Off-label use of Baricitinib improves moderate and severe atopic dermatitis in China through inhibiting MAPK and PI3K/Akt/mTOR pathway via targeting JAK-STAT signaling of CD4+ cells

As an inflammatory disease with a disrupted immune system, cytokine disorders in atopic dermatitis (AD) are closely related to the abnormal activation of JAK-STAT signal pathway. The critical relevance of the JAK-STAT signaling pathway to the pathogenesis of AD provides a strong rationale for JAK inhibitor research. Baricitinib, a small-molecule oral JAK inhibitor, has been proven to inhibit JAK-STAT signaling in a variety of diseases, including AD. It is currently available in China for off-label use. However, its efficacy in China and its mechanism are rarely reported. In our study, we found that the immune status of patients with moderate and severe AD was hyperactive. Among the 49 known immunotherapy targets, JAK1 and JAK2 genes on lymphocytes of AD patients were significantly upregulated, which was closely related to the symptom severity in moderate and severe AD patients. Baricitinib can improve immune hyperresponsiveness and clinical symptoms in moderate and severe AD by inhibiting the activation of Th2 cell subsets and the secretion of Th2-type cytokines through MAPK, mTOR and PI3K-Akt signaling pathways, providing an important theoretical basis for clinical off-label use of Baricitinib to treat moderate and severe AD

Compound Heterozygous CHAT Gene Mutations of a Large Deletion and a Missense Variant in a Chinese Patient With Severe Congenital Myasthenic Syndrome With Episodic Apnea

Congenital myasthenic syndromes (CMSs) are a group of inherited disorders caused by genetic defects in neuromuscular junctions. Mutations in CHAT, encoding choline acetyltransferase, cause congenital myasthenic syndrome with episodic apnea (CMS-EA), a rare autosomal recessive disease characterized by respiratory insufficiency with cyanosis and apnea after infections, fever, vomiting, or excitement. To date, no studies have reported deletions comprised of multiple exons. Here, using next generation sequencing, we identified compound heterozygous mutations, namely a large maternally inherited deletion, including exons 4, 5, and 6, and a paternally inherited missense variant (c.914T>C [p.Ile305Thr]) in CHAT in a Chinese patient with a severe phenotype of CMS-EA. Furthermore, the large deletion was also validated by real-time fluorescence quantitative polymerase chain reaction. The patient was a 10-month-old boy, who presented with a weak cry and feeding difficulties soon after birth, ptosis at 4 months old, episodic apnea after fever at 9 months old, and respiratory insufficiency with cyanosis and apnea that required intubation after a respiratory tract infection at 10 months old. Unfortunately, he died in the Pediatric Intensive Care Unit soon after hospitalization. The patient’s elder sister had similar clinical manifestations, and she died prior to the age of 2 months old without a diagnosis. Genotype-phenotype correlation analysis revealed that loss-of-function mutations in exons 4–6 of CHAT might cause more severe CMS-EA. To our knowledge, this is the first study to show compound heterozygous CHAT mutations consisting of a large deletion and missense mutation in a patient with CMS-EA

SIP-Based Single Neuron Stochastic Predictive Control for Non-Gaussian Networked Control Systems with Uncertain Metrology Delays

In this paper, a novel data-driven single neuron predictive control strategy is proposed for non-Gaussian networked control systems with metrology delays in the information theory framework. Firstly, survival information potential (SIP), instead of minimum entropy, is used to formulate the performance index to characterize the randomness of the considered systems, which is calculated by oversampling method. Then the minimum values can be computed by optimizing the SIP-based performance index. Finally, the proposed strategy, minimum entropy method and mean square error (MSE) are applied to a networked motor control system, and results demonstrated the effectiveness of the proposed strategy

Optimization of Steam Distillation Process for Volatile Oils from <i>Forsythia suspensa</i> and <i>Lonicera japonica</i> according to the Concept of Quality by Design

In this study, the process of steam distillation to collect volatile oils from Forsythia suspensa (F. suspensa) and Lonicera japonica (L. japonica) was optimized according to the concept of quality by design. First, the liquid/material ratio, distillation time, and collection temperature were identified as critical process parameters by a review of the literature and single-factor experiments. Then, a Box–Behnken design was used to study the quantitative relationship between the three process parameters, two raw material properties, and the yield of volatile oil. A mathematical model was established with an R2 value exceeding 0.90. Furthermore, the design space of the volatile oil yield was calculated by a probability-based method. The results of a verification experiment showed that the model was accurate and the design space was reliable. A total of 16 chemical constituents were identified in the volatile oil from mixtures of F. suspensa and L. japonica. The content of β-pinene was the highest (54.75%), and the composition was similar to that of the volatile oil of F. suspensa. The results showed that when F. suspensa and L. japonica were distilled together, the main contribution to the volatile oil was from F. suspensa. The volatile oil yield from the combination of F. suspensa and L. japonica was not higher than that from L. japonica

Optimization of Steam Distillation Process and Chemical Constituents of Volatile Oil from <i>Angelicae</i><i>sinensis</i> Radix

In this study, the steam distillation process of volatile oil from Angelicaesinensis Radix was optimized according to the concept of quality-by-design. A homemade glass volatile oil extractor was used to achieve better cooling of the volatile oil. First, the soaking time, distillation time, and liquid–material ratio were identified as potential critical process parameters by consulting the literature. Then, the three parameters were investigated by single factor experiments. The volatile oil yield increased with the extension in the distillation time, and first increased and then decreased with the increase in soaking time and liquid–material ratio. The results confirmed that soaking time, distillation time, and liquid–material ratio were all critical process parameters. The kinetics models of volatile oil distillation from Angelicaesinensis Radix were established. The diffusion model of spherical particle was found to be the best model and indicated that the major resistance of mass transfer was the diffusion of volatile oil from the inside to the surface of the medicinal herb. Furthermore, the Box–Behnken experimental design was used to study the relationship between the three parameters and volatile oil yield. A second-order polynomial model was established, with R2 exceeding 0.99. The design space of the volatile oil yield was calculated by a probability-based method. In the verification experiments, the average volatile oil yield reached 0.711%. The results showed that the model was accurate and the design space was reliable. In this study, 21 chemical constituents of volatile oil from Angelicaesinensis Radix were identified by gas chromatograph-mass spectrometer(GC-MS), accounting for 99.4% of the total volatile oil. It was found that the content of Z-ligustilide was the highest, accounting for 85.4%

Optimization of Steam Distillation Process and Chemical Constituents of Volatile Oil from Angelicaesinensis Radix

In this study, the steam distillation process of volatile oil from Angelicaesinensis Radix was optimized according to the concept of quality-by-design. A homemade glass volatile oil extractor was used to achieve better cooling of the volatile oil. First, the soaking time, distillation time, and liquid&ndash;material ratio were identified as potential critical process parameters by consulting the literature. Then, the three parameters were investigated by single factor experiments. The volatile oil yield increased with the extension in the distillation time, and first increased and then decreased with the increase in soaking time and liquid&ndash;material ratio. The results confirmed that soaking time, distillation time, and liquid&ndash;material ratio were all critical process parameters. The kinetics models of volatile oil distillation from Angelicaesinensis Radix were established. The diffusion model of spherical particle was found to be the best model and indicated that the major resistance of mass transfer was the diffusion of volatile oil from the inside to the surface of the medicinal herb. Furthermore, the Box&ndash;Behnken experimental design was used to study the relationship between the three parameters and volatile oil yield. A second-order polynomial model was established, with R2 exceeding 0.99. The design space of the volatile oil yield was calculated by a probability-based method. In the verification experiments, the average volatile oil yield reached 0.711%. The results showed that the model was accurate and the design space was reliable. In this study, 21 chemical constituents of volatile oil from Angelicaesinensis Radix were identified by gas chromatograph-mass spectrometer(GC-MS), accounting for 99.4% of the total volatile oil. It was found that the content of Z-ligustilide was the highest, accounting for 85.4%

Increased Expression of β-Catenin, Phosphorylated Glycogen Synthase Kinase 3β, Cyclin D1, and c-myc in Laterally Spreading Colorectal Tumors

Laterally spreading tumors (LSTs) are considered a special subtype of superficial colorectal tumor. This study was performed to characterize the clinicopathological features and examine activation of the Wnt/β-catenin pathway in LSTs and protruded-type colorectal adenomas (PAs). Fifty LSTs and 54 PAs were collected, and their clinicopathological characteristics were compared. The expression of E-cadherin, β-catenin, glycogen synthase kinase-3β (GSK-3β), phosphorylated GSK-3β, (phospho-GSK-3β), cyclin D1, and c-myc was investigated by immunohistochemical staining on serial sections. Patients with LSTs were significantly older than those bearing PAs (63.4 vs 47.4 years old; p<0.001). The mean size of LSTs was significantly larger than that of PAs (27.0 mm vs 14.6 mm; p<0.01). Forty-eight percent of LSTs were located in the proximal colon, which was significantly higher than that of PAs (18.5%; p<0.05). Expression of β-catenin, phospho-GSK-3β, cyclin D1, and c-myc was significantly increased in LSTs compared with PAs (p<0.05). However, E-cadherin and total GSK-3β expression was not significantly different between the two groups. The level of β-catenin expression correlated strongly with phospho-GSK-3β, cyclin D1, and c-myc expression in LSTs but not in PAs. Our findings suggest that activation of the Wnt/β-catenin pathway is more prevalent in LSTs than in PAs, suggesting that phosphorylation-dependent inactivation of GSK-3β may be involved in LST carcinogenesis. (J Histochem Cytochem 57:363–371, 2009

Occurrence and Release of Organophosphite Antioxidants and Novel Organophosphate Esters from Plastic Food Packaging

Organic phosphite antioxidants (OPAs) are widely added in plastic products and can be oxidized to generate oxidized derivatives (OPAs = O), namely organic phosphate esters (OPEs), during production and use processing. Herein, the occurrence of OPEs and OPAs in five plastic food packages was detected by liquid chromatography–tandem mass spectrometry. Three OPEs (TPhP, TCEP, and AO168 = O) and three OPAs (TPhPi, TCEPi, and AO168) were found in the plastic packages, with concentrations of 3OPAs) and 196–831 ng/g (∑3OPEs), respectively. The migration potential of OPAs and OPEs to food was measured by simulation experiments. OPAs and OPEs in plastic can efficiently migrate to oily simulants, alkaline simulants, and acidic simulants. After 14 days, the total concentration of all OPAs and OPEs in the food simulants reached 3OPAs + ∑3OPEs: 18.3–28.9 ng/mL) and in oils (∑3OPAs + ∑3OPEs: 32.7–60.9 ng/mL). Accordingly, the estimated ingestion of OPAs and OPEs through plastic-packaged food can reach 2.6 and 32.7 ng/kg in children and 1.1 and 6.5 ng/kg in adults, indicating a non-negligible exposure risk of organic phosphorus pollutants