bluuebunny/crossref_metadata_2025 huggingface dataset:
Monetary security: some definitions and assessments
Authors:   SI “Institute for Economics and Forecasting of NAS of Ukraine”, KORABLIN Serhii
Published: March 2021

For almost 30 years of independence, Ukraine has experienced a number of deep economic, financial, banking, debt, currency and inflation crises. In some cases, they were extraordinary. As a result, the current real GDP of the country remains a third less than in 1990. One of the reasons for this was the unstable nature of economic recovery and currency price stabilization at the beginning of the zero years and in 2010-2013. After all, during the crises of 2008-2009 and 2014-2015, Ukraine set world anti-records due to falling its GDP up to 14.8 % and 15.8%, respectively. This was accompanied by the deep devaluation crises and the recurrence of uncontrolled inflation. In principle, the systemic relationship between the fragility of production, exchange rate and price dynamics appeared in Ukraine in the 1990s when its real GDP fell by 59%. The scale of that crisis was twice the scale of the Great Depression in the United States, accompanied by devastating devaluation and inflationary shocks. The article is devoted to the study of methodological and practical approaches to the definition of monetary security. The experience of their implementation in Ukraine is considered. The criteria of successful monetary policy applied within the neoliberal discourse are analyzed. The logic and reasons for their gradual transformation over the last 30 years are shown. The decisive role of the global crisis of 2008-2009 in the theoretical and practical changes observed in the world’s leading economies in terms of defining the goals, objectives and instruments of their monetary policy is reflected. An analysis of some outcomes of the implementation of domestic monetary strategy is given. The problematic nature of determining its priority goal is shown. The ambiguity of methods and consequences of targeted reduction of inflation in Ukraine is noted. The impossibility of maintaining its low and stable level under the conditions of free floating exchange rate of hryvnia is substantiated.
Agreements between tax authorities and taxpayers in the context of EU law on state aid
Authors:   SESE “The Academy of Financial Management”, KOSCHUK Tetiana
Published: March 2021

This article analyses how the application of the EU legislation on state aid has impacted the development of cooperation between tax authorities and taxpayers through the various forms of agreements they enter into. These measures of tax administration may qualify as state aid to business entities only if they meet all the criteria for such aid, namely: they should offer an economic advantage to the beneficiary; they should be granted by the state or through state resources; they should be selective; they should distort competition and have an adverse impact on trade. Furthermore, there are some areas to which the general rules of state aid do not apply. The latter include, among others, the operations of agricultural industries and the actions the state is obliged to take under international treaties. The analysis of the European Commission's approaches and case law has given rise to the following conclusions: 1) the write-off, instalment and deferral arrangements for the tax debt of insolvent economic entities will qualify for state aid only if it is proven that more funds would have made it into the budget had the corresponding agreements not been in place (in particular, if the taxpayer had gone bankrupt); 2) to recognize the consequences of the violation of transfer pricing rules as state aid when entering into advance pricing agreements, it is crucial to unequivocally prove that tax legislation has been violated and prove that, in view of all other opportunities for taxation under the "standard" conditions, the company has in fact paid less taxes; 3) involvement in joint legal compliance programs will not be considered a provision of state aid if the terms of such cooperation provide only procedural benefits to the parties to the agreements, rather than entailing any reduced tax liability for a business entity.
Evaluating of the Promotion of Strategic Alliance of Medical Devices Industry with Data Envelopment Analysis
Authors: CHEN Kuan- Hung
Published: March 2021

Applying Data Envelopment Analysis to evaluate efficiency in this study, representative enterprises, in major Medical devices industry production areas of Kaohsiung city, with cooperation with institutional consumers are studied. The research results are summarized as below. according to DEA, 1 DMU presents strong Medical devices industry strategic alliance efficiency, 4 DMUs show the Medical devices industry strategic alliance efficiency between 0.9 and 1, and 5 DMUs reveal the Medical devices industry strategic alliance efficiency lower than 0.9. 2. Sensitivity analysis is utilized for analyzing and finding out key factors in Medical devices industry strategic alliance, and the sensitivity to efficiency is understood by gradually removing inputs and outputs for DEA. According to the results to propose suggestions, it is expected to provide actual assistance for Medical devices industry strategic alliance and reinforce the cooperation between corporate groups and institutional consumers through intra-industry alliance and horizontal alliance.
Recent Advances in Engineered Nanoparticles for RNAi-Mediated Crop Protection Against Insect Pests
Authors: Pugsley Charlotte E. , Isaac R. E. , Warren Nicholas J. , Cayre Olivier J.
Published: March 2021

Since the discovery of RNA interference (RNAi) in the nematode wormCaenorhabditis elegansin 1998 by Fire and Mello et al., strides have been made in exploiting RNAi for therapeutic applications and more recently for highly selective insect pest control. Although triggering mRNA degradation in insects through RNAi offers significant opportunities in crop protection, the application of environmental naked dsRNA is often ineffective in eliciting a RNAi response that results in pest lethality. There are many possible reasons for the failed or weak induction of RNAi, with predominant causes being the degradation of dsRNA in the formulated pesticide, in the field or in the insect once ingested, poor cuticular and oral uptake of the nucleic acid and sometimes the lack of an innate strong systemic RNAi response. Therefore, in the last 10 years significant research effort has focused on developing methods for the protection and delivery of environmental dsRNA to enable RNAi-induced insect control. This review focuses on the design and synthesis of vectors (vehicles that are capable of carrying and protecting dsRNA) that successfully enhance mRNA degradation via the RNAi machinery. The majority of solutions exploit the ability of charged polymers, both synthetic and natural, to complex with dsRNA, but alternative nanocarriers such as clay nanosheets and liposomal vesicles have also been developed. The various challenges of dsRNA delivery and the obstacles in the development of well-designed nanoparticles that act to protect the nucleic acid are highlighted. In addition, future research directions for improving the efficacy of RNA-mediated crop protection are anticipated with inspiration taken from polymeric architectures constructed for RNA-based therapeutic applications.
Circadian Rhythm Gene PER3 Negatively Regulates Stemness of Prostate Cancer Stem Cells via WNT/β-Catenin Signaling in Tumor Microenvironment
Authors: Li Qilin , Xia Ding , Wang Zhihua , Liu Bo , Zhang Jing , Peng Ping , Tang Qiujun , Dong Jie , Guo Juan , Kuang Dong , Chen Weimin , Mao Jing , Li Qiuhui , Chen Xin
Published: March 2021

Prostate cancer (PCa) cells are heterogeneous, containing a variety of cancer cells with phenotypical and functional discrepancies in the tumor microenvironment, where prostate cancer stem cells (PCSCs) play a vital role in PCa development. Our earlier studies have shown that ALDHhiCD44+ (DP) PCa cells and the corresponding ALDHloCD44– (DN) PCa cells manifest as PCSCs and non-PCSCs, respectively, but the underlying mechanisms regulating stemness of the PCSCs are not completely understood. To tackle this issue, we have performed RNA-Sequencing and bioinformatic analysis in DP (versus DN) cells in this study. We discovered that, PER3 (period circadian regulator 3), a circadian rhythm gene, is significantly downregulated in DP cells. Overexpression of PER3 in DP cells significantly suppressed their sphere- and colony-forming abilities as well as tumorigenicity in immunodeficient hosts. In contrast, knockdown of PER3 in DN cells dramatically promoted their colony-forming and tumor-initiating capacities. Clinically, PER3 is downregulated in human prostate cancer specimens and PER3 expression levels are highly correlated with the prognosis of the PCa patient. Mechanistically, we observed that low levels of PER3 stimulates the expression of BMAL1, leading to the phosphorylation of β-catenin and the activation of the WNT/β-catenin pathway. Together, our results indicate that PER3 negatively regulates stemness of PCSCs via WNT/β-catenin signaling in the tumor microenvironment, providing a novel strategy to treat PCa patients.
Remote Ischemic Preconditioning to Prevent Acute Kidney Injury After Cardiac Surgery: A Meta-Analysis of Randomized Controlled Trials
Authors: Liu Zigang , Zhao Yongmei , Lei Ming , Zhao Guancong , Li Dongcheng , Sun Rong , Liu Xian
Published: March 2021

Objective: Randomized controlled trials (RCTs) evaluating the influence of remote ischemic preconditioning (RIPC) on acute kidney injury (AKI) after cardiac surgery showed inconsistent results. We performed a meta-analysis to evaluate the efficacy of RIPC on AKI after cardiac surgery.

Methods: Relevant studies were obtained by search of PubMed, Embase, and Cochrane's Library databases. A random-effect model was used to pool the results. Meta-regression and subgroup analyses were used to determine the source of heterogeneity.

Results: Twenty-two RCTs with 5,389 patients who received cardiac surgery −2,702 patients in the RIPC group and 2,687 patients in the control group—were included. Moderate heterogeneity was detected (p for Cochrane's Q test = 0.03, I2 = 40%). Pooled results showed that RIPC significantly reduced the incidence of AKI compared with control [odds ratio (OR): 0.76, 95% confidence intervals (CI): 0.61–0.94, p = 0.01]. Results limited to on-pump surgery (OR: 0.78, 95% CI: 0.64–0.95, p = 0.01) or studies with acute RIPC (OR: 0.78, 95% CI: 0.63–0.97, p = 0.03) showed consistent results. Meta-regression and subgroup analyses indicated that study characteristics, including study design, country, age, gender, diabetic status, surgery type, use of propofol or volatile anesthetics, cross-clamp time, RIPC protocol, definition of AKI, and sample size did not significantly affect the outcome of AKI. Results of stratified analysis showed that RIPC significantly reduced the risk of mild-to-moderate AKI that did not require renal replacement therapy (RRT, OR: 0.76, 95% CI: 0.60–0.96, p = 0.02) but did not significantly reduce the risk of severe AKI that required RRT in patients after cardiac surgery (OR: 0.73, 95% CI: 0.50–1.07, p = 0.11).

Conclusions: Current evidence supports RIPC as an effective strategy to prevent AKI after cardiac surgery, which seems to be mainly driven by the reduced mild-to-moderate AKI events that did not require RRT. Efforts are needed to determine the influences of patient characteristics, procedure, perioperative drugs, and RIPC protocol on the outcome.
Knowledge Transfer via Pre-training for Recommendation: A Review and Prospect
Authors: Zeng Zheni , Xiao Chaojun , Yao Yuan , Xie Ruobing , Liu Zhiyuan , Lin Fen , Lin Leyu , Sun Maosong
Published: March 2021

Recommender systems aim to provide item recommendations for users and are usually faced with data sparsity problems (e.g., cold start) in real-world scenarios. Recently pre-trained models have shown their effectiveness in knowledge transfer between domains and tasks, which can potentially alleviate the data sparsity problem in recommender systems. In this survey, we first provide a review of recommender systems with pre-training. In addition, we show the benefits of pre-training to recommender systems through experiments. Finally, we discuss several promising directions for future research of recommender systems with pre-training. The source code of our experiments will be available to facilitate future research.
Isotopically Light Cd in Sediments Underlying Oxygen Deficient Zones
Authors: Chen Lena , Little Susan H. , Kreissig Katharina , Severmann Silke , McManus James
Published: March 2021

Cadmium is a trace metal of interest in the ocean partly because its concentration mimics that of phosphate. However, deviations from the global mean dissolved Cd/PO4 relationship are present in oxygen deficient zones, where Cd is depleted relative to phosphate. This decoupling has been suggested to result from cadmium sulphide (CdS) precipitation in reducing microenvironments within sinking organic matter. We present Cd concentrations and Cd isotope compositions in organic-rich sediments deposited at several upwelling sites along the northeast Pacific continental margin. These sediments all have enriched Cd concentrations relative to crustal material. We calculate a net accumulation rate of Cd in margin settings of between 2.6 to 12.0 × 107 mol/yr, higher than previous estimates, but at the low end of a recently published estimate for the magnitude of the marine sink due to water column CdS precipitation. Cadmium in organic-rich sediments is isotopically light (δ114/110CdNIST-3108 = +0.02 ± 0.14‰, n = 26; 2 SD) compared to deep seawater (+0.3 ± 0.1‰). However, isotope fractionation during diagenesis in continental margin settings appears to be small. Therefore, the light Cd isotope composition of organic-rich sediments is likely to reflect an isotopically light source of Cd. Non-quantitative biological uptake of light Cd by phytoplankton is one possible means of supplying light Cd to the sediment, which would imply that Cd isotopes could be used as a tracer of past ocean productivity. However, water column CdS precipitation is also predicted to preferentially sequester light Cd isotopes from the water column, which could obfuscate Cd as a tracer. We also observe notably light Cd isotope compositions associated with elevated solid phase Fe concentrations, suggesting that scavenging of Cd by Fe oxide phases may contribute to the light Cd isotope composition of sediments. These multiple possible sources of isotopically light Cd to sediments, along with evidence for complex particle cycling of Cd in the water column, bring into question the straightforward application of Cd isotopes as a paleoproductivity proxy.
Cardio-Metabolic Indices and Metabolic Syndrome as Predictors of Clinical Severity of Gastroenteropancreatic Neuroendocrine Tumors
Authors: Barrea Luigi , Muscogiuri Giovanna , Modica Roberta , Altieri Barbara , Pugliese Gabriella , Minotta Roberto , Faggiano Antongiulio , Colao Annamaria , Savastano Silvia
Published: March 2021

Background

Obesity, mainly visceral obesity, and metabolic syndrome (MetS) are major risk factors for the development of type 2 diabetes, cardiovascular diseases, and cancer. Data analyzing the association of obesity and MetS with gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) are lacking. Fatty liver index (FLI) is a non-invasive tool for identifying individuals with non-alcoholic fatty liver disease (NAFLD). Visceral adiposity index (VAI) has been suggested as a gender-specific indicator of adipose dysfunction. Both indexes have been proposed as early predictors of MetS. This study aimed to investigate the association of FLI VAI as early predictors of MetS with gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

Methods

A cross-sectional, case–control, observational study was carried out at the ENETS Centers of Excellence Multidisciplinary Group for Neuroendocrine Tumors, University “Federico II”. VAI and FLI were calculated.

Results

We enrolled 109 patients with histologically confirmed G1/G2 GEP-NET (53 M; 57.06 ± 15.96 years), as well as 109 healthy subjects, age, sex- and body mass index-matched. Forty-four GEP-NET patients were G2, of which 21 were with progressive disease, and 27 patients had metastases. GEP-NET patients had a higher value of VAI (p < 0.001) and FLI (p= 0.049) and higher MetS presence (p< 0.001) compared with controls. VAI and FLI values and MetS presence were higher in G2 than in G1 patients (p< 0.001), in patients with progressive disease, and in metastaticvsnon-metastatic patients (p< 0.001). In addition, higher values of VAI and FLI and higher MetS presence were significantly correlated with the worst clinical severity of NENs. The cut-off values for the FLI and MetS to predict high grading of GEP-NETs and the presence of metastasis were also provided.

Conclusions

This is the first study investigating an association between VAI and FLI as early predictors of MetS and GEP-NET. Our findings report that the worsening of clinicopathological characteristics in GEP-NET is associated with higher presence of MetS, NAFLD, evaluated by FLI, and visceral adiposity dysfunction, evaluated by VAI. Addressing the clinical evaluation of MetS presence, NAFLD, and visceral adiposity dysfunction might be of crucial relevance to establish targeted preventive and treatment interventions of NEN-related metabolic comorbidities.
Spatio-Temporal Variability of Peat CH4 and N2O Fluxes and Their Contribution to Peat GHG Budgets in Indonesian Forests and Oil Palm Plantations
Authors: Swails Erin , Hergoualc’h Kristell , Verchot Louis , Novita Nisa , Lawrence Deborah
Published: March 2021

Land-use change in tropical peatlands substantially impacts peat emissions of methane (CH4) and nitrous oxide (N2O) in addition to emissions of carbon dioxide (CO2). However, assessments of full peat greenhouse gas (GHG) budgets are scarce and CH4 and N2O contributions remain highly uncertain. The objective of our research was to assess changes in peat GHG flux and budget associated with peat swamp forest disturbance and conversion to oil palm plantation and to evaluate drivers of variation in trace gas fluxes. Over a period of one and a half year, we monitored monthly CH4 and N2O fluxes together with environmental variables in three undrained peat swamp forests and three oil palm plantations on peat in Central Kalimantan. The forests included two primary forests and one 30-year-old secondary forest. We calculated the peat GHG budget in both ecosystems using soil respiration and litterfall rates measured concurrently with CH4 and N2O fluxes, site-specific soil respiration partitioning ratios, and literature-based values of root inputs and dissolved organic carbon export. Peat CH4 fluxes (kg CH4 ha−1 year−1) were insignificant in oil palm (0.3 ± 0.4) while emissions in forest were high (14.0 ± 2.8), and larger in wet than in dry months. N2O emissions (kg N2O ha−1 year−1) were highly variable spatially and temporally and similar across land-uses (5.0 ± 3.9 and 5.2 ± 3.7 in oil palm and forest). Temporal variation of CH4 was controlled by water table level and soil water-filled pore space in forest and oil palm, respectively. Monthly fluctuations of N2O were linked to water table level in forest. The peat GHG budget (Mg CO2 equivalent ha−1 year−1) in oil palm (31.7 ± 8.6) was nearly eight times the budget in forest (4.0 ± 4.8) owing mainly to decreased peat C inputs and increased peat C outputs. The GHG budget was also ten times higher in the secondary forest (10.2 ± 4.5) than in the primary forests (0.9 ± 3.9) on the account of a larger peat C budget and N2O emission rate. In oil palm 96% of emissions were released as CO2 whereas in forest CH4 and N2O together contributed 65% to the budget. Our study highlights the disastrous atmospheric impact associated with forest degradation and conversion to oil palm in tropical peatlands and stresses the need to investigate GHG fluxes in disturbed undrained lands.
Consuming Costly Prey: Optimal Foraging and the Role of Compensatory Growth
Authors: Langerhans Randall Brian , Goins Taylor R. , Stemp Kenzi M. , Riesch Rüdiger , Araújo Márcio S. , Layman Craig A.
Published: March 2021

Some prey are exceptionally difficult to digest, and yet even non-specialized animals may consume them—why? Durophagy, the consumption of hard-shelled prey, is thought to require special adaptations for crushing or digesting the hard shells to avoid the many potential costs of this prey type. But many animals lacking specializations nevertheless include hard-bodied prey in their diets. We describe several non-mutually exclusive adaptive mechanisms that could explain such a pattern, and point to optimal foraging and compensatory growth as potentially having widespread importance in explaining costly-prey consumption. We first conducted a literature survey to quantify the regularity with which non-specialized teleost fishes consume hard-shelled prey: stomach-content data from 325 teleost fish species spanning 82 families (57,233 stomach samples) demonstrated that non-specialized species comprise ~75% of the total species exhibiting durophagy, commonly consuming hard-shelled prey at low to moderate levels (~10–40% as much as specialists). We then performed a diet survey to assess the frequency of molluscivory across the native latitudinal range of a small livebearing fish,Gambusia holbrooki, lacking durophagy specializations. Molluscivory was regionally widespread, spanning their entire native latitudinal range (>14° latitude). Third, we tested for a higher frequency of molluscivory under conditions of higher intraspecific resource competition in Bahamian mosquitofish (Gambusiaspp.). Examining over 5,300 individuals, we found that molluscivory was more common in populations with higher population density, suggesting that food limitation is important in eliciting molluscivory. Finally, we experimentally tested inG. holbrookiwhether molluscivory reduces growth rate and whether compensatory growth follows a period of molluscivory. We found that consumption of hard-shelled gastropods results in significantly reduced growth rate, but compensatory growth following prior snail consumption can quickly mitigate growth costs. Our results suggest that the widespread phenomenon of costly-prey consumption may be partially explained by its relative benefits when few alternative prey options exist, combined with compensatory growth that alleviates temporary costs.
Genome-Wide Identification of Brassinosteroid Signaling Downstream Genes in Nine Rosaceae Species and Analyses of Their Roles in Stem Growth and Stress Response in Apple
Authors: Zheng Liwei , Yang Yingli , Ma Shengjie , Wang Wenming , Zhang Jimeng , Yue Caipeng , Wang Yongmei , Song Maoping , Hao Xinqi , Huang Jinyong
Published: March 2021

Brassinosteroid signaling downstream genes regulate many important agronomic traits in rice. However, information on such genes is limited in Arabidopsis and Rosaceae species. We identified these genes in Arabidopsis and nine Rosaceae species. They were, respectively, named based on chromosomal locations. Segmental duplication and whole-genome duplication under purifying selection, as determined by Ka/Ks analysis, likely contributed to Rosaceae gene expansion. Apple (Malus domestica), Arabidopsis, and rice genes were generally similar, while several Rosaceae genes differed from their rice homologs in various characteristics, such as gene length, subcellular localization, transmembrane topology, conserved domains, secondary structures, and responses to external signals. The brassinosteroid downstream genes in apple were, respectively, induced or repressed by five phytohormones. Furthermore, these apple downstream genes were differentially expressed in different apple grafting combinations (“Nagafu No. 2”/“Malling 9” and “Nagafu No. 2”/“Nagafu No. 2”) and long–short shoot varieties (“Yanfu No. 6” and “Nagafu No. 2”). Responses of the MdBZR genes to diverse stress signals were examined and candidate hub genes were identified. These findings indicated that several brassinosteroid signaling downstream genes in Rosaceae functionally differed from their rice homologs, and certain apple genes may play roles in plant height and stress responses. This study provided valuable information and presented enriched biological theories on brassinosteroid signaling downstream genes in apple. Identification of such genes serve to help expand apple breeding and growth. This study provides useful information for brassinosteroid signaling downstream genes.
Preliminary Study on the Clinical and Genetic Characteristics of Hereditary Spherocytosis in 15 Chinese Children
Authors: Wu Chongjun , Xiong Ting , Xu Zhongjin , Zhan Chunlei , Chen Feng , Ye Yao , Wang Hong , Yang Yu
Published: March 2021

Objective

To investigate the clinical and genetic characteristics of hereditary spherocythemia (HS) in Chinese children, and to analyze the potential genotypic/phenotypic associations.

Methods

The clinical data and gene test results of children with HS were collected. All patients were diagnosed by gene test results, and the laboratory results were obtained before splenectomy. The data of red blood cell (RBC), hemoglobin (HB), mean red blood cell volume (MCV), mean red blood cell hemoglobin (MCH), mean red blood cell hemoglobin concentration (MCHC), and hematocrit (HCT) were statistically analyzed according to different mutation genes. Statistical methods for comparison between groups Mann–Whitney test analysis, two-terminal p < 0.05 was considered significant difference.

Results

A total of 15 children were enrolled in our hospital, and 14 variants were found (nine variants have not been reported before), including 10 ANK1 mutations (seven ANK1 truncated mutations) and five SPTB mutations. Patients with ANK1 mutations had more severe anemia than those with SPTB mutations (significantly lower RBC, HB, MCHC, and HCT).

Conclusion

This is one of the few studies on the genetic and clinical characteristics of children with HS in China. This study identified the unique genetic and clinical characteristics of Chinese children with HS and analyzed the pathogenic genotype–phenotypic association. The results confirmed that the anemia degree of HS patients caused by ANK1 was more serious than that of patients with SPTB deficiency. However, further study of the correlation between genotype and phenotype requires a larger sample size.
TSPAN1, TMPRSS4, SDR16C5, and CTSE as Novel Panel for Pancreatic Cancer: A Bioinformatics Analysis and Experiments Validation
Authors: Ye Hua , Li Tiandong , Wang Hua , Wu Jinyu , Yi Chuncheng , Shi Jianxiang , Wang Peng , Song Chunhua , Dai Liping , Jiang Guozhong , Huang Yuxin , Yu Yongwei , Li Jitian
Published: March 2021

Pancreatic cancer is a lethal malignancy with a poor prognosis. This study aims to identify pancreatic cancer-related genes and develop a robust diagnostic model to detect this disease. Weighted gene co-expression network analysis (WGCNA) was used to determine potential hub genes for pancreatic cancer. Their mRNA and protein expression levels were validated through reverse transcription PCR (RT-PCR) and immunohistochemical (IHC). Diagnostic models were developed by eight machine learning algorithms and ten-fold cross-validation. Four hub genes (TSPAN1, TMPRSS4, SDR16C5, and CTSE) were identified based on bioinformatics. RT-PCR showed that the four hub genes were expressed at medium to high levels, IHC revealed that their protein expression levels were higher in pancreatic cancer tissues. For the panel of these four genes, eight models performed with 0.87–0.92 area under the curve value (AUC), 0.91–0.94 sensitivity, and 0.84–0.86 specificity in the validation cohort. In the external validation set, these models also showed good performance (0.86–0.98 AUC, 0.84–1.00 sensitivity, and 0.86–1.00 specificity). In conclusion, this study has identified four hub genes that might be closely related to pancreatic cancer: TSPAN1, TMPRSS4, SDR16C5, and CTSE. Four-gene panels might provide a theoretical basis for the diagnosis of pancreatic cancer.
Synthesis and Characterization of a Hydroxyapatite-Sodium Alginate-Chitosan Scaffold for Bone Regeneration
Authors: Liu Dingkun , Liu Zhihui , Zou Jundong , Li Lingfeng , Sui Xin , Wang Bizhou , Yang Nan , Wang Bowei
Published: March 2021

Bone scaffolds play an important role in promoting the healing of large bone defects. However, the type of scaffold material, type of drug loaded into the scaffold, and method of preparation have a significant impact on the scaffold's properties. In this study, we developed a composite scaffold comprising sodium alginate (SA), chitosan (CS), and hydroxyapatite (HA). The composite stent carries vascular endothelial growth factor (VEGF), wrapped in internal microspheres, and vancomycin (VAN). The microspheres are wrapped in an outer matrix formed by SA, CS, and HA, whereas the outer matrix carries VAN. Using Fourier-transform infrared spectroscopy (FTIR), X-ray diffraction, and scanning electron microscopy analyses, we studied the contraction rate, swelling, porosity, mechanical properties, degradation, and drug release ability of all the composite scaffolds. The best scaffold, as demonstrated by the results of these studies, was the HA6(SA/CS)4@VAN/VEGF scaffold. The antibacterial ability of the HA6(SA/CS)4@VAN/VEGF scaffold was determined using Staphylococcus aureus (S. aureus). Cytotoxicity, cell adhesion, and osteogenic properties of the HA6(SA/CS)4@VAN/VEGF scaffold were studied using bone marrow mesenchymal stem cells. The results indicate that the HA6(SA/CS)4@VAN/VEGF scaffold exhibits good physical, chemical, antibacterial, and osteogenic properties, and is, thus, a new type of bone scaffold composite material with good osteogenic potential.
Post-transplantation Cyclophosphamide, Tacrolimus and Low-Dose ATG as GVHD Prophylaxis for Allogeneic Peripheral Stem Cell Transplantation for Adult Patients With Lymphoid Malignancies: A Single Arm Phase II Study
Authors: Jiang Jie-ling , Gao Wen-hui , Wang Li-ning , Wan Ming , Wang Ling , Hu Jiong
Published: March 2021

The PT-Cy was considered as one of the mainstay protocol for graft verus host disease (GVHD) prophylaxis. Recent study demonstrated that PT-Cy combined with other immunosuppressants could further reduce the incidence of GVHD and improve the GVHD and relapse free survival (GRFS). In this prospective phase II study, we evaluated the effect of a new GVHD prophylaxis consist of PT-Cy combined with tacrolimus and low dose anti-thymoglobulin (ATG). A total of 23 patients were enrolled including 20 patients with acute lymphoblastic leukemia (ALL) and three patients with T cell lymphoma. The median age was 29 years (range, 16~58 years). Patients with HLA-matched related donor (MSD, n=7) received PT-Cy combined with tacrolimus, while patients with HLA matched unrelated (MUD, n = 2) or haplo-identical (Haplo, n = 14) donor received additional ATG at 2.5 mg/kg on day 15 or day 22 after engraftment of neutrophils. As to the acute GVHD (aGVHD), only three patients developed grade I (n = 1) or grade II (n = 2) aGVHD with 100-day incidence of all aGVHD and II-IV aGVHD at 13.0 ± 5.1% and 9.1 ± 6.1% respectively. Only two patients had mild and one had moderate chronic GVHD (cGVHD), with 1-year incidence of cGVHD and moderate/severe cGVHD at 15.2 ± 8.7% and 4.6 ± 4.4% respectively. A high incidence of CMV reactivation was documented (14/16 with MUD/Haplo donor and 2/7 with MSD) with only 1 CMV disease documented. There were two EBV reactivation without post-transplantation lymphoproliferative disease (PTLD) documented. With a median follow-up of 303 days (range, 75~700 days), three patients relapsed leading to 1-year cumulative incidence of relapse (CIR) at 12.8 ± 9.2%. Only one patient died of CMV pneumonia on day 91 with both 100-day and 1-year non-relapse mortality (NRM) at 4.6 ± 4.4%. The 1-year overall survival (OS), event-free survival (EFS) and GRFS were 95.5 ± 4.4%, 82.6 ± 9.5%, and 68.0 ± 11.3% respectively. Based on Simon's stage II design, our primary data showed that the PT-Cy+tacrolimus ± ATG protocol was promising in preventing aGVHD and cGVHD, which may translate into low NRM without increased CIR. Further clinical trial with large number of patients should be warranted. This trial was registered at www.clinicaltrials.gov as #NCT 04118075.
Diagnostic and Prognostic Value of Circulating CircRNAs in Cancer
Authors: Wang Mina , Xie Feiyu , Lin Jiaran , Zhao Yihan , Zhang Qian , Liao Zehuan , Wei Peng
Published: March 2021

Cancer has been regarded as one of the leading causes of mortality worldwide. Diagnostic and prognostic biomarkers with high sensitivity and specificity for cancer play a crucial role in preventing or treating cancer. Circular RNAs (circRNAs), which hold great potential for the management of cancer patients due to their abundance, stable property, and high specificity in serum, plasma, and other body fluids, can be used as non-invasive and blood-based biomarkers in cancer diagnosis and prognosis. There are four types of circRNAs including exonic circRNAs (ecircRNA), intronic circRNAs, exon-intron circRNAs (EIciRNA), and intergenic circRNAs. CircRNAs can act as miRNA sponges, affect protein translation, interplay with RNA binding proteins, regulate protein recruitment, and modulate protein scaffolding and assembly. Therefore, the multifunctionalities of circRNAs make them ideal for detecting and predicting cancer. Indeed, circRNAs manifest high sensitivity and specificity in more than ten types of cancer. This review aims to consolidate the types and functions of circRNAs, as well as discuss the diagnostic and prognostic value of circulating circRNAs in cancer.
Correlation Between Pulmonary Sclerosing Pneumocytoma Features and MSCT Imaging Manifestations in 34 Patients: Implications for Precision Medicine
Authors: Xu Gen , Wang Zhaoyu , Xiong Zeng , Li Manqiu , Luo Weijun , Xu Yong , Min Tang
Published: March 2021

Objective: To identify and analyze the multi-slice computed tomography (MSCT) imaging manifestations and clinicopathological features of PSP to improve the preoperative and intraoperative diagnosis of the disease.

Method: This was a retrospective study conducted on the imaging and clinicopathological data of the PSP patients treated in two major hospitals in China from October 2001 to December 2019. The locations of lung lesions, clinical symptoms, surgical complications, MSCT imaging features, and the corresponding relationship with clinicopathological features were assessed. Then, a new diagnostic approach was defined and used to train imaging and pathological doctors (experimental group). Then, the diagnostic accuracy of the experimental group was evaluated in preoperative and intraoperative diagnosis of PSP.

Results: Thirty-four PSP cases were analyzed (mean: 51.42; range: 39–69 years old). The peripheral type was more common, while 92% of the lesions located in the middle lobe of the right lung and the lower lobe of bilateral lungs. The shortest lesion edge-pleura distance ranged 0 to 30 mm and 46% of the lesions (16/34) were attached to the pleura, 62% (21/34) located at 0–5 mm, 92% (31/34) within 20 mm from the pleura. Diameters of the lesions ranged 8.58 to 68.41 mm, while most of them were 20-40 mm. All lesions showed enhancement, and 97% (33/34) were unevenly enhanced. PSP volume was negatively correlated with the total degree of enhancement (r = −0.587, p < 0.01), and the volume difference between the obvious enhancement zone and the slight enhancement zone (r = −0.795, p < 0.01). Welt vessel sign was observed in 61.7% (21/34) of cases, and none of welt vessels entered into the lesions. Vascular-like enhancement area inside the lesion showed no significant correlation with the welt vessels outside the lesion, and no case showed entrance of bronchus into the lesion. The trained experimental group showed significantly greater diagnostic accuracy than the control group. In particular, the accuracy rate of intraoperative frozen section diagnosis was 60% higher in the experimental group than the control group.

Conclusion: PSP has characteristic imaging manifestations, which can be utilized to improve the preoperative and intraoperative diagnostic coincidence rate of PSP.
Different Biological Pathways Between Good and Poor Inhaled Corticosteroid Responses in Asthma
Authors: Kim Byung-Keun , Lee Hyun-Seung , Lee Suh-Young , Park Heung-Woo
Published: March 2021

Gene regulatory networks address how transcription factors (TFs) and their regulatory roles in gene expression determine the responsiveness to anti-asthma therapy. The purpose of this study was to assess gene regulatory networks of adult patients with asthma who showed good or poor lung function improvements in response to inhaled corticosteroids (ICSs). A total of 47 patients with asthma were recruited and classified as good responders (GRs) and poor responders (PRs) based on their responses to ICSs. Genome-wide gene expression was measured using peripheral blood mononuclear cells obtained in a stable state. We used Passing Attributes between Networks for Data Assimilations to construct the gene regulatory networks associated with GRs and PRs to ICSs. We identified the top-10 TFs that showed large differences in high-confidence edges between the GR and PR aggregate networks. These top-10 TFs and their differentially-connected genes in the PR and GR aggregate networks were significantly enriched in distinct biological pathways, such as TGF-β signaling, cell cycle, and IL-4 and IL-13 signaling pathways. We identified multiple TFs and related biological pathways influencing ICS responses in asthma. Our results provide potential targets to overcome insensitivity to corticosteroids in patients with asthma.
Circulating Nucleosomes as Potential Markers to Monitor COVID-19 Disease Progression
Authors: Cavalier Etienne , Guiot Julien , Lechner Katharina , Dutsch Alexander , Eccleston Mark , Herzog Marielle , Bygott Thomas , Schomburg Adrian , Kelly Theresa , Holdenrieder Stefan
Published: March 2021

The severity of coronavirus disease 2019 (COVID-19) varies significantly with cases spanning from asymptomatic to lethal with a subset of individuals developing Severe Acute Respiratory Syndrome (SARS) and death from respiratory failure. To determine whether global nucleosome and citrullinated nucleosome levels were elevated in COVID-19 patients, we tested two independent cohorts of COVID-19 positive patients with quantitative nucleosome immunoassays and found that nucleosomes were highly elevated in plasma of COVID-19 patients with a severe course of the disease relative to healthy controls and that both histone 3.1 variant and citrullinated nucleosomes increase with disease severity. Elevated citrullination of circulating nucleosomes is indicative of neutrophil extracellular trap formation, neutrophil activation and NETosis in severely affected individuals. Importantly, using hospital setting (outpatient, inpatient or ICU) as a proxy for disease severity, nucleosome levels increased with disease severity and may serve as a guiding biomarker for treatment. Owing to the limited availability of mechanical ventilators and extracorporal membrane oxygenation (ECMO) equipment, there is an urgent need for effective tools to rapidly assess disease severity and guide treatment selection. Based on our studies of two independent cohorts of COVID-19 patients from Belgium and Germany, we suggest further investigation of circulating nucleosomes and citrullination as biomarkers for clinical triage, treatment allocation and clinical drug discovery.
Low Diversity of Human Variation Despite Mostly Mild Functional Impact of De Novo Variants
Authors: Mahlich Yannick , Miller Maximillian , Zeng Zishuo , Bromberg Yana
Published: March 2021

Non-synonymous Single Nucleotide Variants (nsSNVs), resulting in single amino acid variants (SAVs), are important drivers of evolutionary adaptation across the tree of life. Humans carry on average over 10,000 SAVs per individual genome, many of which likely have little to no impact on the function of the protein they affect. Experimental evidence for protein function changes as a result of SAVs remain sparse – a situation that can be somewhat alleviated by predicting their impact using computational methods. Here, we used SNAP to examine both observed and in silico generated human variation in a set of 1,265 proteins that are consistently found across a number of diverse species. The number of SAVs that are predicted to have any functional effect on these proteins is smaller than expected, suggesting sequence/function optimization over evolutionary timescales. Additionally, we find that only a few of the yet-unobserved SAVs could drastically change the function of these proteins, while nearly a quarter would have only a mild functional effect. We observed that variants common in the human population localized to less conserved protein positions and carried mild to moderate functional effects more frequently than rare variants. As expected, rare variants carried severe effects more frequently than common variants. In line with current assumptions, we demonstrated that the change of the human reference sequence amino acid to the reference of another species (a cross-species variant) is unlikely to significantly impact protein function. However, we also observed that many cross-species variants may be weakly non-neutral for the purposes of quick adaptation to environmental changes, but may not be identified as such by current state-of-the-art methodology.
Illness Severity Moderated Association Between Trait Anxiety and Amygdala-Based Functional Connectivity in Generalized Anxiety Disorder
Authors: Du Yang , Li Hailong , Xiao Hongqi , Wang Mei , Zhang Wei , Gong Qiyong , Qiu Changjian , Huang Xiaoqi
Published: March 2021

Trait anxiety is considered a vulnerability factor for the development of generalized anxiety disorder (GAD). The amygdala is related to both trait anxiety and GAD. Thus, we investigated amygdala-based functional connectivity (FC) in drug-naive non-comorbid GAD patients and explored its associations with personality, symptoms, and illness severity. FC analyses using the bilateral amygdala as seeds were performed with resting-state functional MRI data from 38 GAD patients and 20 matched healthy controls (HCs). Clinical characteristics were correlated with FC Z-scores from regions showing significant group differences. Furthermore, moderation analyses were used to explore the conditional effect of illness severity measured by the Clinical Global Impression–Severity (CGI-S) scale on the relationship between FC and trait anxiety. Relative to HCs, GAD patients showed hypoconnectivity between the amygdala and the rostral anterior cingulate cortex (rACC), inferior frontal gyrus (IFG), parahippocampal gyrus, and cerebellum and hyperconnectivity between the amygdala and the superior temporal gyrus (STG), insula, and postcentral gyrus. In GAD patients, amygdala–rACC connectivity was negatively associated with symptom severity and trait anxiety, and amygdala–IFG connectivity was positively associated with symptom severity. Moreover, CGI-S scores moderated the negative correlation between trait anxiety and amygdala–rACC FC. We demonstrate that there is extensive amygdala-based network dysfunction in patients with GAD. More importantly, amygdala–rACC connectivity plays a key role in the neural pathology of trait anxiety. Finally, the more severe the illness, the stronger the negative association between trait anxiety and amygdala–rACC FC. Our results emphasize the importance of personalized intervention in GAD.
Aberrant Dynamic Functional Connectivity of Default Mode Network in Schizophrenia and Links to Symptom Severity
Authors: Sendi Mohammad S. E. , Zendehrouh Elaheh , Ellis Charles A. , Liang Zhijia , Fu Zening , Mathalon Daniel H. , Ford Judith M. , Preda Adrian , van Erp Theo G. M. , Miller Robyn L. , Pearlson Godfrey D. , Turner Jessica A. , Calhoun Vince D.
Published: March 2021

Background: Schizophrenia affects around 1% of the global population. Functional connectivity extracted from resting-state functional magnetic resonance imaging (rs-fMRI) has previously been used to study schizophrenia and has great potential to provide novel insights into the disorder. Some studies have shown abnormal functional connectivity in the default mode network (DMN) of individuals with schizophrenia, and more recent studies have shown abnormal dynamic functional connectivity (dFC) in individuals with schizophrenia. However, DMN dFC and the link between abnormal DMN dFC and symptom severity have not been well-characterized.

Method: Resting-state fMRI data from subjects with schizophrenia (SZ) and healthy controls (HC) across two datasets were analyzed independently. We captured seven maximally independent subnodes in the DMN by applying group independent component analysis and estimated dFC between subnode time courses using a sliding window approach. A clustering method separated the dFCs into five reoccurring brain states. A feature selection method modeled the difference between SZs and HCs using the state-specific FC features. Finally, we used the transition probability of a hidden Markov model to characterize the link between symptom severity and dFC in SZ subjects.

Results: We found decreases in the connectivity of the anterior cingulate cortex (ACC) and increases in the connectivity between the precuneus (PCu) and the posterior cingulate cortex (PCC) (i.e., PCu/PCC) of SZ subjects. In SZ, the transition probability from a state with weaker PCu/PCC and stronger ACC connectivity to a state with stronger PCu/PCC and weaker ACC connectivity increased with symptom severity.

Conclusions: To our knowledge, this was the first study to investigate DMN dFC and its link to schizophrenia symptom severity. We identified reproducible neural states in a data-driven manner and demonstrated that the strength of connectivity within those states differed between SZs and HCs. Additionally, we identified a relationship between SZ symptom severity and the dynamics of DMN functional connectivity. We validated our results across two datasets. These results support the potential of dFC for use as a biomarker of schizophrenia and shed new light upon the relationship between schizophrenia and DMN dynamics.