No causal association between pneumoconiosis and three inflammatory immune diseases: a Mendelian randomization study.

Objectives: To investigate the causal relationships between pneumoconiosis and rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and gout. Methods: The random-effects inverse variance weighted (IVW) approach was utilized to explore the causal effects of the instrumental variables (IVs). Sensitivity analyses using the MR-Egger and weighted median (WM) methods were did to investigate horizontal pleiotropy. A leave-one-out analysis was used to avoid the bias resulting from single-nucleotide polymorphisms (SNPs). Results: There was no causal association between pneumoconiosis and SLE, RA or gout in the European population [OR = 1.01, 95% CI: 0.94-1.10, p = 0.74; OR = 1.00, 95% CI: 0.999-1.000, p = 0.50; OR = 1.00, 95% CI: 1.000-1.001, p = 0.55]. Causal relationships were also not found in pneumoconiosis due to asbestos and other mineral fibers and SLE, RA and gout [OR = 1.01, 95% CI: 0.96-1.07, p = 0.66; OR = 1.00, 95% CI: 1.00-1.00, p = 0.68; OR = 1.00, 95% CI: 1.00-1.00, p = 0.20]. Conclusion: Our study suggests that pneumoconiosis may have no causal relationship with the three inflammatory immune diseases.

Combination of UNet++ and ResNeSt to classify chronic inflammation of the choledochal cystic wall in patients with pancreaticobiliary maljunction.

OBJECTIVES: The aim of this study was to establish an automatic classification model for chronic inflammation of the choledoch wall using deep learning with CT images in patients with pancreaticobiliary maljunction (PBM). METHODS: CT images were obtained from 76 PBM patients, including 61 cases assigned to the training set and 15 cases assigned to the testing set. The region of interest (ROI) containing the choledochal lesion was extracted and segmented using the UNet++ network. The degree of severity of inflammation in the choledochal wall was initially classified using the ResNeSt network. The final classification result was determined per decision rules. Grad-CAM was used to explain the association between the classification basis of the network and clinical diagnosis. RESULTS: Segmentation of the lesion on the common bile duct wall was roughly obtained with the UNet++ segmentation model and the average value of Dice coefficient of the segmentation model in the testing set was 0.839 ± 0.150, which was verified through fivefold cross-validation. Inflammation was initially classified with ResNeSt18, which resulted in accuracy = 0.756, sensitivity = 0.611, specificity = 0.852, precision = 0.733, and area under curve (AUC) = 0.711. The final classification sensitivity was 0.8. Grad-CAM revealed similar distribution of inflammation of the choledochal wall and verified the inflammation classification. CONCLUSIONS: By combining the UNet++ network and the ResNeSt network, we achieved automatic classification of chronic inflammation of the choledoch in PBM patients and verified the robustness through cross-validation performed five times. This study provided an important basis for classification of inflammation severity of the choledoch in PBM patients. ADVANCES IN KNOWLEDGE: We combined the UNet++ network and the ResNeSt network to achieve automatic classification of chronic inflammation of the choledoch in PBM. These results provided an important basis for classification of choledochal inflammation in PBM and for surgical therapy.

Glutamatergic synapses from the insular cortex to the basolateral amygdala encode observational pain.

Empathic pain has attracted the interest of a substantial number of researchers studying the social transfer of pain in the sociological, psychological, and neuroscience fields. However, the neural mechanism of empathic pain remains elusive. Here, we establish a long-term observational pain model in mice and find that glutamatergic projection from the insular cortex (IC) to the basolateral amygdala (BLA) is critical for the formation of observational pain. The selective activation or inhibition of the IC-BLA projection pathway strengthens or weakens the intensity of observational pain, respectively. The synaptic molecules are screened, and the upregulated synaptotagmin-2 and RIM3 are identified as key signals in controlling the increased synaptic glutamate transmission from the IC to the BLA. Together, these results reveal the molecular and synaptic mechanisms of a previously unidentified neural pathway that regulates observational pain in mice.

Research progress on screening of pregnancy-related diseases based on fetal cell free DNA / 中华医学遗传学杂志

Fetal cell free DNA (cfDNA) in maternal blood circulation mainly originates from placental trophoblasts which have dual characteristics of apoptotic cells and the embryo, and can be affected by maternal factors. Pregnancy-related diseases including preeclampsia, gestational diabetes mellitus, preeclampsia, macrosomia and fetal growth restriction can seriously affect maternal health and pregnancy outcome. Early prediction and timely intervention are important means to reduce the risk. Fetal cfDNA and prediction of pregnancy-related diseases have become a hot topicfor current research. This paper reviews the latest progress made in the field.

Targeted elimination of mutant mitochondrial DNA in MELAS-iPSCs by mitoTALENs

Mitochondrial diseases are maternally inherited heterogeneous disorders that are primarily caused by mitochondrial DNA (mtDNA) mutations. Depending on the ratio of mutant to wild-type mtDNA, known as heteroplasmy, mitochondrial defects can result in a wide spectrum of clinical manifestations. Mitochondria-targeted endonucleases provide an alternative avenue for treating mitochondrial disorders via targeted destruction of the mutant mtDNA and induction of heteroplasmic shifting. Here, we generated mitochondrial disease patient-specific induced pluripotent stem cells (MiPSCs) that harbored a high proportion of m.3243A>G mtDNA mutations and caused mitochondrial encephalomyopathy and stroke-like episodes (MELAS). We engineered mitochondrial-targeted transcription activator-like effector nucleases (mitoTALENs) and successfully eliminated the m.3243A>G mutation in MiPSCs. Off-target mutagenesis was not detected in the targeted MiPSC clones. Utilizing a dual fluorescence iPSC reporter cell line expressing a 3243G mutant mtDNA sequence in the nuclear genome, mitoTALENs displayed a significantly limited ability to target the nuclear genome compared with nuclear-localized TALENs. Moreover, genetically rescued MiPSCs displayed normal mitochondrial respiration and energy production. Moreover, neuronal progenitor cells differentiated from the rescued MiPSCs also demonstrated normal metabolic profiles. Furthermore, we successfully achieved reduction in the human m.3243A>G mtDNA mutation in porcine oocytes via injection of mitoTALEN mRNA. Our study shows the great potential for using mitoTALENs for specific targeting of mutant mtDNA both in iPSCs and mammalian oocytes, which not only provides a new avenue for studying mitochondrial biology and disease but also suggests a potential therapeutic approach for the treatment of mitochondrial disease, as well as the prevention of germline transmission of mutant mtDNA.

Construction of vascular endothelial growth factor modified muscle-derived stem cells and its expression / 实用医学杂志

Objective To construct the lentiviral vector encoding vascular endothelial growth factor gene and detect the vascular endothelial growth factor (VEGF) expression in muscle-derived stem cells (MDSCs). Methods To culture MDSCs and detect the CD34,CD45,Bcl-2 and Desmin expression in MDSCs by immunofluorescence. A cDNA encoding VEGF gene was amplified by PCR. This fragment was cut with EcoRI and BamHI and ligated with an EcoRI- and BamHI-reated lentiviral vector pCDH-CMV-MCS-EF1-copGFP. Then DNA sequencing analysis was performed to confirm successful construction of pCDH-CMV-MCS-EF1-copGFP -VEGF. The expression of VEGF was confirmed using enzyme-linked immunosorbent assay (ELISA), Western blot, and Real-time PCR analyses. Results The pCDH-CMV-MCS-EF1-copGFP-VEGF lentiviral vector was constructed successfully. When MOI values in the transfection efficiency MDSCs by FCM. were 1,5,15, the transfection rate reached to 16.7%, 45.6%, 66.3% and 85.6% respectively. When MOI value was of 20, the rate was up to 90.1%. Real-time PCR, Western blot and ELISA showed stable expression of VEGF in MDSCs. Conclusion We successfully constructed lentiviral vector carrying the VEGF and stable expression in MDSCs.

Influence of male age on the pregnancy outcomes of IVF-ET / 中华男科学杂志

<p><b>OBJECTIVE</b>To investigate the influence of male age on the pregnancy outcomes of in vitro fertilization-embryo transfer (IVF-ET).</p><p><b>METHODS</b>We retrospectively analyzed 7,533 cycles of IVF-ET performed between January 1, 2009 and October 31, 2013. We divided the samples into three groups according to the female age (< 30, 30-34, and 35-38 yr), each again subdivided into six groups based on the male age (< 30, 30-32, 33-35, 36-38, 39-41, and ≥ 42 yr). We compared the rates of implantation, pregnancy, miscarriage, and live birth among different age groups.</p><p><b>RESULTS</b>There were no statistically significant differences in basal E2, FSH, endometrium thickness on the day of hCG administration, number of oocytes retrieved, and days of embryo transfer among different male age groups (P > 0.05). The implantation rate showed an age-dependent decrease in the < 30, 30-32, 33-35, 36-38, 39-41, and ≥ 42 yr male groups, 41.1, 42.0, 39.5, 31.3, 40.7, and 48.6% among the women aged < 30 years (P < 0.05), 40.3, 36.4, 35.1, 35.3, 29.4, and 37.3% among the women aged 30-34 years (P < 0.05), and 48.2, 17.8, 25.3, 23.5, 22.1, and 23.8% among the women aged 35-38 years (P < 0.05). The miscarriage rate was significantly higher in the ≥ 39 yr than in the 30-32 and 33-35 yr male age groups among the women aged 30-34 years (P < 0.05), but showed no remarkable differences among the other male age groups in the women aged < 30 and 35-38 years (P > 0.05). No statistically significant differences were observed in the rates of pregnancy and live birth among different male age groups (P > 0.05).</p><p><b>CONCLUSION</b>Male age has some influence on the rates of implantation and miscarriage but not on the rates of pregnancy and live birth in IVF-ET.</p>

Displacement measurement using a wavelength-phase-shifting grating interferometer.

A grating interferometer based on the wavelength-modulated phase-shifting method for displacement measurements is proposed. A laser beam with sequential phase shifting can be accomplished using a wavelength-modulated light passing through an unequal-path-length optical configuration. The optical phase of the moving grating is measured by the wavelength-modulated phase-shifting technique and the proposed time-domain quadrature detection method. The displacement of the grating is determined by the grating interferometry theorem with the measured phase variation. Experimental results reveal that the proposed method can detect a displacement up to a large distance of 1 mm and displacement variation down to the nanometer range.

Robo4 regulates the radial migration of newborn neurons in developing neocortex.

During the morphogenesis of neocortex, newborn neurons undergo radial migration from the ventricular zone toward the surface of the cortical plate to form an "inside-out" lamina structure. The spatiotemporal signals that control this stereotyped radial migration remain elusive. Here, we report that a recently identified Robo family member Robo4 (Magic Roundabout), which was considered to be solely expressed in endothelial cells, is expressed in developing brain and regulates the radial migration of newborn neurons in neocortex. Downregulation of Robo4 expression in cortical newborn neurons by using in utero electroporation, with either specific siRNAs in wild-type rodents or with Cre recombinase in floxed-robo4 mutant mice, led to severe defects in the radial migration of newborn neurons with misorientation of these neurons. Moreover, newborn neurons transfected with Robo4 siRNAs exhibited significantly lower motility in a transwell migration assay (Boyden chamber) in the absence of Slit and significantly higher sensitivity to the repulsive effect of Slit in both transwell migration assay and growth cone collapse assay. Overall, our results showed an important role of Robo4 in the regulation of cortical radial migration through Slit-dependent and -independent mechanisms.

PKCdelta regulates cortical radial migration by stabilizing the Cdk5 activator p35.

Cyclin-dependent kinase 5 (Cdk5) and its activator p35 are critical for radial migration and lamination of cortical neurons. However, how this kinase is regulated by extracellular and intracellular signals during cortical morphogenesis remains unclear. Here, we show that PKCdelta, a member of novel PKC expressing in cortical neurons, could stabilize p35 by direct phosphorylation. PKCdelta attenuated the degradation of p35 but not its mutant derivative, which could not be phosphorylated by PKCdelta. Down-regulation of PKCdelta by in utero electroporation of specific small interference RNA (siRNA) severely impaired the radial migration of cortical neurons. This migration defect was similar to that caused by down-regulation of p35 and could be prevented by cotransfection with the wild-type but not the mutant p35. Furthermore, PKCdelta could be activated by the promigratory factor brain-derived neurotrophic factor (BDNF) and was required for the activation of Cdk5 by BDNF. Both PKCdelta and p35 were required for the promigratory effect of BDNF on cultured newborn neurons. Thus, PKCdelta may promote cortical radial migration through maintaining the proper level of p35 in newborn neurons.

Percentage of uric acid calculus and its metabolic character in Dongjiang River valley / 中华外科杂志

<p><b>OBJECTIVE</b>To study the percentage of uric acid calculus in uroliths and its metabolic character in Dongjiang River valley.</p><p><b>METHODS</b>To analyze the chemical composition of 290 urinary stones by infrared (IR) spectroscopy and study the ratio changes of uric acid calculus. Uric acid calculus patients and healthy people were studied. Personal characteristics, dietary habits were collected. Conditional logistic regression was used for data analysis and studied the dietary risk factors of uric acid calculus. Patients with uric acid calculus, calcium oxalate and those without urinary calculus were undergone metabolic evaluation analysis. The results of uric acid calculus patients compared to another two groups to analysis the relations between the formation of uric acid calculus and metabolism factors.</p><p><b>RESULTS</b>Uric acid calculi were found in 53 cases (18.3%). The multiple logistic regression analysis suggested that low daily water intake, eating more salted and animal food, less vegetable were very closely associated with uric acid calculus. Comparing to calcium oxalate patients, the urine volume, the value of pH, urine calcium, urine oxalic acid were lower, but uric acid was higher than it. The value of pH, urine oxalic acid and citric acid were lower than them, but uric acid and urine calcium were higher than none urinary calculus peoples. Blood potassium and magnesium were lower than them.</p><p><b>CONCLUSIONS</b>The percentage of uric acid stones had obvious advanced. Less daily water intake, eating salted food, eating more animal food, less vegetables and daily orange juice intake, eating sea food are the mainly dietary risk factors to the formation of uric acid calculus. Urine volume, the value of pH, citric acid, urine calcium, urine uric acid and the blood natrium, potassium, magnesium, calcium, uric acid have significant influence to the information of uric acid stones.</p>