (OGD/R) model. The results showed that compounds 7979989, Z112553128 and AK-693/21087020 are potential PGK1 activators with protective effects against PQ-induced oxidative stress in the Drosophila model and could effectively ameliorate apoptosis induced by OGD/R-induced neuronal cell injury. Additionally, compounds 7979989 and Z112553128 are effective in alleviating LPS-induced cellular inflammation. This study indicated that these compounds are promising lead compounds that provide theoretical and material basis to the neuroprotective drug discovery.
Crosstalk Between Senescent Bone Cells and the Bone Tissue Microenvironment Influences Bone Fragility During Chronological Age and in Diabetes
Authors: Teissier Thibault , Temkin Vladislav , Pollak Rivka Dresner , Cox Lynne S.
Published: March 2022

Bone is a complex organ serving roles in skeletal support and movement, and is a source of blood cells including adaptive and innate immune cells. Structural and functional integrity is maintained through a balance between bone synthesis and bone degradation, dependent in part on mechanical loading but also on signaling and influences of the tissue microenvironment. Bone structure and the extracellular bone milieu change with age, predisposing to osteoporosis and increased fracture risk, and this is exacerbated in patients with diabetes. Such changes can include loss of bone mineral density, deterioration in micro-architecture, as well as decreased bone flexibility, through alteration of proteinaceous bone support structures, and accumulation of senescent cells. Senescence is a state of proliferation arrest accompanied by marked morphological and metabolic changes. It is driven by cellular stress and serves an important acute tumor suppressive mechanism when followed by immune-mediated senescent cell clearance. However, aging and pathological conditions including diabetes are associated with accumulation of senescent cells that generate a pro-inflammatory and tissue-destructive secretome (the SASP). The SASP impinges on the tissue microenvironment with detrimental local and systemic consequences; senescent cells are thought to contribute to the multimorbidity associated with advanced chronological age. Here, we assess factors that promote bone fragility, in the context both of chronological aging and accelerated aging in progeroid syndromes and in diabetes, including senescence-dependent alterations in the bone tissue microenvironment, and glycation changes to the tissue microenvironment that stimulate RAGE signaling, a process that is accelerated in diabetic patients. Finally, we discuss therapeutic interventions targeting RAGE signaling and cell senescence that show promise in improving bone health in older people and those living with diabetes.
CRIA: An Interactive Gene Selection Algorithm for Cancers Prediction Based on Copy Number Variations
Authors: Wu Qiang , Li Dongxi
Published: March 2022

Genomic copy number variations (CNVs) are among the most important structural variations of genes found to be related to the risk of individual cancer and therefore they can be utilized to provide a clue to the research on the formation and progression of cancer. In this paper, an improved computational gene selection algorithm called CRIA (correlation-redundancy and interaction analysis based on gene selection algorithm) is introduced to screen genes that are closely related to cancer from the whole genome based on the value of gene CNVs. The CRIA algorithm mainly consists of two parts. Firstly, the main effect feature is selected out from the original feature set that has the largest correlation with the class label. Secondly, after the analysis involving correlation, redundancy and interaction for each feature in the candidate feature set, we choose the feature that maximizes the value of the custom selection criterion and add it into the selected feature set and then remove it from the candidate feature set in each selection round. Based on the real datasets, CRIA selects the top 200 genes to predict the type of cancer. The experiments' results of our research show that, compared with the state-of-the-art related methods, the CRIA algorithm can extract the key features of CNVs and a better classification performance can be achieved based on them. In addition, the interpretable genes highly related to cancer can be known, which may provide new clues at the genetic level for the treatment of the cancer.
The Interaction Between CitMYB52 and CitbHLH2 Negatively Regulates Citrate Accumulation by Activating CitALMT in Citrus Fruit
Authors: Liu Shengchao , Liu Xincheng , Gou Bangrui , Wang Dengliang , Liu Chunrong , Sun Jun , Yin Xueren , Grierson Donald , Li Shaojia , Chen Kunsong
Published: March 2022

Citric acid plays significant roles in numerous physiological processes in plants, including carbon metabolism, signal transduction, and tolerance to environmental stress. For fruits, it has a major effect on fruit organoleptic quality by directly influencing consumer taste. Citric acid in citrus is mainly regulated by the balance between synthesis, degradation, and vacuolar storage. The genetic and molecular regulations of citric acid synthesis and degradation have been comprehensively elucidated. However, the transporters for citric acid in fruits are less well understood. Here, an aluminum-activated malate transporter, CitALMT, was characterized. Transient overexpression and stable transformation of CitALMT significantly reduced citrate concentration in citrus fruits and transgenic callus. Correspondingly, transient RNA interference-induced silencing of CitALMT and increased citrate significantly, indicating that CitALMT plays an important role in regulating citrate concentration in citrus fruits. In addition, dual-luciferase assays indicated that CitMYB52 and CitbHLH2 could trans-activate the promoter of CitALMT. EMSA analysis showed that CitbHLH2 could physically interact with the E-box motif in the CitALMT promoter. Bimolecular fluorescence complementation assays, yeast two-hybrid, coimmunoprecipitation and transient overexpression, and RNAi assay indicated that the interaction between CitMYB52 and CitbHLH2 could synergistically trans-activate CitALMT to negatively regulate citrate accumulation.
Pricing Analysis of Online Shopping Platforms Considering Consumer Information Levels
Authors: Chen Hao , Xiong Weiqing , Xiong Peichen
Published: March 2022

To address the problem of frequent dishonest transactions by online shopping platform merchants, we developed monopoly and competitive platform pricing models based on two-sided market theory, which introduce consumer information levels. This article analyzes the incentives of the platforms to improve consumer information levels in platform pricing strategies. Monopoly online shopping platforms aim to maximize profits. The higher the consumer information level is, the lower the fees charged to merchants; this can lead to increased platform profits. The charging of consumers depends on cross-network externalities. Competitive online shopping platforms also aim at maximizing profits. Under the circumstance that the number of consumers remains the same, the higher the consumer information level is, the more merchants the platforms will attract. This reduces bilateral user fees, and platform profits will be lower. From the perspective of consumer information level, the article analyzes the impact of monopoly and competitive platforms adopting return measures to improve the level of consumer information on platform pricing, number of bilateral users, and profits.
Nurse's Psychological Experiences of Caring for Severe COVID-19 Patients in Intensive Care Units: A Qualitative Meta-Synthesis
Authors: Han Peng , Duan Xia , Zhao Sijia , Zhu Xiaoping , Jiang Jinxia
Published: March 2022

Background

COVID-19 has been listed as an international public health emergency. During the pandemic, the nurses were affected physically and mentally when in contact with and caring for patients infected with COVID-19, especially those in intensive care units (ICUs).

Objective

To summarize and evaluate the actual psychological experience of nurses caring for patients with severe pneumonia in the ICUs during the COVID-19 pandemic.

Methods

Relevant publications were identified by systematic searches across 11 databases in December 2021. All qualitative and mixed-method studies in English and Chinese from 2019 that explored the experiences of nurses who cared for severe COVID-19 patients in ICUs were included. The qualitative meta-synthesis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations. Two independent reviewers selected the studies and assessed the quality of each study. Meta-synthesis was performed to integrate the results.

Results

A total of 12 studies revealed 9 sub-themes and 3 descriptive themes: physical reactions and psychological changes, the need for support from multiple sources, and increased adaptation and resilience.

Conclusion

Nurses who treated severe COVID-19 patients have experienced severe work trials and emotional reactions during the pandemic. They have also developed personally in this process. Managers should develop strategies that address the nurse's needs for external support, reasonably respond to public health emergencies, and improve nursing care outcomes.
Tentative Application of a Streamlined Protocol to Determine Organ-Specific Regulations of Deiodinase 1 and Dehalogenase Activities as Readouts of the Hypothalamus-Pituitary-Thyroid-Periphery-Axis
Authors: Renko Kostja , Kerp Helena , Pape Janina , Rijntjes Eddy , Burgdorf Tanja , Führer Dagmar , Köhrle Josef
Published: March 2022

In animal studies, both in basic science and in toxicological assessment of potential endocrine disruptors, the state of the thyroid hormone (TH) axis is often described and defined exclusively by the concentrations of circulating THs and TSH. Although it is known that the local, organ-specific effects of THs are also substantially regulated by local mechanisms such as TH transmembrane transport and metabolism of TH by deiodinases, such endpoint parameters of the axis are rarely assessed in these experiments. Currently developed in vitro assays utilize the Sandell-Kolthoff reaction, a photometric method of iodide determination, to test the effect of chemicals on iodotyrosine and iodothyronine deiodinases. Furthermore, this technology offers the possibility to determine the iodine content of various sample types (e.g., urine, ex vivo tissue) in a simple way. Here, we measured deiodinase type 1 and iodotyrosine dehalogenase activity by means of the Sandell-Kolthoff reaction in ex vivo samples of hypo- and hyperthyroid mice of two age groups (young; 3 months and old; 20 months). In thyroid, liver and kidney, organ-specific regulation patterns emerged across both age groups, which, based on this pilot study, may serve as a starting point for a deeper characterization of the TH system in relevant studies in the future and support the development of Integrated Approach for Testing and Assessment (IATA).