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1.
Nat Med ; 27(1): 66-72, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33432171

RESUMO

The clinical impact of rare loss-of-function variants has yet to be determined for most genes. Integration of DNA sequencing data with electronic health records (EHRs) could enhance our understanding of the contribution of rare genetic variation to human disease1. By leveraging 10,900 whole-exome sequences linked to EHR data in the Penn Medicine Biobank, we addressed the association of the cumulative effects of rare predicted loss-of-function variants for each individual gene on human disease on an exome-wide scale, as assessed using a set of diverse EHR phenotypes. After discovering 97 genes with exome-by-phenome-wide significant phenotype associations (P < 10-6), we replicated 26 of these in the Penn Medicine Biobank, as well as in three other medical biobanks and the population-based UK Biobank. Of these 26 genes, five had associations that have been previously reported and represented positive controls, whereas 21 had phenotype associations not previously reported, among which were genes implicated in glaucoma, aortic ectasia, diabetes mellitus, muscular dystrophy and hearing loss. These findings show the value of aggregating rare predicted loss-of-function variants into 'gene burdens' for identifying new gene-disease associations using EHR phenotypes in a medical biobank. We suggest that application of this approach to even larger numbers of individuals will provide the statistical power required to uncover unexplored relationships between rare genetic variation and disease phenotypes.

2.
Int Urol Nephrol ; 2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33428167

RESUMO

The intestinal barrier is the first line of defense against foreign antigens. Tight junctions play an important role in maintaining the function of the intestinal wall. Zonulin is the only physiological protein discovered in recent years that can reversibly regulate tight junctions in human body. It changes the permeability of intestinal epithelial cells by regulating the state of tight junctions. Increased intestinal permeability can lead to abnormal activation of intestinal mucosal immune and bacterial translocation, then inducing systemic inflammation. It has already been reported that zonulin plays an important pathogenic role in a variety of diseases by regulating tight junctions leading to an abnormal increase of intestinal permeability. However, the research on the pathogenic role and mechanism of zonulin pathway in kidney disease is still in its infancy. Therefore, we reviewed the progress on pathophysiological characteristics of zonulin as well as the pathogenesis of zonulin in kidney disease in this paper.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33403504

RESUMO

PURPOSE: There are limited genes known to cause primary ciliary dyskinesia (PCD)-associated asthenozoospermia. In the present study, we aimed to expand the spectrum of mutations in PCD and to provide new information for genetic counseling diagnoses and the treatment of male infertility in PCD. METHODS: One sterile patient with typical situs inversus was recruited to our center, and semen sample was collected. We performed whole-exome sequencing (WES) on the patient to identify the pathogenic mutations associated with PCD and used transmission electron microscopy to investigate spermatozoal ultrastructure. In addition, western blotting and immunofluorescence staining were used to confirm the untoward impact of the variant on the expression of LRRC6, as well as on the dynein arm proteins in the patient's spermatozoa. RESULTS: We identified a homozygous nonsense variant c.749G>A (p.W250*) of LRRC6 in the PCD patient. This variant severely impaired LRRC6 expression and further led to negative effects on dynein arm protein expression in the spermatozoa of the affected individual, which eventually caused defects in sperm ultrastructure and motility. Moreover, we are the first to report a positive prognosis using intracytoplasmic sperm injection (ICSI) for LRRC6-associated male infertility. CONCLUSIONS: Our findings strongly implicated the homozygous mutation of c.749G>A (p.W250*) in LRRC6 as a new genetic cause of PCD, uncovering its involvement in defective sperm flagella and poor sperm motility. Furthermore, we posit that patients with LRRC6 mutations may have good outcomes with ICSI treatment. These findings add to the literature on the genetic diagnoses and treatment of male infertility associated with PCD.

4.
J Nanosci Nanotechnol ; 21(3): 1462-1473, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33404409

RESUMO

In this work, a novel N-doped magnetic mesoporous carbon (NMC) composite (Fe3O4/NMC) was synthesized by a two-step process. First, NMC was prepared by a template method using a melamine formaldehyde resin as nitrogen and carbon sources, and then, Fe3O4 nanoparticles were loaded into the as-prepared NMC via in-situ coprecipitation process. The morphology, structure, and magnetic properties of Fe3O4/NMC were characterized and its adsorption properties were investigated. It can be found that Fe3O4/NMC with saturation magnetization of 20 emu · g-1 features a mesoporous structure, and its specific surface area reaches 513 m² · g-1. These two excellent specificities are propitious to the adsorption and separation of Ag(I) from aqueous solution. The adsorption behavior of Fe3O4/NMC nanocomposite has been investigated by adsorption kinetics and isotherms adsorption analyses as well. The adsorption isotherm and the adsorption kinetics of Ag(I) onto Fe3O4/NMC agrees well with Langmuir model and pseudo-second-order model, respectively. Moreover, the Fe3O4/NMC was easily to recovery by applied magnetic field, the adsorption capacity of Fe3O4/NMC was about 90.3% of the initial saturation adsorption capacity after five continuous uses.

6.
J Clin Invest ; 131(1)2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33393505

RESUMO

Human herpes simplex virus 1 (HSV-1) encephalitis can be caused by inborn errors of the TLR3 pathway, resulting in impairment of CNS cell-intrinsic antiviral immunity. Deficiencies of the TLR3 pathway impair cell-intrinsic immunity to vesicular stomatitis virus (VSV) and HSV-1 in fibroblasts, and to HSV-1 in cortical but not trigeminal neurons. The underlying molecular mechanism is thought to involve impaired IFN-α/ß induction by the TLR3 recognition of dsRNA viral intermediates or by-products. However, we show here that human TLR3 controls constitutive levels of IFNB mRNA and secreted bioactive IFN-ß protein, and thereby also controls constitutive mRNA levels for IFN-stimulated genes (ISGs) in fibroblasts. Tlr3-/- mouse embryonic fibroblasts also have lower basal ISG levels. Moreover, human TLR3 controls basal levels of IFN-ß secretion and ISG mRNA in induced pluripotent stem cell-derived cortical neurons. Consistently, TLR3-deficient human fibroblasts and cortical neurons are vulnerable not only to both VSV and HSV-1, but also to several other families of viruses. The mechanism by which TLR3 restricts viral growth in human fibroblasts and cortical neurons in vitro and, by inference, by which the human CNS prevents infection by HSV-1 in vivo, is therefore based on the control of early viral infection by basal IFN-ß immunity.

7.
Proc Natl Acad Sci U S A ; 118(3)2021 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-33408250

RESUMO

Genetic variants underlying life-threatening diseases, being unlikely to be transmitted to the next generation, are gradually and selectively eliminated from the population through negative selection. We study the determinants of this evolutionary process in human genes underlying monogenic diseases by comparing various negative selection scores and an integrative approach, CoNeS, at 366 loci underlying inborn errors of immunity (IEI). We find that genes underlying autosomal dominant (AD) or X-linked IEI have stronger negative selection scores than those underlying autosomal recessive (AR) IEI, whose scores are not different from those of genes not known to be disease causing. Nevertheless, genes underlying AR IEI that are lethal before reproductive maturity with complete penetrance have stronger negative selection scores than other genes underlying AR IEI. We also show that genes underlying AD IEI by loss of function have stronger negative selection scores than genes underlying AD IEI by gain of function, while genes underlying AD IEI by haploinsufficiency are under stronger negative selection than other genes underlying AD IEI. These results are replicated in 1,140 genes underlying inborn errors of neurodevelopment. Finally, we propose a supervised classifier, SCoNeS, which predicts better than state-of-the-art approaches whether a gene is more likely to underlie an AD or AR disease. The clinical outcomes of monogenic inborn errors, together with their mode and mechanisms of inheritance, determine the levels of negative selection at their corresponding loci. Integrating scores of negative selection may facilitate the prioritization of candidate genes and variants in patients suspected to carry an inborn error.

8.
Life Sci ; : 119004, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33417960

RESUMO

BACKGROUND: Mesenchymal stem cells (MSCs) are widely applied in various clinical disorders, including acute lung injury (ALI). We aimed to investigate the effects of human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs)-derived exosomal microRNA-22-3p (miR-22-3p) on lipopolysaccharid (LPS)-induced ALI via regulating frizzled class receptor 6 (FZD6). METHODS: Rat lung cells were selected to construct the LPS-induced ALI cell model. The LPS-treated cells were transfected with restored miR-22-3p and depleted FZD6 for investigating their roles in ALI. Human UCB-MSCs were cultured and exosomes were extracted. Rat lung cells were co-cultured with exosomes that had been transfected with restored miR-22-3p and upregulated FZD6 to detect their roles in inflammatory reaction, oxidative stress, cell proliferation activity and apoptosis. The ALI rat model was established through LPS inhalation and the rats were respectively treated. Then, the pathology, apoptosis and expression of the NF-κB signaling pathway-related factors in rat lung tissues were determined. RESULTS: miR-22-3p expression was reduced and FZD6 expression was enhanced in LPS-treated rat lung cells while exosomes raised miR-22-3p expression and decreased FZD6 expression. In LPS-treated cells, up-regulating miR-22-3p or depleting FZD6 reduced inflammatory reaction and oxidative stress response, raised rat lung cell proliferation activity and inhibited cell apoptosis rate. In the in vivo ALI model, exosomes suppressed pathological changes, apoptosis and NF-κB expression in LPS-treated rats. Upregulated miR-22-3p further attenuated ALI. CONCLUSION: Our study highlights the potential of UCB-MSC-exosomal miR-22-3p in preventing ALI. This study may provide further insights into ALI therapy.

9.
Pain Physician ; 24(1): 89-97, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33400432

RESUMO

BACKGROUND: Trigeminal neuralgia is a very painful condition, and radiofrequency therapy is reserved for patients who are resistant or intolerant to pharmacologic therapy. Continuous radiofrequency (CRF) and pulsed radiofrequency (PRF) both have advantages and disadvantages. Recently, studies have found that PRF combined with low-temperature (< 65°C) CRF increases the efficacy of treatment, without leading to a significant increase in complications caused by nerve lesions. However, these reports have some limitations. OBJECTIVES: We plan to conduct a randomized, controlled study to compare the efficacy of applying high-voltage PRF, with and without low-temperature CRF, to the Gasserian ganglion for the treatment of trigeminal neuralgia. STUDY DESIGN: A study protocol for a prospective, open-label, parallel, randomized controlled trial (clinicaltrials.gov; NCT04174443). SETTING: The Department of Pain Management, Beijing Tiantan Hospital, Capital Medical University in Beijing, China. METHODS: One hundred forty-six patients with primary trigeminal neuralgia will be randomly assigned to 1 of 2 groups using an allocation ratio of 1:1. In the high-voltage PRF combined with low-temperature CRF group, 2 Hz of PRF will be applied under the following conditions: a voltage of 70 V, temperature of 42°C, pulse width of 20 ms, and treatment time of 600 s. Low-temperature CRF will then be performed at 60°C, with a treatment time of 270 s. In the high-voltage PRF group, only high-voltage PRF will be performed, using the same treatment parameters. Follow-up process will last for a duration of 1 year. RESULTS: The primary outcome will be the effectiveness of the treatment after 12 months, which is the percentage of patients with a modified Barrow Neurological Institute Pain Intensity Score (BNI) between I and III. The secondary outcome will include the following: BNI score, Numeric Rating Scale, dose of carbamazepine or oxcarbazepine, patient satisfaction score, quality of life, numbness, side effects, and adverse reactions. These will be recorded over a 1-year follow-up period. LIMITATIONS: The open-label study design may influence the measurement of outcomes and introduce bias, for example, performance or ascertainment bias. CONCLUSIONS: To our knowledge, this will be the first prospective, open-label, parallel, randomized controlled trial to compare the efficacy and safety of the application of high-voltage PRF, combined with and without low-temperature (60°C) CRF, for the patients who have failed to respond to pharmacologic treatments for primary trigeminal neuralgia. If proven effective, this will be an important, safe, minimally destructive alternative treatment modality for primary trigeminal neuralgia following an ineffective conservative treatment.

10.
Mol Biol Rep ; 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33394235

RESUMO

We previously reported that Numb, a protein localized to clathrin-coated vesicles, regulates the membrane expression of metabotropic glutamate receptor 5 (mGluR5) and is critical to social behaviors. However, the distinct actions of Numb isoforms on mGluR5 have not been investigated. Here, we showed that the expression patterns of Numb-p72 and Numb-p65, two important isoforms of Numb, were distinct in HEK293T cells. Numb-p72, but not Numb-p65, bound to mGluR5α, and enhanced mGluR5 membrane expression by inhibiting its internalization. Our results suggest that a complete structure is required for Numb to bind to mGluR5 and to modulate mGluR5 trafficking.

11.
Arterioscler Thromb Vasc Biol ; 41(1): 302-316, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33028096

RESUMO

OBJECTIVE: Vascular smooth muscle cells (SMCs) dedifferentiate and initiate expression of macrophage markers with cholesterol exposure. This phenotypic switching is dependent on the transcription factor Klf4 (Krüppel-like factor 4). We investigated the molecular pathway by which cholesterol induces SMC phenotypic switching. Approach and Results: With exposure to free cholesterol, SMCs decrease expression of contractile markers, activate Klf4, and upregulate a subset of macrophage and fibroblast markers characteristic of modulated SMCs that appear with atherosclerotic plaque formation. These phenotypic changes are associated with activation of all 3 pathways of the endoplasmic reticulum unfolded protein response (UPR), Perk (protein kinase RNA-like endoplasmic reticulum kinase), Ire (inositol-requiring enzyme) 1α, and Atf (activating transcription factor) 6. Blocking the movement of cholesterol from the plasma membrane to the endoplasmic reticulum prevents free cholesterol-induced UPR, Klf4 activation, and upregulation of the majority of macrophage and fibroblast markers. Cholesterol-induced phenotypic switching is also prevented by global UPR inhibition or specific inhibition of Perk signaling. Exposure to chemical UPR inducers, tunicamycin and thapsigargin, is sufficient to induce these same phenotypic transitions. Finally, analysis of published single-cell RNA sequencing data during atherosclerotic plaque formation in hyperlipidemic mice provides preliminary in vivo evidence of a role of UPR activation in modulated SMCs. CONCLUSIONS: Our data demonstrate that UPR is necessary and sufficient to drive phenotypic switching of SMCs to cells that resemble modulated SMCs found in atherosclerotic plaques. Preventing a UPR in hyperlipidemic mice diminishes atherosclerotic burden, and our data suggest that preventing SMC transition to dedifferentiated cells expressing macrophage and fibroblast markers contributes to this decreased plaque burden.

12.
Acta Pharmacol Sin ; 42(1): 115-119, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32404981

RESUMO

Acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as erlotinib, remains a major challenge in the targeted therapy of non-small cell lung cancer (NSCLC). HKB99 is a novel allosteric inhibitor of phosphoglycerate mutase 1 (PGAM1) that preferentially suppresses cell proliferation and induces more apoptosis in acquired erlotinib-resistant HCC827ER cells compared with its parental HCC827 cells. In this study we identified the molecular biomarkers for HKB99 response in erlotinib-resistant HCC827ER cells. We showed that HCC827ER cells displayed enhanced invasive pseudopodia structures as well as downregulated plasminogen activator inhibitor-2 (PAI-2). Meanwhile, PAI-2 knockdown by siPAI-2 candidates decreased the sensitivity of HCC827 parental cells to erlotinib. Moreover, HKB99 (5 µM) preferentially inhibited the invasive pseudopodia formation and increased the level of PAI-2 in HCC827ER cells. Collectively, this study provides new insight into the role of PAI-2 in regulating the sensitivity of erlotinib resistant NSCLC cells to PGAM1 inhibitor. Furthermore, PAI-2 level might be considered as a potential biomarker for predicting the efficacy of the PGAM1 allosteric inhibitor on the erlotinib resistant NSCLC cells.

13.
IEEE Trans Neural Netw Learn Syst ; 32(1): 49-62, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32149657

RESUMO

Open-domain dialog generation, which is a crucial component of artificial intelligence, is an essential and challenging problem. In this article, we present a personalized dialog system, which leverages the advantages of multitask learning and reinforcement learning for personalized dialogue generation (MRPDG). Specifically, MRPDG consists of two subtasks: 1) an author profiling module that recognizes user characteristics from the input sentence (auxiliary task) and 2) a personalized dialog generation system that generates informative, grammatical, and coherent responses with reinforcement learning algorithms (primary task). Three kinds of rewards are proposed to generate high-quality conversations. We investigate the effectiveness of three widely used reinforcement learning methods [i.e., Q-learning, policy gradient, and actor-critic (AC) algorithm] in a personalized dialog generation system and demonstrate that the AC algorithm achieves the best results on the underlying framework. Comprehensive experiments are conducted to evaluate the performance of the proposed model on two real-life data sets. Experimental results illustrate that MRPDG is able to produce high-quality personalized dialogs for users with different characteristics. Quantitatively, the proposed model can achieve better performance than the compared methods across different evaluation metrics, such as the human evaluation, BiLingual Evaluation Understudy (BLEU), and perplexity.

14.
J Nutr ; 151(1): 98-103, 2021 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-33188401

RESUMO

BACKGROUND: Vitamin D might have beneficial potential in influencing the natural history of the coronavirus disease 2019 (COVID-19) due to its immunomodulatory and anti-inflammatory properties. OBJECTIVE: The aim was to investigate whether vitamin D deficiency is associated with COVID-19 incidence and disease severity in Chinese people. METHODS: In a cross-sectional study we retrospectively analyzed 335 COVID-19 patients (median: 56.0; IQR: 43.0-64.0 y) who were admitted to the Wuhan Tongji Hospital between 27 February and 21 March 2020. We also included an age- and sex-matched population of 560 individuals (median: 55; IQR: 49.0-60.0 y) who underwent the physical examination program. Their serum 25-hydroxyvitamin D [25(OH)D] concentrations were measured during the same period from 2018-2019. Serum 25(OH)D concentrations were measured for all COVID-19 patients on admission. Severity of COVID-19 was determined based on the level of respiratory involvement. A general linear model with adjustment for covariates was used to compare 25(OH)D concentrations between the COVID-19 and 2018-2019 control groups. Adjusted ORs with 95% CIs for associations between vitamin D status and COVID-19 severity were estimated via multivariable logistic regression. RESULTS: In the general linear model adjusted for age, sex, comorbidities, and BMI, serum 25(OH)D concentrations were significantly lower among COVID-19 patients than the 2018-2019 controls [ln transformed values of 3.32 ± 0.04 vs. 3.46 ± 0.022 ln (nmol/L), P = 0.014]. Multivariable logistic regression showed that male sex (OR: 2.26; 95% CI: 1.06, 4.82), advanced age (≥65 y) (OR: 4.93; 95% CI: 1.44, 16.9), and vitamin D deficiency (<30 nmol/L) (OR: 2.72; 95% CI: 1.23, 6.01) were significantly associated with COVID-19 severity (all P < 0.05). CONCLUSIONS: These findings suggested that vitamin D deficiency impacts COVID-19 hospitalization and severity in the Chinese population.

15.
Arterioscler Thromb Vasc Biol ; 41(1): 269-283, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33054396

RESUMO

OBJECTIVE: Turner syndrome women (monosomy X) have high risk of aortopathies consistent with a role for sex chromosomes in disease development. We demonstrated that sex chromosomes influence regional development of Ang II (angiotensin II)-induced aortopathies in mice. In this study, we determined if the number of X chromosomes regulates regional development of Ang II-induced aortopathies. Approach and Results: We used females with varying numbers of X chromosomes (XX female mice [XXF] or XO female mice [XOF]) on an C57BL/6J (ascending aortopathies) or low-density lipoprotein receptor deficient (Ldlr-/-) background (descending and abdominal aortopathies) compared with XY males (XYM). To induce aortopathies, mice were infused with Ang II. XOF (C57BL/6J) exhibited larger percent increases in ascending aortic lumen diameters than Ang II-infused XXF or XYM. Ang II-infused XOF (Ldlr-/-) exhibited similar incidences of thoracic (XOF, 50%; XYM, 71%) and abdominal aortopathies (XOF, 83%; XYM, 71%) as XYM, which were greater than XXF (XXF, 0%). Abdominal aortic lumen diameters and maximal external diameters were similar between XOF and XYM but greater than XXF, and these effects persisted with extended Ang II infusions. Larger aortic lumen diameters, abdominal aortopathy incidence (XXF, 20%; XOF, 75%), and maximal aneurysm diameters (XXF, 1.02±0.17; XOF, 1.96±0.32 mm; P=0.027) persisted in ovariectomized Ang II-infused XOF mice. Data from RNA-seq demonstrated that X chromosome genes that escape X-inactivation (histone lysine demethylases Kdm5c and Kdm6a) exhibited lower mRNA abundance in aortas of XOF than XXF (P=0.033 and 0.024, respectively). Conversely, DNA methylation was higher in aortas of XOF than XXF (P=0.038). CONCLUSIONS: The absence of a second X chromosome promotes diffuse Ang II-induced aortopathies in females.

16.
Clin Nucl Med ; 46(1): e6-e7, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-32604103

RESUMO

Rectal leiomyoma is an exceedingly rare benign lesion. We here report a case with extraluminal leiomyoma of the middle and lower parts of the rectum showing aberrant hypermetabolism on F-FDG PET/CT in a 54-year-old man.


Assuntos
Fluordesoxiglucose F18 , Leiomioma/diagnóstico por imagem , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Neoplasias Retais/diagnóstico por imagem , Diagnóstico Diferencial , Humanos , Leiomioma/patologia , Masculino , Pessoa de Meia-Idade , Neoplasias Retais/patologia
17.
Exp Cell Res ; 398(1): 112392, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33227315

RESUMO

BACKGROUND: The proliferation of pulmonary arterial smooth muscle cells (PASMCs) and subsequent pulmonary vascular remodeling leads to pulmonary arterial hypertension (PAH). Understanding the underlying mechanisms and identifying molecules that can suppress PASMCs proliferation is critical for developing effective pharmacological treatment. We previously showed that plasminogen activator inhibitor-2 (PAI-2) inhibited human PASMC (hPASMCs) proliferation in vitro. However, its inhibitory effect on PAH remains to be determined, and the mechanism remains to be illustrated. METHODS: We compared serum PAI-2 levels between PAH patients and healthy controls, and examined the correlation between PAI-2 level and disease severity. In monocrotaline-induced PAH rats, we examined the effects of exogenous PAI-2 administration on pulmonary vascular remodeling and PAH development. The effect of PAI-2 and potential mechanisms was further examined in cultured hPASMCs. RESULTS: The serum PAI-2 was decreased in PAH patients compared with controls. PAI-2 level was negatively correlated with mean pulmonary arterial pressure and estimated systolic pulmonary arterial pressure in ultrasonic cardiogram, while positively correlated with 6-min walking distance. In rats, administration of exogenous PAI-2 significantly reversed monocrotaline-induced PAH, as indicated by the decrease in right ventricle systolic pressure, right ventricular hypertrophy index and percent media thickness of pulmonary arterioles. Further mechanistic investigation in hPASMCs showed that PAI-2 inhibited cell proliferation by preventing the activation of PI3K/Akt and ERK pathways. CONCLUSION: PAI-2 is downregulated in PAH patients. PAI-2 attenuates PAH development by suppressing hPASMCs proliferation via the inhibition of PI3K/Akt and ERK pathways. PAI-2 may serve as a potential biomarker and therapeutic target for PAH.

18.
J Clin Invest ; 131(1)2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-32960813

RESUMO

Inborn errors of TLR3-dependent IFN-α/ß- and IFN-λ-mediated immunity in the CNS can underlie herpes simplex virus 1 (HSV-1) encephalitis (HSE). The respective contributions of IFN-α/ß and IFN-λ are unknown. We report a child homozygous for a genomic deletion of the entire coding sequence and part of the 3'-UTR of the last exon of IFNAR1, who died of HSE at the age of 2 years. An older cousin died following vaccination against measles, mumps, and rubella at 12 months of age, and another 17-year-old cousin homozygous for the same variant has had other, less severe, viral illnesses. The encoded IFNAR1 protein is expressed on the cell surface but is truncated and cannot interact with the tyrosine kinase TYK2. The patient's fibroblasts and EBV-B cells did not respond to IFN-α2b or IFN-ß, in terms of STAT1, STAT2, and STAT3 phosphorylation or the genome-wide induction of IFN-stimulated genes. The patient's fibroblasts were susceptible to viruses, including HSV-1, even in the presence of exogenous IFN-α2b or IFN-ß. HSE is therefore a consequence of inherited complete IFNAR1 deficiency. This viral disease occurred in natural conditions, unlike those previously reported in other patients with IFNAR1 or IFNAR2 deficiency. This experiment of nature indicates that IFN-α/ß are essential for anti-HSV-1 immunity in the CNS.

19.
Mol Nutr Food Res ; : e2000864, 2020 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-33258303

RESUMO

SCOPE: Large-leaf yellow tea (YT) exhibits interesting beneficial metabolic effects in previous studies. Here, the authors elucidated the actions of YT on thermogenesis, energy metabolism, and adipocyte metabolic conversion. METHODS AND RESULTS: Five-week-old male C57BL/6 mice are fed low-fat diet, high-fat diet (HFD), and HFD supplemented with 0.5% or 2.5% YT. After treatment for 10 or 14 weeks, YT enhances energy expenditure, O2 consumption and CO2 production. YT strongly boosts thermogenic program in brown adipose tissue (BAT) and subcutaneous adipose tissue (SAT), while only weakly in epididymal adipose tissue (EAT). These are accompanied by higher body temperature, increased mitochondrial copy numbers, and upregulation of thermogenic genes (Ucp1, Pgc1α, etc.) and proteins. The classic brown adipocyte markers (Eva1, Zic1) are induced only in BAT, while beige adipocyte markers (Tbx1, Tmem26) are boosted only in SAT. Furthermore, subcutaneous-originated preadipocytes are induced by YT in vitro to differentiate to brown-like adipocytes - a browning effect. CONCLUSION: Dietary YT induces adaptive thermogenesis through increasing mitochondrial biogenesis in EAT, inducing beigeing in SAT and enhancing browning in the BAT.

20.
Gynecol Obstet Invest ; : 1-8, 2020 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-33279890

RESUMO

OBJECTIVE: To investigate the expression of T-cell immunoglobulin and mucin domain 3 (TIM-3) on peripheral T cells of cervical carcinoma patients. METHODS: Peripheral blood samples from 15 high-grade cervical squamous intraepithelial lesion (HSIL) patients, 24 cervical carcinoma patients, and 21 healthy controls were collected. TIM-3 expressions on the surface of peripheral CD4+ T cells and CD8+ T cells were analyzed with flow cytometry. RESULTS: There was significantly lower expression of CD4+ T cells and CD8+ T cells in HSIL patients and cervical carcinoma patients compared with healthy controls. We also found that TIM-3 expression on peripheral CD4+ T and CD8+ T cells of both HSIL patients and cervical carcinoma patients was significantly increased compared to the control group. Further analyses revealed that the expression of TIM-3 on peripheral CD4+ T and CD8+ T cells significantly increased in stage III-IV cervical carcinoma patients compared to stages I-II. CONCLUSION: The increased expression of TIM-3 on CD4+ T cells and CD8+ T cells of patients with cervical carcinoma and HSIL suggests the potential role of TIM-3 in the development and progression of cervical carcinoma, which may be a novel therapy target for cervical carcinoma.

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