BACKGROUND Osteopetrosis is a rare genetic disorder characterized by increased bone density due to defective bone resorption of osteoclasts.Approximately,80%of autosomal dominant osteopetrosis type II(ADO-II)patients ...BACKGROUND Osteopetrosis is a rare genetic disorder characterized by increased bone density due to defective bone resorption of osteoclasts.Approximately,80%of autosomal dominant osteopetrosis type II(ADO-II)patients were usually affected by heterozygous dominant mutations in the chloride voltage-gated channel 7(ClCN7)gene and present early-onset osteoarthritis or recurrent fractures.In this study,we report a case of persistent joint pain without bone injury or underlying history.CASE SUMMARY We report a 53-year-old female with joint pain who was accidentally diagnosed with ADO-II.The clinical diagnosis was based on increased bone density and typical radiographic features.Two heterozygous mutations in the ClCN7 and Tcell immune regulator 1(TCIRG1)genes by whole exome sequencing were identified in the patient and her daughter.The missense mutation(c.857G>A)occurred in the CLCN7 gene p.R286Q,which is highly conserved across species.The TCIRG1 gene point mutation(c.714-20G>A)in intron 7(near the splicing site of exon 7)had no effect on subsequent transcription.CONCLUSION This ADO-II case had a pathogenic CLCN7 mutation and late onset without the usual clinical symptoms.For the diagnosis and assessment of the prognosis for osteopetrosis,genetic analysis is advised.展开更多
Objective:To investigate the effects of mechanical stretching and lipopolysaccharide(LPS) on the early apoptosis and IL-8 production of alveolar epithelial type II cells A549.Methods:The experimental matrix consisted ...Objective:To investigate the effects of mechanical stretching and lipopolysaccharide(LPS) on the early apoptosis and IL-8 production of alveolar epithelial type II cells A549.Methods:The experimental matrix consisted of three integrated studies.In the first study,A549 cells were subjected to different stretching strain frequency and duration time to see the effects on the early apoptosis.In the second study,A549 cells were subjected to mechanical stretch(13%4 h, 0.3 Hz) and LPS(1 or 100 ng/mL) to see whether mechanical strain and LPS also have an addictive effect on the early apoptosis.In the third study to investigate whether this addictive effect could be induced by LPS and mechanical stretch on IL-8 production,A549 cells were subjected to LPS(100 ng/mL) and mechanical strain(13%.0.3 Hz,4 h).Real time PCR and enzyme linked immunosorbent assay were used to measure mRN A and protein level of IL-8.The early apoptosis was detected by flow cytometry.Results:Mechanical stretch induced the early apoptosis in a force and frequency and time-dependent manner.In the presence of LPS,mechanical stretch enhanced LPS-induced early apoptosis,especially in 100 ng/mL IPS group compared with 1 ng/ mL LPS and the control group.Mechanical stretch increased IL-8 production and enhanced LPS-induced IL-8 screation both in mRNA and protein levels.Conclusions:Mechanical stretch can induce the early apoptosis and IL-8 secretion.Mechanical stretch and LPS have an addictive effect on the early apoptosis and IL-8 production in alveolar type 2 cells,which is one of the mechanisms of ventilator-induced lung injury.展开更多
Achondrogenesis is a very rare lethal skeletal disorder. Here we describe a case of prenatally diagnosed achondrogenesis typeⅡ in a 28 year-old woman at (17+4) wk. She had history of 5 first trimester missed abortion...Achondrogenesis is a very rare lethal skeletal disorder. Here we describe a case of prenatally diagnosed achondrogenesis typeⅡ in a 28 year-old woman at (17+4) wk. She had history of 5 first trimester missed abortions. The couple is consanguineous. Ultrasonography showed extreme micromelia, short neck and trunk, large head and prominent abdomen. Delayed ossification in sacral bones was detected and ossification of pubic rami was poor. There were associated large cystic hygroma, anasarca and also high occipital cephalocele. Posterior fossa was normal. Mild hypothelorism, depressed nasal bridge, low set ear and mild retrognathia were identified too. Amniocentesis result was compatible with a normal female fetus. Post mortem whole body radiography confirmed the diagnosis. To our knowledge, this is the second case report with association of cephalocele and achondrogenesis typeⅡ.展开更多
BACKGROUND Osteopetrosis is a family of extremely rare diseases caused by failure of osteoclasts and impaired bone resorption. Among them, autosomal dominant osteopetrosis type Ⅱ(ADO Ⅱ), related to the chloride chan...BACKGROUND Osteopetrosis is a family of extremely rare diseases caused by failure of osteoclasts and impaired bone resorption. Among them, autosomal dominant osteopetrosis type Ⅱ(ADO Ⅱ), related to the chloride channel 7(CLCN7) gene, is the most frequent form of osteopetrosis. In this study, we report a de novo mutation of CLCN7 in a patient without the family history of ADO Ⅱ.CASE SUMMARY A 5-year-old Chinese boy with ADO Ⅱ was found to have a de novo mutation in the CLCN7 gene [c.746 C>T(p.P249 L)]. Typical clinical manifestations, including thickening of the cortex of spinal bones and long bones, non-traumatic fracture of the femoral neck, and femoral head necrosis, were found in this patient. The patient is the first reported case of ADO Ⅱ with the missense mutation c.746 C>T(p.P249 L) of the CLCN7 gene reported in China. We also review the available literature on ADO Ⅱ-related CLCN7 mutations, including baseline patient clinical features, special clinical significance, and common mutations.CONCLUSION Our report will enrich the understanding of mutations in ADO Ⅱ patients. The possibility of a de novo mutation should be considered in individuals who have no family history of osteopetrosis.展开更多
Peripheral cisternae and double membranes(PCDMs)in erythroid cells are a landmark of typeⅡcongenital dyserythropoietic anemia(CDA).To gain further insights into the mechanism of dyserythropoiesis,erythroblasts and er...Peripheral cisternae and double membranes(PCDMs)in erythroid cells are a landmark of typeⅡcongenital dyserythropoietic anemia(CDA).To gain further insights into the mechanism of dyserythropoiesis,erythroblasts and erythrocytes in bone marrow were studied in 22 Chinese patients with CDAⅡby transmission electron microscopy.The study demonstrated an increase in all patients in erythroblasts with PCDMs with development from pro-erythroblast to red blood cells.PCDMs often connected with cisternae of endoplasmic reticulum(ER)and the perinuclear space,and were accompanied by karyopyknosis,karyolysis and disruption in polychromatic and orthochromatic erythroblasts.The results suggest that PCDMs are transformed from ER during erythropoiesis and participate in the dissolution and deletion of late erythroid cells in patients with CDAⅡ.展开更多
Pulmonary surfactant is a lipid-protein complex secreted by alveolar typeⅡepithelial cells and is essential for the maintenance of the delicate structure of mammalian alveoli to promote efficient gas exchange across ...Pulmonary surfactant is a lipid-protein complex secreted by alveolar typeⅡepithelial cells and is essential for the maintenance of the delicate structure of mammalian alveoli to promote efficient gas exchange across the air-liquid barrier.The Golgi apparatus plays an important role in pulmonary surfactant modification and secretory trafficking.However,the physiological function of the Golgi apparatus in the transport of pulmonary surfactants is unclear.In the present study,deletion of GM130,which encodes for a matrix protein of the cis-Golgi cisternae,was shown to induce the disruption of the Golgi structure leading to impaired secretion of lung surfactant proteins and lipids.Specifically,the results of in vitro and in vivo analysis indicated that the loss of GM130 resulted in trapping of Sftpa in the endoplasmic reticulum,Sftpb and Sftpc accumulation in the Golgi apparatus,and an increase in the compensatory secretion of Sftpd.Moreover,global and epithelial-specific GM130 knockout in mice resulted in an enlargement of alveolar airspace and an increase in alveolar epithelial autophagy;however,surfactant repletion partially rescued the enlarged airspace defects in GM130-deficient mice.Therefore,our results demonstrate that GM130 and the mammalian Golgi apparatus play a critical role in the control of surfactant protein secretion in pulmonary epithelial cells.展开更多
BACKGROUND For Siewert type Ⅱ/Ⅲ adenocarcinoma of gastroesophageal junction(AGE), the efficacy of adjuvant chemoradiotherapy(CRT) after D2/R0 resection remains uncertain.AIM To determine whether CRT was superior to ...BACKGROUND For Siewert type Ⅱ/Ⅲ adenocarcinoma of gastroesophageal junction(AGE), the efficacy of adjuvant chemoradiotherapy(CRT) after D2/R0 resection remains uncertain.AIM To determine whether CRT was superior to chemotherapy(CT) alone after D2/R0 resection for locally advanced Siewert type Ⅱ/Ⅲ AGE.METHODS We identified 316 locally advanced Siewert type Ⅱ/Ⅲ AGE patients who were treated with D2/R0 resection at National Cancer Center from 2011 to 2018.57 patients received adjuvant CRT and 259 patients received adjuvant CT.We followed patients for overall survival(OS), relapse-free survival, and recurrence pattern.RESULTS Five-year OS rates of the CRT group and the CT group for all patients were 66.7% and 41.9%(P = 0.010).Five-year OS rates of the CRT group and the CT group for Siewert type Ⅲ AGE patients were 65.7% and 43.9%(P = 0.006).Among the 195 patients whose recurrence information could be obtained, 18 cases(34.6%) and 61 cases(42.7%) were diagnosed as recurrence in the CRT group and CT group, respectively.The local and regional recurrence rates in the CRT group were lower than that in the CT group(22.2% vs 24.6%, 27.8% vs 39.3%).Multivariable cox regression analysis showed that vascular invasion, nerve invasion, and adjuvant CRT were important prognostic factors for Siewert type Ⅲ AGE.CONCLUSION For locally advanced Siewert type Ⅲ AGE, adjuvant CRT may prolong OS and reduce the regional recurrence rate.展开更多
Type-Ⅱsuperlattice(T2SL)materials are the key element for infrared(IR)detectors.However,it is well known that the characteristics of the detectors with the T2SL layer are greatly affected by the strain developed duri...Type-Ⅱsuperlattice(T2SL)materials are the key element for infrared(IR)detectors.However,it is well known that the characteristics of the detectors with the T2SL layer are greatly affected by the strain developed during the growth process,which determines the performance of IR detectors.Therefore,great efforts have been made to properly control the strain effect and develop relevant analysis methods to evaluate the strain-induced dark current characteristics.In this work,we report the strain-induced dark current characteristics in InAs/GaSb T2SL MWIR photodetector.The overall strain of InAs/GaSb T2SL layer was analyzed by both high-resolution X-ray diffraction(HRXRD)and the dark current measured from the absorber layer at the elevated temperatures(≥110 K),where the major leakage current component is originated from the reduced minority carrier lifetime in the absorber layer.Our findings indicate that minority carrier lifetime increases as the tensile strain on the InAs/GaSb T2SL is more compensated by the compressive strain through‘InSb-like’interface,which reduces the dark current density of the device.Specifically,tensile strain compensated devices exhibited the dark current density of less than 2×10^-5 A/cm^2 at 120 K,which is more than one order of magnitude lower value compared to that of the device without tensile strain relaxation.展开更多
Glucagon-like peptide-1 receptor agonists(GLP-1 RA)are a series of polypeptides broadly applied in the long-term treatment of typeⅡdiabetes.However,administration of GLP-RA is mainly through repetitive subcutaneous i...Glucagon-like peptide-1 receptor agonists(GLP-1 RA)are a series of polypeptides broadly applied in the long-term treatment of typeⅡdiabetes.However,administration of GLP-RA is mainly through repetitive subcutaneous injection,which may seriously decrease the compliance and safety.Herein,a bio-inspired oral delivery system was designed to enhance the oral absorption of liraglutide(Lira),a kind of GLP-1 RA,by mimicking the natural cholesterol assimilation.25-hydroxycholesterol(25HC),a cholesterol derivative,was modified on the surfaced of Lira-loaded PLGA nanoparticles(Lira 25HC NPs)and functioned as a“top-down”actuator to facilitate unidirectional transcytosis across the intestinal epithelium.After oral delivery,Lira 25HC NPs displayed improved therapeutic effect as compared with oral free Lira on typeⅡdiabetes db/db mice,as evidenced by multiple relieved diabetic symptoms including the enhanced glucose tolerance,repressed weight growth,improved liver glucose metabolism,decreased fasting blood glucose,HbA 1c,serum lipid,and increasedβcells activity.Surprisingly,the fasting blood glucose,liver glucose metabolism,and HbA1c of oral Lira-loaded 25HC NPs were comparable to subcutaneous injection of free Lira.Further mechanisms revealed that 25HC ligand could mediate the nanoparticles to mimic natural cholesterol absorption by exerting high affinity towards apical Niemann-Pick C1 Like 1(NPC1L1)and then basolateral ATP binding cassette transporter A1(ABCA1)overexpressed on the opposite side of intestinal epithelium.This cholesterol assimilation-mimicking strategy achieve the unidirectional transport across the intestinal epithelium,thus improving the oral absorption of liraglutide.In general,this study established a cholesterol simulated platform and provide promising insight for the oral delivery of GLP-1 RA.展开更多
基金Supported by the Science and Technology Plan Program of Sichuan of China,No.2018JY0608。
文摘BACKGROUND Osteopetrosis is a rare genetic disorder characterized by increased bone density due to defective bone resorption of osteoclasts.Approximately,80%of autosomal dominant osteopetrosis type II(ADO-II)patients were usually affected by heterozygous dominant mutations in the chloride voltage-gated channel 7(ClCN7)gene and present early-onset osteoarthritis or recurrent fractures.In this study,we report a case of persistent joint pain without bone injury or underlying history.CASE SUMMARY We report a 53-year-old female with joint pain who was accidentally diagnosed with ADO-II.The clinical diagnosis was based on increased bone density and typical radiographic features.Two heterozygous mutations in the ClCN7 and Tcell immune regulator 1(TCIRG1)genes by whole exome sequencing were identified in the patient and her daughter.The missense mutation(c.857G>A)occurred in the CLCN7 gene p.R286Q,which is highly conserved across species.The TCIRG1 gene point mutation(c.714-20G>A)in intron 7(near the splicing site of exon 7)had no effect on subsequent transcription.CONCLUSION This ADO-II case had a pathogenic CLCN7 mutation and late onset without the usual clinical symptoms.For the diagnosis and assessment of the prognosis for osteopetrosis,genetic analysis is advised.
文摘Objective:To investigate the effects of mechanical stretching and lipopolysaccharide(LPS) on the early apoptosis and IL-8 production of alveolar epithelial type II cells A549.Methods:The experimental matrix consisted of three integrated studies.In the first study,A549 cells were subjected to different stretching strain frequency and duration time to see the effects on the early apoptosis.In the second study,A549 cells were subjected to mechanical stretch(13%4 h, 0.3 Hz) and LPS(1 or 100 ng/mL) to see whether mechanical strain and LPS also have an addictive effect on the early apoptosis.In the third study to investigate whether this addictive effect could be induced by LPS and mechanical stretch on IL-8 production,A549 cells were subjected to LPS(100 ng/mL) and mechanical strain(13%.0.3 Hz,4 h).Real time PCR and enzyme linked immunosorbent assay were used to measure mRN A and protein level of IL-8.The early apoptosis was detected by flow cytometry.Results:Mechanical stretch induced the early apoptosis in a force and frequency and time-dependent manner.In the presence of LPS,mechanical stretch enhanced LPS-induced early apoptosis,especially in 100 ng/mL IPS group compared with 1 ng/ mL LPS and the control group.Mechanical stretch increased IL-8 production and enhanced LPS-induced IL-8 screation both in mRNA and protein levels.Conclusions:Mechanical stretch can induce the early apoptosis and IL-8 secretion.Mechanical stretch and LPS have an addictive effect on the early apoptosis and IL-8 production in alveolar type 2 cells,which is one of the mechanisms of ventilator-induced lung injury.
文摘Achondrogenesis is a very rare lethal skeletal disorder. Here we describe a case of prenatally diagnosed achondrogenesis typeⅡ in a 28 year-old woman at (17+4) wk. She had history of 5 first trimester missed abortions. The couple is consanguineous. Ultrasonography showed extreme micromelia, short neck and trunk, large head and prominent abdomen. Delayed ossification in sacral bones was detected and ossification of pubic rami was poor. There were associated large cystic hygroma, anasarca and also high occipital cephalocele. Posterior fossa was normal. Mild hypothelorism, depressed nasal bridge, low set ear and mild retrognathia were identified too. Amniocentesis result was compatible with a normal female fetus. Post mortem whole body radiography confirmed the diagnosis. To our knowledge, this is the second case report with association of cephalocele and achondrogenesis typeⅡ.
文摘BACKGROUND Osteopetrosis is a family of extremely rare diseases caused by failure of osteoclasts and impaired bone resorption. Among them, autosomal dominant osteopetrosis type Ⅱ(ADO Ⅱ), related to the chloride channel 7(CLCN7) gene, is the most frequent form of osteopetrosis. In this study, we report a de novo mutation of CLCN7 in a patient without the family history of ADO Ⅱ.CASE SUMMARY A 5-year-old Chinese boy with ADO Ⅱ was found to have a de novo mutation in the CLCN7 gene [c.746 C>T(p.P249 L)]. Typical clinical manifestations, including thickening of the cortex of spinal bones and long bones, non-traumatic fracture of the femoral neck, and femoral head necrosis, were found in this patient. The patient is the first reported case of ADO Ⅱ with the missense mutation c.746 C>T(p.P249 L) of the CLCN7 gene reported in China. We also review the available literature on ADO Ⅱ-related CLCN7 mutations, including baseline patient clinical features, special clinical significance, and common mutations.CONCLUSION Our report will enrich the understanding of mutations in ADO Ⅱ patients. The possibility of a de novo mutation should be considered in individuals who have no family history of osteopetrosis.
文摘Peripheral cisternae and double membranes(PCDMs)in erythroid cells are a landmark of typeⅡcongenital dyserythropoietic anemia(CDA).To gain further insights into the mechanism of dyserythropoiesis,erythroblasts and erythrocytes in bone marrow were studied in 22 Chinese patients with CDAⅡby transmission electron microscopy.The study demonstrated an increase in all patients in erythroblasts with PCDMs with development from pro-erythroblast to red blood cells.PCDMs often connected with cisternae of endoplasmic reticulum(ER)and the perinuclear space,and were accompanied by karyopyknosis,karyolysis and disruption in polychromatic and orthochromatic erythroblasts.The results suggest that PCDMs are transformed from ER during erythropoiesis and participate in the dissolution and deletion of late erythroid cells in patients with CDAⅡ.
基金supported by the National Natural Sciences Foundation of China(31730051 and 31601164)the National Key Research and Development Program of China(2018YFA0800900)+1 种基金Natural Science Foundation of Shandong Province,China(ZR2019PH076)the Open Project of Forensic Medicine Key Laboratory of Shanxi Province,China(SFM2019001)。
文摘Pulmonary surfactant is a lipid-protein complex secreted by alveolar typeⅡepithelial cells and is essential for the maintenance of the delicate structure of mammalian alveoli to promote efficient gas exchange across the air-liquid barrier.The Golgi apparatus plays an important role in pulmonary surfactant modification and secretory trafficking.However,the physiological function of the Golgi apparatus in the transport of pulmonary surfactants is unclear.In the present study,deletion of GM130,which encodes for a matrix protein of the cis-Golgi cisternae,was shown to induce the disruption of the Golgi structure leading to impaired secretion of lung surfactant proteins and lipids.Specifically,the results of in vitro and in vivo analysis indicated that the loss of GM130 resulted in trapping of Sftpa in the endoplasmic reticulum,Sftpb and Sftpc accumulation in the Golgi apparatus,and an increase in the compensatory secretion of Sftpd.Moreover,global and epithelial-specific GM130 knockout in mice resulted in an enlargement of alveolar airspace and an increase in alveolar epithelial autophagy;however,surfactant repletion partially rescued the enlarged airspace defects in GM130-deficient mice.Therefore,our results demonstrate that GM130 and the mammalian Golgi apparatus play a critical role in the control of surfactant protein secretion in pulmonary epithelial cells.
基金Supported by National Natural Science Foundation of China,No.82072734.
文摘BACKGROUND For Siewert type Ⅱ/Ⅲ adenocarcinoma of gastroesophageal junction(AGE), the efficacy of adjuvant chemoradiotherapy(CRT) after D2/R0 resection remains uncertain.AIM To determine whether CRT was superior to chemotherapy(CT) alone after D2/R0 resection for locally advanced Siewert type Ⅱ/Ⅲ AGE.METHODS We identified 316 locally advanced Siewert type Ⅱ/Ⅲ AGE patients who were treated with D2/R0 resection at National Cancer Center from 2011 to 2018.57 patients received adjuvant CRT and 259 patients received adjuvant CT.We followed patients for overall survival(OS), relapse-free survival, and recurrence pattern.RESULTS Five-year OS rates of the CRT group and the CT group for all patients were 66.7% and 41.9%(P = 0.010).Five-year OS rates of the CRT group and the CT group for Siewert type Ⅲ AGE patients were 65.7% and 43.9%(P = 0.006).Among the 195 patients whose recurrence information could be obtained, 18 cases(34.6%) and 61 cases(42.7%) were diagnosed as recurrence in the CRT group and CT group, respectively.The local and regional recurrence rates in the CRT group were lower than that in the CT group(22.2% vs 24.6%, 27.8% vs 39.3%).Multivariable cox regression analysis showed that vascular invasion, nerve invasion, and adjuvant CRT were important prognostic factors for Siewert type Ⅲ AGE.CONCLUSION For locally advanced Siewert type Ⅲ AGE, adjuvant CRT may prolong OS and reduce the regional recurrence rate.
基金supported by the research fund of Chungnam National University
文摘Type-Ⅱsuperlattice(T2SL)materials are the key element for infrared(IR)detectors.However,it is well known that the characteristics of the detectors with the T2SL layer are greatly affected by the strain developed during the growth process,which determines the performance of IR detectors.Therefore,great efforts have been made to properly control the strain effect and develop relevant analysis methods to evaluate the strain-induced dark current characteristics.In this work,we report the strain-induced dark current characteristics in InAs/GaSb T2SL MWIR photodetector.The overall strain of InAs/GaSb T2SL layer was analyzed by both high-resolution X-ray diffraction(HRXRD)and the dark current measured from the absorber layer at the elevated temperatures(≥110 K),where the major leakage current component is originated from the reduced minority carrier lifetime in the absorber layer.Our findings indicate that minority carrier lifetime increases as the tensile strain on the InAs/GaSb T2SL is more compensated by the compressive strain through‘InSb-like’interface,which reduces the dark current density of the device.Specifically,tensile strain compensated devices exhibited the dark current density of less than 2×10^-5 A/cm^2 at 120 K,which is more than one order of magnitude lower value compared to that of the device without tensile strain relaxation.
基金financial support from National Natural Science Foundation of China (81872818)National Key R&D Program of China (2021YFE0115200)
文摘Glucagon-like peptide-1 receptor agonists(GLP-1 RA)are a series of polypeptides broadly applied in the long-term treatment of typeⅡdiabetes.However,administration of GLP-RA is mainly through repetitive subcutaneous injection,which may seriously decrease the compliance and safety.Herein,a bio-inspired oral delivery system was designed to enhance the oral absorption of liraglutide(Lira),a kind of GLP-1 RA,by mimicking the natural cholesterol assimilation.25-hydroxycholesterol(25HC),a cholesterol derivative,was modified on the surfaced of Lira-loaded PLGA nanoparticles(Lira 25HC NPs)and functioned as a“top-down”actuator to facilitate unidirectional transcytosis across the intestinal epithelium.After oral delivery,Lira 25HC NPs displayed improved therapeutic effect as compared with oral free Lira on typeⅡdiabetes db/db mice,as evidenced by multiple relieved diabetic symptoms including the enhanced glucose tolerance,repressed weight growth,improved liver glucose metabolism,decreased fasting blood glucose,HbA 1c,serum lipid,and increasedβcells activity.Surprisingly,the fasting blood glucose,liver glucose metabolism,and HbA1c of oral Lira-loaded 25HC NPs were comparable to subcutaneous injection of free Lira.Further mechanisms revealed that 25HC ligand could mediate the nanoparticles to mimic natural cholesterol absorption by exerting high affinity towards apical Niemann-Pick C1 Like 1(NPC1L1)and then basolateral ATP binding cassette transporter A1(ABCA1)overexpressed on the opposite side of intestinal epithelium.This cholesterol assimilation-mimicking strategy achieve the unidirectional transport across the intestinal epithelium,thus improving the oral absorption of liraglutide.In general,this study established a cholesterol simulated platform and provide promising insight for the oral delivery of GLP-1 RA.
