[International expert consensus on gene therapy for hereditary hearing loss: based on clinical trials].
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Journal Article↗
Biomedical subjects
Z M Wang
Publications and source records attributed to Z M Wang.
Measuring partial body potassium in the arm versus total body potassium.
Skeletal muscle (SM), the body's main structural support, has been implicated in metabolic, physiological, and disease processes in humans. Despite being the largest tissue in the human body, its assessment remains difficult and indirect. However, being metabolically active it contains over 50% of the total body potassium (TBK) pool. We present our preliminary results from a new system for measuring partial body K (PBK) that presently are limited to the arm yet provide a direct and specific measure of the SM. This uniquely specific quantification of the SM mass in the arm, which is shielded from the body during measurement, allows us to simplify the assumptions used in deriving the total SM, thereby possibly improving the modeling of the human body compartments. Preliminary results show that PBK measurements are consistent with those from the TBK previously obtained from the same subjects, thus offering a simpler alternative to computed tomography and magnetic resonance imaging used for the same purposes. The PBK system, which can be set up in a physician's office or bedside in a hospital, is completely passive, safe, and inexpensive; it can be used on immobilized patients, children, pregnant women, or other at-risk populations.
Adult↗
Ca(2+) calmodulin kinase and calcineurin mediate IGF-1-induced skeletal muscle dihydropyridine receptor alpha(1S) transcription.
The skeletal muscle L-type Ca(2+) channel or dihydropyridine(DHP)-sensitive receptor is a key molecule involved in membrane voltage-sensing, sarcoplasmic reticulum Ca(2+) release, and muscle contraction. Previous work from our laboratory has shown that the insulin-like growth factor-1 (IGF-1) increases skeletal muscle L-type Ca(2+) channel or dihydropyridine-sensitive receptor DHPRalpha(1S) transcriptional activity by acting on the cyclic AMP response element binding protein (CREB) element of the promoter region; however, the cellular signaling mediating this process is not known. In this study, we investigated the signaling pathway whereby IGF-1 enhances the expression of DHPRalpha(1S) in C2C12 myotubes, using a molecular, pharmacological and electrophysiological approach. We found that inhibition of the Ca(2+)/Calmodulin (CaM)-dependent protein kinase or calcineurin, influenced IGF-1-induced increase in DHPRalpha(1S) expression, as detected by recording the luminescence of the DHPRalpha(1S) promoter-luciferase fusion construct and by immunoblot analysis of the DHPR alpha1 subunit. IGF-1 significantly increased CaM kinase and calcineurin activity and the cellular levels of phosphorylated CREB in a time-dependent manner. The role of CaM kinase and calcineurin in DHPRalpha(1S) expression was confirmed by functional recording of the effects of the inhibition of the kinase and phosphatase on IGF-1-mediated enhancement of charge movement. These results support the conclusion that IGF-1 controls CREB phosphorylation by activating a phosphorylation and dephosphorylation cascade, which ultimately modulates the DHPRalpha(1S) gene transcription.
Animals↗
Expression of Trk A receptors in the mammalian inner ear.
Tyrosine kinase receptors, including Trk A, Trk B and Trk C, participate in many different biological processes that are regulated by neurotrophic factors. Nerve growth factor (NGF)-triggered Trk A signaling is involved in growth, survival and differentiation of neurons in the central nervous system and in neural crest-derived cells. Trk A, Trk B and Trk C expression has been reported in the rat ventral cochlear nucleus. In the present study, we explored the immunocytochemical distribution of Trk A in the rodent inner ear. Rat and mouse cochleae were immunolabeled with a rabbit anti-Trk A polyclonal antibody (Chemicon) that has no reported cross-reactivity with Trk B and Trk C. In embryonic day 16 mice, no Trk A immunolabeling could be detected in the developing neuroepithelium. At postnatal day 6, weak Trk A labeling could be observed in both inner and outer hair cells. At postnatal day 12, enhanced punctate Trk A immunoexpression was present in hair cells. In adult mice and rats, intense Trk A labeling was observed in outer and inner hair cell bodies, in supporting cell bodies throughout the cochlea, and in spiral ganglion neurons. Trk A was not observed in stria vascularis, hair cell stereocilia, nor in the Trk B- and Trk C-rich cerebellum. This distribution pattern of Trk A suggests that its ligand, NGF, exerts significant trophic effects in the rodent inner ear.
Animals↗
Assessment by bioimpedance of forearm cell mass: a new approach to calibration.
OBJECTIVE: Changes in skeletal muscle mass are involved in several important clinical disorders including sarcopenia and obesity. Unlike body fat, skeletal muscle is difficult to quantify in vivo, particularly without highly specialized equipment. The present study had a two-fold aim: to develop a regional (40)K counter for non-invasively estimating cell mass in the arm, mainly skeletal muscle cell mass, without radiation exposure; and to test the hypothesis that cell mass in the arm is highly correlated with electrical impedance after adjusting for the arm's length. METHODS: Forearm cell mass was estimated using a rectangular lead-shielded (40)K counter with 4-NaI crystals; impedance of the arm was measured at multiple frequencies using a segmental bioimpedance analysis (BIA) system. The system's within- and between-day coefficient of variation (CV) for (40)K-derived elemental potassium averaged 1.8+/-1.3 and 5.8+/-1.2%, respectively. The corresponding BIA system's CVs were 1.0+/-0.4 and 2.1+/-1.0%, respectively. SUBJECTS AND RESULTS: Participants in the study were 15 healthy adults (eight females, seven males; age 39+/-2.8 y, BMI 22.9+/-4.5 kg/m(2)). The right arm's K (5.2+/-1.7 g) was highly correlated with length-adjusted impedance (r(2)=0.81, 0.82, and 0.83 for 5, 50 and 300 kHz, respectively; all P<0.001); multiple regression analysis showed no additional improvement by adding age or sex to the prediction models. CONCLUSION: These results demonstrate the feasibility of calibrating BIA-measured electrical properties of the arm against estimates of arm cell mass, mainly of skeletal muscle, obtained by regional (40)K counting. This simple and practical approach should facilitate the development of BIA-based regional cell mass prediction formulas
Adult↗
Sexual dimorphism in the energy content of weight change.
BACKGROUND: The energy content of weight change is assumed to be sex- and age-neutral at 3,500 kcal/pound or 32.2 MJ/kg. OBJECTIVES: As sexual dimorphism in body composition generally exists in mammals, the primary hypothesis advanced and tested was that the energy content of weight change differs between men and women. DESIGN: The energy content of 129 adult men and 287 women was measured by neutron activation analysis. Cross-sectional energy content prediction models were developed and then evaluated in two longitudinal samples: one that used the same methods in 26 obese women losing weight; and the other a compilation of 18 previously reported weight change-body composition studies. RESULTS: Multiple regression modeling identified weight, sex, age and height as total energy content predictor variables with significant sex x weight (P<0.001) and age x weight (P<0.001) interactions; total model r(2) and s.e.e. were 0.89 and 107.3 MJ, respectively. The model's predictive value was supported in both longitudinal evaluation samples. Model calculations using characteristics of representative adults gaining or losing weight suggested that the energy content of weight change in women (approximately 30.1-32.2 MJ/kg) is near to the classical value of 32.2 MJ/kg and that in men the value is substantially lower, approximately 21.8-23.8 MJ/kg. The predicted energy content of weight change increases by about 10% in older (age approximately 70 y) vs younger (approximately 35 y) men and women. CONCLUSIONS: Sexual dimorphism and age-dependency appears to exist in the estimated energy content of weight change and these observations have important clinical and research implications.
Adult↗
Magnetic characteristics of new cyano-bridged two-dimensional honeycomb-like bimetallic assemblies containing Ni(II)-N[triple bond]C-Cr(III) or Ni(II)-N[triple bond]C-Cr(I) linkages.
Three cyano-bridged bimetallic assemblies, [NiL(1)](3)[Cr(CN)(6)](2).7H(2)O (1), [NiL(2)](3)[Cr(CN)(6)](2).9H(2)O (2), and [NiL(2)](3)[Cr(CN)(5)(NO)](2).9H(2)O (3) (L(1) = 3,10-dimethyl-1,3,5,8,10,12-hexaazacycloctadecane and L(2) = 3,10-diethyl-1,3,5,8,10,12-hexaazacycloctadecane), have been prepared and characterized structurally and magnetically. Complex 1 crystallizes in the monoclinic space group of C2/c with a = 25.929 A, b = 15.442(3) A, c = 19.553(4) A, beta = 106.21(3) degrees, and Z = 4, while 2 and 3 are in the trigonal space group P3 with a = b = 14.919(2) A, c = 9.5246(19) A, gamma = 120 degrees, and Z = 1 for 2 and a = b = 14.863(2) A, c = 9.3134(19) A, gamma = 120 degrees, and Z = 1 for 3. The structures of 1-3 are similar and consist of cyano-bridged two-dimensional (2D) honeycomb-like neutral Ni(3)Cr(2) layers. In each complex, [Cr(CN)(6)](3-) or [Cr(CN)(5)(NO)](3-) coordinates to three trans-[Ni(macrocycle)](2+) groups using three fac-CN(-) ligands, providing a 2D layered network. The NO group in [Cr(CN)(5)(NO)](3-) remains monodentate. Magnetic studies show the existence of a short-range ferromagnetic interaction in all of the complexes. Complexes 1 and 2 exhibit long-range antiferromagnetic ordering at 13.0 and 11.9 K, respectively, and a metamagnetic transition with critical field of ca. 1.6 kOe for 1 and 1.5 kOe for 2 at 1.8 K. Complex 3 exhibits long-range ferromagnetic ordering below 4.3 K.
Journal Article↗
Determination of the phase difference between even and odd continuum wave functions in atoms through quantum interference measurements.
We establish a technique for the determination of the phase difference between even and odd parity continuum wave functions in atoms. This determination is based upon our detailed measurements of a quantum mechanical interference between two photoionization processes using a two-color laser field. We present our measurement of the phase difference between the continuum p and d waves in atomic rubidium, which is in good agreement with the expected value.
Journal Article↗
In vitro evidence for homologous recombinational repair in resistance to melphalan.
BACKGROUND: The generation of DNA interstrand cross-links is thought to be important in the cytotoxicity of nitrogen mustard alkylating agents, such as melphalan, which have antitumor activity. Cell lines with mutations in recombinational repair pathways are hypersensitive to nitrogen mustards. Thus, resistance to melphalan may require accelerated DNA repair by either recombinational repair mechanisms involving Rad51-related proteins (including x-ray repair cross-complementing proteins Xrcc2, Xrcc3, and Rad52) or by nonhomologous endjoining involving DNA-dependent protein kinase (DNA-PK) and Ku proteins. We investigated the role of DNA repair in melphalan resistance in epithelial tumor cell lines. METHODS: Melphalan cytotoxicity was determined in 14 epithelial tumor cell lines by use of the sulforhodamine assay. Homologous recombinational repair involving Rad51-related proteins was investigated by determining the levels of Rad51, Rad52, and Xrcc3 proteins and the density of nuclear melphalan-induced Rad51 foci, which represent sites of homologous recombinational repair. Nonhomologous endjoining was investigated by determining the levels of Ku70 and Ku86 proteins and DNA-PK activity. Linear regression analysis was used to analyze correlations between the various protein levels, DNA-PK activity, or Rad51 foci formation and melphalan cytotoxicity. All statistical tests were two-sided. RESULTS: Melphalan resistance was correlated with Xrcc3 levels (r =.587; P =.027) and the density of melphalan-induced Rad51 foci (r =.848; P =.008). We found no correlation between melphalan resistance and Rad51, Rad52, or Ku protein levels or DNA-PK activity. CONCLUSION: Correlations of melphalan resistance in epithelial tumor cell lines with Xrcc3 protein levels and melphalan-induced Rad51 foci density suggest that homologous recombinational repair is involved in resistance to this nitrogen mustard.
Antigens, Nuclear↗
Cancer mortality among workers exposed to amphibole-free chrysotile asbestos.
The issue of whether exposure to chrysotile asbestos alone, without contamination from amphibole asbestos, causes lung cancer and mesothelioma was investigated in a 25-year longitudinal study (1972-1996) in Chongqin, China. The study cohort comprised 515 male asbestos plant workers exposed to chrysotile only; the control cohort included 650 non-dust-exposed workers. The results of analysis in which the proportional hazards model was used indicated that mortality due to all causes, all cancers, and lung cancer was related to asbestos exposure; the relative risks, adjusted for age and smoking, were 2.9, 4.3, and 6.6, respectively. Fiber concentrations in the raw material section and the textile section of the plant were 7.6 and 4.5 fibers/ml, respectively. Because of differences between the study and control plants, the authors also compared various sections of the asbestos plant that had different levels of dust exposure. The adjusted relative risk of lung cancer was 8.1 for workers exposed to high versus low levels of asbestos. Two cases of malignant mesothelioma, one pleural and the other peritoneal, were found in the asbestos cohort. These results suggest that heavy exposure to pure chrysotile asbestos alone, with negligible amphibole contamination, can cause lung cancer and malignant mesothelioma in exposed workers.
Age Factors↗
A novel bimetallic cage complex constructed from six V4Co pentatomic rings: hydrothermal synthesis and crystal structure of [(2,2'-Py2NH)2Co]3V8O23.
A bimetallic cluster complex, [(2,2'-Py2NH)2Co]3V8O23 (2,2'-Py2NH = 2,2'-dipyridylamine) 1, has been hydrothermally synthesized; X-ray crystallography reveals that 1 possesses a novel cage topology structure in which the metal cluster core is constructed from six V4Co pentatomic rings.
Journal Article↗
Substance P abolishes the facilitatory effect of ATP on spontaneous glycine release in neurons of the trigeminal nucleus pars caudalis.
Glycine release was facilitated by the activation of presynaptic ATP receptors (P(2X)-type) in a preparation of dissociated trigeminal nucleus pars caudalis neurons in which the native synaptic boutons were preserved. The action of ATP was completely blocked by substance P (SP) without alteration of the miniature IPSC (mIPSC) amplitude distribution. SP itself had no effect on mIPSC frequency or amplitude. The inhibitory effect of SP on ATP action was blocked by CP99994, indicating that the SP receptors are of the neurokinin-1 type. The ATP-induced facilitation of the mIPSC frequency was unaffected by Cd(2+). Moreover, SP did not inhibit the increase in mIPSC frequency induced high K(+) application, suggesting that SP did not modulate voltage-dependent calcium channels or subsequent steps in the release process. KT5720 and phorbol 12-myristate 13-acetate did not block SP action, indicating that neither the cAMP-protein kinase A nor the protein kinase C pathway mediates the SP effects. However, in the presence of N-(6-aminohexyl)-5-chloro-1-naphthalene sulphonamide (W-7), SP was no longer able to inhibit the ATP-induced stimulation of mIPSC frequency. 1-[N,O-bis(5-isoquinolinesulfonyl)-N-methyl-l-tyrosyl]-4-phenylpiperazine also suppressed the SP action, suggesting that SP modulates P(2X) receptors via a Ca(2+)/calmodulin-dependent protein kinase II-mediated pathway. In conventional whole-cell mode, the presence of W-7 in the patch pipette did not affect the SP inhibitory action. Thus, SP is not likely to be generating its modulation through the production of a retrograde signal (involving calmodulin) from the postsynaptic cell to the presynaptic boutons. These results are the first demonstration of the modulation of one presynaptic receptor by another. Because SP inhibits the ATP stimulation of glycine release, SP may play a significant role in hyperalgesia or chronic pain.
Adenosine Triphosphate↗
Expression and characterization of soluble human parainfluenza virus type 1 hemagglutinin-neuraminidase glycoprotein.
Human parainfluenza virus types 1 (hPIV-1), 2, and 3 represent significant respiratory pathogens for which no antiviral treatment is currently available. To characterize the biochemical functions of the hPIV-1 hemagglutinin-neuraminidase (HN) glycoprotein, a potential target for antiviral therapy, we cloned and expressed a soluble portion of hPIV-1 HN (amino acid residues 137-575), lacking the N-terminal hydrophobic membrane anchorage region, in insect cells using the baculovirus secretion expression system. The expressed HN protein was purified through cation-exchange chromatography followed by metal affinity chromatography, using the 6xHis epitope introduced at the carboxyl terminus of the recombinant protein. N-terminal amino acid sequence analysis of purified HN indicated that the honeybee melittin secretion signal peptide was correctly removed during post-translational processing. Further characterization revealed that the purified HN protein was N-glycosylated and exhibited neuraminidase activity whose characteristics resembled those of the native HN protein of hPIV-1 virions. The establishment of this expression and purification system has allowed us to further explore the biochemical characteristics of paramyxovirus HN and to obtain material that could be suitable for X-ray crystallography studies.
Amino Acid Sequence↗
Copper(II) complexes with N,N'-dialkyl-1,10-phenanthroline-2,9-dimethanamine: synthesis, characterization, DNA-binding thermodynamical and kinetic studies.
Copper(II) complexes (Cu-L, L=N,N'-dialkyl-1,10-phenanthroline-2,9-dimethanamine) were synthesized and characterized by elemental analyses, IR spectra and conductance measurement. The interaction of the copper(II) complex with calf thymus DNA was studied by means of UV melting experiments, fluorescence spectra and circular dichroic spectra. Using ethidium bromide as a fluorescence probe, the binding mode of the complexes Cu-L with calf-thymus DNA was studied spectroscopically. The results indicate that the complexes Cu-L perhaps interact with calf-thymus DNA by both intercalative and covalent binding. Kinetics of binding of the cupric complexes to DNA was studied for the first time using ethidium bromide as a fluorescence probe with stopped-flow spectrophotometer under pseudo-first-order condition. The stronger binding of two steps in the process of the complexes Cu-L interacting with DNA was observed, and the probable interaction process was discussed in detail. The corresponding k(obs) and E(a) of binding to DNA (where k(obs) is the observed pseudo-first-order rate constant, E(a) is the observed energy of activation) were obtained.
Amines↗
Multi-component body composition models: recent advances and future directions.
OBJECTIVE: This overview examines concepts related to a category of body composition methods generally referred to as multi-component models, that is, those models that include three or more components. We summarize the rationale for, applications, and types of multi-component models along with sources of error. Our review presents the strengths and limitations of available models and identifies important future research directions.
Body Composition↗
Skeletal muscle mass and aging: regional and whole-body measurement methods.
Skeletal muscle is a large compartment that can now be quantified using research and clinically applicable regional and whole-body methods. The most important advances are the two imaging methods, computed tomography (CT) and magnetic resonance imaging (MRI). Both CT and MRI can serve as regional and whole-body reference methods when evaluating other approaches for estimating skeletal muscle mass. Imaging methods also afford the opportunity to quantify both anatomic skeletal muscle and the smaller adipose-tissue free skeletal muscle component. Other available methods for estimating skeletal muscle, either regional or at the whole body level, include dual-energy x-ray absorptiometry, in vivo neutron activation analysis-whole body counting, anthropometry, ultrasound, bioimpedance analysis, and urinary metabolite markers. Each method is reviewed in the context of the aging process, cost, availability, practicality, and desired accuracy. New insights should be possible when skeletal muscle mass, measured using these methods, is combined with other descriptors of muscle biochemical and mechanical function.
Absorptiometry, Photon↗
cAMP-dependent presynaptic regulation of spontaneous glycinergic IPSCs in mechanically dissociated rat spinal cord neurons.
Spontaneous miniature glycinergic inhibitory postsynaptic currents (mIPSCs) in mechanically dissociated rat sacral dorsal commissural nucleus (SDCN) neurons attached with intact glycinergic presynaptic nerve terminals and evoked IPSCs (eIPSCs) in the slice preparation were investigated using nystatin-perforated patch and conventional whole cell recording modes under the voltage-clamp conditions. Trans-ACPD (tACPD) reversibly reduced the mIPSC frequency without affecting the mean amplitude. The effect was mimicked by a specific metabotropic glutamate receptor (mGluR) II subtype agonist, (2S, 1'S, 2'S)-2-(carboxycyclo propyl) glycine (L-CCG-I), and a specific mGluRIII subtype agonist, 2-amino-4-phosphonobutyrate (L-AP4). These inhibitory effects on mIPSC frequency were blocked by the specific antagonists for mGluRII, alpha-methyl-1-(2S, 1'S, 2'S)-2-(carboxycyclo propyl) glycine and (RS)-alpha-cyclopropyl-4-phosphonophenylglycine. In the slice preparation, eIPSC amplitude and mIPSC frequency were decreased reversibly by L-CCG-I (10(-6) M) and L-AP4 (10(-6) M). In K(+)-free or K(+)-free external solution with Ba(2+) and Cs(+), Ca(2+)-free or Cd(2+) external solution, the inhibitory effect of tACPD on mIPSC frequency was unaltered. Forskolin and 8-Br-cAMP significantly increased presynaptic glycine release, and prevented the inhibitory action of tACPD on mIPSC frequency. Sp-cAMP, however, did not prevent the inhibitory action of tACPD on mIPSC frequency. It was concluded that the activation of mGluRs inhibits glycine release by reducing the action of cAMP/PKA pathway.
8-Bromo Cyclic Adenosine Monophosphate↗
Both extraneuronal monoamine transporter and O(6)-methylguanine-DNA methyltransferase expression influence the antitumor efficacy of 2-chloroethyl-3-sarcosinamide- 1-nitrosourea in human tumor xenografts.
We previously have found that 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) is a selective cytotoxin that enters cells via the extraneuronal transporter for monoamine transmitters (EMT). Both in vitro and in vivo studies demonstrated that SarCNU was more effective than BCNU against human gliomas. To clarify whether EMT expression correlates with antitumor efficacy of SarCNU, we determined human EMT (EMTh) and O(6)-methylguanine-DNA methyltransferase (MGMT) expression in nine human xenograft models using semiquantitative reverse-transcription polymerase chain reaction. These results were compared with the antitumor effects of SarCNU and the standard chloroethylnitrosourea antitumor agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU). There was no significant correlation between EMTh expression and antitumor efficacy of SarCNU or BCNU. Also, there was no significant correlation between MGMT expression and SarCNU efficacy. However, a significant correlation was found between MGMT expression and BCNU antitumor efficacy. Interestingly, multiple regression analysis demonstrated a significant correlation between SarCNU efficacy and EMTh plus MGMT expression, whereas there was no correlation between BCNU efficacy and MGMT plus EMTh expression. Thus, the absence of a linear correlation between SarCNU efficacy and EMTh expression appears to be due, at least in part, to the presence of DNA repair, specifically, MGMT, in these xenograft models. These studies suggest that MGMT expression alone correlates with BCNU activity, whereas both EMTh and MGMT expression are important determinants of SarCNU activity against human tumor xenograft models. SarCNU is in clinical trials and these results may have important clinical implications.
Animals↗