bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-Cell Transcriptome Profiling Unravels Distinct Peripheral Blood Immune Cell Signatures of RRMS and MOG Antibody-Associated Disease
Authors: Liu Ju , Yang Xiaoyan , Pan Jiali , Wei Zhihua , Liu Peidong , Chen Min , Liu Hongbo
Published: January 2022

Relapsing-remitting multiple sclerosis (RRMS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) are inflammatory demyelinating diseases of the central nervous system (CNS). Due to the shared clinical manifestations, detection of disease-specific serum antibody of the two diseases is currently considered as the gold standard for the diagnosis; however, the serum antibody levels are unpredictable during different stages of the two diseases. Herein, peripheral blood single-cell transcriptome was used to unveil distinct immune cell signatures of the two diseases, with the aim to provide predictive discrimination. Single-cell RNA sequencing (scRNA-seq) was conducted on the peripheral blood from three subjects, i.e., one patient with RRMS, one patient with MOGAD, and one patient with healthy control. The results showed that the CD19+ CXCR4+ naive B cell subsets were significantly expanded in both RRMS and MOGAD, which was verified by flow cytometry. More importantly, RRMS single-cell transcriptomic was characterized by increased naive CD8+ T cells and cytotoxic memory-like Natural Killer (NK) cells, together with decreased inflammatory monocytes, whereas MOGAD exhibited increased inflammatory monocytes and cytotoxic CD8 effector T cells, coupled with decreased plasma cells and memory B cells. Collectively, our findings indicate that the two diseases exhibit distinct immune cell signatures, which allows for highly predictive discrimination of the two diseases and paves a novel avenue for diagnosis and therapy of neuroinflammatory diseases.
Clinical Features and Prognosis in Chinese Patients With Dipeptidyl–Peptidase–Like Protein 6 Antibody–Associated Encephalitis
Authors: Miao Ailiang , Shi Yongwei , Wang Xiaoshan , Ge Jianqing , Yu Chuanyong
Published: January 2022

Objectives:

Anti-dipeptidyl–peptidase–like protein 6 (anti-DPPX) encephalitis an extremely rare type of immune-mediated encephalitis. This study aimed to analyze the electroclinical characteristics and prognosis of anti-DPPX encephalitis.

Methods:

Five patients (all male) with anti-DPPX encephalitis in East China from January 2016 to October 2021 was retrospective analyzed. Electroclinical features and outcomes were reviewed.

Results:

All five patients were male. The media age at disease onset was 32 years old with a range of 14–56 years. The main symptoms included psychiatric disturbances (2/5), amnesia (4/5), confusion (3/5), and seizures (3/5). Migrating myoclonus were identified in patient 4 with positive DPPX and contactin-associated protein-like 2 antibodies in blood. All of the patients had positive DPPX antibodies in serum. Only one of them had positive antibody in the cerebrospinal fluid. EEG showed diffuse slowing in two patients, but no epileptiform discharges were observed. Eighty percent (4/5) of the patients showed normal brain magnetic resonance imaging. After immunotherapy, improvement of neuropsychiatric symptoms from all of the patients was observed. Over a mean follow-up of 30.8 weeks, all of the patients had marked improvement in the modified Rankin Scale. To date, no tumors were not observed in any patients.

Conclusions:

Anti-DPPX encephalitis mainly presents as neuropsychiatric symptoms. Cooperation of DPPX antibodies and CASPR2 antibodies might have contributed to the migration of myoclonus in the patient 4. Prompt immunotherapy often results in improvement.
Cognitive Control Processes and Defense Mechanisms That Influence Aggressive Reactions: Toward an Integration of Socio-Cognitive and Psychodynamic Models of Aggression
Authors: Gagnon Jean , Quansah Joyce Emma , McNicoll Paul
Published: January 2022

Research on cognitive processes has primarily focused on cognitive control and inhibitory processes to the detriment of other psychological processes, such as defense mechanisms (DMs), which can be used to modify aggressive impulses as well as self/other images during interpersonal conflicts. First, we conducted an in-depth theoretical analysis of three socio-cognitive models and three psychodynamic models and compared main propositions regarding the source of aggression and processes that influence its enactment. Second, 32 participants completed the Hostile Expectancy Violation Paradigm (HEVP) in which scenarios describe a hostile vs. non-hostile social context followed by a character's ambiguous aversive behavior. The N400 effect to critical words that violate expected hostile vs. non-hostile intent of the behavior was analyzed. Prepotent response inhibition was measured using a Stop Signal task (SST) and DMs were assessed with the Defense Style Questionnaire (DSQ-60). Results showed that reactive aggression and HIA were not significantly correlated with response inhibition but were significantly positively and negatively correlated with image distorting defense style and adaptive defense style, respectively. The present article has highlighted the importance of integrating socio-cognitive and psychodynamic models to account for the full complexity underlying psychological processes that influence reactive aggressive behavior.
Cross-Domain Feature Similarity Guided Blind Image Quality Assessment
Authors: Feng Chenxi , Ye Long , Zhang Qin
Published: January 2022

This work proposes an end-to-end cross-domain feature similarity guided deep neural network for perceptual quality assessment. Our proposed blind image quality assessment approach is based on the observation that features similarity across different domains (e.g., Semantic Recognition and Quality Prediction) is well correlated with the subjective quality annotations. Such phenomenon is validated by thoroughly analyze the intrinsic interaction between an object recognition task and a quality prediction task in terms of characteristics of the human visual system. Based on the observation, we designed an explicable and self-contained cross-domain feature similarity guided BIQA framework. Experimental results on both authentical and synthetic image quality databases demonstrate the superiority of our approach, as compared to the state-of-the-art models.
Netrin-1 Ameliorates Postoperative Delirium-Like Behavior in Aged Mice by Suppressing Neuroinflammation and Restoring Impaired Blood-Brain Barrier Permeability
Authors: Li Ke , Wang Jiayu , Chen Lei , Guo Meimei , Zhou Ying , Li Xiaofeng , Peng Mian
Published: January 2022

Postoperative delirium (POD) is a common and serious postoperative complication in elderly patients, and its underlying mechanism is elusive and without effective therapy at present. In recent years, the neuroinflammatory hypothesis has been developed in the pathogenesis of POD, in which the damaged blood-brain barrier (BBB) plays an important role. Netrin-1 (NTN-1), an axonal guidance molecule, has been reported to have strong inflammatory regulatory and neuroprotective effects. We applied NTN-1 (45 μg/kg) to aged mice using a POD model with a simple laparotomy to assess their systemic inflammation and neuroinflammation by detecting interleukin-6 (IL-6), interleukin-10 (IL-10), and high mobility group box chromosomal protein-1 (HMGB-1) levels. We also assessed the reactive states of microglia and the permeability of the BBB by detecting cell junction proteins and the leakage of dextran. We found that a single dose of NTN-1 prophylaxis decreased the expression of IL-6 and HMGB-1 and upregulated the expression of IL-10 in the peripheral blood, hippocampus, and prefrontal cortex. Nerin-1 reduced the activation of microglial cells in the hippocampus and prefrontal cortex and improved POD-like behavior. NTN-1 also attenuated the anesthesia/surgery-induced increase in BBB permeability by upregulating the expression of tight junction-associated proteins such as ZO-1, claudin-5, and occludin. These findings confirm the anti-inflammatory and BBB protective effects of NTN-1 in an inflammatory environment in vivo and provide better insights into the pathophysiology and potential treatment of POD.
A Metagenomics Investigation of Intergenerational Effects of Non-nutritive Sweeteners on Gut Microbiome
Authors: Wang Weilan , Nettleton Jodi E. , Gänzle Michael G. , Reimer Raylene A.
Published: January 2022

To identify possible mechanisms by which maternal consumption of non-nutritive sweeteners increases obesity risk in offspring, we reconstructed the major alterations in the cecal microbiome of 3-week-old offspring of obese dams consuming high fat/sucrose (HFS) diet with or without aspartame (5–7 mg/kg/day) or stevia (2–3 mg/kg/day) by shotgun metagenomic sequencing (n = 36). High throughput 16S rRNA gene sequencing (n = 105) was performed for dams, 3- and 18-week-old offspring. Maternal consumption of sweeteners altered cecal microbial composition and metabolism of propionate/lactate in their offspring. Offspring daily body weight gain, liver weight and body fat were positively correlated to the relative abundance of key microbes and enzymes involved in succinate/propionate production while negatively correlated to that of lactose degradation and lactate production. The altered propionate/lactate production in the cecum of weanlings from aspartame and stevia consuming dams implicates an altered ratio of dietary carbohydrate digestion, mainly lactose, in the small intestine vs. microbial fermentation in the large intestine. The reconstructed microbiome alterations could explain increased offspring body weight and body fat. This study demonstrates that intense sweet tastants have a lasting and intergenerational effect on gut microbiota, microbial metabolites and host health.
Molecular Characterization and Prognostication of Large Cell Neuroendocrine Carcinoma and Large Cell Carcinoma
Authors: Chen Ying , Cui Xiaoying , Wang Di , Xia Guojie , Xing Minyan , Cheng Lei , Sheng Liming , Du Xianghui
Published: January 2022

Purpose

Large cell neuroendocrine carcinoma (LCNEC) and classic large cell carcinoma (LCC) are two distinct entities with different histological and biological characteristics. However, the mutational profiles and the clinical behavior of the two subtypes of lung cancer remain to be explored.

Patients and Methods

Pathological diagnoses of all screened patients were finally confirmed by three or four experienced pathologists. Patients with uncertain pathological diagnoses were excluded. Finally, we genetically profiled ten patients with LCNEC and seven with LCC. ALL patients were subjected to next-generation sequencing (NGS) test, which included nine patients sequenced with a 139-gene panel and eight patients with a 425-gene panel. Including only intersected mutations from these two panels, survival analysis was further conducted.

Results

Both LCNEC and LCC showed high prevalence in male patients, with no clear association with smoking history. Potential targetable mutations in KRAS and RET were detected in the study cohort. However, LCNEC and LCC showed distinct mutational profiles with an enrichment of RB1/TP53 co-mutations in a subset of LCNEC patients. SMARCA4 and KEAP1 mutations were exclusively found in LCC patients, and RICTOR, BRAF, ROS1 and TET2 mutations were only detected in LCNEC. LCC patients in the cohort had shorter survival compared to LCNEC patients (p=0.006). Survival analysis revealed an association between SMARCA4 mutations and poor outcome in the study cohort and in the LCC subset. Mutations in BRAF were associated with a trend of increased survival in the study cohort, as well as in the LCNEC subset. Finally, TET2 mutations were associated with poor outcome in the LCNEC cohort.

Conclusion

LCC and LCNEC were both heterogeneous diseases with limited treatment options. Our study identified potential targetable mutations and prognostic biomarkers that might provide more therapeutic options and improve individualized patient care.
Accuracy of Mixed Reality Combined With Surgical Navigation Assisted Oral and Maxillofacial Tumor Resection
Authors: Tang Zu-Nan , Hu Lei-Hao , Soh Hui Yuh , Yu Yao , Zhang Wen-Bo , Peng Xin
Published: January 2022

Objective

To evaluate the feasibility and accuracy of mixed reality combined with surgical navigation in oral and maxillofacial tumor surgery.

Methods

Retrospective analysis of data of seven patients with oral and maxillofacial tumors who underwent surgery between January 2019 and January 2021 using a combination of mixed reality and surgical navigation. Virtual surgical planning and navigation plan were based on preoperative CT datasets. Through IGT-Link port, mixed reality workstation was synchronized with surgical navigation, and surgical planning data were transferred to the mixed reality workstation. Osteotomy lines were marked with the aid of both surgical navigation and mixed reality images visualized through HoloLens. Frozen section examination was used to ensure negative surgical margins. Postoperative CT datasets were obtained 1 week after the surgery, and chromatographic analysis of virtual osteotomies and actual osteotomies was carried out. Patients received standard oncological postoperative follow-up.

Results

Of the seven patients, four had maxillary tumors and three had mandibular tumors. There were total of 13 osteotomy planes. Mean deviation between the planned osteotomy plane and the actual osteotomy plane was 1.68 ± 0.92 mm; the maximum deviation was 3.46 mm. Chromatographic analysis showed error of ≤3 mm for 80.16% of the points. Mean deviations of maxillary and mandibular osteotomy lines were approximate (1.60 ± 0.93 mm vs. 1.86 ± 0.93 mm). While five patients had benign tumors, two had malignant tumors. Mean deviations of osteotomy lines was comparable between patients with benign and malignant tumors (1.48 ± 0.74 mm vs. 2.18 ± 0.77 mm). Intraoperative frozen pathology confirmed negative resection margins in all cases. No tumor recurrence or complications occurred during mean follow-up of 15.7 months (range, 6-26 months).

Conclusion

The combination of mixed reality technology and surgical navigation appears to be feasible, safe, and effective for tumor resection in the oral and maxillofacial region.
Cisplatin and Irinotecan as First-Line Chemotherapy for Previously Untreated Metastatic Thymic Carcinoma: Updated Analysis
Authors: Fukuda Akito , Okuma Yusuke , Hakozaki Taiki , Mirokuji Kie , Yomota Makiko , Hishima Tsunekazu , Hosomi Yukio
Published: January 2022

Platinum-based chemotherapy is the de facto standard treatment for metastatic or unresectable thymic carcinoma. The optimal chemotherapy regimen has not yet been determined, including whether this should be combined with a second- or third-generation anti-cancer agent. We retrospectively evaluated the data of patients with metastatic or unresectable thymic carcinoma who were treated with a combination of cisplatin and irinotecan as first-line chemotherapy between 2002 and 2021 (trial registration UMIN000012175). The primary endpoint was response rate according to the RECIST criteria version 1.1. Secondary endpoints were disease control rate, progression-free survival (PFS), overall survival (OS), and toxicity (adverse events). Some patients analyzed in this study were also included in the previous trial, which was terminated early. For this analysis, we included 18 patients with a median age of 56 years and an Eastern Cooperative Oncology Group performance status of 0 or 1. All patients had clinical stage IVa or IVb thymic carcinoma according to the Masaoka-Koga staging system. The response rate was 44% and the disease control rate was 89%. The median PFS was 8.4 months (95% confidence interval (CI): 2.7–11.6 months) and the median OS was 45.6 months (95% CI: 15.7–69.1 months). Grade 3 or worse hematological toxicity was observed in 5 patients and grade 3 or worse non-hematological toxicity was observed in 3 patients. None of the patients developed febrile neutropenia, and no treatment-related deaths occurred. Thus, the combination of cisplatin and irinotecan as first-line chemotherapy for metastatic thymic carcinoma showed efficacy and acceptable toxicity.
Argon–Helium Cryoablation for Cutaneous Squamous Cell Carcinoma in the Elderly
Authors: Huang Qianwen , Xu Wenshen
Published: January 2022

Cutaneous squamous cell carcinoma (cSCC) is a common type of malignant neoplasm in non-melanoma skin cancer (NMSC). Most cases of simple cSCC are considered curable by surgical removal of the lesion. However, clinical treatments for cSCC with medium- or large-sized lesions are difficult. Meanwhile, the effectiveness of the treatments is not guaranteed, especially for elderly patients, because of an intolerance to surgical resection or other adjuvant modalities. In such cases, safe and effective treatments with excellent aesthetic outcomes are urgently needed. In this study, we reported 6 elderly cSCC patients with medium- or large-sized lesions treated with argon–helium cryoablation. The average age of all 6 patients was 78 years (range 72–85 years). They were all diagnosed with cSCC with a median tumor size of 5.8 cm (range 2.5–15.5 cm) and dermal invasion. Complete ablation was achieved in all cases after a single ablation session (2 freeze–thaw cycles). Patients experienced mild pain and hemorrhage after ablation, but the symptoms were manageable. One patient developed infection and fever because of extensive necrosis of the tumor, which was eventually cured after treatment. All patients obtained good cosmetic outcomes, and their quality of life improved significantly. In the 5-year follow-up study, 4 patients were alive while 2 patients died of unrelated diseases 3 years after cryotherapy. None of the 6 patients had a recurrence. These results suggested the feasibility of argon–helium cryoablation as a novel therapeutic strategy for elderly cSCC with medium- or large-sized lesions.
Case Report: Recurrence of Testicular Myofibroblastic Tumor After Surgery
Authors: Liu Jiayi , Bai Zhijie , Li Shuaiqi , Zeng Sheng , Li Chuang , Liu Qian
Published: January 2022

Inflammatory myofibroblastic tumour (IMT), also known as plasma cell granuloma (PCG) or inflammatory pseudotumour (IPT), is a distinctive, rarely metastasizing neoplasm composed of myofibroblastic and fibroblastic spindle cells accompanied by inflammatory infiltration of plasma cells, lymphocytes and/or eosinophils. IMT predominantly affects children and young adults, and the age at presentation ranges from 3 to 89 years. We present a very rare case of recurrent testicular IMT without ALK rearrangement. This case highlights the clinical characteristics and diagnostic factors associated with primary and recurrent foci of this rare tumour, along with key therapeutic approaches.
What Is Most Suitable for Children With Cystic Fibrosis—The Relationship Between Spirometry, Oscillometry, and Multiple Breath Nitrogen Washout
Authors: Postek Magdalena , Walicka-Serzysko Katarzyna , Milczewska Justyna , Sands Dorota
Published: January 2022

Introduction

In cystic fibrosis (CF), pathological lung changes begin early in life. The technological progress currently gives many diagnostic possibilities. However, pulmonary function testing in children remains problematic.

Objectives

Our study aimed to correlate the results of impulse oscillometry (IOS) with those of multiple breath nitrogen washout (MBNW) in our pediatric CF population. We also compared those parameters between the groups with and without spirometric features of obturation.

Methods

We collected 150 pulmonary function test sets, including spirometry, IOS, and MBNW in patients with CF aged 12.08 ± 3.85 years [6–18]. The study group was divided into two subgroups: IA (without obturation) and IB (with obturation). We also compared Sacin, Scond, and oscillometry parameters of 20 patients aged 14–18 years who reached the appropriate tidal volume (VT) during MBNW.

Results

Statistical analysis showed a negative correlation between lung clearance index (LCI) and spimoetric parameters. Comparison of subgroups IA (n = 102) and IB (n = 48) indicated a statistically significant difference in LCI (p < 0.001) and FEV1z-score (p < 0.001), FEV1% pred (p < 0.001), MEF25z-score (p < 0.001), MEF50 z-score (p < 0.001), MEF75 z-score (p < 0.001), R5% pred (p < 0.05), and R20% pred (p < 0.01). LCI higher than 7.91 was found in 75.33% of the study group, in subgroup IB—91.67%, and IA−67.6%.

Conclusions

LCI derived from MBNW may be a better tool than IOS for assessing pulmonary function in patients with CF, particularly those who cannot perform spirometry.
Investigating Toxin Diversity and Abundance in Snake Venom Proteomes
Authors: Tasoulis Theo , Pukala Tara L. , Isbister Geoffrey K.
Published: January 2022

Understanding snake venom proteomes is becoming increasingly important to understand snake venom biology, evolution and especially clinical effects of venoms and approaches to antivenom development. To explore the current state of snake venom proteomics and transcriptomics we investigated venom proteomic methods, associations between methodological and biological variability and the diversity and abundance of protein families. We reviewed available studies on snake venom proteomes from September 2017 to April 2021. This included 81 studies characterising venom proteomes of 79 snake species, providing data on relative toxin abundance for 70 species and toxin diversity (number of different toxins) for 37 species. Methodologies utilised in these studies were summarised and compared. Several comparative studies showed that preliminary decomplexation of crude venom by chromatography leads to increased protein identification, as does the use of transcriptomics. Combining different methodological strategies in venomic approaches appears to maximize proteome coverage. 48% of studies used the RP-HPLC →1D SDS-PAGE →in-gel trypsin digestion → ESI -LC-MS/MS pathway. Protein quantification by MS1-based spectral intensity was used twice as commonly as MS2-based spectral counting (33–15 studies). Total toxin diversity was 25–225 toxins/species, with a median of 48. The relative mean abundance of the four dominant protein families was for elapids; 3FTx–52%, PLA2–27%, SVMP–2.8%, and SVSP–0.1%, and for vipers: 3FTx–0.5%, PLA2–24%, SVMP–27%, and SVSP–12%. Viper venoms were compositionally more complex than elapid venoms in terms of number of protein families making up most of the venom, in contrast, elapid venoms were made up of fewer, but more toxin diverse, protein families. No relationship was observed between relative toxin diversity and abundance. For equivalent comparisons to be made between studies, there is a need to clarify the differences between methodological approaches and for acceptance of a standardised protein classification, nomenclature and reporting procedure. Correctly measuring and comparing toxin diversity and abundance is essential for understanding biological, clinical and evolutionary implications of snake venom composition.
MicroRNA-92a-3p Enhances Cisplatin Resistance by Regulating Krüppel-Like Factor 4-Mediated Cell Apoptosis and Epithelial-to-Mesenchymal Transition in Cervical Cancer
Authors: Yang Jing , Hai Jing , Dong Xuecai , Zhang Mengjie , Duan Shufeng
Published: January 2022

Recent studies have confirmed the existence and key roles of microRNA (miRNAs) in cancer drug resistance, including cervical cancer (CC). The present study aims to establish a novel role for miR-92a-3p and its associated gene networks in cisplatin (DDP) resistance of CC. First, the disparities in miRNA expression between CC tissues and adjacent normal tissues were screened based on GSE19611 microarray data that retrieved from Gene Expression Omnibus (GEO), and we identified several miRs that were significantly downregulated or upregulated in CC tissues including miR-92a-3p. Moreover, miR-92a-3p was significantly up-regulated in DDP-resistant cells and was the most differently expressed miRNA. Functionally, knockdown of miR-92a-3p increased the sensitivity of DDP-resistant cells to DDP via inhibiting cell proliferation, migration and invasion, and promoting apoptosis. Conversely, overexpression of miR-92a-3p significantly induced DDP resistance in CC parental cells including HeLa and SiHa cells. Moreover, Krüppel-like factor 4 (KLF4) was identified as a direct target of miR-92a-3p, and an obvious inverse correlation was observed between the expression of miR-92a-3p and KLF4 in 40 pairs of cancer tissues. Furthermore, KLF4 knockdown reversed the promoting effect of miR-92a-3p inhibition on DDP sensitivity in DDP-resistant CC cells. Besides, high expression of miR-92a-3p was associated with DDP resistance, as well as a short overall survival in clinic. Taken together, these findings provide important evidence that miR-92a-3p targets KLF4 and is significant in DDP resistance in CC, indicating that miR-92a-3p may be an attractive target to increase DDP sensitivity in clinical CC treatment.
Assessment of the Current State of Pharmacovigilance System in Pakistan Using Indicator-Based Assessment Tool
Authors: Khan Muhammad Akhtar Abbas , Hamid Saima , Ur-Rehman Tofeeq , Babar Zaheer-Ud-Din
Published: January 2022

Objectives: Pakistan felt the need for an effective and robust pharmacovigilance (PV) system after one of the deadliest drug-related tragedies causing more than 300 deaths in 2012. The country set up its national PV center in 2015 and joined WHO’s Program for International Drug Monitoring (PIDM) in 2018 as a full member. The current study was aimed to evaluate the PV system’s functionality, identify the gaps, areas of improvement, and a strategy to lead a functional PV system in Pakistan.

Methods: The descriptive cross-sectional study was conducted by providing an interviewer-administered questionnaire of the PV system across Pakistan by utilizing the Indicator based Pharmacovigilance assessment tool (IPAT). By a convenience sampling method 36 study participants were selected from the Drug Regulatory Authority of Pakistan (DRAP), drug administration of provincial health departments of 4 provinces and federally affiliated areas, 5 national public health programs, and 23 public and private hospitals. The assessment includes document review, interviews of the key informants by structured open-ended questions, and a review of websites of relevant organizations.

Results: Drug Regulatory Authority of Pakistan (DRAP) with a national PV center received a 75% overall performance score on IPAT. To be regarded as “minimally functioning,” a country’s PV and drug safety system must meet all core indicators. DRAP scored 80.76% on the core indicators so cannot be deemed functional at this time. The only province with a regional PV center, Punjab, had scored 72.13% on relevant parameters. Despite receiving funding from the Global Fund, none of the National Public Health Programs (PHPs) have PV centers or associated activities. All hospitals except two private hospitals could not qualify the minimum requirements for functional PV. The absence of a legal framework for mandatory ADR reporting, lack of drug information center, budgetary constraints, no active surveillance activities, the nonexistence of pharmacovigilance risk assessment expert committee, and insufficient coordination among stakeholders were identified as major gaps.

Conclusion: The results of the study reveal that Pakistan’s PV system is not fully functional at all levels. A two-phased strategy encompassing the non-financial and financial interventions is proposed to improve the PV systems at the national, provincial, PHPs, and hospitals levels.
Enhancing Choices Regarding the Administration of Insulin Among Patients With Diabetes Requiring Insulin Across Countries and Implications for Future Care
Authors: Mardare Ileana , Campbell Stephen M. , Meyer Johanna C. , Sefah Israel Abebrese , Massele Amos , Godman Brian
Published: January 2022

There are a number of ongoing developments to improve the care of patients with diabetes across countries given its growing burden. Recent developments include new oral medicines to reduce cardiovascular events and death. They also include new modes to improve insulin administration to enhance adherence and subsequent patient management thereby reducing hypoglycaemia and improving long-term outcomes. In the case of insulins, this includes long-acting insulin analogues as well as continuous glucose monitoring (CGM) systems and continuous subcutaneous insulin infusion systems, combined with sensor-augmented pump therapy and potentially hybrid closed-loops. The benefits of such systems have been endorsed by endocrine societies and governments in patients with Type 1 diabetes whose HbA1c levels are not currently being optimised. However, there are concerns with the low use of such systems across higher-income countries, exacerbated by their higher costs, despite studies suggesting their cost-effectiveness ratios are within accepted limits. This is inconsistent in higher-income countries when compared with reimbursement and funding decisions for new high-priced medicines for cancer and orphan diseases, with often limited benefits, given the burden of multiple daily insulin injections coupled with the need for constant monitoring. This situation is different among patients and governments in low- and low-middle income countries struggling to fund standard insulins and the routine monitoring of HbA1c levels. The first priority in these countries is to address these priority issues before funding more expensive forms of insulin and associated devices. Greater patient involvement in treatment decisions, transparency in decision making, and evidence-based investment decisions should help to address such concerns in the future.
Gypenosides Attenuate Pulmonary Fibrosis by Inhibiting the AKT/mTOR/c-Myc Pathway
Authors: Liu Suqing , Yang Qingqing , Dong Binbin , Qi Chunhui , Yang Tao , Li Ming , He Shan , Liu Baojun , Wu Jinfeng
Published: January 2022

Gypenosides (Gyps), the major active constituents isolated from Gynostemma pentaphyllum, possess anti-inflammatory and antioxidant activities. Previous studies have demonstrated that Gyps displayed potent ameliorative effects on liver fibrosis and renal fibrosis. In this study, we found that Gyps significantly reduced the mortality of bleomycin-induced pulmonary fibrosis mice (40% mortality rate of mice in the model group versus 0% in the treatment group). Masson staining showed that Gyps could reduce the content of collagen in the lung tissue of pulmonary fibrosis mice Masson staining and immunohistochemistry demonstrated that the expression of the collagen gene α-SMA and fibrosis gene Col1 markedly decreased after Gyps treatment. The active mitosis of fibroblasts is one of the key processes in the pathogenesis of fibrotic diseases. RNA-seq showed that Gyps significantly inhibited mitosis and induced the G2/M phase cell cycle arrest. The mTOR/c-Myc axis plays an important role in the pathological process of pulmonary fibrosis. RNA-seq also demonstrated that Gyps inhibited the mTOR and c-Myc signaling in pulmonary fibrosis mice, which was further validated by Western blot and immunohistochemistry. AKT functions as an upstream molecule that regulates mTOR. Our western blot data showed that Gyps could suppress the activation of AKT. In conclusion, Gyps exerted anti-pulmonary fibrosis activity by inhibiting the AKT/mTOR/c-Myc pathway.
The Arsenal of Bioactive Molecules in the Skin Secretion of Urodele Amphibians
Authors: Barros Ana L. A. N. , Hamed Abdelaaty , Marani Mariela , Moreira Daniel C. , Eaton Peter , Plácido Alexandra , Kato Massuo J. , Leite José Roberto S. A.
Published: January 2022

Urodele amphibians (∼768 spp.), salamanders and newts, are a rich source of molecules with bioactive properties, especially those isolated from their skin secretions. These include pharmacological attributes, such as antimicrobial, antioxidant, vasoactive, immune system modulation, and dermal wound healing activities. Considering the high demand for new compounds to guide the discovery of new drugs to treat conventional and novel diseases, this review summarizes the characteristics of molecules identified in the skin of urodele amphibians. We describe urodele-derived peptides and alkaloids, with emphasis on their biological activities, which can be considered new scaffolds for the pharmaceutical industry. Although much more attention has been given to anurans, bioactive molecules produced by urodeles have the potential to be used for biotechnological purposes and stand as viable alternatives for the development of therapeutic agents.
Comparative Effectiveness and Safety of Low-Dose Oral Anticoagulants in Patients With Atrial Fibrillation
Authors: Perreault Sylvie , Dragomir Alice , Côté Robert , Lenglet Aurélie , de Denus Simon , Dorais Marc , White-Guay Brian , Brophy James , Schnitzer Mireille E. , Dubé Marie-Pierre , Tardif Jean-Claude
Published: January 2022

Aims: Observational studies of various dose levels of direct oral anticoagulants (DOACs) for patients with atrial fibrillation (AF) found that a high proportion of patients received a dose lower than the target dose tested in randomized controlled trials. There is a need to compare low-dose DOACs with warfarin or other DOACs on effectiveness and safety.

Methods: Using administrative data from Quebec province, Canada, we built a cohort of new warfarin or DOAC users discharged from hospital between 2011 and 2017. We determined CHA2DS2-VASc and HAS-BLED scores, and comorbidities for 3-year prior cohort entry. The primary effectiveness endpoint was a composite of ischemic stroke/systemic embolism (SE), and secondary outcomes included a safety composite of major bleeding (MB) events and effectiveness composite (stroke/SE, death) at 1-year follow-up. We contrasted each low-dose DOAC with warfarin or other DOACs as references using inverse probability of treatment weighting to estimate marginal Cox hazard ratios (HRs).

Results: The cohort comprised 22,969 patients (mean age: 80–86). We did not find a significant risk reduction for the stroke/SE primary effectiveness endpoint for DOACs vs. warfarin; however, we observed a significantly lower risk for low-dose dabigatran vs. warfarin (HR [95%CI]: 0.59 [0.42–0.81]) for effectiveness composite, mainly due to a lower death rate. The differences in effectiveness and safety composites between low-dose rivaroxaban vs. warfarin were not significant. However, low-dose apixaban had a better safety composite (HR: 0.68 [0.53–0.88]) vs. warfarin. Comparisons of dabigatran vs. apixaban showed a lower risk of stroke/SE (HR: 0.53 [0.30–0.93]) and a 2-fold higher risk of MB. The MB risk was higher for rivaroxaban than for apixaban (HR: 1.58 [1.09–2.29]).

Conclusions: The results of this population-based study suggest that low-dose dabigatran has a better effective composite than warfarin. Compared with apixaban, low-dose dabigatran had a better effectiveness composite but a worse safety profile. Low-dose apixaban had a better safety composite than warfarin and other low-dose DOACs. Given that the comparative effectiveness and safety seem to vary from one DOAC to another, pharmacokinetic data for specific populations are now warranted.
Development of IKATP Ion Channel Blockers Targeting Sulfonylurea Resistant Mutant KIR6.2 Based Channels for Treating DEND Syndrome
Authors: Houtman Marien J. C. , Friesacher Theres , Chen Xingyu , Zangerl-Plessl Eva-Maria , Heyden Marcel A. G. van der , Stary-Weinzinger Anna
Published: January 2022

Introduction: DEND syndrome is a rare channelopathy characterized by a combination of developmental delay, epilepsy and severe neonatal diabetes. Gain of function mutations in the KCNJ11 gene, encoding the KIR6.2 subunit of the IKATP potassium channel, stand at the basis of most forms of DEND syndrome. In a previous search for existing drugs with the potential of targeting Cantú Syndrome, also resulting from increased IKATP, we found a set of candidate drugs that may also possess the potential to target DEND syndrome. In the current work, we combined Molecular Modelling including Molecular Dynamics simulations, with single cell patch clamp electrophysiology, in order to test the effect of selected drug candidates on the KIR6.2 WT and DEND mutant channels.

Methods: Molecular dynamics simulations were performed to investigate potential drug binding sites. To conduct in vitro studies, KIR6.2 Q52R and L164P mutants were constructed. Inside/out patch clamp electrophysiology on transiently transfected HEK293T cells was performed for establishing drug-channel inhibition relationships.

Results: Molecular Dynamics simulations provided insight in potential channel interaction and shed light on possible mechanisms of action of the tested drug candidates. Effective IKIR6.2/SUR2a inhibition was obtained with the pore-blocker betaxolol (IC50 values 27–37 μM). Levobetaxolol effectively inhibited WT and L164P (IC50 values 22 μM) and Q52R (IC50 55 μM) channels. Of the SUR binding prostaglandin series, travoprost was found to be the best blocker of WT and L164P channels (IC50 2–3 μM), while Q52R inhibition was 15–20% at 10 μM.

Conclusion: Our combination of MD and inside-out electrophysiology provides the rationale for drug mediated IKATP inhibition, and will be the basis for 1) screening of additional existing drugs for repurposing to address DEND syndrome, and 2) rationalized medicinal chemistry to improve IKATP inhibitor efficacy and specificity.
Large Time Behavior on the Linear Self-Interacting Diffusion Driven by Sub-Fractional Brownian Motion With Hurst Index Large Than 0.5 I: Self-Repelling Case
Authors: Gao Han , Guo Rui , Jin Yang , Yan Litan
Published: January 2022

Let SH be a sub-fractional Brownian motion with index 12<H<1. In this paper, we consider the linear self-interacting diffusion driven by SH, which is the solution to the equation

dXtH=dStH−θ(∫0tXtH−XsHds)dt+νdt,X0H=0,

where θ < 0 and ν∈R are two parameters. Such process XH is called self-repelling and it is an analogue of the linear self-attracting diffusion [Cranston and Le Jan, Math. Ann. 303 (1995), 87–93]. Our main aim is to study the large time behaviors. We show the solution XH diverges to infinity, as t tends to infinity, and obtain the speed at which the process XH diverges to infinity as t tends to infinity.
Compaction Density Evaluation Model of Sand-Gravel Dam Based on Elman Neural Network With Modified Particle Swarm Optimization
Authors: Liu Biao , Zhao Yufei , Wang Wenbo , Liu Biwang
Published: January 2022

The compaction density of sand-gravel materials has a strong gradation correlation, mainly affected by some material source parameters such as P5 content (material proportion with particle size greater than 5 mm), maximum particle size and curvature coefficient. When evaluating the compaction density of sand-gravel materials, the existing compaction density evaluation models have poor robustness and adaptability because they do not take into full consideration the impact of material source parameters. To overcome the shortcomings of existing compaction density models, this study comprehensively considers the impact of material source parameters and compaction parameters on compaction density. Firstly, asymmetric data were fused and a multi-source heterogeneous dataset was established for compaction density analysis. Then, the Elman neural network optimized by the adaptive simulated annealing particle swarm optimization algorithm was proposed to establish the compaction density evaluation model. Finally, a case study of the Dashimen water conservancy project in China is employed to demonstrate the effectiveness and feasibility of the proposed method. The results show that this model performs high-precision evaluation of the compaction density at any position of the entire working area which can timely correct the weak area of compaction density on the spot, and reduce the number of test pit tests.
Fatty Acid Metabolism and Idiopathic Pulmonary Fibrosis
Authors: Geng Jing , Liu Yuan , Dai Huaping , Wang Chen
Published: January 2022

Fatty acid metabolism, including the de novo synthesis, uptake, oxidation, and derivation of fatty acids, plays several important roles at cellular and organ levels. Recent studies have identified characteristic changes in fatty acid metabolism in idiopathic pulmonary fibrosis (IPF) lungs, which implicates its dysregulation in the pathogenesis of this disorder. Here, we review the evidence for how fatty acid metabolism contributes to the development of pulmonary fibrosis, focusing on the profibrotic processes associated with specific types of lung cells, including epithelial cells, macrophages, and fibroblasts. We also summarize the potential therapeutics that target this metabolic pathway in treating IPF.
Structural and Functional Coupling of Calcium-Activated BK Channels and Calcium-Permeable Channels Within Nanodomain Signaling Complexes
Authors: Shah Kunal R. , Guan Xin , Yan Jiusheng
Published: January 2022

Biochemical and functional studies of ion channels have shown that many of these integral membrane proteins form macromolecular signaling complexes by physically associating with many other proteins. These macromolecular signaling complexes ensure specificity and proper rates of signal transduction. The large-conductance, Ca2+-activated K+ (BK) channel is dually activated by membrane depolarization and increases in intracellular free Ca2+ ([Ca2+]i). The activation of BK channels results in a large K+ efflux and, consequently, rapid membrane repolarization and closing of the voltage-dependent Ca2+-permeable channels to limit further increases in [Ca2+]i. Therefore, BK channel-mediated K+ signaling is a negative feedback regulator of both membrane potential and [Ca2+]i and plays important roles in many physiological processes and diseases. However, the BK channel formed by the pore-forming and voltage- and Ca2+-sensing α subunit alone requires high [Ca2+]i levels for channel activation under physiological voltage conditions. Thus, most native BK channels are believed to co-localize with Ca2+-permeable channels within nanodomains (a few tens of nanometers in distance) to detect high levels of [Ca2+]i around the open pores of Ca2+-permeable channels. Over the last two decades, advancement in research on the BK channel’s coupling with Ca2+-permeable channels including recent reports involving NMDA receptors demonstrate exemplary models of nanodomain structural and functional coupling among ion channels for efficient signal transduction and negative feedback regulation. We hereby review our current understanding regarding the structural and functional coupling of BK channels with different Ca2+-permeable channels.
Practical Lessons on 12-Lead ECG Classification: Meta-Analysis of Methods From PhysioNet/Computing in Cardiology Challenge 2020
Authors: Hong Shenda , Zhang Wenrui , Sun Chenxi , Zhou Yuxi , Li Hongyan
Published: January 2022

Cardiovascular diseases (CVDs) are one of the most fatal disease groups worldwide. Electrocardiogram (ECG) is a widely used tool for automatically detecting cardiac abnormalities, thereby helping to control and manage CVDs. To encourage more multidisciplinary researches, PhysioNet/Computing in Cardiology Challenge 2020 (Challenge 2020) provided a public platform involving multi-center databases and automatic evaluations for ECG classification tasks. As a result, 41 teams successfully submitted their solutions and were qualified for rankings. Although Challenge 2020 was a success, there has been no in-depth methodological meta-analysis of these solutions, making it difficult for researchers to benefit from the solutions and results. In this study, we aim to systematically review the 41 solutions in terms of data processing, feature engineering, model architecture, and training strategy. For each perspective, we visualize and statistically analyze the effectiveness of the common techniques, and discuss the methodological advantages and disadvantages. Finally, we summarize five practical lessons based on the aforementioned analysis: (1) Data augmentation should be employed and adapted to specific scenarios; (2) Combining different features can improve performance; (3) A hybrid design of different types of deep neural networks (DNNs) is better than using a single type; (4) The use of end-to-end architectures should depend on the task being solved; (5) Multiple models are better than one. We expect that our meta-analysis will help accelerate the research related to ECG classification based on machine-learning models.
Genome-Wide Identification of JRL Genes in Moso Bamboo and Their Expression Profiles in Response to Multiple Hormones and Abiotic Stresses
Authors: Zhang Zhijun , Huang Bin , Chen Jialu , Jiao Yang , Guo Hui , Liu Shenkui , Ramakrishnan Muthusamy , Qi Guoning
Published: January 2022

Jacalin-related lectins (JRLs) are a new subfamily of plant lectins that has recently been recognized and plays an important role in plant growth, development, and abiotic stress response. Although moso bamboo (Phyllostachys edulis) is an economically and industrially important bamboo worldwide, there has been no systematic identification of JRLs in this species. Here, we identified 25 JRL genes in moso bamboo, and these genes are unequally distributed among 10 genome scaffolds. Phylogenetic analysis showed that the moso bamboo JRLs were clustered into four JRL subgroups: I, II, V, and VII. Numerous stress-responsive and hormone-regulated cis-elements were detected in the upstream promoter regions of the JRLs. Genome collinearity analyses showed that the JRL genes of moso bamboo are more closely related to those of Brachypodium distachyon than to those of Oryza sativa and Zea mays. Sixty-four percent of the PeJRL genes are present as segmental and tandem duplicates. qRT-PCR expression analysis showed that JRL genes in the same subgroup were significantly downregulated in response to salicylic acid (SA), abscisic acid (ABA), and methyl jasmonate (MeJA) treatments and significantly upregulated under low temperature, drought, and salt stress; they also exhibited tissue-specific expression patterns. Subcellular localization experiments revealed that PeJRL04 and PeJRL13 were localized to the cell membrane, nucleus, and cytoplasm. Three dimensional structure prediction and yeast two-hybrid assays were used to verify that PeJRL13 exists as a self-interacting homodimer in vivo. These findings provide an important reference for understanding the functions of specific moso bamboo JRL genes and for the effective selection of stress-related genes.