bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genetic Variants of Glycogen Metabolism Genes Were Associated With Liver PDFF Without Increasing NAFLD Risk
Authors: Yang Liu , Sun Zewen , Li Jiuling , Pan Xingchen , Wen Jianping , Yang Jianli , Wang Qing , Chen Peng 
Published: April 2022

Background/Aims: The storage amount of liver glycogen could affect the liver fibrosis assessment made by MRI-based methods. However, it remained unclear whether glycogen amount could bias the estimation of liver fat content by proton density fat fraction. In this study, we aimed to investigate whether glycogen metabolism gene variants could contribute to the bias of PDFF by genetic association.Methods: We conducted an association study of the glycogen metabolism genes based on the PDFF data of 11,129 participants in the UK Biobank. The effect of the SNPs in these genes on non-alcoholic fatty liver disease was estimated by a meta-analysis of the available NAFLD case-control studies.Results: We identified significant associations of the SNPs near the genes encoding glycogen phosphorylase (PYGM and PYGL) and synthase (GYS2) with PDFF (FDR-corrected p value &lt; 0.05). The genes encoding the regulatory proteins of glycogenolysis (PHKB, CALM2/3), glucose transporter (SLC2A1), and glucose kinase (GCK) were also associated with PDFF. The SNP rs5402 of SLC2A2 and rs547066 of PYGM were associated with NAFLD (p &lt; 0.05) with others being insignificant. Except for the PYGM gene, the PDFF-associated SNPs showed no associations with NAFLD. In addition, the burden tests of rare variants in these genes were not significant after FDR correction.Conclusion: Liver glycogen metabolism genes associated with PDFF were not associated with NAFLD, which implicated a potential bias effect of glycogen storage on the quantification of liver fat content by PDFF.
Identification and Validation of Chromobox Family Members as Potential Prognostic Biomarkers and Therapeutic Targets for Human Esophageal Cancer
Authors: Fang Xuefen , Wang Junjun , Chen Jiabing , Zhuang Mingkai , Huang Tingxuan , Chen Zhixin , Huang Yuehong , Zheng Biyun , Wang Xiaozhong 
Published: April 2022

Background: Chromobox family proteins (CBXs) are vital components of epigenetic regulation complexes and transcriptionally inhibit target genes by modifying the chromatin. Accumulating evidence indicates that CBXs are involved in the initiation and progression of multiple malignancies. However, the expression, function, and clinical relevance such as the prognostic and diagnostic values of different CBXs in esophageal carcinoma (ESCA) are still unclear.Methods: We applied Oncomine, TCGA, GEO, GEPIA, UALCAN, Kaplan–Meier plotter, cBioPortal, Metascape, and TIMER to investigate the roles of CBX family members in ESCA. Additionally, quantitative real-time PCR (RT-PCR), western blot, and immunofluorescence were used to verify the expression of CBX family members in ESCA clinical samples.Results: Compared with normal tissues, the mRNA expression levels of CBX1/3/8 were significantly increased in ESCA, whereas CBX7 mRNA expression was reduced in both the TCGA cohort and GEO cohort. In the TCGA cohort, ROC curves suggested that CBX1/2/3/4/8 had great diagnostic value in ESCA, and the AUCs were above 0.9. Furthermore, upregulation of CBX1/3/8 and downregulation of CBX7 were closely related to the clinicopathological parameters in ESCA patients, such as tumor grades, tumor nodal metastasis status, and TP53 mutation status. The survival analysis indicated that higher CBX1/3/8 mRNA expressions and lower CBX7 expression suggested an unfavorable prognosis in ESCA. High genetic change rate (52%) of CBXs was found in ESCA patients. Functions and pathways of mutations in CBXs and their 50 frequently altered neighbor genes in ESCA patients were investigated; the results showed that DNA repair and DNA replication were correlated to CBX alterations. Moreover, we found a significant correlation between the expression level of CBX family members and the infiltration of immune cells in ESCA. Finally, we verified the expression of CBX family members in clinical samples and found the results were consistent with the databases.Conclusion: Our study implied that CBX1/3/7/8 are potential targets of precision therapy for ESCA patients and new biomarkers for the prognosis.
Multi-Omics Integration Reveals Only Minor Long-Term Molecular and Functional Sequelae in Immune Cells of Individuals Recovered From COVID-19
Authors: Liu Zhaoli , Kilic Gizem , Li Wenchao , Bulut Ozlem , Gupta Manoj Kumar , Zhang Bowen , Qi Cancan , Peng He , Tsay Hsin-Chieh , Soon Chai Fen , Mekonnen Yonatan Ayalew , Ferreira Anaísa Valido , van der Made Caspar I. , van Cranenbroek Bram , Koenen Hans J. P. M. , Simonetti Elles , Diavatopoulos Dimitri , de Jonge Marien I. , Müller Lisa , Schaal Heiner , Ostermann Philipp N. , Cornberg Markus , Eiz-Vesper Britta , van de Veerdonk Frank , van Crevel Reinout , Joosten Leo A. B. , Domínguez-Andrés Jorge , Xu Cheng-Jian , Netea Mihai G. , Li Yang 
Published: April 2022

The majority of COVID-19 patients experience mild to moderate disease course and recover within a few weeks. An increasing number of studies characterized the long-term changes in the specific anti-SARS-CoV-2 immune responses, but how COVID-19 shapes the innate and heterologous adaptive immune system after recovery is less well known. To comprehensively investigate the post-SARS-CoV-2 infection sequelae on the immune system, we performed a multi-omics study by integrating single-cell RNA-sequencing, single-cell ATAC-sequencing, genome-wide DNA methylation profiling, and functional validation experiments in 14 convalescent COVID-19 and 15 healthy individuals. We showed that immune responses generally recover without major sequelae after COVID-19. However, subtle differences persist at the transcriptomic level in monocytes, with downregulation of the interferon pathway, while DNA methylation also displays minor changes in convalescent COVID-19 individuals. However, these differences did not affect the cytokine production capacity of PBMCs upon different bacterial, viral, and fungal stimuli, although baseline release of IL-1Ra and IFN-γ was higher in convalescent individuals. In conclusion, we propose that despite minor differences in epigenetic and transcriptional programs, the immune system of convalescent COVID-19 patients largely recovers to the homeostatic level of healthy individuals.
Immune Dysregulation in Monogenic Inborn Errors of Immunity in Oman: Over A Decade of Experience From a Single Tertiary Center
Authors: Al Farsi Tariq , Ahmed Khwater , Alshekaili Jalila , Al Kindi Mahmood , Cook Matthew , Al-Hosni Aliya , Ansari Zainab , Nasr Iman , Al Sukaiti Nashat 
Published: April 2022

BackgroundInborn errors of immunity (IEIs) are being recognized as an important cause of morbidity and mortality in communities with a high frequency of consanguinity, such as Oman, and thus recessively inherited conditions. Various monogenic causes of IEI have been recently discovered; however, the disease phenotype may be variable and does not always include infection at presentation, leading to a delay in diagnosis and a poor outcome. It is now well recognized that immune dysregulation manifestations are observed in a significant proportion of patients with IEI and occasionally precede infection.MethodsHere, we retrospectively report the epidemiological, clinical, immunological, and molecular findings and outcomes from 239 patients with IEI who were diagnosed and managed at the Royal Hospital, Oman, from January 2010 to October 2021.ResultsThe estimated annual cumulative mean incidence of IEI was 25.5 per 100,000 Omani live births with a total prevalence of 15.5 per 100,000 Omani population. Both the high incidence and prevalence are attributed to the high rate of consanguinity (78.2%). Defects affecting cellular and humoral immunity including severe combined immunodeficiency (SCID), combined immunodeficiency (CID), and CID with syndromic features were the predominant defects in IEI (36%). Immune dysregulation was a prominent manifestation and occurred in approximately a third of all patients with IEI (32%), with a mean age of onset of 81 months and a mean diagnostic delay of 50.8 months. The largest percentage of patients who showed such clinical signs were in the category of diseases of immune dysregulation (41%), followed by predominantly antibody deficiency (18%). The overall mortality rate in our cohort was 25.1%, with higher death rates seen in CID including SCID and diseases of immune dysregulation.ConclusionImmune dysregulation is a frequent manifestation of Omani patients with IEI. Early detection through raising awareness of signs of IEI including those of immune dysregulation and implementation of newborn screening programs will result in early intervention and improved overall outcome.
Posterior Reversible Encephalopathy Syndrome in Guillain-Barré Syndrome: Just a Problem of Immunoglobulins? Controversy From Two Atypical Case Reports
Authors: Belgrado Enrico , Del Negro Ilaria , Bagatto Daniele , Lorenzut Simone , Merlino Giovanni , Gigli Gian L. , Valente Mariarosaria 
Published: April 2022

BackgroundPosterior reversible encephalopathy syndrome (PRES), reversible cerebral vasoconstriction syndrome (RCVS), or the coexistence of these two entities shares similar risk factors and clinical features. For these conditions, a common origin has been supposed. Even if the majority of patients show a favorable course and a good prognosis, a small percentage of cases develop neurological complications. Up to date, only about 30 cases of PRES associated with Guillain-Barré syndrome (GBS) have been reported in the literature.CasesHere, we present two cases of a particularly aggressive PRES/RCVS overlap syndrome, associated with acute motor axonal neuropathy (AMAN) and acute inflammatory demyelinating polyneuropathy (AIDP) variants of GBS, respectively, presenting with similar initial clinical aspects and developing both an atypical and unfavorable outcome. On MRI examination, the first patient showed typical aspects of PRES, while, in the second case, radiological features were atypical and characterized by diffusion restriction on the apparent diffusion coefficient (ADC) map. The first patient demonstrated rapid worsening of clinical conditions until death; the second one manifested and maintained neurological deficits with a permanent disability.ConclusionsWe suggest that PRES may conceal RCVS aspects, especially in most severe cases or when associated with a dysimmune syndrome in which autoimmune system and endothelial dysfunction probably play a prominent role in the pathogenesis. Although the role of IVIg treatment in the pathogenesis of PRES has been proposed, we suggest that GBS itself should be considered an independent risk factor in developing PRES.
Abnormal Vacuole Membrane Protein-1 Expression in Parkinson’s Disease Patients
Authors: Al-Nusaif Murad , Cheng Cheng , Li Tianbai , Jia Congcong , Wang Panpan , Li Song , Le Weidong 
Published: April 2022

BackgroundParkinson’s disease (PD) is pathologically characterized by progressive dopaminergic (DAergic) neuron loss in the substantia nigra pars compacta (SNpc) and accumulation of intracytoplasmic α-synuclein-containing Lewy bodies. Autophagy has been identified as a critical component in the development and progression of PD. Several autophagy genes have been identified as being altered in PD. One of those genes, vacuole membrane protein-1 (VMP1), an autophagy protein localized in the endoplasmic reticulum (ER) in DAergic neurons, has been shown to cause motor disorder, severe loss of DAergic neurons, and autophagy flux disturbance in the VMP1 knockout mouse model.ObjectiveTo evaluate for the first time the alteration on the expression of the VMP1 gene and its clinical correlations in peripheral blood mononuclear cells (PBMCs) of a relatively large sample of PD patients.MethodsWe assessed the VMP1 mRNA levels in PD patients (n = 229) and healthy controls (HC) (n = 209) using real-time quantitative PCR (RT-qPCR), and the VMP1 protein levels in PD patients (n = 27) and HC (n = 27) using Western blot (WB). Then, we analyzed the VMP1 expression levels and clinical features of PD patients.ResultsOur findings revealed that VMP1 levels in the PD group were significantly lower than in the HC group (RT-qPCR p &lt; 0.01 and WB p &lt; 0.001). The VMP1 expression was significantly lower as the disease progressed, which could be ameliorated by administering DAergic receptor agonists. Moreover, receiver operating characteristic (ROC) curve analysis showed that VMP1 mRNA and protein level area under the curves (AUCs) were 64.5%, p &lt; 0.01, and 83.4%, p &lt; 0.01, respectively.ConclusionThis case-control study demonstrates that peripheral VMP1 level altered in PD patients and may serve as a potential endogenous diagnostic marker of PD.
Inflammation Affects Liver Function and the Metabolism of Voriconazole to Voriconazole-N-Oxide in Adult and Elderly Patients
Authors: Liang Zaiming , Yu Mingjie , Liu Zhirui , Liu Fang , Jia Changsheng , Xiong Lirong , Dai Qing , Qin Shiwei , Cheng Lin , Sun Fengjun 
Published: April 2022

Background: The inner association of inflammation with voriconazole (VCZ) metabolism has not been fully investigated. We intend to investigate the effects of inflammation on liver function, VCZ trough concentration (C0), C0/dose ratio and the ratio of VCZ to VCZ-N-oxide concentration (C0/CN) in adult and elderly patients.Methods: A single-center retrospective study was conducted among patients who were treated in our hospital between January 2018 and December 2021. For each eligible patient, demographic details, medical history, laboratory parameters, procalcitonin (PCT), C reactive protein (CRP), and interleukin-6 (IL-6) were collected from the medical chart. VCZ CN, TNF-α, IL-1β, IL-8, and IL-10 concentrations were detected in blood samples.Results: A total of 356 patients were included in our study, with 195 patients in the adult cohort (&lt;60 years) and 161 patients in the elderly cohort (≥60 years). In adult patients, CRP and IL-8 levels showed moderate association with VCZ C0/CN ratio (CRP: r = 0.512, p &lt; 0.001; IL-8: r = 0.476, p = 0.002). IL-6 level shallowly associated with VCZ C0/CN ratio both in adult and elderly patients (r = 0.355, p = 0.003; r = 0.386, p = 0.001). A significantly higher VCZ C0, C0/dose ratio and C0/CN ratio was observed in adult patients with severe inflammation compared with patients with moderate inflammation and no to mild inflammation, as reflected by PCT levels (p &lt; 0.05). However, there was no significant difference observed among different inflammation degrees in elderly patients. Lower albumin (AL) and higher total bilirubin (TBIL) were observed along with the degree of inflammation in both adult and elderly patients, as reflected by CRP and PCT levels (p &lt; 0.05).Conclusion: Inflammation may affect the metabolism of VCZ to VCZ-N-oxide both in adult and elderly patients, and decreased plasma AL levels and increased TBIL levels under inflammatory conditions may also alter VCZ metabolism.
The Actions of Centrally Administered Nesfatin-1 on Emesis, Feeding, and Locomotor Activity in Suncus murinus (House Musk Shrew)
Authors: Lu Zengbing , Cui Dexuan , Liu Julia Yuen Hang , Jiang Bin , Ngan Man Piu , Sakata Ichiro , Takemi Shota , Sakai Takafumi , Lin Ge , Chan Sze Wa , Rudd John A. 
Published: April 2022

Nesfatin-1 is an anorectic peptide expressed in both peripheral tissues and brain areas involved in the regulation of feeding, emotion and emesis. The aim of the present study is to characterize the distribution of NUCB2/nesfatin-1 in Suncus murinus and to investigate the actions of nesfatin-1 to affect gastrointestinal contractility, emesis, food and water intake, and locomotor activity. The deduced amino acid sequence of S. murinus nesfatin-1 using in silico cloning showed high homology with humans and rodents. NUCB2 mRNA was detected throughout the entire brain and in the gastrointestinal tract, including the stomach and gut. Western blot analysis and immunohistochemistry confirmed the expression of nesfatin-1 protein in these regions. The NUCB2 mRNA levels in the hypothalamus, hippocampus and brainstem were significantly decreased, whereas that in the striatum were increased after 24 h starvation compared to ad libitum-fed animals (p &lt; 0.05). In in vitro studies, nesfatin-1 (0.3–1,000 pM) failed to contract or relax the isolated gastric antrum and intestinal segments. In conscious, freely moving animals, intracerebroventricular administration of nesfatin-1 (1–50 pmol) induced emesis (p &lt; 0.05) and suppressed 6-h cumulative food intake (p &lt; 0.05), without affecting the latency to feeding. Nesfatin-1 (25 pmol, i.c.v.) decreased 24-h cumulative food and water intake by 28.3 and 35.4%, respectively (p &lt; 0.01). No significant differences in locomotor activity were observed. In conclusion, NUCB2/nesfatin-1 might be a potent regulator of feeding and emesis in S. murinus. Further studies are required to elucidate the mechanism of actions of this peptide as a mediator linking the brainstem NUCB2/nesfatin-1 to forebrain system.
60-GHz Double-Layer Transmitarray Antenna Using Complementary Structure
Authors: An Wenxing , Zhang Xiaochi , Luo Yu , Wang Jian , Xiong Lin 
Published: April 2022

Abstract—A novel double-layer transmitarray element is presented at 60 GHz with linearly- and circularly-polarized characteristics. A planar frequency-selective structure using the complementary design is adopted to augment the element performance for millimeter-wave applications. By integrating two different types of structure, i.e. cross and slot type, the compensation phase range is extended effectively with a satisfactory transmission magnitude. A transmitarray prototype is fabricated and tested to verify this double-layer complementary design. The measured gain at 60.5 GHz is 33.1 dBi with an aperture efficiency of 42.15%. Low side-lobe and cross-polarization levels are obtained. The proposed double-layer complementary design can reduce the structure complexity effectively and offer a high aperture efficiency at a low cost, which can be a potential candidate for the millimeter-wave transmitarray.
Left Ventricle Biomechanics of Low-Flow, Low-Gradient Aortic Stenosis: A Patient-Specific Computational Model
Authors: Wisneski Andrew D. , Wang Yunjie , Cutugno Salvatore , Pasta Salvatore , Stroh Ashley , Yao Jiang , Nguyen Tom C. , Mahadevan Vaikom S. , Guccione Julius M. 
Published: April 2022

This study aimed to create an imaging-derived patient-specific computational model of low-flow, low-gradient (LFLG) aortic stenosis (AS) to obtain biomechanics data about the left ventricle. LFLG AS is now a commonly recognized sub-type of aortic stenosis. There remains much controversy over its management, and investigation into ventricular biomechanics may elucidate pathophysiology and better identify patients for valve replacement. ECG-gated cardiac computed tomography images from a patient with LFLG AS were obtained to provide patient-specific geometry for the computational model. Surfaces of the left atrium, left ventricle (LV), and outflow track were segmented. A previously validated multi-scale, multi-physics computational human heart model was adapted to the patient-specific geometry, yielding a model consisting of 91,000 solid elements. This model was coupled to a virtual circulatory system and calibrated to clinically measured parameters from echocardiography and cardiac catheterization data. The simulation replicated key physiologic parameters within 10% of their clinically measured values. Global LV systolic myocardial stress was 7.1 ± 1.8 kPa. Mean stress of the basal, middle, and apical segments were 7.7 ± 1.8 kPa, 9.1 ± 3.8 kPa, and 6.4 ± 0.4 kPa, respectively. This is the first patient-specific computational model of LFLG AS based on clinical imaging. Low myocardial stress correlated with low ejection fraction and eccentric LV remodeling. Further studies are needed to understand how alterations in LV biomechanics correlates with clinical outcomes of AS.
Metabolic Flexibility and Mechanical Efficiency in Women Over-60
Authors: Blasco-Lafarga Cristina , Monferrer-Marín Jordi , Roldán Ainoa , Monteagudo Pablo , Chulvi-Medrano Ivan 
Published: April 2022

Purpose: Aging deteriorates metabolic flexibility (MF). Moreover, recent studies show that glycolysis is barely increased despite impoverished lipid metabolism, in addition to increased relevance of muscle power in older adults. This study aims to analyze MF, i.e., fat and carbohydrates oxidation rates (FATox and CHOox), and the point of maximal fat oxidation (MFO), in a group of active women over-60. It also aims to delve into the role of power production and mechanical efficiency regarding MF. This will help to decipher their metabolic behavior in response to increasing intensity.Methods: Twenty-nine women (66.13 ± 5.62 years) performed a submaximal graded cycling test, increasing 10 W each 3-min15-s, from 30 W to the second ventilatory threshold (VT2). Muscle power was adjusted with a Saris-H3 roller, together with a continuous gas analysis by indirect calorimetry (Cosmed K4b2). Pre and post-test blood lactate (BLa) samples were included. Frayn’s equations, MFO and CHOoxpeak (mg/min/kg FFM) were considered for MF analysis (accounting for average VO2 and VCO2 in each last 60-s), whilst delta and gross efficiencies (DE%, GE%), and exercise economy (EC), were added for Mechanical Efficiency. Mean comparisons regarding intensities 60, 80 and 100% at VT2, completed the study together with correlation analysis among the main variables.Results: MFO and CHOoxpeak were small (6.35 ± 3.59 and 72.79 ± 34.76 g/min/kgFFM respectively) for a reduced muscle power (78.21 ± 15.84 W). Notwithstanding, GE% and EC increased significantly (p &lt; 0.01) with exercise intensity. Importantly, coefficients of variation were very large confirming heterogeneity. Whilst muscle power outcomes correlated significantly (p &lt; 0.01) with MFO (r = 0.66) and age (r = −0.62), these latter failed to be associated. Only GE% correlated to CHOoxpeak (r = −0.61, p &lt; 0.01) regarding mechanical efficiency.Conclusions: Despite being active, women over-60 confirmed impaired substrates switching in response to exercise, from both FAT and CHO pathways. This limits their power production affecting exercise capacity. Our data suggest that decreased power with age has a key role above age per se in this metabolic inflexibility. Vice versa, increasing power seems to protect from mitochondrial dysfunction with aging. New studies will confirm if this higher efficiency when coming close to VT2, where GE is the more informative variable, might be a protective compensatory mechanism.