Sexually transmitted diseases （STDs） are among the first ten causes of unpleasant diseases in young adult males in developing countries and the second major cause of unpleasant diseases in young adult women. Adolesc...Sexually transmitted diseases （STDs） are among the first ten causes of unpleasant diseases in young adult males in developing countries and the second major cause of unpleasant diseases in young adult women. Adolescents and young adults （15-24 years old） make up only 25% of the sexually active population, but represent almost 50% of all new acquired STDs. In general, STDs are epidemics and present an enormous health and economic consequences. An adequate screening for STDs should be done on a routine basis in every part of the world. Many STDs are asymptomatic and therefore can difficult to control. The purpose of reporting of STDs is to ensure that persons who are infected will be quickly diagnosed and appropriately treated to control the spread of infection and also so that partners are notified, tested and appropriately treated. It is estimated that reported cases of STDs represent only 50%-80% of reportable STD infections in the United States, reflecting limited screening and low disease reporting. High-risk sexual behavior is a highly contributive factor of this process as it often leads to teenage pregnancies and HIV/AIDS. One possible explanation for this behavior is that people do not have enough information about the transmission of STDs or ignore the precautions required for safe sex. Approximately 60% of new HIV infections worldwide occur in young people. The frequency of high-risk behaviors among youths may also be influenced by opportunity to engage in them, particularly the amount of time that they are unsupervised by adults. However, in diagnosing and treating these patients, we can effectively prevent the spread of HIV/AIDS. Individuals infected with STDs are 5-10 times more likely than uninfected individuals to acquire or transmit HIV through sexual contact. The breaking of the genital tract lining or skin creates a portal of entry for HIV and, hence, HIV-infected individuals with other STDs are more likely to shed HIV in their genital secretions. To date, the condom is the most effective展开更多
Tissue homeostasis requires a carefully-orchestrated balance between cell proliferation, cellular senescence and cell death. Cells proliferate through a cell cycle that is tightly regulated by cyclin-dependent kinase ...Tissue homeostasis requires a carefully-orchestrated balance between cell proliferation, cellular senescence and cell death. Cells proliferate through a cell cycle that is tightly regulated by cyclin-dependent kinase activities. Cellular senescence is a safeguard program limiting the proliferative competence of cells in living organisms. Apoptosis eliminates unwanted cells by the coordinated activity of gene products that regulate and effect cell death. The intimate link between the cell cycle, cellular senes- cence, apoptosis regulation, cancer development and tumor responses to cancer treatment has become eminently apparent. Extensive research on tumor suppressor genes, oncogenes, the cell cycle and apoptosis regulatory genes has revealed how the DNA damage-sensing and -signaling pathways, referred to as the DNA-damage response network, are tied to cell proliferation, cell-cycle arrest, cellular senescence and apoptosis. DNA-damage responses are complex, involving “sensor” proteins that sense the damage, and transmit signals to “transducer” proteins, which, in turn, convey the signals to numerous “effector” proteins implicated in specific cellular pathways, including DNA repair mechanisms, cell-cycle checkpoints, cellular senescence and apoptosis. The Bcl-2 family of proteins stands among the most crucial regulators of apoptosis and performs vital functions in deciding whether a cell will live or die after cancer chemotherapy and irradiation. In addition, several studies have now revealed that members of the Bcl-2 family also interface with the cell cycle, DNA repair/recombination and cellular senescence, effects that are generally distinct from their function in apoptosis. In this review, we report progress in understanding the molecular networks that regulate cell-cycle checkpoints, cellular senescence and apoptosis after DNA damage, and discuss the influence of some Bcl-2 family members on cell-cycle checkpoint regulation.展开更多
AIM: To establish the extent to which contrast enhancement with SonoVue in combination with quantitative evaluation of contrast-medium dynamics facilitates the detection of hepatic tumors. METHODS: One hundred patient...AIM: To establish the extent to which contrast enhancement with SonoVue in combination with quantitative evaluation of contrast-medium dynamics facilitates the detection of hepatic tumors. METHODS: One hundred patients with histologically confirmed malignant or benign hepatic tumor (maximum size 5 cm) were analyzed. Contrast-enhanced ultrasound (bolus injection 2.5 mL SonoVue) was carried out with intermittent breath-holding technique using a multifrequency transducer (2.5-4 MHz). Native vascularization was analyzed with power Doppler. The contrast-enhanced dynamic ultrasound investigation was carried out with contrast harmonic imaging in true detection mode during the arterial,portal venous and late phases. Mechanical index was set at 0.15. Perfusion analysis was performed by post-processing of the raw data time intensity curve (TIC) analysis. The cut-off of the gray value differences between tumor and normal liver tissue was established using Receiver Operating Characteristic (ROC) analysis 64-line multi-slice computed tomography served as reference method in all cases. Magnetic resonance tomography was used additionally in 19 cases. RESULTS: One hundred patients with 59 malignant (43 colon,5 breast,2 endocrine metastases,7 hepatocellular carcinomas and 2 kidney cancers) and 41 benign (15 hemangiomas,7 focal nodular hyperplasias,5 complicated cysts,2 abscesses and 12 circumscribed fatty changes) tumors were included. The late venous phase proved to be the most sensitive for classification of the tumor type. Fifty-eight of the 59 malignant tumors were classified as true positive,and one as false negative. This resulted in a sensitivity of 98.3%. Of the 41 benign tumors,37 were classified as true negative and 4 as false negative,which corresponds to a specificity of 90.2%. Altogether,95.0% of the diagnoses were classified as correct on the basis of the histological classification. No investigator-dependency (P = 0.23) was noted. CONCLUSION: The results show the possibility of accurate prediction of malignancy of 展开更多
This study presents an application of artificial neural network(ANN)and Bayesian network(BN)for evaluation of jamming risk of the shielded tunnel boring machines(TBMs)in adverse ground conditions such as squeezing gro...This study presents an application of artificial neural network(ANN)and Bayesian network(BN)for evaluation of jamming risk of the shielded tunnel boring machines(TBMs)in adverse ground conditions such as squeezing grounds.The analysis is based on database of tunneling cases by numerical modeling to evaluate the ground convergence and possibility of machine entrapment.The results of initial numerical analysis were verified in comparison with some case studies.A dataset was established by performing additional numerical modeling of various scenarios based on variation of the most critical parameters affecting shield jamming.This includes compressive strength and deformation modulus of rock mass,tunnel radius,shield length,shield thickness,in situ stresses,depth of over-excavation,and skin friction between shield and rock.Using the dataset,an ANN was trained to predict the contact pressures from a series of ground properties and machine parameters.Furthermore,the continuous and discretized BNs were used to analyze the risk of shield jamming.The results of these two different BN methods are compared to the field observations and summarized in this paper.The developed risk models can estimate the required thrust force in both cases.The BN models can also be used in the cases with incomplete geological and geomechanical properties.展开更多
Wild potato species have substantial phenotypic and physiological diversity. Here, we report a comprehen- sive assessment of wild and cultivated potato species based on genomic analyses of 201 accessions of Solanum se...Wild potato species have substantial phenotypic and physiological diversity. Here, we report a comprehen- sive assessment of wild and cultivated potato species based on genomic analyses of 201 accessions of Solanum section Petota. We sequenced the genomes of these 201 accessions and identified 6 487 006 high-quality single nucleotide polymorphisms （SNPs） from 167 accessions in clade 4 of Solanum section Petota, including 146 wild and 21 cultivated diploid potato accessions with a broad geographic distribution. Genome-wide genetic variation analysis showed that the diversity of wild potatoes is higher than that of cultivated potatoes, and much higher genetic diversity in the agronomically important disease resistance genes was observed in wild potatoes. Furthermore, by exploiting information about known quantitative trait loci （QTL）, we identified 609 genes under selection, including those correlated with the loss of bitterness in tubers and those involved in tuberization, two major domesticated traits of potato. Phylogenetic analyses revealed a north-south division of all species in clade 4, not just those in the S. brevicaule complex, and further supported So candolleanum as the progenitor of cultivated potato and the monophyletic origin of cultivated potato in southern Peru. In addition, we analyzed the genome of S. candolleanum and identified 529 genes lost in cultivated potato. Collectively, the molecular markers generated in this study provide a valuable resource for the identification of agronomicaUy important genes useful for potato breeding.展开更多
Severe shield jamming events have been reported during excavation of Uluabat tunnel through adverse geological conditions, which resulted in several stoppages at advancing a single shielded tunnel boring machine(TBM)....Severe shield jamming events have been reported during excavation of Uluabat tunnel through adverse geological conditions, which resulted in several stoppages at advancing a single shielded tunnel boring machine(TBM). To study the jamming mechanism, three-dimensional(3D) simulation of the machine and surrounding ground was implemented using the finite difference code FLAC3D. Numerical analyses were performed for three sections along the tunnel with a higher risk for entrapment due to the combination of overburden and geological conditions. The computational results including longitudinal displacement contours and ground pressure profiles around the shield allow a better understanding of ground behavior within the excavation. Furthermore, they allow realistically assessing the impact of adverse geological conditions on shield jamming. The calculated thrust forces, which are required to move the machine forward, are in good agreement with field observations and measurements. It also proves that the numerical analysis can effectively be used for evaluating the effect of adverse geological environment on TBM entrapments and can be applied to prediction of loads on the shield and preestimating of the required thrust force during excavation through adverse ground conditions.展开更多
The aim of this study was to optimize the geometry and the design of metallic/composite single bolted joints subjected to tension-compression loading. For this purpose, it was necessary to evaluate the stress state in...The aim of this study was to optimize the geometry and the design of metallic/composite single bolted joints subjected to tension-compression loading. For this purpose, it was necessary to evaluate the stress state in each component of the bolted join. The multi-material assembly was based on the principle of double lap bolted joint. It was composed of a symmetrical balanced woven glass-epoxy composite material plate fastened to two stainless sheets using a stainless pre-stressed bolt. In order to optimize the design and the geometry of the assembly, ten configurations were proposed and studied: a classical simple bolted joint, two joints with an insert (a BigHead<sup>R</sup> insert and a stair one) embedded in the composite, two “waved” solutions, three symmetrical configurations composed of a succession of metallic and composites layers, without a sleeve, with one and with two sleeves, and two non-symmetrical constituted of metallic and composites layers associated with a stair-insert (one with a sleeve and one without). A tridimensional Finite Element Method (FEM) was used to model each configuration mentioned above. The FE models taked into account the different materials, the effects of contact between the different sheets of the assembly and the pre-stress in the bolt. The stress state was analyzed in the composite part. The concept of stress concentration factor was used in order to evaluate the stress increase in the highly stressed regions and to compare the ten configurations studied. For this purpose, three stress concentration factors were defined: one for a monotonic loading in tension, another for a monotonic loading in compression, and the third for a tension-compression cyclic loading. The results of the FEM computations showed that the use of alternative metallic and composite layers associated with two sleeves gived low values of stress concentration factors, smaller than 1.4. In this case, there was no contact between the bolt and the composite part and the most stressed region was not the 展开更多
Gastrinomas are defined as gastrin secreting tumors that are associated with Zollinger-Ellison syndrome （ZES）. ZES is characterized by elevated fasting gastrin serum levels, positive secretin stimulation test and cl...Gastrinomas are defined as gastrin secreting tumors that are associated with Zollinger-Ellison syndrome （ZES）. ZES is characterized by elevated fasting gastrin serum levels, positive secretin stimulation test and clinical symptoms such as recurrent peptic ulcer disease, gastroesophageal reflux disease and occasional diarrhea. Genetically, nonhereditary （sporadic） gastrinomas are distinguished from hereditary gastrinomas, which are associated with multiple endocrine neoplasia type 1 （MEN1） syndrome. In general, duodenal gastrinomas are small and solitary if they are sporadic and multiple as well as hereditary. The sporadic gastrinomas occur in the duodenum or in the pancreas while the hereditary gastrinomas almost all occur in the duodenum. Our series of 77 sporadic duodenal neuroendocrine tumors （NETs） includes 18 patients （23.4%） with gastrinomas and ZES. Of 535 sporadic NETs in the pancreas collected from the NET archives of the departments of pathology in Zürich, Switzerland, and Kiel, Germany, 24 patients （4.5%） suffered from sporadic pancreatic gastrinomas and ZES. These NETs have to be distinguished from tumors with immunohistochemical positivity for gastrin but without evidence of ZES. An additional 19 patients suffered from MEN1 and ZES. These patients showed exclusively duodenal gastrinomas, but not pancreatic gastrinomas. The prognosis of sporadic and MEN1- associated duodenal gastrinomas is better than that of pancreatic gastrinomas, since they progress slowly to liver metastasis. In summary, sporadic and MEN1- associated gastrinomas in the duodenum and pancreas show different clinico-pathological and genetic features. The incidence of sporadic duodenal gastrin-producing tumors is increasing, possibly due to optimized diagnostic procedures. In contrast, pancreatic MEN1- associated gastrinomas seem to be extremely rare. A considerable subset of tumors with immunohistochemical expression of gastrin but without evidence of ZES should be designated as functionally inactive NETs exp展开更多
Rationale and Objectives: Cystic lung disease may be accurately diagnosed by imaging interpretation of specialist radiologists, without other information. We hypothesized that with minimal training non-specialists cou...Rationale and Objectives: Cystic lung disease may be accurately diagnosed by imaging interpretation of specialist radiologists, without other information. We hypothesized that with minimal training non-specialists could perform similarly to specialist physicians in the diagnosis of cystic lung disease. Methods: 72 cystic lung disease cases and 25 cystic lung disease mimics were obtained from three sources: 1) a prospective acquired diffuse lung disease registry, 2) a retrospective search of medical records and 3) teaching files. Cases were anonymized, randomized and interpreted by 7 diffuse lung disease specialists and 15 non-specialist radiologists and pulmonologists. Clinical information other than age and sex was not provided. Prior to interpretation, non-specialists viewed a short PDF training document explaining cystic lung disease interpretation. Results: Correct first choice diagnosis of 85%-88% may be achieved by high-performing specialist readers and 71%-80% by non-specialists and lower-performing specialists, with mean accuracies in the diagnosis of LAM (91%, p Conclusion: With specific but limited training, non-specialist physicians can diagnose cystic lung diseases from CT appearance alone with similar accuracy to specialists, correctly identifying approximately 75% of cases.展开更多
Purpose: Development of sarcoma is a known late rare negative side effect of radiotherapy. We add two cases to emphasize the need for open-end follow-up and critical evaluation to avoid misinterpretation. Patients, Me...Purpose: Development of sarcoma is a known late rare negative side effect of radiotherapy. We add two cases to emphasize the need for open-end follow-up and critical evaluation to avoid misinterpretation. Patients, Methods, and Results: Two patients developed osteosarcoma as a second malignancy in the humerus after adjuvant radiotherapy of a primary tumor not directly involving the later affected bone. The first patient had a Ewing sarcoma of the scapula at age 13 years. Though after neoadjuvant chemotherapy the resected specimen showed only fibrotic necrotic areas within clear resection margins, the study group indicated adjuvant radiotherapy in a field including the shoulder joint. At age 24 years she developed an osteosarcoma of the humeral head, which was resected and reconstructed with a proximal humerus endoprosthesis. She is alive without disease at age 32 years. The second patient presented with an osteosarcoma of the proximal humerus 29 years after irradiation for breast cancer including the shoulder joint. The sarcoma was misinterpreted as radiation-induced necrosis and the patient was treated with a reverse shoulder endoprosthesis. Pathologic examination of the resected humeral head then showed a typical osteosarcoma. Two years later the humeral reverse shoulder implant was resected and a proximal humerus tumor prosthesis implanted leaving the original glenosphere. Conclusions: In both cases radiation-induced osteosarcoma developed in bone not affected by the primary cancer. Protecting uninvolved structures must be warranted in the planning of radiotherapy. The long latency between the primary and second cancer mandates long-term—best indefinite—follow-up, as with appropriate treatment of a radiation-induced osteosarcoma good healing rates comparable to those of primary osteosarcoma can still be achieved.展开更多
Due to spatial and temporal variability an effective monitoring system for water resources must consider the use of remote sensing to provide information.Synthetic Aperture Radar(SAR)is useful due to timely data acqui...Due to spatial and temporal variability an effective monitoring system for water resources must consider the use of remote sensing to provide information.Synthetic Aperture Radar(SAR)is useful due to timely data acquisition and sensitivity to surface water and flooded vegetation.The ability to map flooded vegetation is attributed to the double bounce scattering mechanism,often dominant for this target.Dong Ting Lake in China is an ideal site for evaluating SAR data for this application due to annual flooding caused by mountain snow melt causing extensive changes in flooded vegetation.A curvelet-based approach for change detection in SAR imagery works well as it highlights the change and suppresses the speckle noise.This paper addresses the extension of this change detection technique to polarimetric SAR data for monitoring surface water and flooded vegetation.RADARSAT-2 images of Dong Ting Lake demonstrate this curvelet-based change detection technique applied to wetlands although it is applicable to other land covers and for post disaster impact assessment.These tools are important to Digital Earth for map updating and revision.展开更多
Regenerative bone implants promote new bone formation and ideally degrade simultaneously to osteogenesis.Although clinically established calcium phosphate bone grafts provide excellent osseointegration and osteoconduc...Regenerative bone implants promote new bone formation and ideally degrade simultaneously to osteogenesis.Although clinically established calcium phosphate bone grafts provide excellent osseointegration and osteoconductive efficacy,they are limited in terms of bioresorption.Magnesium phosphate(MP)based ceramics are a promising alternative,because they are biocompatible,mechanically extremely stable,and degrade much faster than calcium phosphates under physiological conditions.Bioresorption of an implant material can include both chemical dissolution as well as cellular resorption.We investigated the bioresorption of 3D powder printed struvite and newberyite based MP ceramics in vitro by a direct human osteoclast culture approach.The osteoclast response and cellular resorption was evaluated by means of fluorescence and TRAP staining,determination of osteoclast activities(CA II and TRAP),SEM imaging as well as by quantification of the ion release during cell culture.Furthermore,the bioactivity of the materials was investigated via SBF immersion,whereas hydroxyapatite precipitates were analyzed by SEM and EDX measurements.This bioactive coating was resorbed by osteoclasts.In contrast,only chemical dissolution contributed to bioresorption of MP,while no cellular resorption of the materials was observed.Based on our results,we expect an increased bone regeneration effect of MP compared to calcium phosphate based bone grafts and complete chemical degradation within a maximum of 1.5-3.1 years.展开更多
Synaptic vesicles can undergo several modes of exocytosis,endocytosis,and trafficking within individual synapses,and their fates may be linked to different vesicular protein compositions.Here,we mapped the intrasynapt...Synaptic vesicles can undergo several modes of exocytosis,endocytosis,and trafficking within individual synapses,and their fates may be linked to different vesicular protein compositions.Here,we mapped the intrasynaptic distribution of the synaptic vesicle proteins SV2B and SV2A in glutamatergic synapses of the hippocampus using three-dimensional electron microscopy.SV2B was almost completely absent from docked vesicles and a distinct cluster of vesicles found near the active zone.In contrast,SV2A was found in all domains of the synapse and was slightly enriched near the active zone.SV2B and SV2A were found on the membrane in the peri-active zone,suggesting the recycling from both clusters of vesicles.SV2B knockout mice displayed an increased seizure induction threshold only in a model employing high-frequency stimulation.Our data show that glutamatergic synapses generate molecularly distinct populations of synaptic vesicles and are able to maintain them at steep spatial gradients.The almost complete absence of SV2B from vesicles at the active zone of wildtype mice may explain why SV2A has been found more important for vesicle release.展开更多
Despite the generally placid appearance of plants,many dynamicprocesses take place inside a plant cell.One such process thathas garnered attention in recent years is termed"autophagy."While originally discov...Despite the generally placid appearance of plants,many dynamicprocesses take place inside a plant cell.One such process thathas garnered attention in recent years is termed"autophagy."While originally discovered in yeast,our understanding of autophagy in plants has improved significantly.Autophagy is considered a cellular recycling system in which cellular components oreven entire organelles can be encapsulated by a membranestructure(autophagosome)and then transported to the vacuole(in plants)for degradation and re-use.展开更多
To investigate the relation of two different mutations to the outcome of partial external biliary diversion (PEBD) in severe bile salt export pump (BSEP) deficiency. METHODSMutations in the gene encoding BSEP leading ...To investigate the relation of two different mutations to the outcome of partial external biliary diversion (PEBD) in severe bile salt export pump (BSEP) deficiency. METHODSMutations in the gene encoding BSEP leading to severe BSEP deficiency in two unrelated patients were identified by genomic sequencing. Native liver biopsies and transiently transfected human embryonic kidney (HEK) 293 cells expressing either wild-type or mutated BSEP were subjected to immunofluorescence analysis to assess BSEP transporter localization. Bile acid profiles of patient and control bile samples were generated by ultra-performance liquid chromatography-tandem mass spectrometry. Wild-type and mutant BSEP transport of [<sup>3</sup>H]-labeled taurocholate (TC) and taurochenodeoxycholate (TCDC) was assessed by vesicular transport assays. RESULTSA girl (at 2 mo) presented with pruritus, jaundice and elevated serum bile salts (BS). PEBD stabilized liver function and prevented liver transplantation. She was heterozygous for the BSEP deletion p.T919del and the nonsense mutation p.R1235X. At the age of 17 years relative amounts of conjugated BS in her bile were normal, while total BS were less than 3% as compared to controls. An unrelated boy (age 1.5 years) presenting with severe pruritus and elevated serum BS was heterozygous for the same nonsense and another missense mutation, p.G1032R. PEBD failed to alleviate pruritus, eventually necessitating liver transplantation. BS concentration in bile was about 5% of controls. BS were mainly unconjugated with an unusual low amount of chenodeoxycholate derivatives (< 5%). The patients’ native liver biopsies showed canalicular BSEP expression. Both BSEP p.T919del and p.G1032R were localized in the plasma membrane in HEK293 cells. In vitro transport assays showed drastic reduction of transport by both mutations. Using purified recombinant BSEP as quantifiable reference, per-molecule transport rates for TC and TCDC were determined to be 3 and 2 BS molecules per wild-type BSEP transporter per minute,展开更多
文摘Sexually transmitted diseases （STDs） are among the first ten causes of unpleasant diseases in young adult males in developing countries and the second major cause of unpleasant diseases in young adult women. Adolescents and young adults （15-24 years old） make up only 25% of the sexually active population, but represent almost 50% of all new acquired STDs. In general, STDs are epidemics and present an enormous health and economic consequences. An adequate screening for STDs should be done on a routine basis in every part of the world. Many STDs are asymptomatic and therefore can difficult to control. The purpose of reporting of STDs is to ensure that persons who are infected will be quickly diagnosed and appropriately treated to control the spread of infection and also so that partners are notified, tested and appropriately treated. It is estimated that reported cases of STDs represent only 50%-80% of reportable STD infections in the United States, reflecting limited screening and low disease reporting. High-risk sexual behavior is a highly contributive factor of this process as it often leads to teenage pregnancies and HIV/AIDS. One possible explanation for this behavior is that people do not have enough information about the transmission of STDs or ignore the precautions required for safe sex. Approximately 60% of new HIV infections worldwide occur in young people. The frequency of high-risk behaviors among youths may also be influenced by opportunity to engage in them, particularly the amount of time that they are unsupervised by adults. However, in diagnosing and treating these patients, we can effectively prevent the spread of HIV/AIDS. Individuals infected with STDs are 5-10 times more likely than uninfected individuals to acquire or transmit HIV through sexual contact. The breaking of the genital tract lining or skin creates a portal of entry for HIV and, hence, HIV-infected individuals with other STDs are more likely to shed HIV in their genital secretions. To date, the condom is the most effective
基金the Canadian Institutes of Health Research and the Cancer Research Society, and fellowships by the Health Research Funds of Quebec, Canada
文摘Tissue homeostasis requires a carefully-orchestrated balance between cell proliferation, cellular senescence and cell death. Cells proliferate through a cell cycle that is tightly regulated by cyclin-dependent kinase activities. Cellular senescence is a safeguard program limiting the proliferative competence of cells in living organisms. Apoptosis eliminates unwanted cells by the coordinated activity of gene products that regulate and effect cell death. The intimate link between the cell cycle, cellular senes- cence, apoptosis regulation, cancer development and tumor responses to cancer treatment has become eminently apparent. Extensive research on tumor suppressor genes, oncogenes, the cell cycle and apoptosis regulatory genes has revealed how the DNA damage-sensing and -signaling pathways, referred to as the DNA-damage response network, are tied to cell proliferation, cell-cycle arrest, cellular senescence and apoptosis. DNA-damage responses are complex, involving “sensor” proteins that sense the damage, and transmit signals to “transducer” proteins, which, in turn, convey the signals to numerous “effector” proteins implicated in specific cellular pathways, including DNA repair mechanisms, cell-cycle checkpoints, cellular senescence and apoptosis. The Bcl-2 family of proteins stands among the most crucial regulators of apoptosis and performs vital functions in deciding whether a cell will live or die after cancer chemotherapy and irradiation. In addition, several studies have now revealed that members of the Bcl-2 family also interface with the cell cycle, DNA repair/recombination and cellular senescence, effects that are generally distinct from their function in apoptosis. In this review, we report progress in understanding the molecular networks that regulate cell-cycle checkpoints, cellular senescence and apoptosis after DNA damage, and discuss the influence of some Bcl-2 family members on cell-cycle checkpoint regulation.
文摘AIM: To establish the extent to which contrast enhancement with SonoVue in combination with quantitative evaluation of contrast-medium dynamics facilitates the detection of hepatic tumors. METHODS: One hundred patients with histologically confirmed malignant or benign hepatic tumor (maximum size 5 cm) were analyzed. Contrast-enhanced ultrasound (bolus injection 2.5 mL SonoVue) was carried out with intermittent breath-holding technique using a multifrequency transducer (2.5-4 MHz). Native vascularization was analyzed with power Doppler. The contrast-enhanced dynamic ultrasound investigation was carried out with contrast harmonic imaging in true detection mode during the arterial,portal venous and late phases. Mechanical index was set at 0.15. Perfusion analysis was performed by post-processing of the raw data time intensity curve (TIC) analysis. The cut-off of the gray value differences between tumor and normal liver tissue was established using Receiver Operating Characteristic (ROC) analysis 64-line multi-slice computed tomography served as reference method in all cases. Magnetic resonance tomography was used additionally in 19 cases. RESULTS: One hundred patients with 59 malignant (43 colon,5 breast,2 endocrine metastases,7 hepatocellular carcinomas and 2 kidney cancers) and 41 benign (15 hemangiomas,7 focal nodular hyperplasias,5 complicated cysts,2 abscesses and 12 circumscribed fatty changes) tumors were included. The late venous phase proved to be the most sensitive for classification of the tumor type. Fifty-eight of the 59 malignant tumors were classified as true positive,and one as false negative. This resulted in a sensitivity of 98.3%. Of the 41 benign tumors,37 were classified as true negative and 4 as false negative,which corresponds to a specificity of 90.2%. Altogether,95.0% of the diagnoses were classified as correct on the basis of the histological classification. No investigator-dependency (P = 0.23) was noted. CONCLUSION: The results show the possibility of accurate prediction of malignancy of
文摘This study presents an application of artificial neural network(ANN)and Bayesian network(BN)for evaluation of jamming risk of the shielded tunnel boring machines(TBMs)in adverse ground conditions such as squeezing grounds.The analysis is based on database of tunneling cases by numerical modeling to evaluate the ground convergence and possibility of machine entrapment.The results of initial numerical analysis were verified in comparison with some case studies.A dataset was established by performing additional numerical modeling of various scenarios based on variation of the most critical parameters affecting shield jamming.This includes compressive strength and deformation modulus of rock mass,tunnel radius,shield length,shield thickness,in situ stresses,depth of over-excavation,and skin friction between shield and rock.Using the dataset,an ANN was trained to predict the contact pressures from a series of ground properties and machine parameters.Furthermore,the continuous and discretized BNs were used to analyze the risk of shield jamming.The results of these two different BN methods are compared to the field observations and summarized in this paper.The developed risk models can estimate the required thrust force in both cases.The BN models can also be used in the cases with incomplete geological and geomechanical properties.
文摘Wild potato species have substantial phenotypic and physiological diversity. Here, we report a comprehen- sive assessment of wild and cultivated potato species based on genomic analyses of 201 accessions of Solanum section Petota. We sequenced the genomes of these 201 accessions and identified 6 487 006 high-quality single nucleotide polymorphisms （SNPs） from 167 accessions in clade 4 of Solanum section Petota, including 146 wild and 21 cultivated diploid potato accessions with a broad geographic distribution. Genome-wide genetic variation analysis showed that the diversity of wild potatoes is higher than that of cultivated potatoes, and much higher genetic diversity in the agronomically important disease resistance genes was observed in wild potatoes. Furthermore, by exploiting information about known quantitative trait loci （QTL）, we identified 609 genes under selection, including those correlated with the loss of bitterness in tubers and those involved in tuberization, two major domesticated traits of potato. Phylogenetic analyses revealed a north-south division of all species in clade 4, not just those in the S. brevicaule complex, and further supported So candolleanum as the progenitor of cultivated potato and the monophyletic origin of cultivated potato in southern Peru. In addition, we analyzed the genome of S. candolleanum and identified 529 genes lost in cultivated potato. Collectively, the molecular markers generated in this study provide a valuable resource for the identification of agronomicaUy important genes useful for potato breeding.
基金Alexander von Humboldt-Foundation (AvH) for the financial support as a research fellowthe financial support of the Scientific and Technological Research Council of Turkey (TüB_ITAK) under Project No. MAG-114M568
文摘Severe shield jamming events have been reported during excavation of Uluabat tunnel through adverse geological conditions, which resulted in several stoppages at advancing a single shielded tunnel boring machine(TBM). To study the jamming mechanism, three-dimensional(3D) simulation of the machine and surrounding ground was implemented using the finite difference code FLAC3D. Numerical analyses were performed for three sections along the tunnel with a higher risk for entrapment due to the combination of overburden and geological conditions. The computational results including longitudinal displacement contours and ground pressure profiles around the shield allow a better understanding of ground behavior within the excavation. Furthermore, they allow realistically assessing the impact of adverse geological conditions on shield jamming. The calculated thrust forces, which are required to move the machine forward, are in good agreement with field observations and measurements. It also proves that the numerical analysis can effectively be used for evaluating the effect of adverse geological environment on TBM entrapments and can be applied to prediction of loads on the shield and preestimating of the required thrust force during excavation through adverse ground conditions.
文摘The aim of this study was to optimize the geometry and the design of metallic/composite single bolted joints subjected to tension-compression loading. For this purpose, it was necessary to evaluate the stress state in each component of the bolted join. The multi-material assembly was based on the principle of double lap bolted joint. It was composed of a symmetrical balanced woven glass-epoxy composite material plate fastened to two stainless sheets using a stainless pre-stressed bolt. In order to optimize the design and the geometry of the assembly, ten configurations were proposed and studied: a classical simple bolted joint, two joints with an insert (a BigHead<sup>R</sup> insert and a stair one) embedded in the composite, two “waved” solutions, three symmetrical configurations composed of a succession of metallic and composites layers, without a sleeve, with one and with two sleeves, and two non-symmetrical constituted of metallic and composites layers associated with a stair-insert (one with a sleeve and one without). A tridimensional Finite Element Method (FEM) was used to model each configuration mentioned above. The FE models taked into account the different materials, the effects of contact between the different sheets of the assembly and the pre-stress in the bolt. The stress state was analyzed in the composite part. The concept of stress concentration factor was used in order to evaluate the stress increase in the highly stressed regions and to compare the ten configurations studied. For this purpose, three stress concentration factors were defined: one for a monotonic loading in tension, another for a monotonic loading in compression, and the third for a tension-compression cyclic loading. The results of the FEM computations showed that the use of alternative metallic and composite layers associated with two sleeves gived low values of stress concentration factors, smaller than 1.4. In this case, there was no contact between the bolt and the composite part and the most stressed region was not the
基金Supported by the Hensel Stiftung Kiel (F370011, MA and GK),the Swiss National Foundation (SNF 31-61884, AP and PK) andthe German Society of Pathology (MA). Tobias Henopp has afellowship sponsored by Ipsen GMBH, Ettlingen, Germany
文摘Gastrinomas are defined as gastrin secreting tumors that are associated with Zollinger-Ellison syndrome （ZES）. ZES is characterized by elevated fasting gastrin serum levels, positive secretin stimulation test and clinical symptoms such as recurrent peptic ulcer disease, gastroesophageal reflux disease and occasional diarrhea. Genetically, nonhereditary （sporadic） gastrinomas are distinguished from hereditary gastrinomas, which are associated with multiple endocrine neoplasia type 1 （MEN1） syndrome. In general, duodenal gastrinomas are small and solitary if they are sporadic and multiple as well as hereditary. The sporadic gastrinomas occur in the duodenum or in the pancreas while the hereditary gastrinomas almost all occur in the duodenum. Our series of 77 sporadic duodenal neuroendocrine tumors （NETs） includes 18 patients （23.4%） with gastrinomas and ZES. Of 535 sporadic NETs in the pancreas collected from the NET archives of the departments of pathology in Zürich, Switzerland, and Kiel, Germany, 24 patients （4.5%） suffered from sporadic pancreatic gastrinomas and ZES. These NETs have to be distinguished from tumors with immunohistochemical positivity for gastrin but without evidence of ZES. An additional 19 patients suffered from MEN1 and ZES. These patients showed exclusively duodenal gastrinomas, but not pancreatic gastrinomas. The prognosis of sporadic and MEN1- associated duodenal gastrinomas is better than that of pancreatic gastrinomas, since they progress slowly to liver metastasis. In summary, sporadic and MEN1- associated gastrinomas in the duodenum and pancreas show different clinico-pathological and genetic features. The incidence of sporadic duodenal gastrin-producing tumors is increasing, possibly due to optimized diagnostic procedures. In contrast, pancreatic MEN1- associated gastrinomas seem to be extremely rare. A considerable subset of tumors with immunohistochemical expression of gastrin but without evidence of ZES should be designated as functionally inactive NETs exp
文摘Rationale and Objectives: Cystic lung disease may be accurately diagnosed by imaging interpretation of specialist radiologists, without other information. We hypothesized that with minimal training non-specialists could perform similarly to specialist physicians in the diagnosis of cystic lung disease. Methods: 72 cystic lung disease cases and 25 cystic lung disease mimics were obtained from three sources: 1) a prospective acquired diffuse lung disease registry, 2) a retrospective search of medical records and 3) teaching files. Cases were anonymized, randomized and interpreted by 7 diffuse lung disease specialists and 15 non-specialist radiologists and pulmonologists. Clinical information other than age and sex was not provided. Prior to interpretation, non-specialists viewed a short PDF training document explaining cystic lung disease interpretation. Results: Correct first choice diagnosis of 85%-88% may be achieved by high-performing specialist readers and 71%-80% by non-specialists and lower-performing specialists, with mean accuracies in the diagnosis of LAM (91%, p Conclusion: With specific but limited training, non-specialist physicians can diagnose cystic lung diseases from CT appearance alone with similar accuracy to specialists, correctly identifying approximately 75% of cases.
文摘Purpose: Development of sarcoma is a known late rare negative side effect of radiotherapy. We add two cases to emphasize the need for open-end follow-up and critical evaluation to avoid misinterpretation. Patients, Methods, and Results: Two patients developed osteosarcoma as a second malignancy in the humerus after adjuvant radiotherapy of a primary tumor not directly involving the later affected bone. The first patient had a Ewing sarcoma of the scapula at age 13 years. Though after neoadjuvant chemotherapy the resected specimen showed only fibrotic necrotic areas within clear resection margins, the study group indicated adjuvant radiotherapy in a field including the shoulder joint. At age 24 years she developed an osteosarcoma of the humeral head, which was resected and reconstructed with a proximal humerus endoprosthesis. She is alive without disease at age 32 years. The second patient presented with an osteosarcoma of the proximal humerus 29 years after irradiation for breast cancer including the shoulder joint. The sarcoma was misinterpreted as radiation-induced necrosis and the patient was treated with a reverse shoulder endoprosthesis. Pathologic examination of the resected humeral head then showed a typical osteosarcoma. Two years later the humeral reverse shoulder implant was resected and a proximal humerus tumor prosthesis implanted leaving the original glenosphere. Conclusions: In both cases radiation-induced osteosarcoma developed in bone not affected by the primary cancer. Protecting uninvolved structures must be warranted in the planning of radiotherapy. The long latency between the primary and second cancer mandates long-term—best indefinite—follow-up, as with appropriate treatment of a radiation-induced osteosarcoma good healing rates comparable to those of primary osteosarcoma can still be achieved.
基金funded by the Bayern-Pfalz-Foundation in Munich(Germany)and the German Academic Exchange Service(DAAD).The Remote Sensing Science(RSS)program at CCRS also supported this research project.The authors would like to thank both organizations for their financial and administrative support.The RADARSAT-2 data were acquired under the Capacity Building Centre for Earth Observation(CBCEO)agreement between the Chinese Academy of Sciences(CAS)and Earth Science Sector(ESS).ESS Contribution number/Nume´ro de contribution du SST:20100490.
文摘Due to spatial and temporal variability an effective monitoring system for water resources must consider the use of remote sensing to provide information.Synthetic Aperture Radar(SAR)is useful due to timely data acquisition and sensitivity to surface water and flooded vegetation.The ability to map flooded vegetation is attributed to the double bounce scattering mechanism,often dominant for this target.Dong Ting Lake in China is an ideal site for evaluating SAR data for this application due to annual flooding caused by mountain snow melt causing extensive changes in flooded vegetation.A curvelet-based approach for change detection in SAR imagery works well as it highlights the change and suppresses the speckle noise.This paper addresses the extension of this change detection technique to polarimetric SAR data for monitoring surface water and flooded vegetation.RADARSAT-2 images of Dong Ting Lake demonstrate this curvelet-based change detection technique applied to wetlands although it is applicable to other land covers and for post disaster impact assessment.These tools are important to Digital Earth for map updating and revision.
基金funded by the Deutsche Forschungsgemeinschaft,grant number 417069397,as a collaboration project between the Ludwig Maximilians University Munich and the University Clinic of Würzburgthe DFG for funding the crossbeam scanning electron microscope Zeiss CB 340(INST 105022/58-1 FUGG)within the DFG State Major Instrumentation Programme。
文摘Regenerative bone implants promote new bone formation and ideally degrade simultaneously to osteogenesis.Although clinically established calcium phosphate bone grafts provide excellent osseointegration and osteoconductive efficacy,they are limited in terms of bioresorption.Magnesium phosphate(MP)based ceramics are a promising alternative,because they are biocompatible,mechanically extremely stable,and degrade much faster than calcium phosphates under physiological conditions.Bioresorption of an implant material can include both chemical dissolution as well as cellular resorption.We investigated the bioresorption of 3D powder printed struvite and newberyite based MP ceramics in vitro by a direct human osteoclast culture approach.The osteoclast response and cellular resorption was evaluated by means of fluorescence and TRAP staining,determination of osteoclast activities(CA II and TRAP),SEM imaging as well as by quantification of the ion release during cell culture.Furthermore,the bioactivity of the materials was investigated via SBF immersion,whereas hydroxyapatite precipitates were analyzed by SEM and EDX measurements.This bioactive coating was resorbed by osteoclasts.In contrast,only chemical dissolution contributed to bioresorption of MP,while no cellular resorption of the materials was observed.Based on our results,we expect an increased bone regeneration effect of MP compared to calcium phosphate based bone grafts and complete chemical degradation within a maximum of 1.5-3.1 years.
基金supported by grants from Deutsche Forschungsgemeinschaft(DFG)(SFB1089,SCHO 820/4-1,SCHO 820/6-1,SCHO 820/7-1,SCHO 820/5-2,and SPP1757 to S.S.,SFB1089,SPP1757,INST117215,DI853/3-5&7,and INST 217/785-1 to D.D.),the BONFOR program of the University of Bonn Medical Center(S.S.and D.D.),and UCB Pharma.
文摘Synaptic vesicles can undergo several modes of exocytosis,endocytosis,and trafficking within individual synapses,and their fates may be linked to different vesicular protein compositions.Here,we mapped the intrasynaptic distribution of the synaptic vesicle proteins SV2B and SV2A in glutamatergic synapses of the hippocampus using three-dimensional electron microscopy.SV2B was almost completely absent from docked vesicles and a distinct cluster of vesicles found near the active zone.In contrast,SV2A was found in all domains of the synapse and was slightly enriched near the active zone.SV2B and SV2A were found on the membrane in the peri-active zone,suggesting the recycling from both clusters of vesicles.SV2B knockout mice displayed an increased seizure induction threshold only in a model employing high-frequency stimulation.Our data show that glutamatergic synapses generate molecularly distinct populations of synaptic vesicles and are able to maintain them at steep spatial gradients.The almost complete absence of SV2B from vesicles at the active zone of wildtype mice may explain why SV2A has been found more important for vesicle release.
基金supported by the Swedish Research Council(Vetenskapsrådet 2021-04358)the Carl Trygger Foundation(CTS 221981)Jörgen Lindström's Foundation.
文摘Despite the generally placid appearance of plants,many dynamicprocesses take place inside a plant cell.One such process thathas garnered attention in recent years is termed"autophagy."While originally discovered in yeast,our understanding of autophagy in plants has improved significantly.Autophagy is considered a cellular recycling system in which cellular components oreven entire organelles can be encapsulated by a membranestructure(autophagosome)and then transported to the vacuole(in plants)for degradation and re-use.
基金Supported by the German -Research Foun-dation-through the Clin-ical Research Group KFO217“Hepatobiliary tran-sport an-d liver diseases”the Collaborative Research Cen-tre 974“Commun-ication-an-d Systemic Relevan-ce in-Liver Damage an-d Regen-eration-”
文摘To investigate the relation of two different mutations to the outcome of partial external biliary diversion (PEBD) in severe bile salt export pump (BSEP) deficiency. METHODSMutations in the gene encoding BSEP leading to severe BSEP deficiency in two unrelated patients were identified by genomic sequencing. Native liver biopsies and transiently transfected human embryonic kidney (HEK) 293 cells expressing either wild-type or mutated BSEP were subjected to immunofluorescence analysis to assess BSEP transporter localization. Bile acid profiles of patient and control bile samples were generated by ultra-performance liquid chromatography-tandem mass spectrometry. Wild-type and mutant BSEP transport of [<sup>3</sup>H]-labeled taurocholate (TC) and taurochenodeoxycholate (TCDC) was assessed by vesicular transport assays. RESULTSA girl (at 2 mo) presented with pruritus, jaundice and elevated serum bile salts (BS). PEBD stabilized liver function and prevented liver transplantation. She was heterozygous for the BSEP deletion p.T919del and the nonsense mutation p.R1235X. At the age of 17 years relative amounts of conjugated BS in her bile were normal, while total BS were less than 3% as compared to controls. An unrelated boy (age 1.5 years) presenting with severe pruritus and elevated serum BS was heterozygous for the same nonsense and another missense mutation, p.G1032R. PEBD failed to alleviate pruritus, eventually necessitating liver transplantation. BS concentration in bile was about 5% of controls. BS were mainly unconjugated with an unusual low amount of chenodeoxycholate derivatives (< 5%). The patients’ native liver biopsies showed canalicular BSEP expression. Both BSEP p.T919del and p.G1032R were localized in the plasma membrane in HEK293 cells. In vitro transport assays showed drastic reduction of transport by both mutations. Using purified recombinant BSEP as quantifiable reference, per-molecule transport rates for TC and TCDC were determined to be 3 and 2 BS molecules per wild-type BSEP transporter per minute,
