bluuebunny/crossref_metadata_2025 huggingface dataset:
Self-Assembly System Based on Cyclodextrin for Targeted Delivery of Cannabidiol
Authors: Zhu Panyong , Lv Pin , Zhang Yazhou , Liao Rongqiang , Liu Jing , Guo Rong , Chen Xuan , Liao Xiali , Gao Chuanzhu , Zhang Kun , Yang Ming , Yang Bo
Published: November 2021

Cannabidiol (CBD) is one specific kind of the cannabinoid in Cannabis sativa L with a wide range of pharmacological activities. However, the poor water solubility and specificity of CBD limits its application in pharmaceutical field. For solving these problems, in this work, we successfully prepared a targeted carrier by grafting biotin (BIO) onto ethylenediamine-β-Cyclodextrin (EN-CD) in a single step to generate a functionalized supramolecule, named BIO-CD. Subsequently, an amantadine-conjugated cannabinoids (AD-CBD) was prepared and self-assembled with the BIO-CD. A series of methods were used to characterize the inclusion behavior and physicochemical properties of AD-CBD and BIO-CD. The results showed that AD-CBD entered the cavity of BIO-CD and formed a 1:1 host-guest inclusion complex. MTT assay and confocal laser scanning microscopy (CLSM) revealed that the targeting effect and anticancer activity of AD-CBD/BIO-CD inclusion complex against three human cancer cell lines were higher than BIO-CD, AD-CBD and free CBD. Moreover, the inclusion complex could release drugs under weakly acidic conditions. These results demonstrated that AD-CBD/BIO-CD inclusion complex possess excellent targeted and anticancer activity, which is hopeful to be applied in clinic as a new therapeutic approach.
Predicting a Kind of Unusual Multiple-States Dimerization-Modes Transformation in Protein PD-L1 System by Computational Investigation and a Generalized Rate Theory
Authors: Zhou Zhong-Xing , Zhang Hong-Xing , Zheng Qing-Chuan
Published: November 2021

The new cancer immunotherapy has been carried out with an almost messianic zeal, but its molecular basis remains unclear due to the complexity of programmed death ligand 1 (PD-L1) dimerization. In this study, a new and integral multiple dimerization-modes transformation process of PD-L1s (with a new PD-L1 dimerization mode and a new transformation path discovered) and the corresponding mechanism are predicted using theoretical and computational methods. The results of the state analysis show that 5 stable binding states exist in system. A generalized inter-state transformation rate (GITR) theory is also proposed in such multiple-states self-assembly system to explore the kinetic characteristics of inter-state transformation. A “drug insertion” path was identified as the dominant path of the PD-L1 dimerization-modes transformation. Above results can provide supports for both the relative drug design and other multiple-states self-assembly system from the theoretical chemistry perspective.
The Role of METTL3-Mediated N6-Methyladenosine (m6A) of JPH2 mRNA in Cyclophosphamide-Induced Cardiotoxicity
Authors: Zhu Min , Liu Yangong , Song Yuanxiu , Zhang Shiqin , Hang Chengwen , Wu Fujian , Lin Xianjuan , Huang Zenghui , Lan Feng , Xu Ming
Published: November 2021

Cyclophosphamide (CYP)-induced cardiotoxicity is a common side effect of cancer treatment. Although it has received significant attention, the related mechanisms of CYP-induced cardiotoxicity remain largely unknown. In this study, we used cell and animal models to investigate the effect of CYP on cardiomyocytes. Our data demonstrated that CYP-induced a prolonged cardiac QT interval and electromechanical coupling time courses accompanied by JPH2 downregulation. Moreover, N6-methyladenosine (m6A) methylation sequencing and RNA sequencing suggested that CYP induced cardiotoxicity by dysregulating calcium signaling. Importantly, our results demonstrated that CYP induced an increase in the m6A level of JPH2 mRNA by upregulating methyltransferases METTL3, leading to the reduction of JPH2 expression levels, as well as increased field potential duration and action potential duration in cardiomyocytes. Our results revealed a novel mechanism for m6A methylation-dependent regulation of JPH2, which provides new strategies for the treatment and prevention of CYP-induced cardiotoxicity.
The Combined Effects of ENSO and Solar Activity on Mid-Winter Precipitation Anomalies Over Southern China
Authors: Wang Ruili , Ma Hedi , Xiao Ziniu , Li Xing , Gao Chujie , Gao Yuan , Lai Anwei , Li Xiao
Published: November 2021

Both the El Niño-Southern Oscillation (ENSO) and the 11-years solar cycle had been identified as important factors that may influence the wintertime southern China precipitation (SCP). However, the interactions between these two factors remain less noticed. In this study, the combined effects of the ENSO and the solar activity on mid-winter (January) SCP are investigated using observational and reanalysis data. Results suggest that both the ENSO and the solar activity are positively correlated with the SCP, although exhibiting distinct spatial patterns. Under different combinations of the ENSO and solar phases, the SCP anomalies show superposition of these two factors to some extent. Generally, the ENSO-related SCP anomalies tend to be enhanced (disturbed) when the ENSO and the solar activity are in-phase (out-of-phase). But this solar modulation effect appears more clear and significant under cold ENSO (cENSO) phase rather than under warm ENSO (wENSO) phase. Further analysis suggests, during the wENSO phase, solar influences on the Northern Hemisphere circulation are generally weak with little significance. In contrast, during the cENSO phase, the solar effect resembles the positive phase of the Arctic Oscillation but with an evident zonal asymmetric component. Its manifestation over the Asia-Pacific domain features by negative geopotential height anomaly over the West Asia and positive geopotential height anomaly over the East Asian coast, a pattern that is favorable for the SCP, thus causing a significant solar modulation on the cENSO-related precipitation anomalies. Further, the potential physical causes of solar effects on circulation are also discussed. Our results highlight the importance of considering solar cycle phase when ENSO is used to predict the East Asian winter climate.
Spatial Differentiation Characteristics and Driving Mechanism of Rural Settlements Transformation in the Metropolis: A Case Study of Pudong District, Shanghai
Authors: Li Kaiming , Geng Huizhi , Yue Liying , Li Kaishun , Huang Lei
Published: November 2021

Under rapid urbanization, rural China has undergone a drastic transformation, especially in the metropolis. Revealing the evolution laws of rural settlements is critical for effectively providing references. Although many previous studies demonstrated the transformation laws of rural settlements from multiple scales, few focused on the spatial differentiation within the metropolis. This study constructed the spatial conversion intensity index, conversion structure significance index, and landscape metrics to investigate the spatial differentiation characteristics, classify the transformation patterns, and reveal driving mechanisms of rural settlements in the Pudong district at the township level. The results demonstrated a significant decrease in the size of settlements, and the values decreased from urban-rural fringe to exurban area. The conversion structure of settlements varied within urban-fringe, suburban, and exurban areas. The morphology of settlements became more regular and compact, but to a varying degree. Based on these findings, three transformation patterns were summarized: the rapid disappearance pattern, the physical decay pattern, and the orderly transformation pattern. Further analysis indicated that they were mainly caused by urban encroachment, limitation of geographic conditions, and planning policies separately. These conclusions reveal the spatial differentiation characteristics of rural settlements in the metropolis of developing countries and provide scientific guidance for sustainable rural development.
Impact of Light at Night Is Phase Dependent: A Study on Migratory Redheaded Bunting (Emberiza bruniceps)
Authors: Kumar Jayant , Malik Shalie , Bhardwaj Sanjay Kumar , Rani Sangeeta
Published: November 2021

Artificial light at night (LAN) alters the physiology and behavior of an organism; however, very little is known about phase-dependent effects of LAN, particularly, in night migratory songbirds. Therefore, in this study, we investigated whether the effects of LAN on daily activity and photoperiodic responses in the Palearctic Indian migratory songbird, redheaded buntings (Emberiza bruniceps), is dependent on the different phases of the night. Male buntings maintained under short photoperiod (8L:16D; L = 100 lux, D < 0.1 lux) in individual activity cages were exposed to LAN (2 lux) for 6 weeks either in 4 h bin given at the different phases of 16 h night (early, mid, or late at ZT 08–12, ZT 14–18, or ZT 20–24, respectively; n = 9 each group) or throughout 16 h night (all night light, n = 6, ZT 08–24, the time of lights ON was considered as Zeitgeber time 0, ZT 0). A group (n = 6) with no LAN served as control. The results showed that LAN at the different phases of night induced differential effects as shown by an intense activity during the night, altered melatonin and temperature rhythms, and showed an increase in body mass and body fattening, food intake, and gonadal size. Midnight light exposure has a greater impact on migration and reproduction linked phenotypes, which is similar to the ones that received light throughout the night. The highlights of this study are that (i) LAN impacts day-night activity behavior, (ii) its continuity with the day alters the perception of day length, (iii) birds showed differential sensitivity to LAN in a phase-dependent manner, (iv) the direction of placing LAN affects the daily responses, e.g., LAN in the early night was “accepted” as extended dusk but the late night was considered as early dawn, and (v) midnight LAN was most effective and induced similar responses as continuous LAN. Overall, LAN induces long day responses in short days and shows differential sensitivity of the different phases of the night toward the light. This information may be valuable in adopting a part-night lighting approach to help reduce the physiological burden, such as early migration and reproduction, of artificial lighting on the nocturnal migrants.
Systemic Sclerosis in Zimbabwe: Autoantibody Biomarkers, Clinical, and Laboratory Correlates
Authors: Sibanda Elopy N. , Dube Yvonne , Chakawa Mazvita , Mduluza Takafira , Mutapi Francisca
Published: November 2021

Introduction

Systemic sclerosis (SScl) is an autoimmune disease whose prevalence is rarely reported in Africa. Autoantibodies are the biomarkers of the condition, precede overt disease and determine disease phenotypes. SSc specific autoantibodies also vary between racial groupings. Objective: To investigate the clinical and laboratory characteristics of Zimbabwean patients who were reactive SSc specific autoantibodies.

Materials and Method

240 patients, 173 of them female with SSc specific autoantibodies were included. Autoantibodies were detected by indirect immunofluorescence microscopy and immunoblotting using a panel of 13 SScl (Euroimmun Ag., Germany). Demographic, clinical and laboratory parameters relevant to the monitoring of SScl were captured. These included pulmonary function tests, hematology, clinical chemistry, serology and thyroid function tests. Allergy skin prick tests (SPT) to inhalant and food allergen sources were conducted when indicated.

Results

All the 240 patients (median age was 36 years) expressed SSc specific autoantibodies. 86% were Black, 11% White and 3% Asian and a fifth (20%) were younger than 16 years. Eleven (4.6%) fulfilled the ACR/EULAR classification of SSc. Clinically they had limited cutaneous (n=6), diffuse cutaneous (n=3) and SScl/inflammatory myopathy overlap (n=2). The most frequently detected antibodies anti-RNA polymerase III (RNAP) 55%, anti-Th/To (28%) anti-RNAP 11 (22%), anti-CENPB (18%) and anti-Scl-70/ATA (13%). Racial variations in the expression of these antibodies were apparent between Black, White and Asian patients. The majority (95%), who did not fulfil the ARA/EULAR criteria were symptomatic. Raynaud’s Phenomenon was documented in 24%. Respiratory symptoms included coughing, dyspnea and wheezing. There was a restrictive ventilatory defect with increased FEV1/FVC ratio. Pruritus, urticaria and skin depigmentation were the main cutaneous features while constipation, bloating, Gastroesophageal reflux disease (GERD) and abdominal pain dominated GI symptoms. Mean blood pressure readings while normal varied with biomarkers. Haematology and biochemistry parameters were within normal reference ranges.

Conclusion

The expression of SSc specific autoantibodies is common and associated with known SSc symptoms. The types and frequency of autoantibodies varied with racial groupings. A fifth of the patients were children below the age of 16 years.
β2 Integrin CD11d/CD18: From Expression to an Emerging Role in Staged Leukocyte Migration
Authors: Blythe Eoin N. , Weaver Lynne C. , Brown Arthur , Dekaban Gregory A.
Published: November 2021

CD11d/CD18 is the most recently discovered and least understood β2 integrin. Known CD11d adhesive mechanisms contribute to both extravasation and mesenchymal migration – two key aspects for localizing peripheral leukocytes to sites of inflammation. Differential expression of CD11d induces differences in monocyte/macrophage mesenchymal migration including impacts on macrophage sub-set migration. The participation of CD11d/CD18 in leukocyte localization during atherosclerosis and following neurotrauma has sparked interest in the development of CD11d-targeted therapeutic agents. Whereas the adhesive properties of CD11d have undergone investigation, the signalling pathways induced by ligand binding remain largely undefined. Underlining each adhesive and signalling function, CD11d is under unique transcriptional control and expressed on a sub-set of predominately tissue-differentiated innate leukocytes. The following review is the first to capture the nearly three decades of CD11d research and discusses the emerging role of CD11d in leukocyte migration and retention during the progression of a staged immune response.
Impact of the Addition of Baricitinib to Standard of Care Including Tocilizumab and Corticosteroids on Mortality and Safety in Severe COVID-19
Authors: Masiá Mar , Padilla Sergio , García José Alberto , García-Abellán Javier , Navarro Andrés , Guillén Lucía , Telenti Guillermo , Mascarell Paula , Botella Ángela , Gutiérrez Félix
Published: November 2021

Background: Baricitinib is a Janus kinase (JAK) inhibitor with a broader anti-inflammatory activity than tocilizumab and an antiviral potential although no head-to-head trials are available. The benefits of adding baricitinib to patients with COVID-19 experiencing clinical progression despite the standard of care (SOC), including corticosteroids and tocilizumab, are also unknown.

Methods: A cohort study included microbiologically confirmed COVID-19 hospitalizations. The primary outcome was 28-day mortality. Secondary outcomes were 60- and 90-day mortality, the composite outcome “28-day invasive mechanical ventilation (IMV) or death” and the safety of the combination. Propensity score (PS) matching was used to identify the association between baricitinib use and the outcomes of interest.

Results: Of 1,709 admissions, 994 patients received corticosteroids and tocilizumab and 110 of them received baricitinib after tocilizumab. PS matched 190 (95:95) patients with baricitinib + SOC vs. SOC, of whom 69.5% received remdesivir. No significant effect of baricitinib was observed on 28-day [39 events; adjusted hazard ratio (aHR), 0.76; 95% CI, 0.31–1.86], 60-day (49 events, aHR, 1.17; 95% CI, 0.55–2.52), or 90-day mortality (49 events; aHR, 1.14; 95% CI, 0.53–2.47), or on the composite outcome 28-day IMV/death (aHR, 0.88; 95% CI, 0.45–1.72). Secondary infections during hospitalization were not different between groups (17.9 vs. 10.5%, respectively; p = 0.212) and thromboembolic events were higher with baricitinib (11.6% vs. 3.2%; p = 0.048), but differences vanished after the adjustment [aHR 1.89 (0.31–11.57), p = 0.490].

Conclusion: The addition of baricitinib did not substantially reduce mortality in hospitalized patients with COVID-19 having clinical progression despite the therapy with tocilizumab and corticosteroids. The combination of baricitinib and tocilizumab was not associated with an increased risk of secondary infections or thromboembolic events.
Emerging Developments in Management of Melanoma During the COVID-19 Era
Authors: Li Andraia R. , Valdebran Manuel , Reuben Daniel Y.
Published: November 2021

In March 2020, the designation of the COVID-19 outbreak as a worldwide pandemic marked the beginning of an unprecedented era in modern medicine. Facing the possibility of resource precincts and healthcare rationing, leading dermatological and cancer societies acted expeditiously to adapt their guidelines to these contingencies. Melanoma is a lethal and aggressive skin cancer necessitating a multidisciplinary approach to management and is associated with significant healthcare and economic cost in later stages of disease. In revisiting how the pandemic transformed guidelines from diagnosis and surveillance to surgical and systemic management of melanoma, we appraise the evidence behind these decisions and their enduring implications.
Influence of Statin Therapy on the Incidence of Cardiovascular Events, Cancer, and All-Cause Mortality in People Living With HIV: A Meta-Analysis
Authors: Li Yanping , Wang Zhandi , Xia Haimei , Zhang Ju
Published: November 2021

Background: Possible influences of statin therapy on the risk of cardiovascular events, cancer, and all-cause mortality in people living with HIV (PLWH) remain unclear. We performed a meta-analysis to systematically evaluate the efficacy of statin in PLWH.

Methods: Relevant cohort studies were retrieved via a search of the Medline, the Embase, and the Web of Science databases until June 14, 2021. The data were combined with a random-effects model by incorporating the between-study heterogeneity.

Results: A total of 12 multivariate cohort studies with 162,252 participants were eligible for the meta-analysis and 36,253 (22.3%) of them were statin users. Pooled results showed that statin use was independently related to a reduced mortality risk in PLWH [adjusted risk ratio (RR): 0.56, 95% CI: 0.44 to 0.72, p < 0.001, I2 = 41%]. In addition, results of the meta-analysis showed that statin use was not significantly associated with a reduced risk of cardiovascular events in PLWH compared to the statin non-users (RR: 1.14, 95% CI: 0.80 to 1.63, p = 0.48, I2 = 42%). However, statin use was significantly related to a reduced risk of cancer in PLWH (RR: 0.73, 95% CI: 0.58 to 0.93, p = 0.009, I2 = 49%). Sensitivity analyses by excluding one study at a time showed consistent results. No significant publication biases were observed.

Conclusion: Statin use is associated with reduced all-cause mortality in PLWH. In addition, statin use is related to a reduced risk of cancer, although the risk of cardiovascular events seems not significantly affected.
Glymphatic Dysfunction in Patients With Ischemic Stroke
Authors: Toh Cheng Hong , Siow Tiing Yee
Published: November 2021

Objectives: Rodent experiments have provided some insight into the changes of glymphatic function in ischemic stroke. The diffusion tensor image analysis along the perivascular space (DTI-ALPS) method offers an opportunity for the noninvasive investigation of the glymphatic system in patients with ischemic stroke. We aimed to investigate the changes of glymphatic function in ischemic stroke and the factors associated with the changes.

Materials and Methods: A total of 50 patients (mean age 56.7 years; 30 men) and 44 normal subjects (mean age 53.3 years; 23 men) who had preoperative diffusion-tensor imaging for calculation of the analysis along the perivascular space (ALPS) index were retrospectively included. Information collected from each patient included sex, age, time since stroke onset, infarct location, hemorrhagic change, infarct volume, infarct apparent diffusion coefficient (ADC), infarct fractional anisotropy (FA), and ALPS index of both hemispheres. Interhemispheric differences in ALPS index (infarct side vs. contralateral normal side) were assessed with a paired t-test in all patients. ALPS index was normalized by calculating ALPS ratios (right-to-left and left-to-right) for comparisons between patients and normal subjects. Comparisons of ALPS ratios between patients and normal subjects were performed using analysis of covariance with adjustments for age and sex. Linear regression analyses were performed to identify factors associated with the ALPS index.

Results: In patients, the mean ALPS index ipsilateral to infarct was 1.162 ± 0.126, significantly lower (P < 0.001) than that of the contralateral side (1.335 ± 0.160). The right-to-left ALPS index ratio of patients with right cerebral infarct was 0.84 ± 0.08, significantly lower (P < 0.001) than that of normal subjects (0.95 ± 0.07). The left-to-right ALPS ratio of patients with left cerebral infarct was 0.92 ± 0.09, significantly (P < 0.001) lower than that of normal subjects (1.05 ± 0.08). On multiple linear regression analysis, time since stroke onset (β = 0.794, P < 0.001) was the only factor associated with the ALPS index.

Conclusion: The ALPS index showed lower values in ischemic stroke suggesting impaired glymphatic function. Following initial impairment, the ALPS index increased with the time since stroke onset, which is suggestive of glymphatic function recovery.
Assessing Plasma Levels of α-Synuclein and Neurofilament Light Chain by Different Blood Preparation Methods
Authors: Chang Kuo-Hsuan , Liu Kou-Chen , Lai Chao-Sung , Yang Shieh-Yueh , Chen Chiung-Mei
Published: November 2021

The potential biomarkers of Parkinson’s disease are α-synuclein and neurofilament light chain (NFL). However, inconsistent preanalytical preparation of plasma could lead to variations in levels of these biomarkers. Different types of potassium salts of EDTA and different centrifugation temperatures during plasma preparation may affect the results of α-synuclein and NFL measurements. In this study, we prepared plasma from eight patients with Parkinson’s disease (PD) and seven healthy controls (HCs) by using di- and tri-potassium (K2- and K3-) EDTA tubes and recruited a separated cohort with 42 PD patients and 40 HCs for plasma samples prepared from whole blood by centrifugation at room temperature and 4°C, respectively, in K2-EDTA tubes. The plasma levels of α-synuclein and NFL in K2- and K3-EDTA were similar. However, the levels of α-synuclein in the plasma prepared at 4°C (101.57 ± 43.43 fg/ml) were significantly lower compared with those at room temperature (181.23 ± 196.31 fg/ml, P < 0.001). Room temperature preparation demonstrated elevated plasma levels of α-synuclein in PD patients (256.6 ± 50.2 fg/ml) compared with the HCs (102.1 ± 0.66 fg/ml, P < 0.001), whereas this increase in PD was not present by preparation at 4°C. Both plasma preparations at room temperature and 4°C demonstrated consistent results of NFL, which are increased in PD patients compared with HCs. Our findings confirmed that K2- and K3-EDTA tubes were interchangeable for analyzing plasma levels of α-synuclein and NFL. Centrifugation at 4°C during plasma preparation generates considerable reduction and variation of α-synuclein level that might hinder the detection of α-synuclein level changes in PD.
Controlling Alzheimer’s Disease Through the Deep Brain Stimulation to Thalamic Relay Cells
Authors: Yang XiaoLi , Zhang RuiXi , Sun ZhongKui , Kurths Jürgen
Published: November 2021

Experimental and clinical studies have shown that the technique of deep brain stimulation (DBS) plays a potential role in the regulation of Alzheimer’s disease (AD), yet it still desires for ongoing studies including clinical trials, theoretical approach and action mechanism. In this work, we develop a modified thalamo-cortico-thalamic (TCT) model associated with AD to explore the therapeutic effects of DBS on AD from the perspective of neurocomputation. First, the neuropathological state of AD resulting from synapse loss is mimicked by decreasing the synaptic connectivity strength from the Inter-Neurons (IN) neuron population to the Thalamic Relay Cells (TRC) neuron population. Under such AD condition, a specific deep brain stimulation voltage is then implanted into the neural nucleus of TRC in this TCT model. The symptom of AD is found significantly relieved by means of power spectrum analysis and nonlinear dynamical analysis. Furthermore, the therapeutic effects of DBS on AD are systematically examined in different parameter space of DBS. The results demonstrate that the controlling effect of DBS on AD can be efficient by appropriately tuning the key parameters of DBS including amplitude A, period P and duration D. This work highlights the critical role of thalamus stimulation for brain disease, and provides a theoretical basis for future experimental and clinical studies in treating AD.
Posterior Fossa Venous Drainage
Authors: de Miquel María Angeles
Published: November 2021

This paper aims to make simple the evaluation of the main veins related to the brainstem and cerebellum. Posterior fossa venous drainage is best understood in context with its three main collectors: superior: toward the Vein of Galen; posterior: toward the torcular complex; and anterior: toward the superior petrosal sinus. A fourth possible drainage path, often harder to distinguish, is directed toward the inferior petrosal sinus. Veins of these four systems are frequently connected to one another. Despite traditionally being considered less regular than its arterial disposition, posterior fossa venous anatomy follows specific patterns that are easy to identify. The three more representative veins of each venous confluent have been selected, to help in recognizing them angiographically. Since pial large veins are primarily located over the surface of the encephalon, most related anatomical structures can be confidently identified. This is of special interest when angiographic 2D or 3D studies are evaluated and provide fundamental assistance in locating precise structures. To better aid in understanding venous disposition, an overview of embryologic and fetal development is also discussed.
Clinical Presentations and Genetic Characteristics of Late-Onset MADD Due to ETFDH Mutations in Five Patients: A Case Series
Authors: Tang Zhenchu , Gao Shan , He Miao , Chen Qihua , Fang Jia , Luo Yingying , Yan Weiqian , Shi Xiaoliu , Huang Hui , Tang Jianguang
Published: November 2021

Background: Late-onset multiple acyl-CoA dehydrogenase deficiency (LO-MADD) describes a curable autosomal recessive genetic disease caused by ETFDH mutations that result in defects in ETF-ubiquinone oxidoreductase. Almost all patients are responsive to riboflavin. This study describes the clinical presentations and genetic characteristics of five LO-MADD patients.

Methods: From 2018 to 2021, we collected clinical and genetic data on five patients diagnosed with LO-MADD at our hospital and retrospectively analyzed their clinical characteristics, laboratory examination, electromyography, muscle biopsy, genetic analysis, and outcome data.

Results: This study included three males and two females with mean onset age of 37.8 years. Fluctuating exercise intolerance was the most common presentation. Serum creatine kinase (CK) levels were significantly elevated in all patients, and plasma acylcarnitine profiles revealed an increase in long-chain acylcarnitine species in three cases. The urinary organic acid study revealed a high level of hydroxyglutaric acid in all patients. Electrophysiology demonstrated myogenic impairment. Muscle biopsies revealed lipid storage myopathy. Molecular analysis identified nine mutations (three novels and six reported) in ETFDH. Exercise intolerance and muscle weakness were dramatically improved in all patients treated with riboflavin (100 mg) daily following diagnosis.

Conclusions: LO-MADD is caused by ETFDH variants and responds well to riboflavin. Three novel ETFDH pathogenic variants were identified, expanding their spectrum in the Chinese population and facilitating future interpretation and analysis of ETFDH mutations.
Migraine With Aura Is Related to Delayed Motor Control Reaction and Imbalance Following External Perturbations
Authors: Carvalho Gabriela F. , Luedtke Kerstin , Pinheiro Carina F. , Moraes Renato , Lemos Tenysson W. , Bigal Marcelo E. , Dach Fabiola , Bevilaqua-Grossi Debora
Published: November 2021

Background: It is evidenced that migraineurs present balance deficits. However, the balance recovery following unexpected ground perturbations, which reflect conditions of everyday activities, has not been investigated in this population.

Aim: We aimed to assess the reactive postural responses among patients with migraine with and without aura, chronic migraine, and controls. We further aimed to assess the factors associated with greater self-report of falls.

Methods: Ninety patients diagnosed by headache specialists were equally classified into three migraine subgroups according to the presence of aura and chronic migraine. Thirty controls were also recruited. All participants underwent the motor control test (MCT) and adaptation test (ADT) protocols of dynamic posturography tests (EquiTest®, NeuroCom, USA). Clinical and headache features and information on falls in the previous year, fear of falling, and vestibular symptoms were also assessed.

Results: Patients with aura presented a greater sway area in most of the MCT conditions than the other three groups (p = 0.001). The aura group also presented delayed latency responses after perturbations compared with controls and patients without aura (p < 0.03). In the ADT, a greater sway area was observed in patients with aura than in groups without aura, chronic migraine, and controls (p < 0.0001). The MCT and ADT sway area, the frequency of aura, and the fear of falling explained 46% of the falls in the previous 12 months.

Conclusion: Patients with aura exhibited greater delay and sway area after unexpected ground perturbations than controls and other migraine subgroups, which are related to the reported number of falls.
Oregano Essential Oils Promote Rumen Digestive Ability by Modulating Epithelial Development and Microbiota Composition in Beef Cattle
Authors: Zhang Rui , Wu Jianping , Lei Yu , Bai Yunpeng , Jia Li , Li Zemin , Liu Ting , Xu Yangbin , Sun Jianxiang , Wang Ying , Zhang Ke , Lei Zhaomin
Published: November 2021

This study aimed to explore the effects of oregano essential oils (OEO) on the rumen digestive ability using multi-omics sequencing techniques. Twenty-seven castrated Pingliang red cattle were randomly separated into three groups (3 cattle/pen; n = 9) and fed on a daily basal diet supplemented with 0 (Con group), 130 mg (L group), and 260 mg (H group) OEO. The finishing trial lasted for 390 days, and all cattle were slaughtered to collect rumen tissue and content samples. We found that the rumen papillae length in the H group was higher than in the Con group. Amylase concentrations were decreased in the H group than the Con group, whereas the β-glucosidase and cellulase concentrations increased. Compared to the Con group, the relative abundance of propionate and butyrate in the H group was significantly higher. Higher relative abundance of Parabacteroides distasonis and Bacteroides thetaiotaomicron were observed with increasing OEO concentration. The function of rumen microbiota was enriched in the GH43_17 family, mainly encoding xylanase. Besides, metabolites, including heparin, pantetheine, sorbic acid, aspirin, and farnesene concentrations increased with increasing OEO dose. A positive correlation was observed between Parabacteroides distasonis, Bacteroides thetaiotaomicron, and β-glucosidase, cellulase and propionate. The abundance of Parabacteroides distasonis and Parabacteroides_sp._CAG:409 were positively correlated with sorbic acid and farnesene. In summary, OEO supplementation increased the rumen digestive ability by modulating epithelial development and microbiota composition in beef cattle. This study provides a comprehensive insight into the OEO application as an alternative strategy to improve ruminant health production.
Anthropometric Profile of Latin American Population: Results From the ELANS Study
Authors: Herrera-Cuenca Marianella , Kovalskys Irina , Gerardi Alejandro , Hernandez Pablo , Sifontes Yaritza , Gómez Georgina , Yépez García Martha Cecilia , Méndez-Pérez Betty , Landaeta-Jimenez Maritza , Pareja Rossina , Cortés Lilia Yadira , Rigotti Attilio , Fisberg Mauro , Zimberg Iona Zalcman
Published: November 2021

Background: Latin America has experienced changes in lifestyle since 1960.

Aim: The aim was to determine the prevalence of obesity and stunting among eight countries of Latin American and to identify the determinant risk factors for obesity.

Subjects and Methods: Data were obtained from 9,218 participants of the Latin American Study of Nutrition and Health (ELANS), a multicenter cross-sectional study of the representative samples in eight Latin American countries. All the participants completed a standard protocol to investigate the nutrient intake and anthropometric variables (weight, height, and circumferences) analyzed by country, gender, age, and socioeconomic status.

Results: The prevalence of obesity was higher in Costa Rica and Venezuela (29%) and lower in Colombia (16%), stunting was reported higher in Peru (47%) and lower in Argentina (17%), and waist and neck circumferences showed the higher values in Costa Rica (43%) and Chile (52%) and lower values in Colombia (23 and 26%).

Conclusion: This study indicates an increasing trend toward overweight and obesity that are associated with lower socioeconomic status, being a woman, and concurs with inadequate intakes of calcium, which may be related to poor quality diet and in the long term could constitute risk factors for the chronic diseases and a health burden to the region.
Genetic Contributions to Prostate Cancer Disparities in Men of West African Descent
Authors: Johnson Jabril R. , Woods-Burnham Leanne , Hooker Stanley E. , Batai Ken , Kittles Rick A.
Published: November 2021

Prostate cancer (PCa) is the second most frequently diagnosed malignancy and the second leading cause of death in men worldwide, after adjusting for age. According to the International Agency for Research on Cancer, continents such as North America and Europe report higher incidence of PCa; however, mortality rates are highest among men of African ancestry in the western, southern, and central regions of Africa and the Caribbean. The American Cancer Society reports, African Americans (AAs), in the United States, have a 1.7 increased incidence and 2.4 times higher mortality rate, compared to European American’s (EAs). Hence, early population history in west Africa and the subsequent African Diaspora may play an important role in understanding the global disproportionate burden of PCa shared among Africans and other men of African descent. Nonetheless, disparities involved in diagnosis, treatment, and survival of PCa patients has also been correlated to socioeconomic status, education and access to healthcare. Although recent studies suggest equal PCa treatments yield equal outcomes among patients, data illuminates an unsettling reality of disparities in treatment and care in both, developed and developing countries, especially for men of African descent. Yet, even after adjusting for the effects of the aforementioned factors; racial disparities in mortality rates remain significant. This suggests that molecular and genomic factors may account for much of PCa disparities.
The Pathological Mechanisms of Estrogen-Induced Cholestasis: Current Perspectives
Authors: Zu Yue , Yang Jinyu , Zhang Chengliang , Liu Dong
Published: November 2021

Estrogens are steroid hormones with a wide range of biological activities. The excess of estrogens can lead to decreased bile flow, toxic bile acid (BA) accumulation, subsequently causing intrahepatic cholestasis. Estrogen-induced cholestasis (EIC) may have increased incidence during pregnancy, and within women taking oral contraception and postmenopausal hormone replacement therapy, and result in liver injury, preterm birth, meconium-stained amniotic fluid, and intrauterine fetal death in pregnant women. The main pathogenic mechanisms of EIC may include deregulation of BA synthetic or metabolic enzymes, and BA transporters. In addition, impaired cell membrane fluidity, inflammatory responses and change of hepatocyte tight junctions are also involved in the pathogenesis of EIC. In this article, we review the role of estrogens in intrahepatic cholestasis, and outlined the mechanisms of EIC, providing a greater understanding of this disease.
Pharmacological Basis for Use of a Novel Compound in Hyperuricemia: Anti-Hyperuricemic and Anti-Inflammatory Effects
Authors: Zhao Lei , Li Yihang , Yao Dahong , Sun Ran , Liu Shifang , Chen Xi , Lin Congcong , Huang Jian , Wang Jinhui , Li Guang
Published: November 2021

Background: The prevalence of hyperuricemia is considered high worldwide. Hyperuricemia occurs due to decreased excretion of uric acid, increased synthesis of uric acid, or a combination of both mechanisms. There is growing evidence that hyperuricemia is associated with a decline of renal function.

Purpose: This study is aimed at investigating the effects of the novel compound on lowering the serum uric acid level and alleviating renal inflammation induced by high uric acid in hyperuricemic mice.

Methods: Hyperuricemic mice model was induced by potassium oxonate and used to evaluate the effects of the novel compound named FxUD. Enzyme-linked immunosorbent assay was used to detect the related biochemical markers. Hematoxylin-eosin (HE) staining was applied to observe pathological changes. The mRNA expression levels were tested by qRT-PCR. The protein levels were determined by Western blot. In parallel, human proximal renal tubular epithelial cells (HK-2) derived from normal kidney was used to further validate the anti-inflammatory effects in vitro.

Results: FxUD administration significantly decreased serum uric acid levels, restored the kidney function parameters, and improved the renal pathological injury. Meanwhile, treatment with FxUD effectively inhibited serum and liver xanthine oxidase (XOD) levels. Reversed expression alterations of renal inflammatory cytokines, urate transporter 1 (URAT1) and glucose transporter 9 (GLUT9) were observed in hyperuricemic mice. Western blot results illustrated FxUD down-regulated protein levels of inflammasome components. Further studies showed that FxUD inhibited the activation of NF-κB signaling pathway in the kidney of hyperuricemic mice. In parallel, the anti-inflammatory effect of FxUD was also confirmed in HK-2.

Conclusion: Our study reveals that FxUD exhibits the anti-hyperuricemic and anti-inflammatory effects through regulating hepatic XOD and renal urate reabsorption transporters, and suppressing NF-κB/NLRP3 pathway in hyperuricemia. The results provide the evidence that FxUD may be potential for the treatment of hyperuricemia with kidney inflammation.
Tunable Topological Surface States of Three-Dimensional Acoustic Crystals
Authors: Lai Hua-Shan , Xu Yu-Li , He Bo , Sun Xiao-Chen , He Cheng , Chen Yan-Feng
Published: November 2021

Topological design for band structures of artificial materials such as acoustic crystals provides a powerful tool to manipulate wave propagating in a robust and symmetry-protected way. In this paper, based on the band folding and breaking mechanism by building blocks with acoustic atoms, we construct a three-dimensional topological acoustic crystal with a large complete bandgap. At a mirror-symmetry domain wall, two gapped symmetry and anti-symmetry surface states can be found in the bandgap, originated from two opposite Su-Schrieffer-Heeger chains. Remarkably, by enforcing a glide symmetry on the domain wall, we can tune the original gapped surface states in a gapless fashion at the boundaries of surface Brillouin zone, acting as omnidirectional acoustic quantum spin Hall effect. Our tunable yet straightforward acoustic crystals offer promising potentials in realizing future topological acoustic devices.
Transcription Factor E2F1 Knockout Promotes Mice White Adipose Tissue Browning Through Autophagy Inhibition
Authors: Xiong Mingchen , Hu Weijie , Tan Yufang , Yu Honghao , Zhang Qi , Zhao Chongru , Yi Yi , Wang Yichen , Wu Yiping , Wu Min
Published: November 2021

Obesity is associated with energy metabolic disturbance and is caused by long-term excessive energy storage in white adipose tissue (WAT). The WAT browning potentially reduces excessive energy accumulation, contributing an attractive target to combat obesity. As a pivotal regulator of cell growth, the transcription factor E2F1 activity dysregulation leads to metabolic complications. The regulatory effect and underlying mechanism of E2F1 knockout on WAT browning, have not been fully elucidated. To address this issue, in this study, the in vivo adipose morphology, mitochondria quantities, uncoupling protein 1 (UCP-1), autophagy-related genes in WAT of wild-type (WT) and E2F1–/– mice were detected. Furthermore, we evaluated the UCP-1, and autophagy-related gene expression in WT and E2F1–/– adipocyte in vitro. The results demonstrated that E2F1 knockout could increase mitochondria and UCP-1 expression in WAT through autophagy suppression in mice, thus promoting WAT browning. Besides, adipocytes lacking E2F1 showed upregulated UCP-1 and downregulated autophagy-related genes expression in vitro. These results verified that E2F1 knockout exerted effects on inducing mice WAT browning through autophagy inhibition in vivo and in vitro. These findings regarding the molecular mechanism of E2F1-modulated autophagy in controlling WAT plasticity, provide a novel insight into the functional network with the potential therapeutic application against obesity.
LC–MS Based Draft Map of the Arabidopsis thaliana Nuclear Proteome and Protein Import in Pattern Triggered Immunity
Authors: Ayash Mohamed , Abukhalaf Mohammad , Thieme Domenika , Proksch Carsten , Heilmann Mareike , Schattat Martin Hartmut , Hoehenwarter Wolfgang
Published: November 2021

Despite its central role as the ark of genetic information and gene expression the plant nucleus is surprisingly understudied. We isolated nuclei from the Arabidopsis thaliana dark grown cell culture left untreated and treated with flg22 and nlp20, two elicitors of pattern triggered immunity (PTI) in plants, respectively. An liquid chromatography mass spectrometry (LC–MS) based discovery proteomics approach was used to measure the nuclear proteome fractions. An enrichment score based on the relative abundance of cytoplasmic, mitochondrial and Golgi markers in the nuclear protein fraction allowed us to curate the nuclear proteome producing high quality catalogs of around 3,000 nuclear proteins under untreated and both PTI conditions. The measurements also covered low abundant proteins including more than 100 transcription factors and transcriptional co-activators. We disclose a list of several hundred potentially dual targeted proteins including proteins not yet found before for further study. Protein import into the nucleus in plant immunity is known. Here we sought to gain a broader impression of this phenomenon employing our proteomics data and found 157 and 73 proteins to possibly be imported into the nucleus upon stimulus with flg22 and nlp20, respectively. Furthermore, the abundance of 93 proteins changed significantly in the nucleus following elicitation of immunity. These results suggest promiscuous ribosome assembly and a role of prohibitins and cytochrome C in the nucleus in PTI.
Identification of MBW Complex Components Implicated in the Biosynthesis of Flavonoids in Woodland Strawberry
Authors: Xu Pengbo , Wu Liang , Cao Minghao , Ma Chao , Xiao Kun , Li Yanbang , Lian Hongli
Published: November 2021

Flavonoids belong to the family of polyphenolic secondary metabolites and contribute to fruit quality traits. It has been shown that MBW complexes (MYB-bHLH-WD40) regulate the flavonoids biosynthesis in different plants, but only a limited number of MBW complexes have been identified in strawberry species in general. In this study, we identified 112 R2R3-MYB proteins in woodland strawberry; 12 of them were found to have potential functions in regulating flavonoids biosynthesis by phylogenetic analysis. qRT-PCR assays showed that FvMYB3, FvMYB9, FvMYB11, FvMYB22, FvMYB64, and FvMYB105 mostly expressed at green stage of fruit development, aligned with proanthocyanidins accumulation; FvMYB10 and FvMYB41 showed higher expression levels at turning and ripe stages, aligned with anthocyanins accumulation. These results suggest that different MYBs might be involved in flavonoids biosynthesis at specific stages. Furthermore, FvMYB proteins were demonstrated to interact with FvbHLH proteins and induce expression from the promoters of CHS2 and DFR2 genes, which encode key enzymes in flavonoids biosynthesis. The co-expression of FvMYB and FvbHLH proteins in strawberry fruits also promoted the accumulation of proanthocyanidins. These findings confirmed and provided insights into the biofunction of MBW components in the regulation of flavonoid biosynthesis in woodland strawberry.
PpMYB36 Encodes a MYB-Type Transcription Factor That Is Involved in Russet Skin Coloration in Pear (Pyrus pyrifolia)
Authors: Ma Changqing , Wang Xu , Yu Mengyuan , Zheng Xiaodong , Sun Zhijuan , Liu Xiaoli , Tian Yike , Wang Caihong
Published: November 2021

Fruit color is one of the most important external qualities of pear (Pyrus pyrifolia) fruits. However, the mechanisms that control russet skin coloration in pear have not been well characterized. Here, we explored the molecular mechanisms that determine the russet skin trait in pear using the F1 population derived from a cross between russet skin (‘Niitaka’) and non-russet skin (‘Dangshansu’) cultivars. Pigment measurements indicated that the lignin content in the skin of the russet pear fruits was greater than that in the non-russet pear skin. Genetic analysis revealed that the phenotype of the russet skin pear is associated with an allele of the PpRus gene. Using bulked segregant analysis combined with the genome sequencing (BSA-seq), we identified two simple sequence repeat (SSR) marker loci linked with the russet-colored skin trait in pear. Linkage analysis showed that the PpRus locus maps to the scaffold NW_008988489.1: 53297-211921 on chromosome 8 in the pear genome. In the mapped region, the expression level of LOC103929640 was significantly increased in the russet skin pear and showed a correlation with the increase of lignin content during the ripening period. Genotyping results demonstrated that LOC103929640 encoding the transcription factor MYB36 is the causal gene for the russet skin trait in pear. Particularly, a W-box insertion at the PpMYB36 promoter of russet skin pears is essential for PpMYB36-mediated regulation of lignin accumulation and russet coloration in pear. Overall, these results show that PpMYB36 is involved in the regulation of russet skin trait in pear.