bluuebunny/crossref_metadata_2025 huggingface dataset:
Salix spp. Bark Hot Water Extracts Show Antiviral, Antibacterial, and Antioxidant Activities—The Bioactive Properties of 16 Clones
Authors: Tienaho Jenni , Reshamwala Dhanik , Sarjala Tytti , Kilpeläinen Petri , Liimatainen Jaana , Dou Jinze , Viherä-Aarnio Anneli , Linnakoski Riikka , Marjomäki Varpu , Jyske Tuula
Published: December 2021

Earlier studies have shown that the bark of Salix L. species (Salicaceae family) is rich in extractives, such as diverse bioactive phenolic compounds. However, we lack knowledge on the bioactive properties of the bark of willow species and clones adapted to the harsh climate conditions of the cool temperate zone. Therefore, the present study aimed to obtain information on the functional profiles of northern willow clones for the use of value-added bioactive solutions. Of the 16 willow clones studied here, 12 were examples of widely distributed native Finnish willow species, including dark-leaved willow (S. myrsinifolia Salisb.) and tea-leaved willow (S. phylicifolia L.) (3 + 4 clones, respectively) and their natural and artificial hybrids (3 + 2 clones, respectively). The four remaining clones were commercial willow varieties from the Swedish willow breeding program. Hot water extraction of bark under mild conditions was carried out. Bioactivity assays were used to screen antiviral, antibacterial, antifungal, yeasticidal, and antioxidant activities, as well as the total phenolic content of the extracts. Additionally, we introduce a fast and less labor-intensive steam-debarking method for Salix spp. feedstocks. Clonal variation was observed in the antioxidant properties of the bark extracts of the 16 Salix spp. clones. High antiviral activity against a non-enveloped enterovirus, coxsackievirus A9, was found, with no marked differences in efficacy between the native clones. All the clones also showed antibacterial activity against Staphylococcus aureus and Escherichia coli, whereas no antifungal (Aspergillus brasiliensis) or yeasticidal (Candida albicans) efficacy was detected. When grouping the clone extract results into Salix myrsinifolia, Salix phylicifolia, native hybrid, artificial hybrid, and commercial clones, there was a significant difference in the activities between S. phylicifolia clone extracts and commercial clone extracts in the favor of S. phylicifolia in the antibacterial and antioxidant tests. In some antioxidant tests, S. phylicifolia clone extracts were also significantly more active than artificial clone extracts. Additionally, S. myrsinifolia clone extracts showed significantly higher activities in some antioxidant tests than commercial clone extracts and artificial clone extracts. Nevertheless, the bark extracts of native Finnish willow clones showed high bioactivity. The obtained knowledge paves the way towards developing high value-added biochemicals and other functional solutions based on willow biorefinery approaches.
Oncogenic Activation of YAP Signaling Sensitizes Ferroptosis of Hepatocellular Carcinoma via ALOXE3-Mediated Lipid Peroxidation Accumulation
Authors: Qin Yifei , Pei Zhuo , Feng Zhuan , Lin Peng , Wang Shijie , Li Yong , Huo Fei , Wang Quancheng , Wang Zhiping , Chen Zhi-Nan , Wu Jiao , Wang Yi-Fei
Published: December 2021

Ferroptosis, a form of programmed cell death process driven by iron-dependent lipid peroxidation, plays an important role in tumor suppression. Although previous study showed that intracellular Merlin-Hippo signaling suppresses ferroptosis of epithelial tumor cells through the inactivation of YAP signaling, it remains elusive if the proto-oncogenic transcriptional co-activator YAP could serve as a potential biomarker to predict cancer cell response to ferroptosis-inducing therapies. In this study, we show that both total YAP staining and nuclear YAP staining were more prevalent in HCC tissues than in nontumorous regions. Compared to low-density HCC cells, high-density cells showed decreased nuclear localization of YAP and conferred significant resistance to ferroptosis. Oncogenic activation of YAP signaling by overexpression of YAP(S127A) mutant sensitized ferroptosis of HCC cells cultured in confluent density or in the 3D tumor spheroid model. Furthermore, we validated the lipoxygenase ALOXE3 as a YAP-TEAD target gene that contributed to YAP-promoted ferroptosis. Overexpression of ALOXE3 effectively increased the vulnerability of HCC cells to ferroptotic cell death. In an orthotopic mouse model of HCC, genetic activation of YAP rendered HCC cells more susceptible to ferroptosis. Finally, an overall survival assay further revealed that both a high expression of YAP and a low expression of GPX4 were correlated with increased survival of HCC patients with sorafenib treatment, which had been proven to be an inducer for ferroptosis by inhibition of the xc-amino acid antiporter. Together, this study unveils the critical role of intracellular YAP signaling in dictating ferroptotic cell death; it also suggests that pathogenic alterations of YAP signaling can serve as biomarkers to predict cancer cell responsiveness to future ferroptosis-inducing therapies.
Identification of HCC Subtypes With Different Prognosis and Metabolic Patterns Based on Mitophagy
Authors: Wang Yao , Wang Zhen , Sun Jingjing , Qian Yeben
Published: December 2021

Background:Mitophagy is correlated with tumor initiation and development of malignancy. However, HCC heterogeneity with reference to mitophagy has yet not been systematically explored.

Materials and Methods:Mitophagy-related, glycolysis-related, and cholesterol biosynthesis-related gene sets were obtained from the Reactome database. Mitophagy-related and metabolism-related subtypes were identified using the ConsensusClusterPlus algorithm. Univariate Cox regression was analysis was performed to identify prognosis-related mitophagy regulators. Principal component analysis (PCA) was used to create composite measures of the prognosis-related mitophagy regulators (mitophagyscore). Individuals with a mitophagyscore higher or lower than the median value were classified in high- or low-risk groups. Kaplan-Meier survival and ROC curve analyses were utilized to evaluate the prognostic value of the mitophagyscore. The nomogram and calibration curves were plotted using the“rms” R package. The package “limma” was used for differential gene expression analysis. Differentially expressed genes (DEGs) between high- and low-risk groups were used as queries in the CMap database. R package “pRRophetic” and Genomics of Drug Sensitivity in Cancer (GDSC) database were used to determine the sensitivity of 21 previously reported anti-HCC drugs.

Results:Three distinct HCC subtypes with different mitophagic accumulation (low, high, and intermediate mitophagy subtypes) were identified. High mitophagy subtype had the worst outcome and highest glycolysis level. The lowest degree of hypoxia and highest cholesterol biosynthesis was observed in the low mitophagy subtype; oncogenic dedifferentiation level in the intermediate mitophagy subtype was the lowest. Mitophagyscore could serve as a novel prognostic indicator for HCC.High-risk patients had a poorer prognosis (log-rank test,p< 0.001). The area under the ROC curve for mitophagyscore in 1-year survival was 0.77 in the TCGA cohort and 0.75 in the ICGC cohort. Nine candidate small molecules which were potential drugs for HCC treatment were identified from the CMap database. A decline in the sensitivity towards 21 anti-HCC drugs was observed in low-risk patients by GDSC database. We also identified a novel key gene, SPP1, which was highly associated with different mitophagic subtypes.

Conclusion:Based on bioinformatic analyses, we systematically examined the HCC heterogeneity with reference to mitophagy and observed three distinct HCC subtypes having different prognoses and metabolic patterns.
Recent Advances in Combinations of TLC With MALDI and Other Desorption/Ionization Mass-Spectrometry Techniques
Authors: Borisov Roman , Kanateva Anastasiia , Zhilyaev Dmitry
Published: December 2021

The combination of planar chromatography with desorption/ionization mass-spectrometry (MS) techniques provides chemists with unique tools for fast and simple separation of mixtures followed by the detection of analytes by the most powerful analytical method. Since its introduction in the early 1990s, thin-layer chromatography (TLC)/matrix-assisted mass spectrometry (MALDI) has been used for the analysis of a wide range of analytes, including natural and synthetic organic compounds. Nowadays, new desorption/ionization approaches have been developed and applied in conjunction with planar chromatography competing with MALDI. This review covers recent developments in the combination of TLC with various desorption/ionization MS methods which were made in recent several years.
Excellent Ultracold Molecular Candidates From Group VA Hydrides: Whether Do Nearby Electronic States Interfere?
Authors: Li Donghui , Bian Wensheng
Published: December 2021

By means of highly accurate ab initio calculations, we identify two excellent ultracold molecular candidates from group VA hydrides. We find that NH and PH are suitable for the production of ultracold molecules, and the feasibility and advantage of two laser cooling schemes are demonstrated, which involve different spin-orbit states (A3Π2 and X3Σ1− ). The internally contracted multireference configuration interaction method is applied in calculations of the six low-lying Λ-S states of NH and PH with the spin-orbit coupling effects included, and excellent agreement is achieved between the computed and experimental spectroscopic data. We find that the locations of crossing point between the A3Π and Σ−5 states of NH and PH are higher than the corresponding v′ = 2 vibrational levels of the A3Π state indicating that the crossings with higher electronic states would not affect laser cooling. Meanwhile, the extremely small vibrational branching loss ratios of the A3Π2 → a1Δ2 transition for NH and PH (NH: 1.81 × 10–8; PH: 1.08 × 10–6) indicate that the a1Δ2 intermediate electronic state will not interfere with the laser cooling. Consequently, we construct feasible laser-cooling schemes for NH and PH using three lasers based on the A3Π2 → X3Σ1− transition, which feature highly diagonal vibrational branching ratio R00 (NH: 0.9952; PH: 0.9977), the large number of scattered photons (NH: 1.04×105; PH: 8.32×106) and very short radiative lifetimes (NH: 474 ns; PH: 526 ns). Our work suggests that feasible laser-cooling schemes could be established for a molecular system with extra electronic states close to those chosen for laser-cooling.
Machine Learning for the Prediction of Complications in Patients After Mitral Valve Surgery
Authors: Jiang Haiye , Liu Leping , Wang Yongjun , Ji Hongwen , Ma Xianjun , Wu Jingyi , Huang Yuanshuai , Wang Xinhua , Gui Rong , Zhao Qinyu , Chen Bingyu
Published: December 2021

Background: This study intended to use a machine learning model to identify critical preoperative and intraoperative variables and predict the risk of several severe complications (myocardial infarction, stroke, renal failure, and hospital mortality) after cardiac valvular surgery.

Study Design and Methods: A total of 1,488 patients undergoing cardiac valvular surgery in eight large tertiary hospitals in China were examined. Fifty-four perioperative variables, such as essential demographic characteristics, concomitant disease, preoperative laboratory indicators, operation type, and intraoperative information, were collected. Machine learning models were developed and validated by 10-fold cross-validation. In each fold, Recursive Feature Elimination was used to select key variables. Ten machine learning models and logistic regression were developed. The area under the receiver operating characteristic (AUROC), accuracy (ACC), Youden index, sensitivity, specificity, F1-score, positive predictive value (PPV), and negative predictive value (NPV) were used to compare the prediction performance of different models. The SHapley Additive ex Planations package was applied to interpret the best machine learning model. Finally, a model was trained on the whole dataset with the merged key variables, and a web tool was created for clinicians to use.

Results: In this study, 14 vital variables, namely, intraoperative total input, intraoperative blood loss, intraoperative colloid bolus, Classification of New York Heart Association (NYHA) heart function, preoperative hemoglobin (Hb), preoperative platelet (PLT), age, preoperative fibrinogen (FIB), intraoperative minimum red blood cell volume (Hct), body mass index (BMI), creatinine, preoperative Hct, intraoperative minimum Hb, and intraoperative autologous blood, were finally selected. The eXtreme Gradient Boosting algorithms (XGBOOST) algorithm model presented a significantly better predictive performance (AUROC: 0.90) than the other models (ACC: 81%, Youden index: 70%, sensitivity: 89%, specificity: 81%, F1-score:0.26, PPV: 15%, and NPV: 99%).

Conclusion: A model for predicting several severe complications after cardiac valvular surgery was successfully developed using a machine learning algorithm based on 14 perioperative variables, which could guide clinical physicians to take appropriate preventive measures and diminish the complications for patients at high risk.
Elevated Levels of Circulating Biomarkers Related to Leaky Gut Syndrome and Bacterial Translocation Are Associated With Graves’ Disease
Authors: Zheng Dekai , Liao Huimin , Chen Shuze , Liu Xiuying , Mao Chuyin , Zhang Cangui , Meng Min , Wang Zhi , Wang Ying , Jiang Qinrui , Xue Yaoming , Zhou Lin , Chen Ye
Published: December 2021

Background

A growing number of studies have found dysbiosis of the intestinal microbiota in patients with Graves’ disease (GD). The intestinal epithelial barrier serves as the first line of defense, protecting the immune system from excessive stimulation of microbiota and toxins. Most autoimmune diseases are associated with a gut barrier dysfunction (leaky gut) which allows bacterial translocation. However, to date, potential correlations between intestinal barrier dysfunction and GD have not been explored.

Methods

Serum lipopolysaccharide (LPS), intestinal fatty acid-binding protein (I-FABP), zonulin, D-lactate, and diamine oxidase (DAO) were measured to assess barrier integrity in 91 patients with GD (61 initial GD and 30 euthyroid GD) and 44 healthy controls. The quality of life (QOL) of patients with GD was assessed using the thyroid-specific patient-reported outcome (ThyPRO-39) questionnaire.

Results

The serum levels of LPS, I-FABP, zonulin, and D-lactate were significantly higher in patients with initial GD than in healthy controls. Logistic regression analysis revealed that zonulin and D-lactate were independently associated with risk for GD and circulating zonulin could effectively distinguish patients with initial GD from healthy controls. Correlation analyses showed that I-FABP, LPS, and D-lactate were positively associated with FT4 and negatively associated with TSH. In addition, circulating LPS, zonulin, and D-lactate levels were all independent predictors of TRAb levels. Moreover, higher circulating LPS levels in patients with GD were associated with more severe hyperthyroidism (higher concentrations of FT3, FT4, and TRAb and lower TSH concentrations) and worse scores of hyperthyroid and eye symptoms.

Conclusion

Patients with initial GD show a disrupted intestinal barrier, characterized by elevated levels of leaky gut biomarkers. Increased intestinal permeability and bacterial translocation were associated with TRAb levels and hyperthyroidism in GD. Further research is required to elucidate the underlying mechanisms.
Should Skeletal Maturation Be Manipulated for Extra Height Gain?
Authors: Wit Jan M.
Published: December 2021

Skeletal maturation can be delayed by reducing the exposure to estrogens, either by halting pubertal development through administering a GnRH analogue (GnRHa), or by blocking the conversion of androgens to estrogens through an aromatase inhibitor (AI). These agents have been investigated in children with growth disorders (off-label), either alone or in combination with recombinant human growth hormone (rhGH). GnRHa is effective in attaining a normal adult height (AH) in the treatment of children with central precocious puberty, but its effect in short children with normal timing of puberty is equivocal. If rhGH-treated children with growth hormone deficiency or those who were born small-for-gestational age are still short at pubertal onset, co-treatment with a GnRHa for 2-3 years increases AH. A similar effect was seen by adding rhGH to GnRHa treatment of children with central precocious puberty with a poor AH prediction and by adding rhGH plus GnRHa to children with congenital adrenal hyperplasia with a poor predicted adult height on conventional treatment with gluco- and mineralocorticoids. In girls with idiopathic short stature and relatively early puberty, rhGH plus GnRHa increases AH. Administration of letrozole to boys with constitutional delay of growth puberty may increase AH, and rhGH plus anastrozole may increase AH in boys with growth hormone deficiency or idiopathic short stature, but the lack of data on attained AH and potential selective loss-of-follow-up in several studies precludes firm conclusions. GnRHas appear to have a good overall safety profile, while for aromatase inhibitors conflicting data have been reported.
Evolution by Sexual Selection
Authors: Petrie Marion
Published: December 2021

Charles Darwin published his second book “Sexual selection and the descent of man” in 1871 150 years ago, to try to explain, amongst other things, the evolution of the peacock’s train, something that he famously thought was problematic for his theory of evolution by natural selection. He proposed that the peacock’s train had evolved because females preferred to mate with males with more elaborate trains. This idea was very controversial at the time and it wasn’t until 1991 that a manuscript testing Darwin’s hypothesis was published. The idea that a character could arise as a result of a female preference is still controversial. Some argue that there is no need to distinguish sexual from natural selection and that natural selection can adequately explain the evolution of extravagant characteristics that are characteristic of sexually selected species. Here, I outline the reasons why I think that this is not the case and that Darwin was right to distinguish sexual selection as a distinct process. I present a simple verbal and mathematical model to expound the view that sexual selection is profoundly different from natural selection because, uniquely, it can simultaneously promote and maintain the genetic variation which fuels evolutionary change. Viewed in this way, sexual selection can help resolve other evolutionary conundrums, such as the evolution of sexual reproduction, that are characterised by having impossibly large costs and no obvious immediate benefits and which have baffled evolutionary biologists for a very long time. If sexual selection does indeed facilitate rapid adaptation to a changing environment as I have outlined, then it is very important that we understand the fundamentals of adaptive mate choice and guard against any disruption to this natural process.
Increased Pathogenicity of the Nematophagous Fungus Drechmeria coniospora Following Long-Term Laboratory Culture
Authors: Courtine Damien , Zhang Xing , Ewbank Jonathan J.
Published: December 2021

Domestication provides a window into adaptive change. Over the course of 2 decades of laboratory culture, a strain of the nematode-specific fungus Drechmeria coniospora became more virulent during its infection of Caenorhabditis elegans. Through a close comparative examination of the genome sequences of the original strain and its more pathogenic derivative, we identified a small number of non-synonymous mutations in protein-coding genes. In one case, the mutation was predicted to affect a gene involved in hypoxia resistance and we provide direct corroborative evidence for such an effect. The mutated genes with functional annotation were all predicted to impact the general physiology of the fungus and this was reflected in an increased in vitro growth, even in the absence of C. elegans. While most cases involved single nucleotide substitutions predicted to lead to a loss of function, we also observed a predicted restoration of gene function through deletion of an extraneous tandem repeat. This latter change affected the regulatory subunit of a cAMP-dependent protein kinase. Remarkably, we also found a mutation in a gene for a second protein of the same, protein kinase A, pathway. Together, we predict that they result in a stronger repression of the pathway for given levels of ATP and adenylate cyclase activity. Finally, we also identified mutations in a few lineage-specific genes of unknown function that are candidates for factors that influence virulence in a more direct manner.
Interleukin-6-Mediated-Ca2+ Handling Abnormalities Contributes to Atrial Fibrillation in Sterile Pericarditis Rats
Authors: Liao Jie , Zhang Shaoshao , Yang Shuaitao , Lu Yang , Lu Kai , Wu Yuwei , Wu Qiongfeng , Zhao Ning , Dong Qian , Chen Lei , Du Yimei
Published: December 2021

Pre-existing Ca2+ handling abnormalities constitute the arrhythmogenic substrate in patients developing postoperative atrial fibrillation (POAF), a common complication after cardiac surgery. Postoperative interleukin (IL)-6 levels are associated with atrial fibrosis in several animal models of POAF, contributing to atrial arrhythmias. Here, we hypothesize that IL-6-mediated-Ca2+ handling abnormalities contribute to atrial fibrillation (AF) in sterile pericarditis (SP) rats, an animal model of POAF. SP was induced in rats by dusting atria with sterile talcum powder. Anti-rat-IL-6 antibody (16.7 μg/kg) was administered intraperitoneally at 30 min after the recovery of anesthesia. In vivo electrophysiology, ex vivo optical mapping, western blots, and immunohistochemistry were performed to elucidate mechanisms of AF susceptibility. IL-6 neutralization ameliorated atrial inflammation and fibrosis, as well as AF susceptibility in vivo and the frequency of atrial ectopy and AF with a reentrant pattern in SP rats ex vivo. IL-6 neutralization reversed the prolongation and regional heterogeneity of Ca2+ transient duration, relieved alternans, reduced the incidence of discordant alternans, and prevented the reduction and regional heterogeneity of the recovery ratio of Ca2+ transient. In agreement, western blots showed that IL-6 neutralization reversed the reduction in the expression of ryanodine receptor 2 (RyR2) and phosphorylated phospholamban. Acute IL-6 administration to isolated rat hearts recapitulated partial Ca2+ handling phenotype in SP rats. In addition, intraperitoneal IL-6 administration to rats increased AF susceptibility, independent of fibrosis. Our results reveal that IL-6-mediated-Ca2+ handling abnormalities in SP rats, especially RyR2-dysfunction, independent of IL-6-induced-fibrosis, early contribute to the development of POAF by increasing propensity for arrhythmogenic alternans.
Prostate Cancer: Early Detection and Assessing Clinical Risk Using Deep Machine Learning of High Dimensional Peripheral Blood Flow Cytometric Phenotyping Data
Authors: Cosma Georgina , McArdle Stéphanie E. , Foulds Gemma A. , Hood Simon P. , Reeder Stephen , Johnson Catherine , Khan Masood A. , Pockley A. Graham
Published: December 2021

Detecting the presence of prostate cancer (PCa) and distinguishing low- or intermediate-risk disease from high-risk disease early, and without the need for potentially unnecessary invasive biopsies remains a significant clinical challenge. The aim of this study is to determine whether the T and B cell phenotypic features which we have previously identified as being able to distinguish between benign prostate disease and PCa in asymptomatic men having Prostate-Specific Antigen (PSA) levels < 20 ng/ml can also be used to detect the presence and clinical risk of PCa in a larger cohort of patients whose PSA levels ranged between 3 and 2617 ng/ml. The peripheral blood of 130 asymptomatic men having elevated Prostate-Specific Antigen (PSA) levels was immune profiled using multiparametric whole blood flow cytometry. Of these men, 42 were subsequently diagnosed as having benign prostate disease and 88 as having PCa on biopsy-based evidence. We built a bidirectional Long Short-Term Memory Deep Neural Network (biLSTM) model for detecting the presence of PCa in men which combined the previously-identified phenotypic features (CD8+CD45RA-CD27-CD28- (CD8+ Effector Memory cells), CD4+CD45RA-CD27-CD28- (CD4+ Effector Memory cells), CD4+CD45RA+CD27-CD28- (CD4+ Terminally Differentiated Effector Memory Cells re-expressing CD45RA), CD3-CD19+ (B cells), CD3+CD56+CD8+CD4+ (NKT cells) with Age. The performance of the PCa presence ‘detection’ model was: Acc: 86.79 ( ± 0.10), Sensitivity: 82.78% (± 0.15); Specificity: 95.83% (± 0.11) on the test set (test set that was not used during training and validation); AUC: 89.31% (± 0.07), ORP-FPR: 7.50% (± 0.20), ORP-TPR: 84.44% (± 0.14). A second biLSTM ‘risk’ model combined the immunophenotypic features with PSA to predict whether a patient with PCa has high-risk disease (defined by the D’Amico Risk Classification) achieved the following: Acc: 94.90% (± 6.29), Sensitivity: 92% (± 21.39); Specificity: 96.11 (± 0.00); AUC: 94.06% (± 10.69), ORP-FPR: 3.89% (± 0.00), ORP-TPR: 92% (± 21.39). The ORP-FPR for predicting the presence of PCa when combining FC+PSA was lower than that of PSA alone. This study demonstrates that AI approaches based on peripheral blood phenotyping profiles can distinguish between benign prostate disease and PCa and predict clinical risk in asymptomatic men having elevated PSA levels.
Is It Possible to Intervene in the Capacity of Trypanosoma cruzi to Elicit and Evade the Complement System?
Authors: Ramírez-Toloza Galia , Aguilar-Guzmán Lorena , Valck Carolina , Menon Smrithi S. , Ferreira Viviana P. , Ferreira Arturo
Published: December 2021

Chagas’ disease is a zoonotic parasitic ailment now affecting more than 6 million people, mainly in Latin America. Its agent, the protozoanTrypanosoma cruzi, is primarily transmitted by endemic hematophagous triatomine insects. Transplacental transmission is also important and a main source for the emerging global expansion of this disease. In the host, the parasite undergoes intra (amastigotes) and extracellular infective (trypomastigotes) stages, both eliciting complex immune responses that, in about 70% of the cases, culminate in permanent immunity, concomitant with the asymptomatic presence of the parasite. The remaining 30% of those infected individuals will develop a syndrome, with variable pathological effects on the circulatory, nervous, and digestive systems. Herein, we review an important number ofT. cruzimolecules, mainly located on its surface, that have been characterized as immunogenic and protective in various experimental setups. We also discuss a variety of parasite strategies to evade the complement system - mediated immune responses. Within this context, we also discuss the capacity of theT. cruziinfective trypomastigote to translocate the ER-resident chaperone calreticulin to its surface as a key evasive strategy. Herein, it is described thatT. cruzicalreticulin inhibits the initial stages of activation of the host complement system, with obvious benefits for the parasite. Finally, we speculate on the possibility to experimentally intervene in the interaction of calreticulin and otherT. cruzimolecules that interact with the complement system; thus resulting in significant inhibition ofT. cruziinfectivity.
Designing a Scoring System for Differential Diagnosis From Reactive Thrombocytosis and Essential Thrombocytosis
Authors: Shen Chih-Lung , Hsieh Tsung-Cheng , Wang Tso-Fu , Huang Wei-Han , Chu Sung-Chao , Wu Yi-Feng
Published: December 2021

Background: Thrombocytosis is a common finding in hospitalized patients and is of two main types, essential thrombocytosis (ET) and reactive thrombocytosis (RT). It is important to distinguish the two due to increased risk of developing marrow fibrosis, acute leukemia, and thrombosis in the former. Molecular studies are the main tools to differentiate the two but are not available in all hospitals. We aimed to design a highly sensitive scoring system using routine lab data to classify thrombocytosis as essential or reactive.

Methods: A total of 145 patients were enrolled in this study. Potential predictors included patient demographics and clinical laboratory parameters. Receiver operating characteristic curve analysis was used to decide the optimal cutoff level. Multivariate logistic regression with forward model selection method was performed to decide the predictors.

Results: The risk scores by multivariate analysis were as follows: 1 point for WBC > 13,500/μL; 2.5 points for Hb > 10.9 g/dL; 3 points for platelet count > 659,000/μL; and 2 points for MPV > 9.3 fL. The cut off value was set as 4.5 points, and sensitivity of 91.1% and specificity of 75.8% were noted.

Conclusion: In this study, we investigated lab data and developed a high-sensitivity convenient-to-use scoring system to differentiate ET from RT. The scoring system was assigned to the resulting model to make it more economical, simple, and convenient for clinical practice.
Mosaic PKHD1 in Polycystic Kidneys Caused Aberrant Protein Expression in the Mitochondria and Lysosomes
Authors: Xu Chengxian , Yang Chenxi , Ye Qing , Xu Jie , Tong Lingxiao , Zhang Yuchen , Shen Huijun , Lu Zhihong , Wang Jingjing , Lai Enyin , Mao Jianhua , Jiang Pingping
Published: December 2021

Autosomal recessive polycystic kidney disease (ARPKD) is a severe renal cystic disease caused mainly by the polycystic kidney and hepatic disease 1 (PKHD1). However, the genetic cause, pathologic features, and mechanism of action of ARPKD are not well known. Here, we identified a family with ARPKD. Two siblings harbored biallelic variants in PKHD1 (c.7205G>A, c.7973T>A). We determined that the “de novo” variant, c.7205G>A, arose from the mosaicism of the father and had a 7.4% level. Pathologic characterization, using biopsy analysis, was evidenced with predominant cystic dilation in proximal tubules, slight ectasia of collecting ducts, defective ciliogenesis, and impaired cell-cell junctions in renal tubules and collecting ducts. Exosome proteomics in the urine from patients with ARPKD were markedly different from those of controls, with the most significant alterations occurring in mitochondrial and lysosomal proteins. Expression of the proteins of OXPHOS was downregulated sharply, in parallel with upregulated expression of the proteins involved in glycolysis in patients with ARPKD. Several lysosomal proteins associated with renal lesions were more abundant in the exosome of the patient than in controls. Moreover, the lysosomal enzyme sulfamidase, which is produced by the SGSH gene, was abrupt uniquely in the exosome of the patient. Consistently, swollen mitochondria and abundant lysosomes were visualized in the mutant tubular epithelial cells of patients with mutant PKHD1. Collectively, these findings provide new insights on the pathophysiology of the polycystic kidney due to PKHD1 deficiency. PKHD1 mosaicism should be considered in genetic testing of ARPKD patients.
The Global, Regional, and National Burden of Psoriasis: Results and Insights From the Global Burden of Disease 2019 Study
Authors: Damiani Giovanni , Bragazzi Nicola Luigi , Karimkhani Aksut Chante , Wu Dongze , Alicandro Gianfranco , McGonagle Dennis , Guo Cui , Dellavalle Robert , Grada Ayman , Wong Priscilla , La Vecchia Carlo , Tam Lai-Shan , Cooper Kevin D. , Naghavi Mohsen
Published: December 2021

Background: Psoriasis is a common, chronic, inflammatory, debilitating, systemic disease with a great impact on healthcare systems worldwide. As targeted therapies have transformed the therapeutic landscape, updated estimates of the Global Burden of Disease (GBD) imposed by psoriasis are necessary in order to evaluate the effects of past health care policies and to orient and inform new national and international healthcare strategies.

Methods: Data were extracted from the GBD 2019 study, which collates a systematic review of relevant scientific literature, national surveys, claims data, and primary care sources on the prevalence of psoriasis. Prevalence data were combined with disability weight (DW) to yield years lived with disability (YLDs). Measures of burden at global, regional, and national levels were generated for incidence, prevalence, and YLDs, due to psoriatic disease. All measures were reported as absolute numbers, percentages, and crude and age-adjusted rates per 100,000 persons. In addition, psoriasis burden was assessed by socio-demographic index (SDI).

Findings: According to the GBD 2019 methodology, there were 4,622,594 (95% uncertainty interval or UI 4,458,904–4,780,771) incident cases of psoriasis worldwide in 2019. The age-standardized incidence rate in 2019 was 57.8 (95% UI 55.8–59.7) per 100,000 people. With respect to 1990, this corresponded to a decrease of 20.0% (95% UI −20.2 to −19.8). By sex, the age-standardized incidence rate was similar between men [57.8 (95% UI 55.8–59.8) per 100,000 people] and women [(57.8 (95% UI 55.8–59.7) per 100,000 people]. With respect to 1990, this corresponded to a decrease by 19.5% (95% UI −19.8 to −19.2) and by 20.4% (95% UI −20.7 to −20.2) for men and women, respectively. The age-standardized incidence rate per 100,000 persons was found to vary widely across geographic locations. Regionally, high-income countries and territories had the highest age-standardized incidence rate of psoriasis [112.6 (95% UI 108.9–116.1)], followed by high-middle SDI countries [69.4 (95% UI 67.1–71.9)], while low SDI countries reported the lowest rate [38.1 (95% UI 36.8–39.5)]. Similar trends were detected for prevalence and YLDs.

Conclusion: In general, psoriasis burden is greatest in the age group of 60–69 years, with a relatively similar burden among men and women. The burden is disproportionately greater in high-income and high SDI index countries of North America and Europe. With advances in psoriasis therapeutics, objective evaluation of psoriasis disease burden is critical to track the progress at the population level.
Proximity to Heavy Traffic Roads and Patient Characteristics of Late of Onset Asthma in an Urban Asthma Center
Authors: Lin Ting-Yu , Lin Horng-Chyuan , Liu Yun-Sheng , Lo Yu-Lun , Wang Chun-Hua , Chang Po-Jui , Lo Chun-Yu , Lin Shu-Min
Published: December 2021

Background: Traffic-related pollution is associated with the onset of asthma and the development of different phenotypes of asthma. Few studies have investigated the association between traffic proximity and late-onset of asthma (LOA) and early-onset asthma (EOA). This study was conducted to investigate the associations of LOA phenotypes with a function of the distance between residence and heavy traffic roads (HTRs).

Methods: The study group consisted of 280 patients who were (LOA: 78.4%) recruited consecutively from a pay-for-performance asthma program to clarify the patient characteristics and proximity to HTRs within 1,000 m from their residences between EOA and LOA in three urban centers in Taiwan. The subsequent analysis focused on patients with LOA (n = 210) linking phenotypes and distance to HTRs.

Results: Subjects with LOA tended to be older than those with EOA and had shorter asthma duration, poorer lung function, lower atopy, and less exposure to fumes or dust at home. Patients with LOA were more likely than those with EOA to live within 900 m of two or more HTRs (14.3 vs. 3.4%, p = 0.02). Among patients with LOA, minimum distance to an HTR was negatively associated with numbers of specific IgE as well as positively associated with the age of onset and body weight significantly. A higher proportion of patients with atopy (26.3 vs. 20.6%, p = 0.001. odds ratio [OR]: 2.82) and anxiety/depression (21.0 vs. 18.1%, p = 0.047. OR: 1.81) and a trend of lower proportion of patients with obese (5.7 vs. 12.4%, p = 0.075) were found to be living within 900 m from HTRs.

Conclusions: Late-onset of asthma (LOA) tended to live in areas of higher HTR density compared to EOAs. Among patients with LOA living close to HTRs, the interaction between traffic-related pollution, allergy sensitization, and mood status were the factors associated with asthma onset early. Obesity may be the factor for later onset who live far from HTRs.
Fluid-Attenuated Inversion Recovery Vascular Hyperintensity in Cerebrovascular Disease: A Review for Radiologists and Clinicians
Authors: Zeng Lichuan , Chen Jinxin , Liao Huaqiang , Wang Qu , Xie Mingguo , Wu Wenbin
Published: December 2021

Neuroradiological methods play important roles in neurology, especially in cerebrovascular diseases. Fluid-attenuated inversion recovery (FLAIR) vascular hyperintensity (FVH) is frequently encountered in patients with acute ischemic stroke and significant intracranial arterial stenosis or occlusion. The mechanisms underlying this phenomenon and the clinical implications of FVH have been a matter of debate. FVH is associated with large-vessel occlusion or severe stenosis, as well as impaired hemodynamics. Possible explanations suggested for its appearance include stationary blood and slow antegrade or retrograde filling of the leptomeningeal collateral circulation. However, the prognostic value of the presence of FVH has been controversial. FVH can also be observed in patients with transient ischemic attack (TIA), which may have different pathomechanisms. Its presence can help clinicians to identify patients who have a higher risk of stroke after TIA. In this review article, we aim to describe the mechanism and influencing factors of FVH, as well as its clinical significance in patients with cerebrovascular disease.
Pharmacological Investigations in Glia Culture Model of Inflammation
Authors: Ismail Fatme Seval , Corvace Franco , Faustmann Pedro M. , Faustmann Timo Jendrik
Published: December 2021

Astrocytes and microglia are the main cell population besides neurons in the central nervous system (CNS). Astrocytes support the neuronal network via maintenance of transmitter and ion homeostasis. They are part of the tripartite synapse, composed of pre- and postsynaptic neurons and perisynaptic astrocytic processes as a functional unit. There is an increasing evidence that astroglia are involved in the pathophysiology of CNS disorders such as epilepsy, autoimmune CNS diseases or neuropsychiatric disorders, especially with regard to glia-mediated inflammation. In addition to astrocytes, investigations on microglial cells, the main immune cells of the CNS, offer a whole network approach leading to better understanding of non-neuronal cells and their pathological role in CNS diseases and treatment. An in vitro astrocyte-microglia co-culture model of inflammation was developed by Faustmann et al. (2003), which allows to study the endogenous inflammatory reaction and the cytokine expression under drugs in a differentiated manner. Commonly used antiepileptic drugs (e.g., levetiracetam, valproic acid, carbamazepine, phenytoin, and gabapentin), immunomodulatory drugs (e.g., dexamethasone and interferon-beta), hormones and psychotropic drugs (e.g., venlafaxine) were already investigated, contributing to better understanding mechanisms of actions of CNS drugs and their pro- or anti-inflammatory properties concerning glial cells. Furthermore, the effects of drugs on glial cell viability, proliferation and astrocytic network were demonstrated. The in vitro astrocyte-microglia co-culture model of inflammation proved to be suitable as unique in vitro model for pharmacological investigations on astrocytes and microglia with future potential (e.g., cancer drugs, antidementia drugs, and toxicologic studies).
Cerebral Revascularization for the Management of Symptomatic Pure Arterial Malformations
Authors: Lu Xiaocheng , Fang Xinggen , Huang Yabo , Zhou Peng , Wang Zhong , Brinjikji Waleed , Chen Gang
Published: December 2021

Background: Pure arterial malformations (PAMs) are extremely rare abnormalities defined as dilated, overlapping, and tortuous arteries with a coil-like appearance in the absence of venous components. Over the last half century, only seven published reports have described cases of patients with PAMs who received treatment.

Methods: Here, we report two cases of women with PAMs who received surgical treatment, and we present a systematic review of the literature. We searched the PubMed, Embase, Web of Science, and Medline databases (up until October 1, 2021) for relevant publications. We performed independent-sample t-tests and Fisher's exact tests to compare continuous and categorical characteristics among the available cases.

Results: Our first patient was a 43-year-old woman with PAM of the left internal carotid artery (ICA), who received an ICA-radial artery (RA)-M2 bypass. Post-operative digital subtraction angiography (DSA) revealed the disappearance of the left ICA PAM without ischemic events during follow-up. The second patient was a 53-year-old woman with PAMs of the right ICA and posterior cerebral artery. The P1 lesion was treated by proximal occlusion combined with a superficial temporal artery-P2 bypass. During the 12-month follow-up period, the size of the PAMs decreased significantly as indicated by the post-operative DSA showing the absence of hemorrhages. Our systematic review, which includes 56 PAMs, shows that the reported PAMs were more common in the anterior circulation (33/56, 58.9%) than in the posterior circulation (11/56, 19.7%). Bilateral PAMs were more likely to affect bilateral anterior cerebral arteries (ACA) (ACAbilateral vs. ACAunilateral: 63.6 vs. 26.2%, p = 0.02). In addition, PAMs involving the anterior circulation were likely to affect multiple arteries (anteriormulti vs. posteriormulti: 30.3 vs. 0%, p = 0.038).

Conclusion: We found very few reports on treated PAMs; further studies with large sample sizes and long follow-up periods are required to explore the appropriate treatment strategy for PAMs.
Selected Thiadiazine-Thione Derivatives Attenuate Neuroinflammation in Chronic Constriction Injury Induced Neuropathy
Authors: Qureshi Sonia , Ali Gowhar , Idrees Muhammad , Muhammad Tahir , Kong Il-Keun , Abbas Muzaffar , Shah Muhammad Ishaq Ali , Ahmad Sajjad , Sewell Robert D. E. , Ullah Sami
Published: December 2021

Neuropathic pain refers to a lesion or disease of peripheral and/or central somatosensory neurons and is an important body response to actual or potential nerve damage. We investigated the therapeutic potential of two thiadiazine-thione [TDT] derivatives, 2-(5-propyl-6-thioxo-1, 3, 5-thiadiazinan-3-yl) acetic acid [TDT1] and 2-(5-propyl-2-thioxo-1, 3, 5-thiadiazinan-3-yl) acetic acid [TDT2] against CCI (chronic constriction injury)-induced neuroinflammation and neuropathic pain. Mice were used for assessment of acute toxicity of TDT derivatives and no major toxic/bizarre responses were observed. Anti-inflammatory activity was assessed using the carrageenan test, and both TDT1 and TDT2 significantly reduced carrageenan-induced inflammation. We also used rats for the induction of CCI and performed allodynia and hyperalgesia-related behavioral tests followed by biochemical and morphological analysis using RT-qPCR, immunoblotting, immunohistochemistry and immunofluorescence. Our findings revealed that CCI induced clear-cut allodynia and hyperalgesia which was reversed by TDT1 and TDT2. To determine the function of TDT1 and TDT2 in glia-mediated neuroinflammation, Iba1 mRNA and protein levels were measured in spinal cord tissue sections from various experimental groups. Interestingly, TDT1 and TDT2 substantially reduced the mRNA expression and protein level of Iba1, implying that TDT1 and TDT2 may mitigate CCI-induced astrogliosis. In silico molecular docking studies predicted that both compounds had an effective binding affinity for TNF-α and COX-2. The compounds interactions with the proteins were dominated by both hydrogen bonding and van der Waals interactions. Overall, these results suggest that TDT1 and TDT2 exert their neuroprotective and analgesic potentials by ameliorating CCI-induced allodynia, hyperalgesia, neuroinflammation and neuronal degeneration in a dose-dependent manner.
Impact of Neurofascin on Chronic Inflammatory Demyelinating Polyneuropathy via Changing the Node of Ranvier Function: A Review
Authors: Gao Ying , Kong Lingxin , Liu Shan , Liu Kangding , Zhu Jie
Published: December 2021

The effective conduction of action potential in the peripheral nervous system depends on the structural and functional integrity of the node of Ranvier and paranode. Neurofascin (NF) plays an important role in the conduction of action potential in a saltatory manner. Two subtypes of NF, NF186, and NF155, are involved in the structure of the node of Ranvier. In patients with chronic inflammatory demyelinating polyneuropathy (CIDP), anti-NF antibodies are produced when immunomodulatory dysfunction occurs, which interferes with the conduction of action potential and is considered the main pathogenic factor of CIDP. In this study, we describe the assembling mechanism and anatomical structure of the node of Ranvier and the necessary cell adhesion molecules for its physiological function. The main points of this study are that we summarized the recent studies on the role of anti-NF antibodies in the changes in the node of Ranvier function and its impact on clinical manifestations and analyzed the possible mechanisms underlying the pathogenesis of CIDP.