bluuebunny/crossref_metadata_2025 huggingface dataset:
Efficient Tissue Clearing and Multi-Organ Volumetric Imaging Enable Quantitative Visualization of Sparse Immune Cell Populations During Inflammation
Authors: Hofmann Julian , Gadjalova Iana , Mishra Ritu , Ruland Jürgen , Keppler Selina J.
Published: January 2021

Spatial information of cells in their tissue microenvironment is necessary to understand the complexity of pathophysiological processes. Volumetric imaging of cleared organs provides this information; however, current protocols are often elaborate, expensive, and organ specific. We developed a simplified, cost-effective, non-hazardous approach for efficient tissue clearing and multi-organ volumetric imaging (EMOVI). EMOVI enabled multiplexed antibody-based immunolabeling, provided adequate tissue transparency, maintained cellular morphology and preserved fluorochromes. Exemplarily, EMOVI allowed the detection and quantification of scarce cell populations during pneumonitis. EMOVI also permitted histo-cytometric analysis of MHC-II expressing cells, revealing distinct populations surrounding or infiltrating glomeruli of nephritic kidneys. Using EMOVI, we found widefield microscopy with real-time computational clearing as a valuable option for rapid image acquisition and detection of rare cellular events in cleared organs. EMOVI has the potential to make tissue clearing and volumetric imaging of immune cells applicable for a broad audience by facilitating flexibility in organ, fluorochrome and microscopy usage.
Neutrophil-Derived Myeloperoxidase Facilitates Both the Induction and Elicitation Phases of Contact Hypersensitivity
Authors: Strzepa Anna , Gurski Cody J. , Dittel Landon J. , Szczepanik Marian , Pritchard Kirkwood A. , Dittel Bonnie N.
Published: January 2021

Background

Allergic contact dermatitis (ACD) is a common skin disorder affecting an estimated 15-20% of the general population. The mouse model of ACD is contact hypersensitivity (CHS), which consists of two phases: induction and elicitation. Although neutrophils are required for both CHS disease phases their mechanisms of action are poorly understood. Neutrophils release myeloperoxidase (MPO) that through oxidation of biomolecules leads to cellular damage.

Objectives

This study investigated mechanisms whereby MPO contributes to CHS pathogenesis.

Methods

CHS was induced in mice using oxazolone (OX) as the initiating hapten applied to the skin. After 7 days, CHS was elicited by application of OX to the ear and disease severity was measured by ear thickness and vascular permeability in the ear. The role of MPO in the two phases of CHS was determined utilizing MPO-deficient mice and a specific MPO inhibitor.

Results

During the CHS induction phase MPO-deficiency lead to a reduction in IL-1β production in the skin and a subsequent reduction in migratory dendritic cells (DC) and effector T cells in the draining lymph node. During the elicitation phase, inhibition of MPO significantly reduced both ear swelling and vascular permeability.

Conclusion

MPO plays dual roles in CHS pathogenesis. In the initiation phase MPO promotes IL-1β production in the skin and activation of migratory DC that promote effector T cell priming. In the elicitation phase MPO drives vascular permeability contributing to inflammation. These results indicate that MPO it could be a potential therapeutic target for the treatment of ACD in humans.
Tumor Microenvironment Status Predicts the Efficacy of Postoperative Chemotherapy or Radiochemotherapy in Resected Gastric Cancer
Authors: Duan Ran , Li Xiaoqin , Zeng Dongqiang , Chen Xiaofeng , Shen Bo , Zhu Dongqin , Zhu Liuqing , Yu Yangyang , Wang Deqiang
Published: January 2021

Purpose

Chemotherapy (CT) and radiochemotherapy (RCT) are currently the standard postoperative treatments for resected gastric cancer (GC). However, owing to a lack of predictive biomarkers, their efficacy is currently suboptimal. As tumor microenvironment (TME) has the potential to determine treatment response, we investigated the association of TME status with the efficacy of fluoropyrimidine (FU)-based postoperative CT/RCT in resected GC.

Methods

Patients with transcriptome data were screened and selected in three independent cohorts. Favorable (fTME) and poor TME (pTME) were defined by a transcriptome-based TME qualification method. Immune infiltration and hypoxia were assessed.

Results

A total of 535 patients were eligible. fTME, indicating the presence of immune activation, was characterized by NK cell rather than CD8+ T cell infiltration. However, postoperative CT/RCT improved overall survival and disease-free survival time more evidently in patients with pTME GC than those with fTME GC. Stratified by stage in fTME GC, stage III patients benefited from postoperative CT/RCT while stage Ib/II patients did not. In comparison, patients with pTME GC benefited from postoperative CT/RCT, regardless of stage. Furthermore, fTME was more hypoxic than pTME, accompanied by a stronger expression of thymidylate synthase (TS)—the target of FU. Stage Ib/II fTME GC was the most hypoxic and had the strongest TS expression across all the subgroups stratified by TME status and stage.

Conclusions

We found that fTME, with the enrichment of NK cells, may predict the lack of postoperative CT/RCT efficacy in stage Ib/II GC, which may be associated with hypoxia and TS expression. Further validations and mechanism researches are needed.
Advances in Hypofractionated Irradiation-Induced Immunosuppression of Tumor Microenvironment
Authors: Wang Yuxia
Published: January 2021

Hypofractionated radiotherapy is external beam irradiation delivered at higher doses in fewer fractions than conventional standard radiotherapy, which can stimulate innate and adaptive immunity to enhance the body’s immune response against cancer. The enhancement effect of hypofractionated irradiation to immune response has been widely investigated, which is considered an approach to expand the benefit of immunotherapy. Meanwhile, increasing evidence suggests that hypofractionated irradiation may induce or enhance the suppression of immune microenvironments. However, the suppressive effects of hypofractionated irradiation on immunomicroenvironment and the molecular mechanisms involved in these conditions are largely unknown. In this context, we summarized the immune mechanisms associated with hypofractionated irradiation, highlighted the advances in its immunosuppressive effect, and further discussed the potential mechanism behind this effect. In our opinion, besides its immunogenic activity, hypofractionated irradiation also triggers homeostatic immunosuppressive mechanisms that may counterbalance antitumor effects. And this may suggest that a combination with immunotherapy could possibly improve the curative potential of hypofractionated radiotherapy.
B Cells in Patients With Melanoma: Implications for Treatment With Checkpoint Inhibitor Antibodies
Authors: Willsmore Zena N. , Harris Robert J. , Crescioli Silvia , Hussein Khuluud , Kakkassery Helen , Thapa Deepika , Cheung Anthony , Chauhan Jitesh , Bax Heather J. , Chenoweth Alicia , Laddach Roman , Osborn Gabriel , McCraw Alexa , Hoffmann Ricarda M. , Nakamura Mano , Geh Jenny L. , MacKenzie-Ross Alastair , Healy Ciaran , Tsoka Sophia , Spicer James F. , Papa Sophie , Barber Linda , Lacy Katie E. , Karagiannis Sophia N.
Published: January 2021

The contributions of the humoral immune response to melanoma are now widely recognized, with reports of positive prognostic value ascribed to tumor-infiltrating B cells (TIL-B) and increasing evidence of B cells as key predictors of patient response to treatment. There are disparate views as to the pro- and anti-tumor roles of B cells. B cells appear to play an integral role in forming tumor-associated tertiary lymphoid structures (TLSs) which can further modulate T cell activation. Expressed antibodies may distinctly influence tumor regulation in the tumor microenvironment, with some isotypes associated with strong anti-tumor immune response and others with progressive disease. Recently, B cells have been evaluated in the context of cancer immunotherapy. Checkpoint inhibitors (CPIs), targeting T cell effector functions, have revolutionized the management of melanoma for many patients; however, there remains a need to accurately predict treatment responders. Increasing evidence suggests that B cells may not be simple bystanders to CPI immunotherapy. Mature and differentiated B cell phenotypes are key positive correlates of CPI response. Recent evidence also points to an enrichment in activatory B cell phenotypes, and the contribution of B cells to TLS formation may facilitate induction of T cell phenotypes required for response to CPI. Contrastingly, specific B cell subsets often correlate with immune-related adverse events (irAEs) in CPI. With increased appreciation of the multifaceted role of B cell immunity, novel therapeutic strategies and biomarkers can be explored and translated into the clinic to optimize CPI immunotherapy in melanoma.
Case Report: Management of a Multidrug-Resistant CMV-Strain in a Renal Transplant Recipient by High-Dose CMV-Specific Immunoglobulins, Modulation in Immunosuppression, and Induction of CMV-Specific Cellular Immunity
Authors: Wiening Vanessa , Schmidt Tina , Dahmen Maximilian , Siam Sami , Reuter Stefan , Pavenstädt Hermann-Joseph , Sester Martina , Suwelack Barbara
Published: January 2021

The management of multidrug-resistant strains of cytomegalovirus after solid organ transplantation is challenging. This case report demonstrates the successful treatment of a multidrug-resistant strain of cytomegalovirus that may represent a valuable option for problematic cases. This report illustrates the emergence of a multidrug-resistant cytomegalovirus (CMV) UL54 mutant strain in a renal transplant recipient with severe lymphopenia and thrombocytopenia. We show that the combined treatment with high-dose intravenous cytomegalovirus-specific immunoglobulins (CMV-IVIG) after the switch to a mammalian target of rapamycin (mTOR)-inhibitor and cyclosporine A was a successful treatment alternative to direct antiviral treatment with high-dose ganciclovir and foscarnet. This treatment was associated with a quantitative induction of CMV-specific CD4 and CD8 T cells that showed maturation in phenotype and functionality with decreasing viral load. Our case report illustrates that high-dose CMV-IVIG and conversion of immunosuppressive drugs to mTOR inhibitors and cyclosporine A can be a successful treatment in a situation where the use of direct antiviral drugs was considered insufficient.
CFD Optimization of the Pre-Chamber Geometry for a Gasoline Spark Ignition Engine
Authors: Ge Haiwen , Bakir Ahmad Hadi , Yadav Suren , Kang Yunseon , Parameswaran Siva , Zhao Peng
Published: January 2021

In the present paper, an efficient optimization method based on Bayesian updating strategy is developed for the design of a spark-ignition engine equipped with pre-chamber. 3D computational fluid dynamics (CFD) simulation coupled with strategies including design of experiment, genetic algorithm, and machine learning methods is used to optimize the pre-chamber with desired combustion phasing. The optimization process starts from a design of experiment matrix of 11 design parameters, which are used to analytically characterize the pre-chamber geometry and set up the 3D combustion CFD. Taking CA50 as the single objective, the CFD results are then used to train the machine learning models. Different machine learning models are evaluated based on their Root Mean Square Error. Five machine learning models from five different categories are selected for second round evaluation. The trained machine learning model is used in the genetic algorithm optimization, which yields the optimized configuration and is again justified by CFD. The new CFD results based on the optimized design are added into the database to further refine the machine learning model. After 24 iterations for each selected machine learning models, the medium Gaussian support vector machine model is identified as the best method for the present application. Iterations using the medium Gaussian support vector machine model continue until a satisfactory result is achieved. Detailed combustion analysis is conducted to investigate the physical mechanism about how the design of pre-chamber influences the engine's performance. It is found that larger volume of the upper part of the pre-chamber results in stronger jet flow and turbulent intensity which further accelerates the flame propagation inside the pre-chamber, dominating the contrary effects from reduced pressure and temperature. Regression analysis shows that the radius of the pre-chamber is the most influential design parameter. The current work not only sheds light on the optimization of engine design, but also has demonstrated a general strategy applicable to the purpose of arbitrary engine optimization and mechanical system design.
Dynamics and Concordance Abnormalities Among Indices of Intrinsic Brain Activity in Individuals With Subjective Cognitive Decline: A Temporal Dynamics Resting-State Functional Magnetic Resonance Imaging Analysis
Authors: Yang Yiwen , Zha Xinyi , Zhang Xiaodong , Ke Jun , Hu Su , Wang Ximing , Su Yunyan , Hu Chunhong
Published: January 2021

Individuals with subjective cognitive decline (SCD) are more likely to develop into Alzheimer disease (AD) in the future. Resting-state functional magnetic resonance imaging (rs-fMRI) studies have shown alterations of intrinsic brain activity (IBA) in SCD individuals. However, rs-fMRI studies to date have mainly focused on static characteristics of IBA, with few studies reporting dynamics- and concordance-related changes in IBA indices in SCD individuals. To investigate these aberrant changes, a temporal dynamic analysis of rs-fMRI data was conducted on 94 SCD individuals (71.07 ± 6.18 years, 60 female), 75 (74.36 ± 8.42 years, 35 female) mild cognitive impairment (MCI) patients, and 82 age-, gender-, and education-matched controls (NCs; 73.88 ± 7.40 years, 49 female) from the Alzheimer's Disease Neuroimaging Initiative database. The dynamics and concordance of the rs-fMRI indices were calculated. The results showed that SCD individuals had a lower amplitude of low-frequency fluctuations dynamics in bilateral hippocampus (HP)/parahippocampal gyrus (PHG)/fusiform gyrus (FG) and bilateral cerebellum, a lower fractional amplitude of low-frequency fluctuation dynamics in bilateral precuneus (PreCu) and paracentral lobule, and a lower regional homogeneity dynamics in bilateral cerebellum, vermis, and left FG compared with the other two groups, whereas those in MCI patients were higher (Gaussian random field–corrected, voxel-level P < 0.001, cluster-level P < 0.05). Furthermore, SCD individuals had higher concordance in bilateral HP/PHG/FG, temporal lobe, and left midcingulate cortex than NCs, but those in MCI were lower than those in NCs. No correlation between concordance values and neuropsychological scale scores was found. SCD individuals showed both dynamics and concordance-related alterations in IBA, which indicates a compensatory mechanism in SCD individuals. Temporal dynamics analysis offers a novel approach to capturing brain alterations in individuals with SCD.
iTRAQ-Based Proteomic Analysis of Dentate Gyrus in Temporal Lobe Epilepsy With Hippocampal Sclerosis
Authors: Xiao Wenbiao , Yang Zhiquan , Yan Xiaoxin , Feng Li , Long Lili , Tu Tian , Deng Na , Chen Wenjuan , Xiao Bo , Long Hongyu , Zeng Yi
Published: January 2021

Temporal lobe epilepsy (TLE) is the most frequent type of focal epilepsy in adults, typically resistant to pharmacological treatment, and mostly presents with cognitive impairment and psychiatric comorbidities. The most common neuropathological hallmark in TLE patients is hippocampal sclerosis (HS). However, the underlying molecular mechanisms involved remain poorly characterized. The dentate gyrus (DG), one specific hippocampal subarea, structural and functional changes imply a key involvement of the DG in the development of TLE. In this study, a isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomic technique was performed for the analysis of hippocampal DG obtained from patients with TLE-HS compared to control samples obtained from autopsy. Our proteomic data identified 5,583 proteins, of which 82 proteins were upregulated and 90 proteins were downregulated. Bioinformatics analysis indicated that differentially expressed proteins were enriched in “synaptic vesicle,” “mitochondrion,” “cell-cell adhesion,” “regulation of synaptic plasticity,” “ATP binding,” and “oxidative phosphorylation.” Protein-protein interaction network analysis found a pivotal module of 10 proteins that were related to “oxidative phosphorylation.” This study has investigated proteomic alterations in the DG region of TLE-HS patients, and paved the way for the better understanding of epileptogenesis mechanisms and future therapeutic intervention.
Nicotinamide Improves Cognitive Function in Mice With Chronic Cerebral Hypoperfusion
Authors: Liu Bin , Zhao Guifeng , Jin Ling , Shi Jingping
Published: January 2021

Normal brain function requires steady blood supply to maintain stable energy state. When blood supply to the brain becomes suboptimal for a long period of time, chronic cerebral hypoperfusion (CCH) and a variety of brain changes may occur. CCH causes white matter injury and cognitive impairment. The present study investigated the effect of nicotinamide (NAM) on CCH-induced cognitive impairment and white matter damage in mice. Male C57Bl/6J mice aged 10–12 weeks (mean age = 11 ± 1 weeks) and weighing 24 - 29 g (mean weight = 26.5 ± 2.5 g) were randomly assigned to three groups (eight mice/group): sham group, CCH group and NAM group. Chronic cerebral hypoperfusion (CCH) was induced using standard methods. The treatment group mice received intraperitoneal injection of NAM at a dose of 200 mg/kg body weight (bwt) daily for 30 days. Learning, memory, anxiety, and depression-like behaviors were measured using Morris water maze test (MWMT), open field test (OFT), sucrose preference test (SPT), and forced swim test (FST), respectively. White matter damage and remodeling were determined via histological/ immunohistochemical analyses, and western blotting, respectively. The results showed that the time spent in target quadrant, number of crossings and escape latency were significantly lower in CCH group than in sham group, but they were significantly increased by NAM (p < 0.05). Mice in NAM group moved significantly faster and covered longer distances, when compared with those in CCH group (p < 0.05). The percentage of time spent in open arms and the number of entries to the open arms were significantly lower in CCH group than in NAM group (p < 0.05). Moreover, anhedonia and histologic scores (index of myelin injury) were significantly higher in CCH group than in sham group, but they were significantly reduced by NAM (p < 0.05). The results of immunohistochemical staining and Western blotting showed that the protein expressions of 2′, 3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase) and synaptophysin were significantly downregulated in CCH group, relative to sham group, but they were significantly upregulated by NAM (p < 0.05). These results indicate that NAM improves cognitive function in mice with CCH.
Closed-Loop Phase-Dependent Vibration Stimulation Improves Motor Imagery-Based Brain-Computer Interface Performance
Authors: Zhang Wenbin , Song Aiguo , Zeng Hong , Xu Baoguo , Miao Minmin
Published: January 2021

The motor imagery (MI) paradigm has been wildly used in brain-computer interface (BCI), but the difficulties in performing imagery tasks limit its application. Mechanical vibration stimulus has been increasingly used to enhance the MI performance, but its improvement consistence is still under debate. To develop more effective vibration stimulus methods for consistently enhancing MI, this study proposes an EEG phase-dependent closed-loop mechanical vibration stimulation method. The subject’s index finger of the non-dominant hand was given 4 different vibration stimulation conditions (i.e., continuous open-loop vibration stimulus, two different phase-dependent closed-loop vibration stimuli and no stimulus) when performing two tasks of imagining movement and rest of the index finger from his/her dominant hand. We compared MI performance and brain oscillatory patterns under different conditions to verify the effectiveness of this method. The subjects performed 80 trials of each type in a random order, and the average phase-lock value of closed-loop stimulus conditions was 0.71. It was found that the closed-loop vibration stimulus applied in the falling phase helped the subjects to produce stronger event-related desynchronization (ERD) and sustain longer. Moreover, the classification accuracy was improved by about 9% compared with MI without any vibration stimulation (p = 0.012, paired t-test). This method helps to modulate the mu rhythm and make subjects more concentrated on the imagery and without negative enhancement during rest tasks, ultimately improves MI-based BCI performance. Participants reported that the tactile fatigue under closed-loop stimulation conditions was significantly less than continuous stimulation. This novel method is an improvement to the traditional vibration stimulation enhancement research and helps to make stimulation more precise and efficient.
Defined Tau Phosphospecies Differentially Inhibit Fast Axonal Transport Through Activation of Two Independent Signaling Pathways
Authors: Morris Sarah L. , Tsai Ming-Ying , Aloe Sarah , Bechberger Karin , König Svenja , Morfini Gerardo , Brady Scott T.
Published: January 2021

Tau protein is subject to phosphorylation by multiple kinases at more than 80 different sites. Some of these sites are associated with tau pathology and neurodegeneration, but other sites are modified in normal tau as well as in pathological tau. Although phosphorylation of tau at residues in the microtubule-binding repeats is thought to reduce tau association with microtubules, the functional consequences of other sites are poorly understood. The AT8 antibody recognizes a complex phosphoepitope site on tau that is detectable in a healthy brain but significantly increased in Alzheimer’s disease (AD) and other tauopathies. Previous studies showed that phosphorylation of tau at the AT8 site leads to exposure of an N-terminal sequence that promotes activation of a protein phosphatase 1 (PP1)/glycogen synthase 3 (GSK3) signaling pathway, which inhibits kinesin-1-based anterograde fast axonal transport (FAT). This finding suggests that phosphorylation may control tau conformation and function. However, the AT8 includes three distinct phosphorylated amino acids that may be differentially phosphorylated in normal and disease conditions. To evaluate the effects of specific phosphorylation sites in the AT8 epitope, recombinant, pseudophosphorylated tau proteins were perfused into the isolated squid axoplasm preparation to determine their effects on axonal signaling pathways and FAT. Results from these studies suggest a mechanism where specific phosphorylation events differentially impact tau conformation, promoting activation of independent signaling pathways that differentially affect FAT. Implications of findings here to our understanding of tau function in health and disease conditions are discussed.
Diagnostic Performance of Theranostic Radionuclides Used in Transarterial Radioembolization for Liver Cancer
Authors: Li Rou , Li Danni , Jia Guorong , Li Xiao , Sun Gaofeng , Zuo Changjing
Published: January 2021

Primary liver tumor with hepatocellular carcinoma accounting for 75–80% of all such tumors, is one of the global leading causes of cancer-related death, especially in cirrhotic patients. Liver tumors are highly hypervascularized via the hepatic artery, while normal liver tissues are mainly supplied by the portal vein; consequently, intra-arterially delivered treatment, which includes transarterial chemoembolization (TACE) and transarterial radioembolization (TARE), is deemed as a palliative treatment. With the development of nuclear technology and radiochemistry, TARE has become an alternative for patients with hepatic cancer, especially for patients who failed other therapies, or for patients who need tumor downstaging treatment. In practice, some radionuclides have suitable physicochemical characteristics to act as radioactive embolism agents. Among them, 90Y emits β rays only and is suitable for bremsstrahlung single photon emission computed tomography (BS SPECT) and positron emission tomography (PET); meanwhile, some others, such as 131I, 153Sm, 166Ho, 177Lu, 186Re, and 188Re, emit both β and γ rays, enabling embolism beads to play a role in both therapy and single photon emission computed tomography (SPECT) imaging. During TARE, concomitant imaging provide additive diagnostic information and help to guide the course of liver cancer treatment. Therefore, we review the theranostic radionuclides that have been used or could potentially be used in TARE for liver cancer and focus on the clinical benefits of diagnostic applications, including real-time monitoring of embolism beads, evaluating irradiation dose, predicting therapy effects, and corresponding adjustments to TARE.
Prognostic Factors and Clinical Features of Neonatal Splenic Rupture/Hemorrhage: Two Cases Reports and Literature Review
Authors: Chang Han-Pi , Fu Ren-Huei , Lin Jainn-Jim , Chiang Ming-Chou
Published: January 2021

Background:Neonatal splenic rupture/hemorrhage (SRH), an extremely rare and potentially fatal presentation, can spontaneously resolve without surgical treatment; However, treatment approaches remain controversial. The present study aimed to describe and analyze the clinical features and therapies of neonatal SRH and therapeutic approaches.

Methods:We present the cases of two patients and review another 37 cases reported in English-literature. The literature search included all articles published in PUBMED from inception between January 1968 and December 2019. Demographic data, precipitating factors, clinical characteristics including presenting symptoms and signs, presenting time, age at SRH presentation, imaging findings, as well as treatments and outcomes were analyzed.

Results:In addition to the two cases treated at our hospital, 37 neonates with SRH were reported during the study period. The rate of full-term neonates was 72% (28/39). The cause was idiopathic in most cases, and congenital coagulation disorders were underlying causes in 13% (5/39) of the cases. The most common presenting symptom and sign of neonatal SRH were pallor or anemia, followed by abdominal discoloration/distension. Additionally, 18% (7/39) of the cases presented with scrotal hematoma or swelling. The age at SRH presentation ranged between 3 h and 5 days of age. Abdominal ultrasonography or computed tomography was used as the diagnostic tool. Twenty-seven cases (69%) received surgical management. The prognosis was comparable between the neonates treated with splenectomy and those treated with non-surgical approaches. The mortality rate was 18% (7/39) in the study cohort. SRH presentation at ≤12 h of age was associated with higher mortality compared to SRH presenting time at >12 h of age (odds ratio 25.0, 95% CI 2.514–248.575,p= 0.001).

Conclusion:Our literature review revealed that the mortality rate of neonatal SRH was 18% and that the mortality risk was higher in neonates presenting with SRH symptoms and signs at ≤12 h of age.
Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2
Authors: Chen Catherine Z. , Shinn Paul , Itkin Zina , Eastman Richard T. , Bostwick Robert , Rasmussen Lynn , Huang Ruili , Shen Min , Hu Xin , Wilson Kelli M. , Brooks Brianna M. , Guo Hui , Zhao Tongan , Klump-Thomas Carleen , Simeonov Anton , Michael Samuel G. , Lo Donald C. , Hall Matthew D. , Zheng Wei
Published: January 2021

Drug repurposing is a rapid approach to identify therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drugs and 49 investigational drugs. The anti-SARS-CoV-2 activities of 230 of these confirmed compounds, of which 38 are approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA-approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set is a useful resource for drug repurposing efforts, including design of new drug combinations for clinical trials for SARS-CoV-2.
Depression with Comorbid Diabetes: What Evidence Exists for Treatments Using Traditional Chinese Medicine and Natural Products?
Authors: Lu Yanting , An Tao , Tian Hu , Gao Xueqin , Wang Furong , Wang Shijun , Ma Ke
Published: January 2021

Comorbidity between diabetes mellitus (DM) and depression, two chronic and devastating diseases spreading worldwide, has been confirmed by a large body of epidemiological and clinical studies. Due to the bidirectional relationship between DM and depression, this comorbidity leads to poorer outcomes in both conditions. Given the adverse effects and limited effectiveness of the existing therapies for depression associated with diabetes, the development of novel therapeutic drugs with more potency and fewer side effects is still the most important goal. Hence, many researchers have made great efforts to investigate the potential usefulness of traditional Chinese medicine (TCM) and natural products, including natural extracts and purified compounds, in the treatment of comorbid depression in diabetes. Here, we reviewed the related literature on TCM and natural products that can remedy the comorbidity of diabetes and depression and presented them on the basis of their mechanism of action, focusing on shared risk factors, including insulin resistance, oxidative stress and inflammation, and nervous disturbances. In short, this review suggests that TCM and natural products could expand the therapeutic alternatives to ameliorate the association between DM and depressive disorders.
Effective Dose of Rhizoma Coptidis Extract Granules for Type 2 Diabetes Treatment: A Hospital-Based Retrospective Cohort Study
Authors: Huang Yueh-Hsiang , Liu Geng-Hao , Hsu Tzu-Yang , Yang Lan-Yan , Lee Ming-Chung , Huang Chun-Teng , Wu Yi-Hong
Published: January 2021

Rhizoma Coptidis is a popular phytomedicine for the treatment of type 2 diabetes in Asia, but its effective dose for diabetes treatment remains confused because of diverse origins. This study aimed to investigate the dose-response effects of Rhizoma Coptidis extract granules (RCEG), produced with standardized quality control, on hypoglycemic effects in patients with type 2 diabetes. We conducted a retrospective analysis of Chang Gung Research Database from January 01, 2008 to November 30, 2017. Outpatients visiting traditional Chinese medicine clinics and receiving RCEG for type 2 diabetes treatment were included. Plasma glucose, lipid, and other parameters were analyzed from 93 patients with a total of 737 visits within 60 weeks. Scatter plots with the LOESS analysis were used to explore the association between RCEG dose and hypoglycemic effect. The minimal effective dose was chosen to divide the study population into the high-dose and low-dose RCEG groups. Non-parametric tests were used for between-group and within-group comparisons. The multivariate nonlinear mixed-effects model was applied to access the effect of treatment length and groups simultaneously on the change of HbA1c and fasting plasma glucose. The “arule” package in R was used to present the network diagram of RCEG and other co-prescriptions. We first discovered a significant relationship between RCEG dose and HbA1c reduction when the dose reached 0.08 g/kg/day or higher. We thus defined 0.08 g/kg/day of RCEG as the minimum effective dose, and a threshold to separate patients into the high-dose (≥0.08 g/kg/d) and low-dose (<0.08 g/kg/d) RCEG groups. In the high-dose RCEG group, a significant decrease in total cholesterol and a trend toward triglyceride reduction were also noted. Patients more effectively responded to RCEG treatment if they had a higher initial HbA1c level, higher heart rates, better liver function tests, and better tolerance to the higher dose and treatment duration of RCEG. In addition, digestive/tonic/dampness draining formulas and blood regulation recipes were two of the most frequent co-prescriptions with RCEG. This study concluded that RCEG at a dose exceeding 0.08 g/kg/d had beneficial effects on glycemic and lipid control, without showing nephro- or hepatotoxicity, in patients with type 2 diabetes.
Isorhamnetin Enhances the Radiosensitivity of A549 Cells Through Interleukin-13 and the NF-κB Signaling Pathway
Authors: Du Yarong , Jia Cong , Liu Yan , Li Yehua , Wang Jufang , Sun Kun
Published: January 2021

Isorhamnetin (ISO), a naturally occurring plant flavonoid, is widely used as a phytomedicine. The major treatment modality for non-small-cell lung carcinoma (NSCLC) is radiotherapy. However, radiotherapy can induce radioresistance in cancer cells, thereby resulting in a poor response rate. Our results demonstrated that pretreatment with ISO induced radiosensitizing effect in A549 cells using colony formation, micronucleus, and γH2AX foci assays. In addition, ISO pretreatment significantly enhanced the radiation-induced incidence of apoptosis, the collapse of mitochondrial membrane potential, and the expressions of proteins associated with cellular apoptosis and suppressed the upregulation of NF-κBp65 induced by irradiation in A549 cells. Interestingly, the expression of interleukin-13 (IL-13), an anti-inflammatory cytokine, was positively correlated with the ISO-mediated radiosensitization of A549 cells. The knockdown of IL-13 expression by RNA interference decreased the IL-13 level and thus reduced ISO-mediated radiosensitivity in cells. We also found that the IR-induced NF-κB signaling activation was inhibited by ISO pretreatment, and it was abrogated in IL-13 silenced cells. We speculated that ISO may confer radiosensitivity on A549 cells via increasing the expression of IL-13 and inhibiting the activation of NF-κB. To our knowledge, this is the first report demonstrating the effects of ISO treatment on the responsiveness of lung cancer cells to irradiation through IL-13 and the NF-κB signaling pathway. In summary, ISO is a naturally occurring radiosensitizer with a potential application in adjuvant radiotherapy.
The Connectedness of the Coronavirus Disease Pandemic in the World: A Study Based on Complex Network Analysis
Authors: Zhu Sha , Kou Meng , Lai Fujun , Feng Qingxiang , Du Guorong
Published: January 2021

Since the coronavirus disease (COVID-19) pandemic started at the beginning of 2020, it has seriously affected various countries’ economic and social development and accelerated the economic recession worldwide. Therefore, the connectedness of the global COVID-19 network across countries is studied in this article. Based on COVID-19 correlations in 122 countries, we construct a complex network of COVID-19 from January 19, 2020, to August 15, 2020. We then deconstruct the overall global network connectedness and analyze the connectedness characteristics. Moreover, we empirically investigate the network connectedness influencing factors by using various countries’ macroeconomic and social data. We find that the global COVID-19 pandemic network has some prominent complex network properties, such as low path length, high clustering, and good community structure. Furthermore, population density, economic size, trade, government spending, and quality of medical treatment are significant macrofactors affecting COVID-19 connectedness in different countries.
Effectiveness of Single Nucleotide Polymorphism Markers in Genotyping Germplasm Collections of Coffea canephora Using KASP Assay
Authors: Akpertey Abraham , Padi Francis K. , Meinhardt Lyndel , Zhang Dapeng
Published: January 2021

Accurate genotype identification is imperative for effective use ofCoffea canephoraL. germplasm to breed new varieties with tolerance or resistance to biotic and abiotic stresses (including moisture stress and pest and disease stresses such as coffee berry borer and rust) and for high yield and improved cup quality. The present study validated 192 published single nucleotide polymorphism (SNP) markers and selected a panel of 120 loci to examine parentage and labeling errors, genetic diversity, and population structure in 400C. canephoraaccessions assembled from different coffee-producing countries and planted in a field gene bank in Ghana. Of the 400 genotypes analyzed, both synonymous (trees with same SNP profiles but different names, 12.8%) and homonymous (trees with same name but different SNP profiles, 5.8%) mislabeling were identified. Parentage analysis showed that 33.3% of the progenies derived from controlled crossing and 0% of the progenies derived from an open pollinated biclonal seed garden had parentage (both parents) corresponding to breeder records. The results suggest mislabeling of the mother trees used in seed gardens and pollen contamination from unwanted paternal parents. After removing the duplicated accessions, Bayesian clustering analysis partitioned the 270 unique genotypes into two main populations. Analysis of molecular variance (AMOVA) showed that the between-population variation accounts for 41% of the total molecular variation and the genetic divergence was highly significant (Fst = 0.256;P< 0.001). Taken together, our results demonstrate the effectiveness of using the selected SNP panel in gene bank management, varietal identification, seed garden management, nursery verification, and coffee bean authentication forC. canephorabreeding programs.
Valine-Glutamine Proteins in Plant Responses to Oxygen and Nitric Oxide
Authors: León José , Gayubas Beatriz , Castillo Mari-Cruz
Published: January 2021

Multigene families coding for valine-glutamine (VQ) proteins have been identified in all kind of plants but chlorophytes. VQ proteins are transcriptional regulators, which often interact with WRKY transcription factors to regulate gene expression sometimes modulated by reversible phosphorylation. Different VQ-WRKY complexes regulate defense against varied pathogens as well as responses to osmotic stress and extreme temperatures. However, despite these well-known functions, new regulatory activities for VQ proteins are still to be explored. Searching public Arabidopsis thaliana transcriptome data for new potential targets of VQ-WRKY regulation allowed us identifying several VQ protein and WRKY factor encoding genes that were differentially expressed in oxygen-related processes such as responses to hypoxia or ozone-triggered oxidative stress. Moreover, some of those were also differentially regulated upon nitric oxide (NO) treatment. These subsets of VQ and WRKY proteins might combine into different VQ-WRKY complexes, thus representing a potential regulatory core of NO-modulated and O2-modulated responses. Given the increasing relevance that gasotransmitters are gaining as plant physiology regulators, and particularly considering the key roles exerted by O2 and NO in regulating the N-degron pathway-controlled stability of transcription factors, VQ and WRKY proteins could be instrumental in regulating manifold processes in plants.
Computerized Adaptive Testing for Schizotypal Personality Disorder: Detecting Individuals at Risk
Authors: Li Yaling , She Menghua , Tu Dongbo , Cai Yan
Published: January 2021

As schizotypal personality disorder (SPD) increasingly prevails in the general population, a rapid and comprehensive measurement instrument is imperative to screen individuals at risk for SPD. To address this issue, we aimed to develop a computerized adaptive testing for SPD (CAT-SPD) using a non-clinical Chinese sample (N = 999), consisting of a calibration sample (N1 = 497) and a validation sample (N2 = 502). The item pool of SPD was constructed from several widely used SPD scales and statistical analyses based on the item response theory (IRT) via a calibration sample using a graded response model (GRM). Finally, 90 items, which measured at least one symptom of diagnostic criteria of SPD in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) and had local independence, good item fit, high slope, and no differential item functioning (DIF), composed the final item pool for the CAT-SPD. In addition, a simulated CAT was conducted in an independent validation sample to assess the performance of the CAT-SPD. Results showed that the CAT-SPD not only had acceptable reliability, validity, and predictive utility but also had shorter but efficient assessment of SPD which can save significant time and reduce the test burden of individuals with less information loss.
Coronavirus Disease Stress Among Italian Healthcare Workers: The Role of Coping Humor
Authors: Canestrari Carla , Bongelli Ramona , Fermani Alessandra , Riccioni Ilaria , Bertolazzi Alessia , Muzi Morena , Burro Roberto
Published: January 2021

The study aimed to understand how coping strategies in general and humor-based coping strategies in particular modulate the perception of pandemic-related stress in a sample of Italian healthcare workers during the coronavirus disease (COVID-19) outbreak in Italy. A total of 625 healthcare workers anonymously and voluntarily completed a 10-min questionnaire, which included psychometrically valid measurements preceded by a set of questions aimed at determining workers’ exposure to COVID-19. The Perceived Stress Scale was used to measure healthcare workers’ stress levels, and the Brief COPE Scale and Coping Humor Scale were used to assess participants’ avoidant or approach coping style and verify the degree to which they relied on humor to cope with stress. The results show that (1) levels of perceived stress were higher in healthcare workers who were more exposed to COVID-19 (i.e., who came into contact with COVID-19 patients or worked in wards dedicated to COVID-19) in comparison to less-exposed workers; (2) participants who reported a higher use of avoidant coping strategies perceived the situation as more stressful than those who used them less; and (3) healthcare workers who reported higher use of humor-based coping strategies perceived the situation as less stressful in comparison with those who reported less use of coping humor. Such findings expanded other research studies by including coping humor as a potential factor to mitigate the perceived stress related to COVID-19. The paper concludes with a discussion of implications for future research and limitations of the study.
Justice Sensitivity in Middle Childhood: A Replication and Extension of Findings
Authors: Bondü Rebecca , Kleinfeldt Maria
Published: January 2021

Previous research showed justice sensitivity (JS) – the tendency to perceive and negatively respond to injustice as a victim, observer, or perpetrator – to be reliably and validly measurable in middle childhood, but unexpected findings concerning mean values and measurement invariance (MI) require replication, and retest reliabilities, longitudinal relations with prosocial and aggressive behavior, and relations with teacher ratings are currently unknown. This study, therefore, examined mean values, factor structure, retest reliabilities, and MI of self- and parent-rated JS as well as their relations with parent- and teacher-rated prosocial and aggressive behavior and a range of social skills in a sample of 1,329 children between 5 and 12 years of age (first measurement: M = 8.05, SD = 1.02, 51.1% girls). Using self- and parent ratings, we could replicate the intended factor structure of three related yet distinct JS subscales (victim, observer, and perpetrator). We found strong MI between those ratings. Retest reliabilities of parent ratings were similar to older age groups, but lower for self-ratings. All JS perspectives were positively related with theory of mind and empathy, indicating a good understanding of others’ internal states. Victim JS was negatively related to affective and behavioral self-regulation, whereas observer and perpetrator JS showed positive relations. Victim JS negatively and observer and perpetrator JS positively predicted prosocial behavior. The opposite pattern was found regarding aggressive behavior. This study provides additional support that JS can be measured via self- and other reports in childhood and that it may influence behavior early on. It adds to explaining the relations with prosocial and aggressive behavior.
Prior Specification for More Stable Bayesian Estimation of Multilevel Latent Variable Models in Small Samples: A Comparative Investigation of Two Different Approaches
Authors: Zitzmann Steffen , Helm Christoph , Hecht Martin
Published: January 2021

Bayesian approaches for estimating multilevel latent variable models can be beneficial in small samples. Prior distributions can be used to overcome small sample problems, for example, when priors that increase the accuracy of estimation are chosen. This article discusses two different but not mutually exclusive approaches for specifying priors. Both approaches aim at stabilizing estimators in such a way that the Mean Squared Error (MSE) of the estimator of the between-group slope will be small. In the first approach, the MSE is decreased by specifying a slightly informative prior for the group-level variance of the predictor variable, whereas in the second approach, the decrease is achieved directly by using a slightly informative prior for the slope. Mathematical and graphical inspections suggest that both approaches can be effective for reducing the MSE in small samples, thus rendering them attractive in these situations. The article also discusses how these approaches can be implemented in Mplus.
Social Cognition and Interpersonal Problems in Persistent Depressive Disorder vs. Episodic Depression: The Role of Childhood Maltreatment
Authors: Struck Nele , Gärtner Thomas , Kircher Tilo , Brakemeier Eva-Lotta
Published: January 2021

Objective: Little is known about the specific psychological features that differentiate persistent depressive disorder (PDD) and episodic depression (ED). Thus, the present study aimed to investigate differences in social cognition and interpersonal problems between these two forms of depression and healthy controls. In addition, we aimed to examine childhood maltreatment (CM) as a possible origin of these alterations.

Methods: In a cross-sectional study, adult patients with a current PDD (n = 34) or in a current episode of ED (n = 38), and healthy controls (n = 39) completed questionnaires about depression severity, empathy, interpersonal problems, and CM, as well as tests of affective theory of mind and facial emotion recognition.

Results: Patients with PDD reported higher empathic distress than patients with ED and healthy controls. Both depressive groups recognized angry faces with higher accuracy and reported more interpersonal problems, with no differences between PDD and ED. Empathic distress and interpersonal problems mediated the link between CM and depression in the combined sample.

Limitations: Patient groups were not drug-naïve and antidepressant intake might have influenced social-cognitive functions. Self-report measures of empathy and interpersonal problems are vulnerable to bias. The cross-sectional design does not allow causal conclusions.

Conclusion: Depressed patients may not show deficits in decoding the affective states of others and in feeling with others. However, depressed individuals—in particular patients with PDD—may feel easily overwhelmed by emotionally tense situations, resulting in empathic distress and avoidant/submissive interpersonal behavior. Exposure to CM might be an origin of alterations in social cognition and interpersonal problems.