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1.
Front Cell Infect Microbiol ; 11: 734416, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34760716

RESUMO

Microbiome data are becoming increasingly available in large health cohorts, yet metabolomics data are still scant. While many studies generate microbiome data, they lack matched metabolomics data or have considerable missing proportions of metabolites. Since metabolomics is key to understanding microbial and general biological activities, the possibility of imputing individual metabolites or inferring metabolomics pathways from microbial taxonomy or metagenomics is intriguing. Importantly, current metabolomics profiling methods such as the HMP Unified Metabolic Analysis Network (HUMAnN) have unknown accuracy and are limited in their ability to predict individual metabolites. To address this gap, we developed a novel metabolite prediction method, and we present its application and evaluation in an oral microbiome study. The new method for predicting metabolites using microbiome data (ENVIM) is based on the elastic net model (ENM). ENVIM introduces an extra step to ENM to consider variable importance (VI) scores, and thus, achieves better prediction power. We investigate the metabolite prediction performance of ENVIM using metagenomic and metatranscriptomic data in a supragingival biofilm multi-omics dataset of 289 children ages 3-5 who were participants of a community-based study of early childhood oral health (ZOE 2.0) in North Carolina, United States. We further validate ENVIM in two additional publicly available multi-omics datasets generated from studies of gut health. We select gene family sets based on variable importance scores and modify the existing ENM strategy used in the MelonnPan prediction software to accommodate the unique features of microbiome and metabolome data. We evaluate metagenomic and metatranscriptomic predictors and compare the prediction performance of ENVIM to the standard ENM employed in MelonnPan. The newly developed ENVIM method showed superior metabolite predictive accuracy than MelonnPan when trained with metatranscriptomics data only, metagenomics data only, or both. Better metabolite prediction is achieved in the gut microbiome compared with the oral microbiome setting. We report the best-predictable compounds in all these three datasets from two different body sites. For example, the metabolites trehalose, maltose, stachyose, and ribose are all well predicted by the supragingival microbiome.


Assuntos
Microbioma Gastrointestinal , Microbiota , Criança , Pré-Escolar , Microbioma Gastrointestinal/genética , Humanos , Metaboloma , Metabolômica , Metagenoma , Metagenômica
2.
Front Pharmacol ; 12: 744826, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34603058

RESUMO

Idiopathic pulmonary fibrosis (IPF) is a fatal disease in which the normal alveolar network is gradually replaced by fibrotic scars. Current evidence suggests that metabolic alterations correlate with myofibroblast activation in IPF. Anlotinib has been proposed to have antifibrotic effects, but the efficacy and mechanisms of anlotinib against lung fibrosis have not been systematically evaluated. The antifibrotic effects of anlotinib were evaluated in bleomycin-induced mouse models and transforming growth factor-beta 1 (TGF-ß1)-stimulated lung fibroblasts. We measured lactate levels, 2-NBDG glucose uptake and the extracellular acidification rate (ECAR) to assess glycolysis in fibroblasts. RNA-protein coimmunoprecipitation (RIP) and polysome analyses were performed to investigate novel mechanisms of glycolytic reprogramming in pulmonary fibrosis. We found that anlotinib diminished myofibroblast activation and inhibited the augmentation of glycolysis. Moreover, we show that PCBP3 posttranscriptionally increases PFKFB3 expression by promoting its translation during myofibroblast activation, thus promoting glycolysis in myofibroblasts. Regarding mechanism, anlotinib exerts potent antifibrotic effects by downregulating PCBP3, reducing PFKFB3 translation and inhibiting glycolysis in myofibroblasts. Furthermore, we observed that anlotinib had preventative and therapeutic antifibrotic effects on bleomycin-induced pulmonary fibrosis. Therefore, we identify PCBP3 as a protein involved in the regulation of glycolysis reprogramming and lung fibrogenesis and propose it as a therapeutic target for pulmonary fibrosis. Our data suggest that anlotinib has antifibrotic effects on the lungs, and we provide a novel mechanism for this effect. Anlotinib may constitute a novel and potent candidate for the treatment of pulmonary fibrosis.

3.
Exp Ther Med ; 22(5): 1221, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34603518

RESUMO

Lower back pain (LBP) is an extremely common symptom and is recognized as a leading contributor to disability and disease burden globally. Intervertebral disc degeneration (IDD) represents a major cause of LBP. However, the molecular mechanisms involved in the pathogenesis of IDD remain unclear, and currently available treatments, including conservative and surgical options, fail to effectively delay, stop or reverse the progression of IDD. Circular RNAs (circRNAs) are a newly discovered group of covalently closed, single-stranded and endogenous non-coding RNAs. A growing body of research has revealed that a number of circRNAs are widely and aberrantly expressed in IDD tissues. Furthermore, they play important roles in the pathogenesis of IDD, including proliferation, apoptosis, senescence, mitophagy, inflammation and extracellular matrix metabolism, mainly by acting as sponges for microRNAs. The present review aims to summarize the current understanding on the mechanisms of circRNA-mediated regulation in IDD.

4.
Stereotact Funct Neurosurg ; : 1-9, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34535594

RESUMO

OBJECTIVE: The aim of the study was to retrospectively evaluate the effect of directional deep brain stimulation (DBS) on ataxia in an essential tremor patient population. MATERIALS AND METHODS: A retrospective chart review of documented Scale for Assessment and Rating of Ataxia (SARA) scores were analyzed using a case-control design. All subjects we evaluated were treated at a single, tertiary care academic center. We reviewed 14 patients who underwent bilateral ventral intermediate nucleus of the thalamus (VIM) implantation with microelectrode recording, with electrodeposition and segmented contact orientation confirmed via postoperative computed tomography. The main outcome was to determine change in ataxia scores between directional versus monopolar circumferential stimulation. RESULTS: Fourteen patients (9 males, median age at implantation 69 [range 63-82]) underwent surgery between October 2017 and July 2020 at the UNC Movement Disorders Center. SARA scores between directional stimulation and monopolar circumferential stimulation demonstrated a significant reduction in total scores with best possible segmented stimulation (n = 13, p < 0.0001, 95% confidence interval [CI] -3.496 to -6.789). This difference remained statistically significant even after removing the SARA tremor subscore (n = 13, p < 0.0001, 95% CI -3.155 to -6.274). In line with prior reports, SARA score changes from the preoperative state were generally worsened when applying monopolar circumferential stimulation bilaterally (n = 13, p = 0.655; 95% CI -2.836 to 4.359), but improved with directional stimulation (n = 13, p = 0.010; 95% CI -1.216 to -7.547). CONCLUSION: This retrospective analysis appears to show evidence for improved outcomes through directional stimulation in bilateral VIM DBS implantation with reduction of ataxic side effects that have traditionally plagued postoperative results, all while providing optimized tremor reduction via stimulation.

5.
Cancer Manag Res ; 13: 6785-6795, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512018

RESUMO

Purpose: Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis, and researchers are interested in further studying its diagnosis and treatment. Our study aims to identify new potential therapeutic targets in ACC. Patients and Methods: The core genes CDK1 and CCNB1 were previously screened using ACC data from The Cancer Genome Atlas (TCGA) as the most relevant to Bclaf1 and tumour prognosis. We used siRNA- or shRNA-based models to explore the role of Bcl-2-associated transcription factor 1 (Bclaf1) in SW-13 cell lines. Western blotting and qPCR were used to determine the effects of Bclaf1 on CDK1 and Cyclin B1. Results: Based on biological information analysis, we found that Bcl-2-associated transcription factor 1 (Bclaf1) affected the progression of ACC and was associated with the cell cycle. Downregulated Bclaf1 expression inhibited the proliferation of SW-13 cells and affected the cell cycle process of SW-13 cells. BCLAF1 was correlated with CDK1 and CCNB1 and can regulate their mRNA and protein levels. Conclusion: Bclaf1 might promote the development of ACC by regulating CDK1 and Cyclin B1 to drive mitosis.

6.
Front Pharmacol ; 12: 708462, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34497513

RESUMO

Pulmonary fibrosis is characterized by alveolar epithelial cell injury, lung fibroblast proliferation, differentiation, and extracellular matrix (ECM) deposition. Our previous study indicated that extracellular HSP90α (eHSP90α) promotes pulmonary fibrosis by activating the MAPK signaling pathway. Thus, treatment with 1G6-D7 (a selective HSP90α monoclonal antibody) to antagonize eHSP90α could effectively ameliorate fibrosis. This study aimed to elucidate the mechanism underlying the effects of eHSP90α in pulmonary fibrosis by focusing on its link with endoplasmic reticulum (ER) stress. Our results showed that eHSP90α promoted lung fibroblast differentiation by activating ER stress. Treatment with the ER stress inhibitor tauroursodeoxycholate (TUDCA) or glucose-regulated protein 78 kDa (GRP78) depletion significantly abrogated the effect of eHSP90α on ER stress and fibroblast activation. In addition, eHSP90α induced ER stress in fibroblasts via the phosphoinositide-4,5-bisphosphate 3-kinase (PI3K)-protein kinase B (AKT) signaling pathway, which could be blocked by the PI3K/AKT inhibitor LY294002, and blockade of eHSP90α by 1G6-D7 markedly inhibited ER stress in the model, indicating preventive and therapeutic applications. Intriguingly, we observed that TUDCA effectively reduced the secretion of eHSP90α in vitro and in vivo. In conclusion, this study shows that the interaction between eHSP90α and ER stress plays a crucial role in pulmonary fibrosis, indicating a positive feedback in lung fibroblasts. Targeting eHSP90α and alleviating fibroblast ER stress may be promising therapeutic approaches for pulmonary fibrosis.

7.
Ecotoxicol Environ Saf ; 224: 112667, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34425536

RESUMO

Cadmium is a severe environmental pollutant that mainly targets kidney and causes kidney disease in the end. However, the mechanism of cadmium-induced kidney disease is still unclear. In this study, we treated SD rats, kidney epithelial or fibroblast cells with cadmium, and examined the renal fibrosis process and underlying cellular and molecular mechanism. Rats received daily (Monday-Friday) subcutaneous injections of CdCl2, 0.6 mg/kg, for 6 weeks or 12 weeks, and NRK-52E cells were treated with CdCl2 of 8 µM for 24 h. Sirius red staining and immunohistochemistry assay showed that sub-chronic exposure to cadmium caused interstitial fibrosis in rat kidneys. Cell experiments showed that cadmium treatment in NRK-52E cells only changed levels of α-SMA, vimentin and E-cadherin, but not collagen1, indicating that cells other than EMT cells might be responsible for the extracellular matrix production. By contrast, co-culture of NRK-49F cells with cadmium-treated NRK-52E cells produced collagen1. Assays of supernatant of NRK-52E cell culture showed that the secreted Wnt1, Wnt4 were increased, while miR-503-5p was decreased by cadmium treatment. RT-QPCR assay found that miR-503-5p was downregulated in both kidney of rats and NRK-52E cells exposed to cadmium. miR-503-5p was further shown to be competent in hindering epithelial-mesenchymal transition and fibroblast activation. Given the well established involvement of Wnt/ß-catenin pathway in fibrosis, this study suggested that dysregulations of Wnts and miR-503-5p coordinate in mediating cadmium-induced kidney fibrosis. Our findings might provide new insight in the cellular and molecular mechanisms of kidney interstitial fibrosis and novel therapeutic targets for cadmium-induced kidney disease.

8.
Biomed Res Int ; 2021: 9916492, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34368358

RESUMO

Stroke is one of the leading causes of death and the primary cause of acquired disability worldwide. Many stroke survivors have difficulty using their upper limbs, which have important functional roles in the performance of daily life activities. Consequently, the independence and quality of life of most stroke patients are reduced. Robot-assisted therapy is an effective intervention for improving the upper limb function of individuals with stroke. Human-robot collaborative interaction force control technology is critical for improving the flexibility and followability of the robot's motion, thereby improving rehabilitation training outcomes. However, there are few reports on the effect of robot-assisted rehabilitative training on upper limb function. We applied this technology using a robot to assist patients with task-oriented training. Posttreatment changes in Fugl-Meyer and modified Barthel index (MBI) scores were assessed to determine whether this technology could improve the upper limb function of stroke patients. One healthy adult and five stroke patients, respectively, participated in functional and clinical experiments. The MBI and Fugl-Meyer scores of the five patients in the clinical experiments showed significant improvements after the intervention. The experimental results indicate that human-robot collaborative interaction force control technology is valuable for improving robots' properties and patients' recovery. This trial was registered in the Chinese clinical trial registry (ChiCTR2000038676).


Assuntos
Robótica , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/terapia , Análise e Desempenho de Tarefas , Extremidade Superior/fisiopatologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reabilitação do Acidente Vascular Cerebral
9.
Mol Cancer Ther ; 20(10): 1880-1892, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34376581

RESUMO

As a conserved molecular chaperone, heat shock protein 90 (Hsp90) maintains the stability and homeostasis of oncoproteins and helps cancer cells survive. DNA-dependent protein kinase catalytic subunit (DNA-PKcs) plays a pivotal role in the non-homologous end joining pathway for DNA double-strand breaks (DSB) repair. Tumor cells contain higher levels of DNA-PKcs to survive by the hostile tumor microenvironment and various antitumor therapies. Here, we showed that increased levels of Hsp90α, Hsp90ß, and DNA-PKcs correlated with a poor overall survival in hepatocellular carcinoma (HCC). We revealed that Hsp90 N-terminal domain and C-terminal domain have different effects on DNA-PKcs protein and mRNA levels. The stability of DNA-PKcs depended on Hsp90α N-terminal nucleotide binding domain. Transcription factor SP1 regulates the transcription of PRKDC (gene name of DNA-PKcs) and is a client protein of Hsp90. Inhibition of Hsp90 N-terminal by STA9090 decreased the location of Hsp90α in nucleus, Hsp90α-SP1 interaction, SP1 level, and the binding of Hsp90α/SP1 at the proximal promoter region of PRKDC Because hyperthermia induces DSBs with increases level of DNA-PKcs, combined STA9090 treatment with hyperthermia effectively delayed the tumor growth and significantly decreased DNA-PKcs levels in xenografts model. Consistently, inhibition of Hsp90 increased the number of heat shock-induced γ-H2AX foci and delayed the repair of DSBs. Altogether, our results suggest that Hsp90 inhibitor STA9090 decreases DNA-PKcs protein stability and PRKDC mRNA level, which provide a theoretical basis for the promising combination therapy of hyperthermia and Hsp90 inhibitor in HCC.

10.
Aquat Toxicol ; 238: 105912, 2021 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-34303158

RESUMO

Although the individual toxicity of lead (Pb) and cadmium (Cd) was intensively studied, little is known about their joint toxicity on the development of circadian behavioral rhythm. Therefore, we co-exposed zebrafish to Pb and Cd to investigate the alterations of behavioral rhythm and the potential mechanism. Inductively coupled plasma mass spectrometry analysis was used to detect the internal exposure level of heavy metals. The behavioral rhythm was monitored by a video-track tracking system. The changes of gene expression regarding melatonin-related molecules and clock genes were analyzed by quantitative polymerase chain reaction and JTK-Cycle analysis. The results showed that the level of Pb2+ and Cd2+ accumulated in the co-exposure group were significantly lower than that in the Pb or Cd group. Exposed to Pb reduced the locomotor activity; the behavioral rhythms were disrupted by Cd, while the pattern in the co-exposure group showed an antagonistic effect on locomotor activity and behavioral rhythm. The expression rhythm of aanat1 was disturbed and the expression levels of mtnr1aa and mtnr1bb were decreased by co-exposure treatment, but mtnr1c was increased in Pb and Cd group, respectively. Exposure to Cd caused the disruption of expression rhythm in clock genes, like clock1b, clock2, and cry1b, while only the rhythm of clock2 was disrupted in the co-exposure group. The results suggest that the behavioral rhythm disruption caused by Cd exposure is associated with the disturbance of certain circadian genes, whereas Pb exposure only abates the locomotor activity; an antagonistic effect on the behavioral pattern when co-exposed zebrafish larvae to Pb and Cd.

11.
Am J Transl Res ; 13(6): 6846-6854, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34306435

RESUMO

OBJECTIVE: This study was designed to demonstrate the predictive value of Pulse indicate Contour Cardiac Output (PiCCO) monitoring technique combined with troponin I (cTnI) detection in septic myocardial dysfunction (SMD) of the elderly. METHODS: One hundred and nineteen elderly patients with SMD treated in our hospital from March 2016 to September 2019 were enrolled and allocated into the joint group (JG; 64 cases) for capacity management of fluid resuscitation under the guidance of PiCCO monitoring technique and cTnI detection, and the control group (CG; 55 cases) for conventional capacity management. Clinical indicators, hemodynamics, improvement of myocardial injury markers and inflammatory factors 6 h and 36 h post intervention, fluid balance 6 h, 12 h and 36 h post intervention, drug consumption (norepinephrine), treatment effect and 28-day hospitalization mortality were compared between the two groups. RESULTS: After resuscitation, the urine volume per hour and the fluid resuscitation volume were higher while the blood lactic acid (BLA) expression was lower in JG as compared to CG. JG presented a remarkably lower central venous pressure (CVP) than CG after resuscitation, with notably higher mean arterial pressure (MAP) and central venous oxygen saturation (ScvO2). In comparison with CG, JG displayed dramatically lower cTnI and N-terminal pro-brain natriuretic peptide (NT-ProBNP) 6 h and 36 h post intervention, as well as evidently reduced interleukin-6 (IL-6), procalcitonin (PCT) and high-sensitivity C-reactive protein (hs-CRP). After 36 h of intervention, the fluid balance was evidently lower in JG than in CG. JG showed statistically less use of norepinephrine, less time of mechanical ventilation and ICU stay, and noticeably lower incidence of multiple organ dysfunction syndrome (MODS), as well as dramatically lower 28-day hospitalization mortality than CG post intervention. CONCLUSIONS: PiCCO monitoring technique combined with cTnI detection is high-performing in fluid resuscitation of elderly patients with SMD, which can meliorate the myocardial function of patients, reduce medication and facilitate disease recovery.

12.
Biochem Biophys Res Commun ; 560: 72-79, 2021 06 30.
Artigo em Inglês | MEDLINE | ID: mdl-33975248

RESUMO

Tumor metastasis is a leading cause of mortality in patients with breast cancer (BC). As a predominant component of inflammasome, Nod-like receptor protein 3 (NLRP3) was found to be required for tumor progression, while the role of NLRP3 in BC metastasis remains largely undefined. In current study, we found that invasive BC had aberrant upregulation of NLRP3 expression, especially in the claudin-low subtype. And higher expression of NLRP3 predicted poor survival of BC patients. Further investigation suggested that NLRP3 promotes the migration and invasion, as well as the metastasis of BC cells. Moreover, we revealed that NLRP3 induces the autocrine secretion of IL-1ß to promote epithelial-mesenchymal transition via a Caspase-1-dependent manner. Hence, this study suggested that upregulation of NLRP3 in BC induces the autocrine secretion of IL-1ß and promotes EMT and metastasis of BC cells.


Assuntos
Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal , Interleucina-1beta/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Animais , Comunicação Autócrina , Neoplasias da Mama/mortalidade , Linhagem Celular Tumoral , Movimento Celular , Feminino , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Invasividade Neoplásica , Metástase Neoplásica , Prognóstico , Peixe-Zebra
13.
J Cell Mol Med ; 2021 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-33993645

RESUMO

To investigate the regulatory effect of carbohydrate sulfotransferase 3 (CHST3) in cartilage endplate-derived stem cells (CESCs) on the molecular mechanism of intervertebral disc degeneration after nucleus pulposus repair in rats. We performed GO and KEGG analysis of GSE15227 database to select the differential genes CHST3 and CSPG4 in grade Ⅱ, Ⅲ and Ⅳ intervertebral disc degeneration, IHC and WB to detect the protein profile of CHST3 and CSPG4, Co-IP for the interaction between CHST3 and CSPG4. Then, immunofluorescence was applied to measure the level of CD90 and CD105, and flow cytometry indicated the level of CD73, CD90 and CD105 in CESCs. Next, Alizarin red staining, Alcian blue staining and TEM were performed to evaluate the effects of CESCs into osteoblasts and chondroblasts, respectively, CCK8 for the cell proliferation of osteoblasts and chondroblasts after induction for different times; cell cycle of osteoblasts or chondroblasts was measured by flow cytometry after induction, and WB for the measurement of specific biomarkers of OC and RUNX in osteoblasts and aggrecan, collagen II in chondroblasts. Finally, colony formation was applied to measure the cell proliferation of CESCs transfected with ov-CHST3 or sh-CHST3 when cocultured with bone marrow cells, WB for the protein expression of CHST3, CSPG4 and ELAVL1 in CSECs, transwell assay for the migration of CESCs to bone marrow cells, TEM image for the cellular characteristics of bone marrow cells, and WB for the protein profile of VCAN, VASP, NCAN and OFD1 in bone marrow cells. CHST3 and CSPG4 were differentially expressed and interacted in grade Ⅱ, Ⅲ and Ⅳ intervertebral disc degeneration; CD73, CD90 and CD105 were lowly expressed in CESCs, osteogenic or chondroblastic induction changed the characteristics, proliferation, cell cycle and specific biomarkers of osteoblasts and chondroblasts after 14 or 21 days,; CHST3 affected the cell proliferation, protein profile, migration and cellular features of cocultured CESCs or bone marrow cells. CHST3 overexpression promoted CESCs to regulate bone marrow cells through interaction with CSPG4 to repair the grade Ⅱ, Ⅲ and Ⅳ intervertebral disc degeneration.

14.
Nat Commun ; 12(1): 3008, 2021 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-34021151

RESUMO

Study of human disease remains challenging due to convoluted disease etiologies and complex molecular mechanisms at genetic, genomic, and proteomic levels. Many machine learning-based methods have been developed and widely used to alleviate some analytic challenges in complex human disease studies. While enjoying the modeling flexibility and robustness, these model frameworks suffer from non-transparency and difficulty in interpreting each individual feature due to their sophisticated algorithms. However, identifying important biomarkers is a critical pursuit towards assisting researchers to establish novel hypotheses regarding prevention, diagnosis and treatment of complex human diseases. Herein, we propose a Permutation-based Feature Importance Test (PermFIT) for estimating and testing the feature importance, and for assisting interpretation of individual feature in complex frameworks, including deep neural networks, random forests, and support vector machines. PermFIT (available at https://github.com/SkadiEye/deepTL ) is implemented in a computationally efficient manner, without model refitting. We conduct extensive numerical studies under various scenarios, and show that PermFIT not only yields valid statistical inference, but also improves the prediction accuracy of machine learning models. With the application to the Cancer Genome Atlas kidney tumor data and the HITChip atlas data, PermFIT demonstrates its practical usage in identifying important biomarkers and boosting model prediction performance.


Assuntos
Biomarcadores , Doença/genética , Aprendizado de Máquina , Algoritmos , Humanos , Neoplasias/genética , Redes Neurais de Computação , Proteômica , Máquina de Vetores de Suporte
15.
Microbiol Immunol ; 65(9): 373-382, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34019717

RESUMO

Human cytomegalovirus (HCMV) is most likely to damage the central nervous system (CNS) during early embryonic development; however, the early neurodevelopmental abnormalities caused by HCMV infection and the regulation of cytokines remain unclear. Therefore, we investigated neuronal factors in the serum and cerebrospinal fluid (CSF) of newborns infected with HCMV using protein microarray technology with a view to elucidating the changes in specific neuronal factors for use in the development of a reliable index for predicting CNS injury caused by HCMV infection. Serum and CSF were collected from four newborns with HCMV infection and CNS injury (HCMV-infected group) and from four newborns without CNS infection (control group). A protein microarray containing 29 kinds of CNS-related cytokines was used to identify differentially expressed neuronal factors in the serum and CSF of the HCMV-infected and control groups. The levels of the differentially expressed proteins were verified further in 30 CSF samples from an HCMV-infected group using enzyme-linkedimmunosorbent assay (ELISA). Between newborns in the HCMV-infected and control groups, the protein microarray analysis identified three differentially expressed neurotrophic factors in the CSF samples: Acrp30, MMP-3, and interleukin-1 alpha (IL-1α). No differential cytokine expression was seen in the serum. ELISA showed significantly higher expression levels of Acrp30 and MMP-3 in the CSF of the 30 newborns with HCMV infection and CNS injury than in those in the control group, whereas the expression of IL-1α was significantly lower. Our results demonstrate that changes in the expression levels of Acrp30, MMP-3, and IL-1α in the CSF of newborns infected with HCMV may be related to the pathogenesis of CNS infection.


Assuntos
Infecções por Citomegalovirus , Citomegalovirus , Citocinas , Citomegalovirus/genética , Humanos , Recém-Nascido , Fatores de Crescimento Neural , Reação em Cadeia da Polimerase
16.
World Neurosurg ; 150: e705-e713, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33798780

RESUMO

OBJECTIVE: Surgical treatment is widely used to treat patients with Hirayama disease (HD). However, postoperative follow-up with abundant samples is still scarce. This study investigated short-term to midterm clinical outcomes after anterior cervical discectomy and fusion (ACDF) among patients with HD. METHODS: We enrolled 115 patients with HD who had undergone ACDF. Radiographic parameters included cervical lordosis (CL), sagittal vertical axis, segment lordosis (SL), T1 slope (T1S), T1S minus CL, range of motion (ROM), upper/lower adjacent segment ROM, and upper adjacent SL. Electrophysiologic parameters included the maximal compound muscle action potentials (CMAPs) of abductor digit minimi and abductor pollicis brevis, the latency of the ulnar nerve F reaction, and abnormal spontaneous action potentials. Clinical assessment included the selected brief-Michigan Hand Questionnaire and Odom scale. RESULTS: The average age was 19.5 ± 4.5 years. The mean follow-up time was 16.35 ± 9.21 months. CL, SL, and T1S increased, whereas sagittal vertical axis and ROM decreased at the final follow-up (P < 0.001). Upper adjacent SL, upper adjacent ROM, and lower adjacent ROM were stable after ACDF (P > 0.05). The maximal CMAPs of abductor digit minimi and the latency of the ulnar nerve F reaction improved bilaterally (P < 0.05), whereas there was no significance in the maximal CMAPs of abductor pollicis brevis (P > 0.05). Abnormal spontaneous action potentials reduced remarkably. The selected brief-Michigan Hand Questionnaire score increased after surgery (P < 0.001). The Odom scale showed a ratio of 79.1% (excellent and good ratio). CONCLUSIONS: This study showed favorable radiologic, electrophysiologic, and clinical outcomes after ACDF among patients with HD.


Assuntos
Discotomia/métodos , Fusão Vertebral/métodos , Atrofias Musculares Espinais da Infância/cirurgia , Adolescente , Adulto , Vértebras Cervicais/cirurgia , Seguimentos , Humanos , Masculino , Resultado do Tratamento , Adulto Jovem
17.
Neural Plast ; 2021: 6641506, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33777135

RESUMO

Flaccid paralysis in the upper extremity is a severe motor impairment after stroke, which exists for weeks, months, or even years. Electroacupuncture treatment is one of the most widely used TCM therapeutic interventions for poststroke flaccid paralysis. However, the response to electroacupuncture in different durations of flaccid stage poststroke as well as in the topological configuration of the cortical network remains unclear. The objectives of this study are to explore the disruption of the cortical network in patients in different durations of flaccid stage and observe dynamic network reorganization during and after electroacupuncture. Resting-state networks were constructed from 18 subjects with flaccid upper extremity by partial directed coherence (PDC) analysis of multichannel EEG. They were allocated to three groups according to time after flaccid paralysis: the short-duration group (those with flaccidity for less than two months), the medium-duration group (those with flaccidity between two months and six months), and the long-duration group (those with flaccidity over six months). Compared with short-duration flaccid subjects, weakened effective connectivity was presented in medium-duration and long-duration groups before electroacupuncture. The long-duration group has no response in the cortical network during electroacupuncture. The global network measures of EEG data (sPDC, mPDC, and N) indicated that there was no significant difference among the three groups. These results suggested that the network connectivity reduced and weakly responded to electroacupuncture in patients with flaccid paralysis for over six months. These findings may help us to modulate the formulation of electroacupuncture treatment according to different durations of the flaccid upper extremity.


Assuntos
Eletroacupuntura/métodos , Eletroencefalografia/métodos , Paralisia/fisiopatologia , Paralisia/terapia , Acidente Vascular Cerebral/fisiopatologia , Acidente Vascular Cerebral/terapia , Adulto , Idoso , Ritmo beta/fisiologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Paralisia/etiologia , Projetos Piloto , Acidente Vascular Cerebral/complicações
18.
Biometrics ; 2021 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-33786811

RESUMO

Polygenic risk scores (PRS) have gained substantial attention for complex traits prediction in genome-wide association studies (GWAS). Motivated by the polygenic model of complex traits, we study the statistical properties of PRS under the high-dimensional but sparsity free setting where the triplet ( n , p , m ) → ( ∞ , ∞ , ∞ ) with n , p , m being the sample size, the number of assayed single-nucleotide polymorphisms (SNPs), and the number of assayed causal SNPs, respectively. First, we derive asymptotic results on the out-of-sample (prediction) R-squared for PRS. These results help understand the widespread observed gap between the in-sample heritability (or partial R-squared due to the genetic features) estimate and the out-of-sample R-squared for most complex traits. Next, we investigate how features should be selected (e.g., by a p-value threshold) for constructing optimal PRS. We reveal that the optimal threshold depends largely on the genetic architecture underlying the complex trait and the sample size of the training GWAS, or the m / n ratio. For highly polygenic traits with a large m / n ratio, it is difficult to separate causal and null SNPs and stringent feature selection in principle often leads to poor PRS prediction. We numerically illustrate the theoretical results with intensive simulation studies and real data analysis on 33 complex traits with a wide range of genetic architectures in the UK Biobank database.

19.
Ann Palliat Med ; 10(2): 2238-2253, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33725777

RESUMO

BACKGROUND: Abnormal microangiogenesis and microenvironmental disturbances within the Nasopharyngeal carcinoma (NPC) can exacerbate tumor hypoxia, which may increase radiotherapy resistance and thus lead to poor prognosis in NPC patients. A non-invasive imaging technique, dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), which can reflect the tumor blood perfusion and angiogenesis status, was used to investigate the relationships of DCE-MRI parameters with hypoxia-inducible factor 1 alpha (HIF-1α) expression and tumor grades in NPC patients. METHODS: 42 treatment-naive patients with pathologically confirmed NPC were enrolled in this analysis. Plain magnetic resonance scans and DCE-MRI scans were performed before treatment, and post-processing was performed to calculate the relative enhancement (RE), maximum relative enhancement (MRE), maximum enhancement (ME), wash-in rate (WIR), wash-out rate (WOR), time to peak (TTP), and area under the curve (AUC). Immunohistochemistry was used to detect HIF-1α expression in electronasopharyngeal fiberoscopic specimens. The clinical grade/stage of NPC was jointly assessed by an experienced radiologist and a radiotherapist. The potential correlations of the DCE-MRI parameters with HIF-1α expression and clinical grades were analyzed. The statistical analysis was performed using SPSS 17.0 software package. RESULTS: Among DCE-MRI parameters, RE, ME, and MRE were associated with the positive expression of HIF-lα in NPC and could reflect the hypoxic status in the local microenvironment of the cancer foci in vivo. RE, ME, and MRE were significantly higher in the positive HIF-1α expression group than in the negative HIF-1α expression group (F=5.281, P=0.027; F=11.923, P=0.001; F=6.228, P=0.017). RE, ME, and MRE were significantly correlated with clinical grade (F=3.646, P=0.021; F=3.204, P=0.034, F=3.050, P=0.040) and T stage (F=6.578, P=0.001; F=3.540, P=0.023; F=4.384, P=0.010). The values of RE, MRE, and ME gradually increased as the clinical grade and T stage increased. CONCLUSIONS: DCE-MRI is a valuable imaging technique for the noninvasive evaluation of hypoxia in NPC, the development of individualized treatment protocols, and the prediction of efficacy.


Assuntos
Meios de Contraste , Neoplasias Nasofaríngeas , Humanos , Hipóxia , Imageamento por Ressonância Magnética , Carcinoma Nasofaríngeo/diagnóstico por imagem , Carcinoma Nasofaríngeo/radioterapia , Neoplasias Nasofaríngeas/diagnóstico por imagem , Neoplasias Nasofaríngeas/radioterapia , Microambiente Tumoral
20.
G3 (Bethesda) ; 11(5)2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33772539

RESUMO

Allelic imbalance (AI) occurs when alleles in a diploid individual are differentially expressed and indicates cis acting regulatory variation. What is the distribution of allelic effects in a natural population? Are all alleles the same? Are all alleles distinct? The approach described applies to any technology generating allele-specific sequence counts, for example for chromatin accessibility and can be applied generally including to comparisons between tissues or environments for the same genotype. Tests of allelic effect are generally performed by crossing individuals and comparing expression between alleles directly in the F1. However, a crossing scheme that compares alleles pairwise is a prohibitive cost for more than a handful of alleles as the number of crosses is at least (n2-n)/2 where n is the number of alleles. We show here that a testcross design followed by a hypothesis test of AI between testcrosses can be used to infer differences between nontester alleles, allowing n alleles to be compared with n crosses. Using a mouse data set where both testcrosses and direct comparisons have been performed, we show that the predicted differences between nontester alleles are validated at levels of over 90% when a parent-of-origin effect is present and of 60%-80% overall. Power considerations for a testcross, are similar to those in a reciprocal cross. In all applications, the testing for AI involves several complex bioinformatics steps. BayesASE is a complete bioinformatics pipeline that incorporates state-of-the-art error reduction techniques and a flexible Bayesian approach to estimating AI and formally comparing levels of AI between conditions. The modular structure of BayesASE has been packaged in Galaxy, made available in Nextflow and as a collection of scripts for the SLURM workload manager on github (https://github.com/McIntyre-Lab/BayesASE).


Assuntos
Desequilíbrio Alélico , Polimorfismo de Nucleotídeo Único , Alelos , Teorema de Bayes , Genótipo
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