bluuebunny/crossref_metadata_2025 huggingface dataset:
Elevated Neddylation Pathway Promotes Th2 Cells Infiltration by Transactivating STAT5A in Hepatocellular Carcinoma
Authors: Zhou Lisha , Zhang Luyi , Chen Siyuan , Sun Dongsheng , Qu Jianhua
Published: November 2021

Neddylation is a process in which a ubiquitin-like molecule NEDD8 is conjugated to a lysine residue of the substrate protein via successive enzymatic cascade reactions. Inactivation of neddylation pathway triggers tumor cell apoptosis or senescence to suppress the tumor growth. So far, there has been limited research on the role of the neddylation pathway (NEDD8-UBE2M-RBX1 axis) in the immune response. In this study, we investigated the association between the neddylation pathway and immune function in HCC by comprehensively analyzing transcriptome and clinical data of HCC samples from TCGA database. The analysis showed that the mRNA expression of neddylation pathway components was up-regulated in HCC and increased with disease severity. Moreover, we observed that activated neddylation pathway was associated with enriched infiltration of T helper 2 (Th2) cells in HCC, while transactivation of STAT5A signaling may mediate this association. On the contrary, no significant correlation between the neddylation pathway and Th1 cells infiltration was identified. Taken together, these findings suggest a potential role of the neddylation pathway in promoting a shift in Th1/Th2 balance toward Th2-dominant immunosuppression. Hence, targeting neddylation pathway could serve as an attractive immunotherapy strategy for suppressing the development of Th2 cells.
An 11-Gene Signature Risk-Prediction Model Based on Prognosis-Related miRNAs and Their Target Genes in Lung Adenocarcinoma
Authors: Zhou Ning , Zhou Min , Ding Ning , Li Qinglin , Ren Guangming
Published: November 2021

Aberrant expression of microRNAs may affect tumorigenesis and progression by regulating their target genes. This study aimed to construct a risk model for predicting the prognosis of patients with lung adenocarcinoma (LUAD) based on differentially expressed microRNA-regulated target genes. The miRNA sequencing data, RNA sequencing data, and patients’ LUAD clinical data were downloaded from the The Cancer Genome Atlas (TCGA) database. Differentially expressed miRNAs and genes were screened out by combining differential analysis with LASSO regression analysis to further screen out miRNAs associated with patients’ prognosis, and target gene prediction was performed for these miRNAs using a target gene database. Overlapping gene screening was performed for target genes and differentially expressed genes. LASSO regression analysis and survival analysis were then used to identify key genes. Risk score equations for prognostic models were established using multifactorial COX regression analysis to construct survival prognostic models, and the accuracy of the models was evaluated using subject working characteristic curves. The groups were divided into high- and low-risk groups according to the median risk score, and the correlation with the clinicopathological characteristics of the patients was observed. A total of 123 up-regulated miRNAs and 22 down-regulated miRNAs were obtained in this study. Five prognosis-related miRNAs were screened using LASSO regression analysis and Kaplan-Meier method validation, and their target genes were screened with the overlap of differentially expressed genes before multifactorial COX analysis finally resulted in an 11-gene risk model for predicting patient prognosis. The area under the ROC curve proved that the model has high accuracy. The 11-gene risk-prediction model constructed in this study may be an effective predictor of prognosis.
The Role and Clinical Potentials of Circular RNAs in Prostate Cancer
Authors: Taheri Mohammad , Najafi Sajad , Basiri Abbas , Hussen Bashdar Mahmud , Baniahmad Aria , Jamali Elena , Ghafouri-Fard Soudeh
Published: November 2021

Globally, prostate cancer (PCa) is the second most commonly diagnosed cancer in men globally. Early diagnosis may help in promoting survival in the affected patients. Circular RNAs (circRNAs) are a novel class of non-coding RNAs (ncRNAs) which have been found to show extensive dysregulation in a handful of human diseases including cancers. Progressions in RNA identification techniques have provided a vast number of circRNAs exhibiting either up-regulation or down-regulation in PCa tissues compared to normal adjacent tissues. The mechanism of action is not clear for most of dysregulated circRNAs. Among them, function of a number of newly identified dysregulated circRNAs have been assessed in PCa cells. Increase in cell proliferation, migration, invasion, and metastasis have been reported for up-regulated circRNAs which suggest their role as oncogenes. On the other hand, down-regulated circRNAs have shown tumor suppressing actions in experimental studies. Furthermore, in a majority of studies, circRNAs have been found to sponge microRNAs (miRNAs), negatively regulating expression or activity of the downstream miRNAs. Additionally, they have been identified in interaction with regulatory proteins. This axis consequently regulates a signaling pathway, a tumor suppressor, or an oncogene. Easy, quick, and reliable detection of circRNAs in human body fluids also suggests their potentials as biomarker candidates for diagnosis and prediction of prognosis in PCa patients. In this review, we have discussed the role and potentials of a number of dysregulated circRNAs in PCa.
Unsupervised Machine Learning Approaches Reveal Distinct Phenotypes of Perceived Bladder Pain: A Pilot Study
Authors: Mwesigwa Patricia J. , Jackson Nicholas J. , Caron Ashley T. , Kanji Falisha , Ackerman James E. , Webb Jessica R. , Scott Victoria C. S. , Eilber Karyn S. , Underhill David M. , Anger Jennifer T. , Ackerman A. Lenore
Published: November 2021

Interstitial cystitis/bladder pain syndrome (IC/BPS) is defined as an unpleasant sensation perceived to be related to the bladder with associated urinary symptoms. Due to difficulties discriminating pelvic visceral sensation, IC/BPS likely represents multiple phenotypes with different etiologies that present with overlapping symptomatic manifestations, which complicates clinical management. We hypothesized that unique bladder pain phenotypes or “symptomatic clusters” would be identifiable using machine learning analysis (unsupervised clustering) of validated patient-reported urinary and pain measures. Patients (n = 145) with pelvic pain/discomfort perceived to originate in the bladder and lower urinary tract symptoms answered validated questionnaires [OAB Questionnaire (OAB-q), O'Leary-Sant Indices (ICSI/ICPI), female Genitourinary Pain Index (fGUPI), and Pelvic Floor Disability Index (PFDI)]. In comparison to asymptomatic controls (n = 69), machine learning revealed three bladder pain phenotypes with unique, salient features. The first group chiefly describes urinary frequency and pain with the voiding cycle, in which bladder filling causes pain relieved by bladder emptying. The second group has fluctuating pelvic discomfort and straining to void, urinary frequency and urgency without incontinence, and a sensation of incomplete emptying without urinary retention. Pain in the third group was not associated with voiding, instead being more constant and focused on the urethra and vagina. While not utilized as a feature for clustering, subjects in the second and third groups were significantly younger than subjects in the first group and controls without pain. These phenotypes defined more homogeneous patient subgroups which responded to different therapies on chart review. Current approaches to the management of heterogenous populations of bladder pain patients are often ineffective, discouraging both patients and providers. The granularity of individual phenotypes provided by unsupervised clustering approaches can be exploited to help objectively define more homogeneous patient subgroups. Better differentiation of unique phenotypes within the larger group of pelvic pain patients is needed to move toward improvements in care and a better understanding of the etiologies of these painful symptoms.
Floating-Harbor Syndrome Treated With Recombinant Human Growth Hormone: A Case Report and Literature Review
Authors: Bo Hui , Jiang Lihong , Zheng Jiaqi , Sun Jie
Published: November 2021

Introduction: We aimed to summarize the clinical characteristics of Floating-Harbor syndrome (FHS) and the effect of recombinant human growth hormone (rhGH) to increase height.

Methods: The clinical manifestations, gene sequencing results, treatment, and regression of one child with FHS were reported at the Department of Pediatrics, General Hospital of Tianjin Medical University, in July 2020. PubMed was searched using the keyword “Floating-Harbor Syndrome” up to March 2021 to obtain clinical information on children with FHS for review.

Results: The child, who was a male aged 6 years and 9 months, presented to the clinic with main complaints of delayed language development since childhood and a short stature for 4 years. The child's short stature, peculiar facial features, delayed language development, and delayed bone development were considered alongside genetic testing and Sanger sequencing to verify the results. A heterozygous mutation (c.7401delC; p.Ile2468Phefs*7) was identified in exon 34 of the SRCAP gene, which was a frameshift mutation, and Sanger verification showed that neither parent had this mutation. The child was administered subcutaneous injection of rhGH (0.13 U/kg/day) and was followed up regularly. At the time of writing, the child had been treated for 6 months and was 7 years and 3 months old with a height of 106.3 cm (−3.69 SDS), which was a height increase of 6.3 cm. The patient did not complain of discomfort during treatment and presented normal laboratory tests results. Twenty-two children with FHS treated with rhGH were included in the literature review, and most of these patients demonstrated an increase in height SDS without adverse effects.

Conclusion: Short stature, delayed skeletal maturation, impaired language expression, intellectual deficits, and peculiar facial features are the main clinical features of FHS. rhGH can be used as a treatment to increase height in patients with FHS, but its effectiveness and safety still need to be monitored in larger sample sizes over longer periods of time.
Azithromycin Attenuates Bleomycin-Induced Pulmonary Fibrosis Partly by Inhibiting the Expression of LOX and LOXL-2
Authors: Tong Xiang , Zhang Shijie , Wang Dongguang , Zhang Li , Huang Jizheng , Zhang Tianli , Fan Hong
Published: November 2021

Pulmonary fibrosis (PF) is a chronic and progressive process of tissue repair. Azithromycin (AZM) may be beneficial for the treatment of PF because AZM has anti-inflammatory and immune regulatory roles and inhibits remodeling, but the mechanism is not entirely clear. In this study, we established a mouse PF model induced by bleomycin (BLM) and primary mouse lung fibroblasts stimulated by transforming growth factor (TGF)-β1 to explore the possible mechanisms of AZM in PF. Results showed that AZM reduces mortality and lung inflammation and attenuates BLM-induced PF in mice. AZM effectively reduced the expression of α-smooth muscle actin (SMA) and type I collagen. Meanwhile, expression of lysyl oxidase (LOX) and lysyl oxidase-like protein (LOXL)-2 in the lung tissue of mice after AZM treatment was significantly lower than in the BLM group. In addition, this study found that AZM significantly inhibits the TGF-β1/Smad and JNK/c-Jun signaling pathways in vivo, and expression of a-SMA, type I collagen, LOX and LOXL-2 in the lung tissue of mice treated with AZM was significantly lower than that in the BLM group. In vitro, AZM also effectively inhibited type I collagen, LOX, LOXL-2 and JNK-c-Jun signaling pathways in TGF-β1-stimulated primary mouse fibroblasts, and this effect was similar to that of a JNK-specific inhibitor (SP600125). In conclusion, AZM effectively attenuated BLM-induced PF in mice, which may play a role by partially inhibiting the JNK/c-Jun and TGF-β1/Smad signaling pathways and reducing production of LOX and LOXL2.
Monitoring Tacrolimus Concentrations in Whole Blood and Peripheral Blood Mononuclear Cells: Inter- and Intra-Patient Variability in a Cohort of Pediatric Patients
Authors: De Nicolò Amedeo , Pinon Michele , Palermiti Alice , Nonnato Antonello , Manca Alessandra , Mula Jacopo , Catalano Silvia , Tandoi Francesco , Romagnoli Renato , D’Avolio Antonio , Calvo Pier Luigi
Published: November 2021

Tacrolimus (TAC) is a first-choice immunosuppressant for solid organ transplantation, characterized by high potential for drug-drug interactions, significant inter- and intra-patient variability, and narrow therapeutic index. Therapeutic drug monitoring (TDM) of TAC concentrations in whole blood (WB) is capable of reducing the incidence of adverse events. Since TAC acts within lymphocytes, its monitoring in peripheral blood mononuclear cells (PBMC) may represent a valid future alternative for TDM. Nevertheless, TAC intracellular concentrations and their variability are poorly described, particularly in the pediatric context. Therefore, our aim was describing TAC concentrations in WB and PBMC and their variability in a cohort of pediatric patients undergoing constant immunosuppressive maintenance therapy, after liver transplantation. TAC intra-PBMCs quantification was performed through a validated UHPLC–MS/MS assay over a period of 2–3 months. There were 27 patients included in this study. No significant TAC changes in intracellular concentrations were observed (p = 0.710), with a median percent change of −0.1% (IQR −22.4%–+46.9%) between timings: this intra-individual variability was similar to the one in WB, −2.9% (IQR −29.4–+42.1; p = 0.902). Among different patients, TAC weight-adjusted dose and age appeared to be significant predictors of TAC concentrations in WB and PBMC. Intra-individual seasonal variation of TAC concentrations in WB, but not in PBMC, have been observed. These data show that the intra-individual variability in TAC intracellular exposure is comparable to the one observed in WB. This opens the way for further studies aiming at the identification of therapeutic ranges for TAC intra-PBMC concentrations.
The Quality Monitoring of Cistanches Herba (Cistanche deserticola Ma): A Value Chain Perspective
Authors: Jiang Linlin , Zhou Baochang , Wang Xiaoqin , Bi Yaqiong , Guo Wenfang , Wang Jianhua , Yao Ruyu , Li Minhui
Published: November 2021

Cistanche deserticola Ma was used as a medicine food homology, which was mainly produced in the Alxa region of northwest China. In recent years, it has been widely used in various food items. The increasing demand for Cistanches Herba has led to problems such as overexploitation and quality deterioration. The quality and safety of herbal medicines are critical and have been shown to be affected by the value chain (VC). Using the VC framework, the study is embedded in a larger study aiming to investigate the effects of different VCs types on the quality and stakeholders of Cistanches Herba. In this study, 90 Cistanches Herba samples were collected during fieldwork. An additional 40 samples were obtained from the herbal markets and medicine purchasing stations. Semi-structured interviews and key informant interviews were performed to collect data on stakeholders in major production areas. These samples were analyzed using high performance liquid chromatography (HPLC) coupled with the k-means clustering method; a targeted quality assessment strategy based on chemical analysis was adopted to understand the quality of Cistanches Herba. Based on market research, the collected samples were divided into different grades through k-means clustering analysis. Moreover, quality differences of Cistanches Herba in Alxa region were explored through DNA barcoding and chemical analysis. Accordingly, 10 different types of VCs were determined in the production of Cistanches Herba. The results show that there is a close relationship between the quality of Cistanches Herba and stakeholder benefits. Vertical integration at different levels was found for independent farmer-based VCs, horizontal collaboration was found in the cooperative-based VCs. The vertical coordination has led to a more consistent traceability system and strict regulation of supply chains. At the same time, the Cistanches Herba were divided into three grades. Through DNA barcoding and chemical analysis, we found that the quality differences between Cistanches Herba in the Alxa area were not significant. It was found that geographical suitability and vertical integration could impact the quality and sustainable production of Cistanches Herba. At the same time, the well-developed VCs can provide products with reliable quality, and ensure adequate financial revenue for relevant stakeholders.
Densest-Packed Columnar Structures of Hard Spheres: An Investigation of the Structural Dependence of Electrical Conductivity
Authors: Ma Panpan , Chan Ho-Kei
Published: November 2021

Identical hard spheres in cylindrical confinement exhibit a rich variety of densest-packed columnar structures. Such structures, which generally vary with the corresponding cylinder-to-sphere diameter ratio D, serve as structural models for a variety of experimental systems at the micro- or nano-scale. In this research, the electrical conductivity as a function of D has been studied for four different types of such columnar structures. It was found that, for increasing D, the electrical conductivity of each type of structures decreases monotonously, as a result of the system’s resistive components becoming more densely packed along the long axis of the cylindrical space. However, there exists a discontinuous rise in the system’s electrical conductivity at D=1+3/2 (discontinuous zigzag-to-single-helix transition) and D = 2 (discontinuous double-helix-to-double-helix transition), respectively, as a result of the establishment of additional conducting paths upon an abrupt increase in the number of inter-particle contacts. This is not the case for the continuous single-helix-to-double-helix transition at D=1+43/7. The results, which tell us how the system’s electrical conductivity can be tuned through a variation of D, could serve as a guide for the development of quasi-one-dimensional materials with a structurally tunable electrical conductivity.
Potential Mechanisms of SGLT2 Inhibitors for the Treatment of Heart Failure With Preserved Ejection Fraction
Authors: Pabel Steffen , Hamdani Nazha , Singh Jagdeep , Sossalla Samuel
Published: November 2021

Heart failure with preserved ejection fraction (HFpEF) is an unsolved and growing concern in cardiovascular medicine. While no treatment options that improve prognosis in HFpEF patients has been established so far, SGLT2 inhibitors (SGLT2i) are currently being investigated for the treatment of HFpEF patients. SGLT2i have already been shown to mitigate comorbidities associated with HFpEF such as type 2 diabetes and chronic renal disease, however, more recently there has been evidence that they may also directly improve diastolic function. In this article, we discuss some potential beneficial mechanisms of SGLT2i in the pathophysiology of HFpEF with focus on contractile function.
RhWRKY33 Positively Regulates Onset of Floral Senescence by Responding to Wounding- and Ethylene-Signaling in Rose Plants
Authors: Jing Weikun , Zhao Qingcui , Zhang Shuai , Zeng Daxing , Xu Jiehua , Zhou Hougao , Wang Fenglan , Liu Yang , Li Yonghong
Published: November 2021

Rose plants are one of the most important horticultural crops, whose commercial value mainly depends on long-distance transportation, and wounding and ethylene are the main factors leading to their quality decline and accelerated senescence in the process. However, underlying molecular mechanisms of crosstalk between wounding and ethylene in the regulation of flower senescence remain poorly understood. In relation to this, transcriptome analysis was performed on rose flowers subjected to various treatments, including control, wounding, ethylene, and wounding- and ethylene- (EW) dual treatment. A large number of differentially expressed genes (DEGs) were identified, ranging from 2,442 between the ethylene- and control-treated groups to 4,055 between the EW- and control-treated groups. Using weighted gene co-expression network analysis (WGCNA), we identified a hub geneRhWRKY33(rchiobhmchr5g0071811), accumulated in the nucleus, where it may function as a transcription factor. Moreover, quantitative reverse transcription PCR (RT-qPCR) results showed that the expression ofRhWRKY33was higher in the wounding-, ethylene, and EW-treated petals than in the control-treated petals. We also functionally characterized theRhWRKY33gene through virus-induced gene silencing (VIGS). The silencing ofRhWRKY33significantly delayed the senescence process in the different treatments (control, wounding, ethylene, and EW). Meanwhile, we found that the effect ofRhWRKY33-silenced petals under ethylene and EW dual-treatment were stronger than those under wounding treatment in delaying the petal senescence process, implying thatRhWRKY33is closely involved with ethylene and wounding mediated petal senescence. Overall, the results indicate thatRhWRKY33positively regulates the onset of floral senescence mediated by both ethylene and wounding signaling, but relies heavily on ethylene signaling.
The Dark Triad Traits and the Prediction of Eudaimonic Wellbeing
Authors: Liu Yaqian , Zhao Na , Ma Min
Published: November 2021

Although numerous studies have focused on personality traits related to well-being, the relationship between the Dark Triad Traits and eudaimonic well-being is still unclear. The purpose of the present study was to explore how the Dark Triad Traits (i.e., narcissism, Machiavellianism, and psychopathy) affect eudaimonic well-being. Further, this study also aimed to explore the mediation effect of family support and hedonic wellbeing. The results showed that the present model had a good model fit (χ2/df = 1.91, p < 0.001, comparative-fit-index (CFI) = 0.96, tucker-lewis-index (TLI) = 0.95, root mean square error of approximation (RMSEA) = 0.04, standardized root mean square residual (SRMR) = 0.04). There is a significant association between the Dark Triad Traits and eudaimonic wellbeing. Specifically, narcissism directly predicts eudaimonic wellbeing, while the effects of Machiavellianism and psychopathy on eudaimonic wellbeing are serial two-mediator models, which are mediated by family support and hedonic wellbeing. The results would enrich theoretical studies on personality while providing some practical evidence on how to improve the subjective well-being of individuals.
Psychosocial Effects of the COVID-19 Pandemic on Patients With Schizophrenia and Their Caregivers
Authors: Caqueo-Urízar Alejandra , Urzúa Alfonso , Ponce-Correa Felipe , Ferrer Rodrigo
Published: November 2021

The aim of this study was to analyze the psychosocial effects of the COVID-19 pandemic on 120 patients with schizophrenia, and their caregivers (control group), in the city of Arica, northern Chile. The hypotheses of this study hold that (1) self-reports of the impact of the COVID-19 pandemic among patients and caregivers would be positively correlated, (2) caregivers would self-report a greater impact of the pandemic on their daily lives, and (3) patients infected with COVID-19 would experience lower levels of mental health improvement and higher levels of psychological distress. Hypotheses were tested using correlations, mean differences, and effect sizes (Cohen’s d). The results showed that patients with schizophrenia who had been in quarantine for almost a year showed similar levels of concern as their caregivers in the domains of health and social life. However, caregivers showed significant differences from patients in the areas of income, concern, and employment status. In addition, patients who were infected with COVID-19 showed lower levels of well-being and worse psychological recovery. The implications of the findings highlight the need to incorporate mental health interventions in the pandemic health context for caregivers of people with schizophrenia. Finally, the results suggest that Covid-19 infection has a significant effect on the recovery and psychological well-being of patients with schizophrenia.
Age-Related Differences in Motivation of Recreational Runners, Marathoners, and Ultra-Marathoners
Authors: Gerasimuk Dagmara , Malchrowicz-Mośko Ewa , Stanula Arkadiusz , Bezuglov Eduard , Achkasov Evgenij , Swinarew Andrzej , Waśkiewicz Zbigniew
Published: November 2021

Aim: This study was aimed to investigate the influence of age on the motivations of various types of runners, namely, marathoners, ultra-marathoners, and non-starters.

Methods: A total of 1,537 runners including 380 women (24.7%) and 1,157 men (75.3%) took part in the diagnostic survey and completed the motivations of marathoners’ scales questionnaire (MOMS). The effect sizes were estimated.

Results: The article presents several statistically significant differences in the impact of age on the motivations of runners in different categories and compares the motivations of marathon runners, ultramarathon runners, and non-starters. The results show that young non-starters decide to run for personal goal achievement, and for both marathon and ultramarathon runners, recognition and competition are important. However, for older people in all groups (non-starters, marathoners, and ultramarathoners), personal goal achievement is of the least importance. Among the oldest runners, the most important motives were self-esteem for non-starters and health orientation for marathoners and ultramarathoners.
Unique Trans-fatty Acid Profile in Children With Attention Deficit Hyperactivity Disorder
Authors: Armon-Omer Ayelet , Amir Eti , Neuman Hadar , Khateeb Saleh , Mizrachi Itai , Shalan Monia , Tamir Snait , Yatzkar Uri
Published: November 2021

Background: Attention deficit hyperactivity disorder (ADHD) is the most common developmental disorder in children. Studies suggest an association between fatty acids composition and ADHD pathogenesis. We aimed to investigate whether children diagnosed with ADHD present unique fatty acid profiles in red blood cells (RBC), as compared to children without ADHD.

Method: We examined 60 children aged 6–14 years, out of which 32 were diagnosed with ADHD, and 28 were not. Blood was collected from all children to quantify an array of 26 fatty acids from RBC membranes. Fatty acid methyl esters were generated by acid transesterification and analyzed by gas chromatography.

Results: We found that children with ADHD presented unique fatty acid profiles on RBC membranes with significantly higher levels of most of the trans-fatty acids (Total trans-fatty acids 0.64 ± 0.21 vs. 0.49 ± 0.18 p = 0.003) and lower levels of docosahexaenoic acid (DHA), as compared to controls (4.06 ± 0.79 vs. 4.68 ± 1.37 p = 0.040). Additionally, total trans-fatty acids were higher in children with extremely severe clinical ADHD condition score, as compared to milder ADHD scores and to control children (0.72 ± 0.18, 0.64 ± 0.20, 0.61 ± 0.22, 0.49 ± 0.18, p = 0.010, accordingly).

Conclusion: Children with ADHD have higher levels of trans-fatty acids in RBCs, compared to children without ADHD. This study points to a possible link between trans-fatty acids and ADHD. Understanding these findings and the clinical meaning will potentially contribute to a more targeted dietary intervention.
Task and Non-task Brain Activation Differences for Assessment of Depression and Anxiety by fNIRS
Authors: Wen Dan , Lang Xuenan , Zhang Hang , Li Qiqi , Yin Qin , Chen Yulu , Xu Yong
Published: November 2021

Diagnosis and treatment of the patients with major depression (MD) or the combined anxiety and depression (A&D) depend on the questionnaire, sometimes accompanied by tasks such as verbal fluency task (VFT). Functional near infrared spectroscopy (fNIRS) is emerging as an auxiliary diagnostic tool to evaluate brain function, providing an objective criterion to judge psychoses. At present, the conclusions derived from VFT or rest (non-task) studies are controversial. The purpose of this study is to evaluate if task performs better than non-task in separating healthy people from psychiatric patients. In this study, healthy controls (HCs) as well as the patients with MD or A&D were recruited (n = 10 for each group) to participate in the non-task and VFT tasks, respectively, and the brain oxygenation was longitudinally evaluated by using fNIRS. An approach of spectral analysis is used to analyze cerebral hemoglobin parameters (i.e., Oxy and Deoxy), characterizing the physiological fluctuations in the non-task and task states with magnitude spectrum and average power. Moreover, the standard deviation of oxygenation responses during the non-task was compared with the peak amplitude during the task, with the aim to explore the sensitivity of the VFT task to brain activation. The results show that there is no significant difference (p > 0.05) among the three groups in average power during non-task. The VFT task greatly enhanced the magnitude spectrum, leading to significant difference (p < 0.05) in average power between any of two groups (HC, MD, and A&D). Moreover, 40% patients with A&D have an intermediate peak (around 0.05 Hz) in the magnitude spectrum when performing the VFT task, indicating its advantage in characterizing A&D. We defined a rate of the non-task standard variation to the task peak amplitude (namely, SD-to-peak rate) and found that this rate is larger than 20% in 90% of the MD subjects. By contrast, only 40% HC subjects have an SD-to-peak rate larger than 20%. These results indicate that the non-task may not be sufficient to separate MD or A&D from HC. The VFT task could enhance the characteristics of the magnitude spectrum, but its intensity needs to be elevated so as to properly explore brain functions related to psychoses.
Applying the Hierarchy of Controls: What Occupational Safety Can Teach us About Safely Navigating the Next Phase of the Global COVID-19 Pandemic
Authors: Sehgal Neil J. , Milton Donald K.
Published: November 2021

Eighteen months into the COVID-19 pandemic, and as the world struggles with global vaccine equity, emerging variants, and the reality that eradication is years away at soonest, we add to notion of “layered defenses” proposing a conceptual model for better understanding the differential applicability and effectiveness of precautions against SARS-CoV-2 transmission. The prevailing adaptation of Reason's Swiss cheese model conceives of all defensive layers as equally protective, when in reality some are more effective than others. Adapting the hierarchy of controls framework from occupational safety provides a better framework for understanding the relative benefit of different hazard control strategies to minimize the spread of SARS-CoV-2.
Is the Scope of Costs Considered in Budget Impact Analyses for Anticancer Drugs Rational? A Systematic Review and Comparative Study
Authors: Ma Yue , Li Yuxin , Ma Aixia , Li Hongchao
Published: November 2021

Background: With the increasing disease burden of cancer worldwide, more and more anticancer drugs have been approved in many countries, and the results of budget impact analyses (BIAs) have become important evidence for related reimbursement decisions.

Objectives: We systematically reviewed whether BIAs for anticancer drugs consider the scope of costs rationally and compared the results of different cost scopes to provide suggestions for future analyses and decision-making.

Methods: Eligible BIAs published in PubMed, Embase, Web of Science, and the Cochrane Library from 2016 to 2021 were identified based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We extracted 15 terms from the included studies and analyzed how they considered the scope of costs. In addition, a budget impact model was developed for the introduction of geptanolimab to China's National Reimbursement Drug List to enable a comparison of two cost-scope scenarios.

Results: A total of 29 studies were included in the systematic review. All 29 studies considered the costs of anticancer drugs, and 25 (86%) also considered condition-related costs, but only 11 (38%) considered subsequent treatment costs. In the comparative study, the predicted budget impacts from 2022 to 2024 were significantly impacted by subsequent treatment costs, with annual differences between the two cost-scope scenarios of $39,546,664, $65,866,161, and $86,577,386, respectively.

Conclusions: The scope of costs considered in some existing BIAs for anticancer drugs are not rational. The variations between different cost scopes in terms of budget impact were significant. Thus, BIAs for anticancer drugs should consider a rational scope of costs that adheres to BIA guidelines. Researchers and decision-makers should pay more attention to the scope of costs to achieve better-quality BIAs for anticancer drugs and enhance reimbursement decision-making.
Using Biological Elicitation to Improve Type 2 Diabetes Targeted Food Quality of Stored Apple
Authors: Ankolekar Chandrakant , Sarkar Dipayan , Greene Duane , Shetty Kalidas
Published: November 2021

Food quality improvements of fresh fruits targeting both food preservation and human health is essential to advance healthy dietary options and to mitigate imbalanced nutrition-linked non-communicable chronic disease (NCDs) challenges globally. Specifically, protective phenolic bioactives of fruits with dual functional benefits can be harnessed to advance innovations for improving nutritional quality and post-harvest shelf-life of perishable fruits. Based on this rationale the dual functional benefits of plant phenolics were harnessed using novel biological elicitation strategies to modulate phenolic bioactive-linked protective responses in apple during storage in two interrelated studies. Bioprocessed food-grade elicitors [water soluble chitosan oligosaccharide -(COS) and phenolic enriched oregano extracts-(OX)] were targeted as post-harvest dipping treatments (2 & 4 g/ L) and compared with diphenylamine (DPA) (1 & 2 g/L) to enhance phenolic-linked antioxidant and anti-diabetic (type 2 diabetes) relevant properties of Cortland apple during 3 months of storage (4°C). The selection of bio-elicitors and respective doses were based on the foundations of the previous related study, which resulted in reduction of superficial scald of Cortland apple during storage. Apples sampled over 3 months as aqueous and ethanol (12%) extracts of peel and pulp were analyzed separately for total soluble phenolic content, phenolic profile, antioxidant activity, and glucose metabolism relevant α-amylase and α-glucosidase enzyme inhibitory activities using in vitro assay models. Enhanced soluble phenolic content and associated antioxidant activity were observed in ethanol (12%) extracts of apple peel with 4 g/L COS elicitor treatments after 2 and 3 months of storage. High chlorogenic acid and quercetin derivatives were found in peel extracts of Cortland apple, while pulp extracts had high chlorogenic and gallic acids. Additionally, high α-glucosidase enzyme inhibitory activity, which is relevant for managing post-prandial hyperglycemia of type 2 diabetes was also observed in bio-elicited apple peel and pulp extracts. Therefore, results of these two interrelated studies indicate that bioprocessed food grade elicitor such as OX and COS can be recruited as a novel tool to enhance protective phenolic responses for improving type 2 diabetes targeted food quality and post-harvest storage quality of apple.
Optimized Dissolved Oxygen Fuzzy Control for Recombinant Escherichia coli Cultivations
Authors: Akisue Rafael Akira , Harth Matheus Lopes , Horta Antonio Carlos Luperni , de Sousa Junior Ruy
Published: November 2021

Due to low oxygen solubility and mechanical stirring limitations of a bioreactor, ensuring an adequate oxygen supply during a recombinant Escherichia coli cultivation is a major challenge in process control. Under the light of this fact, a fuzzy dissolved oxygen controller was developed, taking into account a decision tree algorithm presented in the literature, and implemented in the supervision software SUPERSYS_HCDC. The algorithm was coded in MATLAB with its membership function parameters determined using an Adaptive Network-Based Fuzzy Inference System tool. The controller was composed of three independent fuzzy inference systems: Princ1 and Princ2 assessed whether there would be an increment or a reduction in air and oxygen flow rates (respectively), whilst Delta estimated the size of these variations. To test the controller, simulations with a neural network model and E. coli cultivations were conducted. The fuzzification of the decision tree was successful, resulting in smoothing of air and oxygen flow rates and, hence, in an attenuation of dissolved oxygen oscillations. Statistically, the average standard deviation of the fuzzy controller was 2.45 times lower than the decision tree (9.48%). Results point toward an increase in the flow meter lifespan and a possible reduction of the metabolic stress suffered by E. coli during the cultivation.
Insulin Regulation of Escherichia coli Abiotic Biofilm Formation: Effect of Nutrients and Growth Conditions
Authors: Patel Nina , Curtis Jeremy C. , Plotkin Balbina J.
Published: November 2021

Escherichia coli plays an important role in biofilm formation across a wide array of disease and ecological settings. Insulin can function as an adjuvant in the regulation of biofilm levels. The modulation of insulin-regulated biofilm formation by environmental conditions has not been previously described. In the present study, the effects that various environmental growth conditions and nutrients have on insulin-modulated levels of biofilm production were measured. Micropipette tips were incubated with E. coli ATCC® 25922™ in a Mueller Hinton broth (MH), or a yeast nitrogen base with 1% peptone (YNBP), which was supplemented with glucose, lactose, galactose and/or insulin (Humulin®-R). The incubation conditions included a shaking or static culture, at 23 °C or 37 °C. After incubation, the biofilm production was calculated per CFU. At 23 °C, the presence of insulin increased biofilm formation. The amount of biofilm formation was highest in glucose > galactose >> lactose, while the biofilm levels decreased in shaking cultures, except for galactose (3-fold increase; 0.1% galactose and 20 μU insulin). At 37 °C, regardless of condition, there was more biofilm formation/CFU under static conditions in YNBP than in MH, except for the MH containing galactose. E. coli biofilm formation is influenced by aeration, temperature, and insulin concentration in combination with the available sugars.
Operational Analysis and Medium-Term Forecasting of the Greenhouse Gas Generation Intensity in the Cryolithozone
Authors: Timofeev Andrey V. , Piirainen Viktor Y. , Bazhin Vladimir Y. , Titov Aleksander B.
Published: November 2021

We proposed a new approach to solving the problem of operational analysis and medium-term forecasting of the greenhouse gas generation (CO2, CH4) intensity in a certain area of the cryolithozone using data from a geographically distributed network of multimodal measuring stations. A network of measuring stations, capable of functioning autonomously for long periods of time, continuously generated a data flow of the CO2, CH4 concentration, soil moisture, and temperature, as well as a number of other parameters. These data, taking into account the type of soil, were used to build a spatially distributed dynamic model of greenhouse gas emission intensity of the permafrost area depending on the temperature and moisture of the soil. This article presented models for estimating and medium-term predicting ground greenhouse gases emission intensity, which are based on artificial intelligence methods. The results of the numerical simulations were also presented, which showed the adequacy of the proposed approach for predicting the intensity of greenhouse gas emissions.
HIV-1 Gag Non-Cleavage Site PI Resistance Mutations Stabilize Protease/Gag Substrate Complexes In Silico via a Substrate-Clamp
Authors: Laco Gary S.
Published: November 2021

HIV-1 protease active site inhibitors are a key part of antiretroviral therapy, though resistance can evolve rendering therapy ineffective. Protease inhibitor resistance typically starts with primary mutations around the active site, which reduces inhibitor binding, protease affinity for substrate cleavage site residues P4-P4′, and viral replication. This is often followed by secondary mutations in the protease substrate-grooves which restore viral replication by increasing protease affinity for cleavage site residues P12-P5/P5′-P12′, while maintaining resistance. However, mutations in Gag alone can also result in resistance. The Gag resistance mutations can occur in cleavage sites (P12-P12′) to increase PR binding, as well as at non-cleavage sites. Here we show in silico that Gag non-cleavage site protease inhibitor resistance mutations can stabilize protease binding to Gag cleavage sites which contain structured subdomains on both sides: SP1/NC, SP2/p6, and MA/CA. The Gag non-cleavage site resistance mutations coordinated a network of H-bond interactions between the adjacent structured subdomains of the Gag substrates to form a substrate-clamp around the protease bound to cleavage site residues P12-P12′. The substrate-clamp likely slows protease disassociation from the substrate, restoring the cleavage rate in the presence of the inhibitor. Native Gag substrates can also form somewhat weaker substrate-clamps. This explains the 350-fold slower cleavage rate for the Gag CA/SP1 cleavage site in that the CA-SP1 substrate lacks structured subdomains on both sides of the cleavage site, and so cannot form a substrate-clamp around the PR.
Activation of a Ductal-to-Endocrine Transdifferentiation Transcriptional Program in the Pancreatic Cancer Cell Line PANC-1 Is Controlled by RAC1 and RAC1b through Antagonistic Regulation of Stemness Factors
Authors: Schmidtlein Paula Marie , Volz Clara , Hackel Alexander , Thürling Isabel , Castven Darko , Braun Rüdiger , Wellner Ulrich Friedrich , Konukiewitz Björn , Riemekasten Gabriela , Lehnert Hendrik , Marquardt Jens-Uwe , Ungefroren Hendrik
Published: November 2021

Epithelial–mesenchymal transition (EMT) is a driving force for tumor growth, metastatic spread, therapy resistance, and the generation of cancer stem cells (CSCs). However, the regained stem cell character may also be exploited for therapeutic conversion of aggressive tumor cells to benign, highly differentiated cells. The PDAC-derived quasimesenchymal-type cell lines PANC-1 and MIA PaCa-2 have been successfully transdifferentiated to endocrine precursors or insulin-producing cells; however, the underlying mechanism of this increased plasticity remains elusive. Given its crucial role in normal pancreatic endocrine development and tumor progression, both of which involve EMT, we analyzed here the role of the small GTPase RAC1. Ectopic expression in PANC-1 cells of dominant negative or constitutively active mutants of RAC1 activation blocked or enhanced, respectively, the cytokine-induced activation of a ductal-to-endocrine transdifferentiation transcriptional program (deTDtP) as revealed by induction of the NEUROG3, INS, SLC2A2, and MAFA genes. Conversely, ectopic expression of RAC1b, a RAC1 splice isoform and functional antagonist of RAC1-driven EMT, decreased the deTDtP, while genetic knockout of RAC1b dramatically increased it. We further show that inhibition of RAC1 activation attenuated pluripotency marker expression and self-renewal ability, while depletion of RAC1b dramatically enhanced stemness features and clonogenic potential. Finally, rescue experiments involving pharmacological or RNA interference-mediated inhibition of RAC1 or RAC1b, respectively, confirmed that both RAC1 isoforms control the deTDtP in an opposite manner. We conclude that RAC1 and RAC1b antagonistically control growth factor-induced activation of an endocrine transcriptional program and the generation of CSCs in quasimesenchymal PDAC cells. Our results have clinical implications for PDAC patients, who in addition to eradication of tumor cells have a need for replacement of insulin-producing cells.
Disruption of Mitochondrial Homeostasis: The Role of PINK1 in Parkinson’s Disease
Authors: Vizziello Maria , Borellini Linda , Franco Giulia , Ardolino Gianluca
Published: November 2021

The progressive reduction of the dopaminergic neurons of the substantia nigra is the fundamental process underlying Parkinson’s disease (PD), while the mechanism of susceptibility of this specific neuronal population is largely unclear. Disturbances in mitochondrial function have been recognized as one of the main pathways in sporadic PD since the finding of respiratory chain impairment in animal models of PD. Studies on genetic forms of PD have provided new insight on the role of mitochondrial bioenergetics, homeostasis, and autophagy. PINK1 (PTEN-induced putative kinase 1) gene mutations, although rare, are the second most common cause of recessively inherited early-onset PD, after Parkin gene mutations. Our knowledge of PINK1 and Parkin function has increased dramatically in the last years, with the discovery that a process called mitophagy, which plays a key role in the maintenance of mitochondrial health, is mediated by the PINK1/Parkin pathway. In vitro and in vivo models have been developed, supporting the role of PINK1 in synaptic transmission, particularly affecting dopaminergic neurons. It is of paramount importance to further define the role of PINK1 in mitophagy and mitochondrial homeostasis in PD pathogenesis in order to delineate novel therapeutic targets.
Impacts of OFDI on Host Country Energy Consumption and Home Country Energy Efficiency Based on a Belt and Road Perspective
Authors: Zhou Xing , Guo Quan , Zhang Ming
Published: November 2021

Under the Belt and Road concepts of mutual benefit and win–win cooperation, China is strengthening its energy cooperation with other countries. We used several econometric models and social network analysis models to study the impacts of China’s outward foreign direct investment (OFDI) on the host and home countries. We first examined China’s OFDI location preference and analysed the effects of OFDI on energy consumption in host countries. Meanwhile, we observed the impact of the reverse spillover effect of OFDI on China’s energy efficiency. The results indicate that (1) the impact of China’s OFDI on energy consumption in host countries has been lower than that on neighbouring countries, and increased significantly after 2014. (2) The space network of energy consumption in Belt and Road countries has a strict hierarchical structure. However, it was disbanded by the Belt and Road policy in 2014. The network centres are situated primarily in Middle Eastern and European countries, and the network’s periphery is mainly in South-East and West Asian countries. (3) The reverse spillover effects of OFDI, FDI, domestic R&D absorptive capacity, human capital, and financial development levels are conducive to improving China’s energy efficiency whereas regional professionalism does the opposite.
COVID-19 and Fake News
Authors: Bustos Díaz Javier , Nicolas-Sans Ruben
Published: November 2021

COVID-19 can be defined as a global pandemic caused by a coronavirus that first surfaced in 2019. Fake news refers to false reports that can be found in digital media. The combination of these two concepts creates an especially mismanaged situation that can result in widespread unease among the population, to whom the news appears continuously and without quality filters.