Metformin alleviates bevacizumab-induced vascular endothelial injury in mice through growth differentiation factor 15 upregulation.

Objectives: Bevacizumab is a commonly used anticancer drug in clinical practice, but it often leads to adverse reactions such as vascular endothelial damage, hypertension, arterial and venous thrombosis, and bleeding. This study investigated the protective effects of metformin against bevacizumab-induced vascular injury in a mouse model and examined the possible involvement of GDF15/PI3K/AKT/FOXO/PPARγ signaling in the effects. Materials and Methods: C57 male mice were purchased. To investigate metformin, the mice were assigned to the saline, bevacizumab (15 mg every 3 days), metformin (1200 mg/day), and bevacizumab+metformin groups. To investigate GDF15, the mice were assigned to the siNC+bevacizumab, siNC+bevacizumab+metformin, siGDF15+bevacizumab, and siGDF15+bevacizumab+metformin groups. Histological staining was used to evaluate vascular injury. Flow cytometry was used to evaluate apoptosis. ELISA was used to measure plasma endothelial injury markers and proinflammatory cytokines. qRT-PCR and western blot were used to determine the expression of GDF15 and PI3K/AKT/FOXO/PPARγ in aortic tissues. Results: Metformin alleviated bevacizumab-induced abdominal aortic injury, endothelial cell apoptosis, and systemic inflammation in mice (all P<0.05). Metformin up-regulated GDF15 expression and PI3K/AKT/FOXO/PPARγ signaling in the abdominal aorta of mice treated with bevacizumab (all P<0.05). siGDF15 abolished the vascular protective and anti-inflammatory effects of metformin (all P<0.05). siGDF15 suppressed PI3K/AKT/FOXO/PPARγ signaling in the abdominal aorta of mice treated with bevacizumab (all P<0.05). Conclusion: Metformin attenuates bevacizumab-induced vascular endothelial injury, apoptosis, and systemic inflammation by activating GDF15/PI3K/AKT/FOXO/PPARγ signaling.

Comparison of antihypertensive drugs amlodipine and perindopril on blood pressure variability after long-term treatment of hypertension induced by apatinib and bevacizumab.

The purpose of this study was to elucidate the therapeutic effect of different antihypertensive drugs (amlodipine and perindopril) on hypertension induced by apatinib and bevacizumab. Sixty patients with hypertension treated with apatinib or bevacizumab were selected and divided into two groups: one group was treated with amlodipine and the other group was treated with perindopril. Before and after treatment, the dynamic blood pressure (BP) measurement (systolic BP [SBP] and diastolic BP [DBP]), echocardiography (left ventricular end-diastolic diameter, interventricular septal thickness [IVST], left ventricular posterior wall thickness [LVPWT], and left atrial diameter [LAD]), and detection of nitric oxide (NO) content in venous blood were performed. In the amlodipine group, the 24hSBP, 24hSSD, 24hSCV, daytime mean SBP (dSBP), daytime mean SSD (dSSD), daytime mean SBP CV, night mean SBP (nSBP), night mean SSD, 24hDBP, 24hDSD, 24 h DBP CV, daytime mean DBP (dDBP), daytime mean DSD (dDSD), daytime mean DBP CV, night mean DBP (nDBP), LAD, and LAD index (LADi) after treatment were all lower than before treatment, while NO was higher than before treatment (all P < 0.05). In the perindopril group, the 24hSBP, dSBP, nSBP, 24hDBP, dDBP, nDBP, LAD, LADi, IVST, LVPWT, and left ventricular mass index (LVMI) after treatment were lower than before treatment, and NO level after treatment was higher than before treatment (all P < 0.05). After treatment, the 24hSBP, 24hSSD, dSBP, dSSD, nSBP, 24hDBP, 24hDSD, dDBP, dDSD, nDBP, night mean DSD, and NO were all lower while the LAD, LADi, IVST, LVPWT, and LVMI were higher in the amlodipine group than those in the perindopril group (all P < 0.05). Our study suggests that the SBP and DBP variability of amlodipine in the treatment of hypertension induced by apatinib and bevacizumab is slightly better than that of perindopril, but the effect of perindopril in improving endothelial function indices NO and echocardiographic data is better than that of amlodipine.

Effectiveness of Noninvasive Positive Pressure Ventilation Combined with Enteral Nutrition in the Treatment of Patients with Combined Respiratory Failure after Lung Cancer Surgery and Its Effect on Blood Gas Indexes.

Purpose: To investigate the effect of noninvasive positive pressure ventilation (NIPPV) combined with enteral nutrition support in the treatment of patients with combined respiratory failure after lung cancer surgery and its effect on blood gas indexes. Methods: A total of 82 patients with combined respiratory failure after lung cancer surgery who were treated in our hospital from March 2016∼September 2021 were selected as the research subjects, and according to the random number table method, they were equally divided into the parenteral nutrition group (n = 41) with NIPPV + parenteral nutrition support treatment and the enteral nutrition group (n = 41) with NIPPV + enteral nutrition support treatment. The curative effects of two groups after treatment were compared, and the pulmonary function indexes (maximum expiratory pressure (PEmax), maximum midexpiratory flow rate (MMF), and maximum ventilation volume (MVV)), blood gas indexes (blood oxygen partial pressure (PaO2) and partial pressure of carbon dioxide (PaCO2)), oxygen metabolism indicators [mixed venous oxygen tension (PvO2) and central venous oxygen saturation (ScvO2)], nutritional status indicators (hemoglobin (HGB), serum albumin (ALB), and total protein (TP)), and nutritional score before and after treatment in two groups were detected, and the 6-month follow-up of the two groups was recorded. Results: After treatment, the total effective rate of the enteral nutrition group 95.12% (39/41) was higher than that of the parenteral nutrition group 80.49% (33/41) (P < 0.05). At 3, 12, 24, and 48 hours after the operation, the levels of PEmax, MMF, and MVV in two groups were higher than those before treatment, and the enteral nutrition group was higher than the parenteral nutrition group at the same time point (P < 0.05). At 3, 12, 24, and 48 hours after the operation, the PaO2 levels in two groups were higher than those before treatment, and the PaCO2 levels were lower than those before treatment. The PaO2 levels in the enteral nutrition group were higher than those in the parenteral nutrition group at the same time point, and the PaCO2 levels were lower than those in the parenteral nutrition group at the same time point (P < 0.05). At 3, 12, 24, and 48 hours after the operation, the levels of PvO2 and ScvO2 in two groups were higher than those before treatment, and the enteral nutrition group was higher than the parenteral nutrition group at the same time point (P < 0.05). After treatment, the levels of HGB, ALB, and TP in two groups were higher than those before treatment, and the enteral nutrition group was higher than the parenteral nutrition group (P < 0.05). After treatment, the nutritional scores of the two groups were higher than those before treatment, and the enteral nutrition group was higher than the parenteral nutrition group (P < 0.05). At 6-month postoperative follow-up, the incidence of death in the enteral nutrition group 2.44% (1/41) was lower than that of the parenteral nutrition group 17.07% (7/41) (P < 0.05). Conclusions: The efficacy of NIPPV combined with enteral nutrition support in treating patients with combined respiratory failure after lung cancer surgery is remarkable. It can improve patients' pulmonary function and blood gas index, correct patients' hypoxia status and the patients' nutritional level was significantly improved, which helped to reduce the mortality rate and improve the prognosis.

Incidence and Related Factors for Low-Extremity Deep Vein Thrombosis in Breast Cancer Patients Who Underwent Surgical Resection: What Do We Know and What Should We Care.

Malignancy, surgical resection, and neoadjuvant and/or adjuvant chemotherapy increase the low-extremity deep vein thrombosis (LDVT) risk in patients with breast cancer, bringing in great physical burdens, disabilities, and worse survivals. However, LDVT in surgical breast cancer patients is scarcely reported. Therefore, this study aimed to evaluate the incidence and related factors for LDVT in these patients. Patients with breast cancer who underwent surgical resection were included. LDVT was examined on the day of discharge and 1 month after the discharge. A total of 491 eligible patients were included, among which 11 (2.2%) patients occurred LDVT. Besides, higher age, history of diabetes mellitus, advanced T and tumor node metastasis (TNM) stages, higher platelet count, and shorter activated partial thromboplastin time (APTT) were correlated with increased LDVT incidence (all p < 0.05). Additionally, higher age [p = 0.004, odds ratio (OR) (95% CI): 1.082 (1.023-1.144)], history of diabetes mellitus [p = 0.003, OR (95% CI): 10.426 (2.219-48.986)], and a higher platelet count [p = 0.008, OR (95% CI): 1.017 (1.004-1.029)] were independent factors for increased LDVT incidence, while higher APTT [p = 0.004, OR (95% CI): 0.636 (0.467-0.866)] was an independent factor for decreased LDVT incidence. Lastly, the risk prediction model involving age, history of diabetes mellitus, platelet count, and APTT showed a good ability to predict LDVT occurrence (area under curve: 0.919, 95% CI: 0.869-0.968). In conclusion, the LDVT incidence is 2.2%, and its independent factors consist of age, history of diabetes mellitus, platelet count, and APTT in patients with breast cancer who underwent surgical resection, which provides evidence for the prevention and surveillance of LDVT in surgical breast cancer.

Anti-fatigue effect from Ginseng Radix et Rhizoma: a suggestive and promising treatment for long COVID.

Two years after the coronavirus disease 2019 (COVID-19) outbreak, an increasing number of patients continue to suffer from long COVID (LC), persistent symptoms, and/or delayed or long-term complications beyond the initial 4 weeks from the onset of symptoms. Constant fatigue is one of the most common LC symptoms, leading to severely reduced quality of life among patients. Ginseng Radix et Rhizoma-known as the King of Herbs in traditional Chinese medicine-has shown clinical anti-fatigue effects. In this review, we summarize the underlying anti-fatigue mechanisms of Ginseng Radix et Rhizoma extracts and their bioactive compounds, with a special focus on anti-viral, immune remodeling, endocrine system regulation, and metabolism, suggesting that Ginseng Radix et Rhizoma is a potentially promising treatment for LC, especially in regard to targeting fatigue.

Ecological niche modeling of Astragalus membranaceus var. mongholicus medicinal plants in Inner Mongolia, China.

Radix Astragali is commonly used in traditional Chinese medicine, and its quality is closely related to ecological factors, such as climate and soil, in the production area. To provide high-quality Radix Astragali to Chinese and foreign markets, we used maximum entropy model and statistical analysis method, combined with data on ecological factors, Astragalus membranaceus var. mongholicus geographical distribution, and index component content to predict the ecological suitability distribution of A. membranaceus var. mongholicus and establish the relationship between astragaloside IV and calycosin-7-glucoside in this species and ecological factors. Subsequently, we could determine the suitability regionalization of high-quality A. membranaceus var. mongholicus in Inner Mongolia, China. The results showed that the standard deviation of seasonal changes in temperature (40.6%), precipitation in October (15.7%), vegetation type (14.3%), soil type (9.2%), and mean sunshine duration in the growing season (9.1%) were the top five most influential factors out of the 17 main ecological factors affecting the distribution of A. membranaceus var. mongholicus. The standard deviation of seasonal changes in temperature, precipitation in October, precipitation in April, soil pH, and mean sunshine duration in the growing season were found to be the key ecological factors affecting the accumulation of astragaloside IV and calycosin-7-glucoside in A. membranaceus var. mongholicus. The regions with the highest-quality A. membranaceus var. mongholicus were distributed in Baotou (Guyang County), Hohhot (Wuchuan County), and central Wulanchabu (Chahar Right Middle Banner, Chahar Right Back Banner, and Shangdu County) and its surroundings in Inner Mongolia. Baotou, Hohhot, and their surrounding areas were the main traditional production areas of A. membranaceus var. mongholicus, and central Wulanchabu was a potentially suitable distribution area of this species. The main production areas were consistent with the actual production base of A. membranaceus var. mongholicus. This study therefore provides a scientific basis to guide the cultivation of A. membranaceus var. mongholicus.

Unaccompanied mechanosensory domain mediates low expression of glycoprotein Ibα: implications for Bernard-Soulier syndrome.

BACKGROUND: Disruption of protein folding or inter-subunit interactions in the platelet glycoprotein (GP)Ib-IX complex leads to its abnormally low expression in the plasma membrane, the hallmark of Bernard-Soulier syndrome (BSS). OBJECTIVE: To discover the molecular mechanism by which GPIbα in the absence of GPIbß and GPIX subunits is targeted for rapid degradation. METHOD: The expression of GPIbα mutants with deletion or replacement of various domains were measured in transiently transfected Chinese hamster ovary cells. RESULTS: We report evidence to suggest that induction of the unfolded protein response by the unaccompanied mechanosensory domain (MSD) is a major factor for intracellular degradation and low expression of GPIbα. Removal of the MSD produced the first GPIbα variant that, even in the absence of GPIbß and GPIX, expressed at a level comparable to that of wild-type GPIbα in the GPIb-IX complex, while retaining its native ligand-binding activity. CONCLUSION: Our finding has important implications on the molecular pathogenesis of BSS and the function of the GPIb-IX complex.

The mechanism and application of the protein-stabilized gold nanocluster sensing system.

Protein-stabilized gold nanoclusters (protein-Au NCs) have been an attractive frontier of nanoparticle research. Due to their unique fluorescence properties, high stability, environmentally friendly synthetic routes and nontoxicity, protein-Au NCs could find applications in highly sensitive and selective detection of metal ions, inorganic ions and biomolecules in food, soil, water and biological samples. The past few years have witnessed the development of many successful strategies for the preparation of numerous protein-Au NC-based sensing systems. In this review, we focus on a number of sensing systems based on protein-Au NCs for the detection of various analytes of interest with a special emphasis on their corresponding sensing mechanisms.

Preparation of Au Nanoclusters-Modified Polylactic Acid Fiber with Bright Red Fluorescence and its Use as Sensing Probe.

In present work, the Au nanoclusters-modified polylactic acid fiber (PLA-Au NCs) with bright red fluorescence were fabricated by the encapsulation of Au nanoclusters (Au NCs) in the PLA fiber treated with H2O2. The Au25 nanoclusters stabilized by bovine serum albumin (BSA-Au NCs) were prepared via an improved "green" synthetic routine. With pretreatment of the PLA fiber in H2O2 concentration of 12 and 18 %, the as-prepared PLA-Au NCs exhibited brighter red emission with a strong peak centered at ~640 nm than BSA-Au NCs. The fluorescence can be quenched by nitric oxide (NO). A good linear relationship between the relative fluorescence quenching intensity of the as-prepared PLA-Au NCs and the concentration of NO can be obtained in the range of 0.0732 to 0.7320 mM, and the detection limit was 0.0070 mM.

[Three dimensional reconstruction and measurement of the proximal femur in adult developmental dysplasia of the hip].

OBJECTIVE: To investigate characteristics and the differences of the anatomical parameters of the proximal femur of the developmental dysplasia of the hip (DDH). METHODS: A total of 38 patients(47 hips) diagnosed as DDH with CT scan data and the pelvis radiograph from January 2012 to December 2014 in China-Japan Union Hospital of Jilin University were retrospectively analyzed. All the hips were divided into 3 groups according to Crowe classification method. Thirty normal hips were selected as controls who admitted at the same time. CT data of the patients were imported into Mimics 17.0. The three-dimensional models of the proximal femur were then reconstructed, and the following parameters were measured: neck-shaft angle, neck length, offset, height of the centre of femoral head, height of the isthmus, height of greater trochanter, the medullary canal diameter of isthmus (Di), the medullary canal diameter 10 mm above the apex of the lesser trochanter (DT+ 10), the medullary canal diameter 20 mm below the apex of the lesser trochanter (DT-20), and then DT+ 10/Di, DT-20/Di and DT+ 10/DT-20 were calculated.Variance discrepancy analysis was used to compare the difference among the four groups, and LSD method was used to compare the difference between either two groups. RESULTS: The parameters of neck-shaft angle of DDH with Crowe I, Crowe II-III, Crowe IV and the control group were (131.8°±7.1°), (131.7°±6.5°), (122.8°±11.4°) and (131.8°±5.9°), respectively; the parameters of neck-shaft angle of DDH with Crowe IV was smaller than that of DDH with Crowe I, Crowe II-III and control group (all P<0.05). The parameters of the neck length of DDH with Crowe IV ((44.6±6.6) mm) was smaller than that of DDH with Crowe I ((48.6±6.7) mm), Crowe II-III ((50.4±4.7) mm) (all P<0.05). There is no statistic difference in the offset among the groups (F=2.392, P>0.05). The parameters of the height of greater trochanter of DDH with Crowe IV ((12.1±6.1) mm) was bigger than that of DDH with Crowe I ((8.9±7.2) mm), Crowe II-III ((7.5±3.3) mm) and control group ((6.1±3.9) mm) (all P<0.05). The parameters of the height of the centre of femoral head of DDH with Crowe I, Crowe II-III, Crowe IV were (39.6±6.5) mm, (39.1±4.2) mm, (38.8±8.6) mm, which were smaller than that of the control group ((46.5±6.2) mm) (all P<0.05). The parameters of Di of DDH with Crowe I, Crowe II-III, Crowe IV and the control group were (9.9±2.2) mm, (8.3±1.8) mm, (8.7±1.7) mm and (10.1±1.4) mm; the parameters of Di of DDH with Crowe II-III and Crowe IV were smaller than that of the control group (all P<0.05). The parameters of DT+ 10 ((17.2±5.3) mm) and DT-20 ((12.2±3.0) mm) of DDH with Crowe IV were smaller than that of DDH with Crowe I ((25.2±3.4) mm, (17.1±2.3) mm) and Crowe II-III ((21.9±4.2) mm, (16.3±3.2) mm) (all P<0.05). The parameter of the height of the isthmus of DDH with Crowe IV ((94.1±19.7) mm) was smaller than that of DDH with Crowe I ((106.2±13.8) mm), Crowe II-III ((108.8±10.5) mm) and control group ((116.5±10.6) mm), respectively (P=0.010, 0.008, 0.000). The parameters of DT+ 10/Di (2.0±0.4) and DT-20/Di (1.4±0.2) of DDH with Crowe IV were smaller than that of DDH with Crowe I (2.6±0.5, 1.8±0.3), Crowe II-III (2.7±0.60, 1.9±0.3) (all P<0.05). CONCLUSIONS: Comparing to DDH with Crowe I-III and control group, DDH with Crowe IV has a dramatic change in the intramedullary and extramedullary parameters. The isthmus and the great trochanter are higher and there is apparent narrowing of the medullary canal around the level of the lesser trochanter.

Novel mutations in congenital factor XII deficiency.

Several mutations in factor XII have been reported in patients with factor XII deficiency. Here, we described three mutations in the F12 gene (c. 6635G more than A (p. G259E), c. 6658G more than C (p. R267G) and c. 8489G more than A (p. E521K)) of five patients with congenital FXII deficiency. Among these, two were heterozygous mutations. All five patients had prolonged activated partial thromboplastin time, as well as markedly decreased FXII activity and antigen levels. In vitro studies in transiently transfected HEK 293T cells demonstrated that these mutations significantly lowered the FXII levels in the culture media, but had no impact on transcription. Further protein degradation inhibition experiments with various inhibitors suggested that the three mutants were degraded intracellularly through the proteasome pathway in the pre-Golgi compartment. Moreover, G259E and R267G mutations exhibited dominant negative effects, consistent with the phenotypes observed in the heterozygous carriers. Such dominant negative effects were not due to the dimerization of FXII. Our findings suggest that the three mutations in the F12 gene are the causing reasons for the cross-reactive material-negative FXII deficiencies.

Assessment of the effect of three-dimensional mantle density heterogeneity on earth rotation in tidal frequencies.

In this paper we report the assessment of the effect of the three-dimensional (3D) density heterogeneity in the mantle on Earth Orientation Parameters (EOP) (i.e., the polar motion, or PM, and the length of day, or LOD) in the tidal frequencies. The 3D mantle density model is estimated based upon a global S-wave velocity tomography model (S16U6L8) and the mineralogical knowledge derived from laboratory experiment. The lateral density variation is referenced against the Preliminary Reference Earth Model (PREM). Using this approach the effects of the heterogeneous mantle density variation in all three tidal frequencies (zonal long periods, tesseral diurnal, and sectorial semidiurnal) are estimated in both PM and LOD. When compared with mass or density perturbations originated on the earth's surface such as the oceanic and barometric changes, the heterogeneous mantle only contributes less than 10% of the total variation in PM and LOD in tidal frequencies. Nevertheless, including the 3D variation of the density in the mantle into account explained a substantial portion of the discrepancy between the observed signals in PM and LOD extracted from the lump-sum values based on continuous space geodetic measurement campaigns (e.g., CONT94) and the computed contribution from ocean tides as predicted by tide models derived from satellite altimetry observations (e.g., TOPEX/Poseidon). In other word, the difference of the two, at all tidal frequencies (long-periods, diurnals, and semi-diurnals) contains contributions of the lateral density heterogeneity of the mantle. Study of the effect of mantle density heterogeneity effect on torque-free earth rotation may provide useful constraints to construct the Reference Earth Model (REM), which is the next major objective in global geophysics research beyond PREM.

Heparin defends against the toxicity of circulating histones in sepsis.

Although circulating histones were demonstrated as major mediators of death in septic mice models, their roles in septic patients are not clarified. The present study sought to evaluate the clinical relevance of the circulating histone levels in septic children, and the antagonizing effects of heparin on circulating histones. Histone levels in the plasma of septic children were significantly higher than healthy controls, and positively correlated with disease severity. Histone treatment could activate NF-κB pathway of the endothelial cells and induce the secretion of large amount of cytokines that further amplify inflammation, subsequently leading to organ damage. Co-injection of low dose heparin with lethal dose histones could protect mouse from organ damage and death by antagonizing circulating histones, and similar effects were also observed in other septic models. Collectively, these findings indicated that circulating histones might serve as key factors in the pathogenesis of sepsis and their levels in plasma might be a marker for disease progression and prognosis. Furthermore, low dose heparin might be an effective therapy to hamper sepsis progression and reduce the mortality.

A novel CHD7 mutation in a Chinese patient with CHARGE syndrome.

In Genetics Out-patient Department of Shanghai Children's Medical Center, we consulted a 3-year-old boy with multiple anomaly syndrome (congenital heart disease, cryptorchidism, congenital deafness, mental retardation, exophthalmos, laryngeal cartilage dysplasia and high arched palate). We ruled out the possibility of multiple deformities caused by genomic imbalances. The patient was then clinically considered to have CHARGE syndrome, an autosomal dominant multi-system disorder involving defects in multiple organs, and CHD7 is the only known gene associated with the syndrome. Sequencing analysis of CHD7 of the proband identified a de novo heterogeneous mutation (c.2916_2917del, p.Gln972HisfsX22), a two-nucleotide deletion causing reading frame shift and resulting in a truncated CHD7 protein. Computational structure analysis suggests that the truncated protein only contains the chromodomains of CHD7, but lacks the SWI2/SNF2-like ATPase/helicase domain and the DNA binding domain, which are indispensable for the proper function of the protein, especially on chromatin remodeling. The patient then received follow up treatment in different clinical departments in a long period. To our best knowledge, this is the first CHARGE syndrome in Chinese patients diagnosed by gene analysis. In summary, the clinical symptoms and the description of treatment in the present case, combined with genetic test and functional prediction of CHD7, are helpful for further understanding and genetic counseling of the CHARGE syndrome.

[Abnormal expression of the platelet membrane receptor glycoprotein Ib-IX-V complex in transiently transfected HEK 293T cells].

The structure and function of the glycoprotein (GP) Ib-IX-V complex has been extensively investigated over the decades due to its vital role in platelet activation. For the lack of nucleus in platelets, researchers usually need to study the GPIb-IX-V complex by transfecting wild type or mutant GPIb-IX-V plasmids into other mammalian cell lines, such as CHO or HEK 293T. Therefore, whether the characteristics of the GPIb-IX-V complex in these cell lines can truly represent that in platelets is pivotal to determine whether these cell lines are appropriate for GPIb-IX-V complex studies. In order to determine the most appropriate cell line to study the GPIb-IX-V complex, the surface expression level of the complex in different cell lines was detected and whether difference among cell lines will affect expression of the complex was explored in the present study. The different combinations of the GPIb-IX-V subunits were transfected into cell lines from different species or different tissues, such as CHO, HEK293T and HeLa, and the surface expression levels of the complex were detected by flow cytometry. The results indicated that in both transiently and stably transfected CHO cells, surface expression of GPV depended on the presence of the GPIb-IX complex, which is consistent with that in human platelets. In contrast, GPV could be efficiently expressed on surface in HEK 293T cells even in the absence of GPIb-IX, although the inter-subunit dependence within the GPIb-IX complex is still similar to that in CHO cells or human platelets. Further studies in HeLa, MES13 and HUVEC cell lines revealed that GPV could be efficiently expressed on the surface by itself in HeLa and MES13 cells, but not in HUVEC, suggesting different behaviors of the GPIb-IX-V complex in difference cell lines. It is concluded that this study provides some guidance and advice to future GPIb-IX-V complex studies, especially to the choice of suitable cell line. HEK 293T cell line, for example, is likely to provide misleading results since it could not represent the fact in human platelets, thus is not the optimal choice for the GPIb-IX-V complex, particularly the GPV subunit.

Characterization of six missense mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in Chinese children with hypophosphatasia.

AIMS: Hypophosphatasia, a rare inherited disease characterized by defective mineralization of bone and teeth, is caused by various mutations in the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP) gene. Our aim was to determine the mutations on TNSALP gene in three Chinese children diagnosed as having hypophosphatasia. METHODS: Genomic DNA was extracted from whole blood samples of patients and their parents. The TNSALP coding regions were then sequenced. Plasmids expressing wild-type or various mutants were built and in vitro studies were performed in order to determine whether these amino acid replacements could affect the TNSALP enzymatic activity. RESULTS: Six missense mutations were identified from three independent pedigrees. Of the six missense mutations, four were novel and two had been previously reported. The Y28D, A111T and T389N mutants displayed only negligible ALP activity in vitro compared to the wild-type (WT) TNSALP. The defect was mainly due to the significantly decreased protein expression in the 66 KD immature forms and the nearly undetectable protein expression in the 80 KD mature forms. Moreover, all three mutants had a dominant negative effect on the WT protein when co-transfected with TNSALP (WT). M219V and R136L mutants both exhibited partial enzymatic activities which were consistent with reduced protein expression in both forms of TNSALP which further exhibited moderate dominant-negative effect. In addition, Y388H mutant showed weak ALP activity. Western blot analysis indicated that the extreme reduction in signal from the mature forms of TNSALP could be the main cause of decreased enzymatic activity, since a strong signal was observed in the immature forms. CONCLUSION: Six missense mutations were identified in three Chinese hypophosphatasia pedigrees with subnormal serum ALP activity. Our results show that the low activity of serum ALP in the three patients is due mainly to a defect in the protein expression of the mutants. This may be the underling molecular mechanism for hypophosphatasia in these patients.

Transcranial thermoacoustic tomography: a comparison of two imaging algorithms.

Thermoacoustic tomography (TAT) is a novel, non-invasive medical imaging technique but has encountered obstacles in imaging through the cranium. In this paper we present two methods for transcranial TAT: Kirchhoff migration (KM) and reverse-time migration (RTM). The two methods' imaging qualities are verified and compared based on both synthetic and experimental data. RTM proves to have better velocity variance and imaging quality, and little noise with spatial aliasing. RTM is a promising approach for achieving transcranial TAT in further studies.

The effect of buildings on acoustic pulse propagation in an urban environment.

Experimental measurements were conducted using acoustic pulse sources in a full-scale artificial village to investigate the reverberation, scattering, and diffraction produced as acoustic waves interact with buildings. These measurements show that a simple acoustic source pulse is transformed into a complex signature when propagating through this environment, and that diffraction acts as a low-pass filter on the acoustic pulse. Sensors located in non-line-of-sight (NLOS) positions usually recorded lower positive pressure maxima than sensors in line-of-sight positions. Often, the first arrival on a NLOS sensor located around a corner was not the largest arrival, as later reflection arrivals that traveled longer distances without diffraction had higher amplitudes. The waveforms are of such complexity that human listeners have difficulty identifying replays of the signatures generated by a single pulse, and the usual methods of source location based on the direction of arrivals may fail in many cases. Theoretical calculations were performed using a two-dimensional finite difference time domain (FDTD) method and compared to the measurements. The predicted peak positive pressure agreed well with the measured amplitudes for all but two sensor locations directly behind buildings, where the omission of rooftop ray paths caused the discrepancy. The FDTD method also produced good agreement with many of the measured waveform characteristics.

Acoustic pulse propagation near a right-angle wall.

Experimental measurements were conducted around a right-angle wall to investigate the effect of this obstacle on sound propagation outdoors. Using small explosions as the source of the acoustic waves allowed reflected and diffracted arrivals to be discerned and investigated in detail. The measurements confirm that diffraction acts as a low-pass filter on acoustic waveforms in agreement with simple diffraction theory, reducing the peak pressure and broadening the waveform shape received by a sensor in the shadow zone. In addition, sensors mounted directly on the wall registered pressure doubling for nongrazing angles of incidence in line-of-sight conditions. A fast two-dimensional finite difference time domain (FDTD) model was developed and provided additional insight into the propagation around the wall. Calculated waveforms show good agreement with the measured waveforms.