Biomedical subjects

Ming Lei

Publications and source records attributed to Ming Lei.

At least 19 recordsLinked to original sources

PubMed2026

Genome-Wide Characterization of PEBP, FD, and GRF Families in Amomum villosum Lour. and Their Potential Roles in Flowering.

A detailed understanding of the molecular mechanisms governing the flowering time of Amomum villosum Lour., a medicinal plant within the Zingiberaceae family, is currently lacking. In modern plants, the florigen activation complex (FAC), which includes PEBP, FD/bZIP, and GRF proteins, is known to regulate flowering. In this study, we identified 13 PEBP, 5 FD, and 19 GRF genes within the A. villosum genome and conducted phylogenetic, structural and promoter analysis. Notably, cross-species protein-protein interaction predictions and yeast two-hybrid assays uncovered an unexpected interaction pattern: an AREB3-like FD protein (AvFD5) and a GRF protein (AvGRF13) directly interact with specific PEBP members, whereas canonical FD-like proteins (AvFD1 and AvFD4) did not, which contrasts with the classical rice FAC model (Hd3a-14-3-3-OsFD1). These results imply that FAC assembly in A. villosum may involve alternative components or regulatory mechanisms, potentially indicating lineage-specific divergence within monocots. This research represents the first systematic characterization of FAC core gene families in A. villosum and Zingiberaceae, laying the groundwork for understanding flowering time regulation and facilitating future molecular breeding efforts in this economically significant plant.

Amomum villosum↗

PubMed2025

Inflammation and mutational burden differentially associated with nivolumab or ipilimumab combination efficacy in colorectal cancer.

Nivolumab alone and in combination with ipilimumab demonstrated durable clinical benefit in patients with previously treated microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer in the phase 2 CheckMate 142 study. Here, we report exploratory biomarker analyses from CheckMate 142 evaluating associations between various tissue biomarkers and the efficacy of nivolumab monotherapy and nivolumab plus ipilimumab combination in these patients. Higher expression of inflammation-related gene expression signatures is associated with improved response per investigator assessment and survival benefit with nivolumab monotherapy. In contrast, higher tumor mutational burden, tumor indel burden, and degrees of microsatellite instability are associated with improved response per investigator assessment and survival benefit with nivolumab plus ipilimumab. While interpretation is limited by the exploratory nature of these analyses, they suggest that tumor antigenicity rather than baseline tumor inflammation might be important for the combinatorial efficacy. Validation of these findings in larger, randomized studies is necessary.

Humans↗

PubMed2006

Organisation of the mouse sinoatrial node: structure and expression of HCN channels.

OBJECTIVE: To reveal the structural characteristics of the sinoatrial node (SAN) and the distribution of hyperpolarization-activated cyclic nucleotide-gated cation channels (HCN) in the SAN in the mouse. METHODS: The structure of the SAN and the distribution of HCN channels in the SAN in the mouse were studied by histology and immunolabelling of ANP, Cx43 and HCN channels. RESULTS: The mouse SAN is a comma-shaped structure with a length of approximately 1.5 mm parallel to the crista terminalis and is separated from atrial muscle by connective tissue at the border both with the crista terminalis and the atrial septum. A unique compact nodal structure with densely-packed nodal cells was identified at the head of the comma-shaped SAN. Cell size and fibre orientation vary regionally in the SAN: the cells in the compact node are small and are orientated perpendicular to the crista terminalis, whereas the cells in the more inferior part are larger and more loosely-packed and are orientated parallel to the crista terminalis. All SAN cells exhibited labelling of HCN4, but no cell exhibited detectable labelling of HCN1, HCN2, ANP and Cx43, while surrounding atrial cells exhibited labelling of ANP and Cx43, but not HCN1, HCN2 and HCN4. A specialised interface between the SAN and surrounding atrial muscle was also identified: strands of HCN4-positive nodal cells protrude into the atrial muscle and strands of Cx43-positive atrial cells protrude into the SAN; thus, there are interdigitations between the SAN and atrial muscle. CONCLUSIONS: In the mouse, (i) the SAN is structurally complex with a densely-packed head and loosely-packed tail; (ii) HCN4 is the only HCN isoform detectable and is present throughout the SAN; and (iii) there is a specialised interface between the SAN and surrounding atrium that may be necessary for the SAN to drive the more hyperpolarized atrial muscle.

Action Potentials↗

PubMed2006

Crystal structure of human histone lysine-specific demethylase 1 (LSD1).

Lysine-specific demethylase 1 (LSD1) was recently identified as the first histone demethylase that specifically demethylates monomethylated and dimethylated histone H3 at K4. It is a component of the CoREST and other corepressor complexes and plays an important role in silencing neuronal-specific genes in nonneuronal cells, but the molecular mechanisms of its action remain unclear. The 2.8-A-resolution crystal structure of the human LSD1 reveals that LSD1 defines a new subfamily of FAD-dependent oxidases. The active center of LSD1 is characterized by a remarkable 1,245-A3 substrate-binding cavity with a highly negative electrostatic potential. Although the protein core of LSD1 resembles other flavoenzymes, its enzymatic activity and functions require two additional structural modules: an N-terminal SWIRM domain important for protein stability and a large insertion in the catalytic domain indispensable both for the demethylase activity and the interaction with CoREST. These results provide a framework for further probing the catalytic mechanism and the functional roles of LSD1.

Catalytic Domain↗

PubMed2006

Remodeling of the cardiac pacemaker L-type calcium current and its beta-adrenergic responsiveness in hypertension after neuronal NO synthase gene transfer.

Hypertension is associated with abnormal neurohumoral activation. We tested the hypothesis that beta-adrenergic hyperresponsiveness in the sinoatrial node (SAN) of the spontaneously hypertensive rat occurs at the level of the L-type calcium current because of altered cyclic nucleotide-dependent signaling. Furthermore, we hypothesized that NO, a modulator of cGMP and cAMP, would normalize the beta-adrenergic phenotype in the hypertensive rat. Chronotropic responsiveness to norepinephrine (NE), together with production of cAMP and cGMP, was assessed in isolated atrial preparations from age-matched hypertensive and normotensive rats. Right atrial/SAN pacemaking tissue was injected with adenovirus encoding enhanced green fluorescent protein (control vector) or neuronal NO synthase (nNOS). In addition, L-type calcium current was measured in cells isolated from the SAN of transfected animals. Basal levels of cGMP were lower in hypertensive rat atria. These atria were hyperresponsive to NE at all of the concentrations tested, with elevated production of cAMP. This was accompanied by increased basal and norepinephrine-stimulated L-type calcium current. Using enhanced green fluorescent protein, we observed transgene expression within both tissue sections and isolated pacemaking cells. Adenoviral nNOS increased right atrial nNOS protein expression and cGMP content. NE-stimulated cAMP concentration and L-type calcium current were also attenuated by adenoviral nNOS, along with the chronotropic responsiveness to NE in hypertensive rat atria. Decreased calcium current after cardiac nNOS gene transfer contributes to the normalization of beta-adrenergic hyperresponsiveness in the SAN from hypertensive rats by modulating cyclic nucleotide signaling.

Adrenergic alpha-Agonists↗

PubMed2006

The FK506-binding protein, Fpr4, is an acidic histone chaperone.

Fpr4, a FK506-binding protein (FKBP), is a recently identified novel histone chaperone. How it interacts with histones and facilitates their deposition onto DNA, however, are not understood. Here, we report a functional analysis that shows Fpr4 forms complexes with histones and facilitates nucleosome assembly like previously characterized acidic histone chaperones. We also show that the chaperone activity of Fpr4 resides solely in an acidic domain, while the peptidylprolyl isomerase domain conserved among all FKBPs inhibits the chaperone activity. These observations argue that Fpr4, while unique structurally, deposits histones onto DNA for nucleosome assembly through the well-established mechanism shared by other chaperones.

Histone Chaperones↗

PubMed2006

Erythropoietin protects cardiomyocytes from apoptosis via up-regulation of endothelial nitric oxide synthase.

OBJECTIVE: Erythropoietin (EPO), a cytokine best known for its ability to increase red blood cell mass, has recently been shown to protect cardiomyocytes from apoptotic cell death. The objective of the present study was to investigate the role of endothelial nitric oxide synthase (eNOS) in the anti-apoptotic effects of EPO in cardiomyocytes. METHODS AND RESULTS: Neonatal mouse ventricular cardiomyocytes were isolated and cultured from wild-type and eNOS(-/-) mice. Treatment with EPO significantly reduced apoptosis induced by norepinephrine (NE) in the wild-type cardiomyocytes. The reduction of apoptosis was associated with significant increases in eNOS expression, phosphorylation and NO production. However, the anti-apoptotic effects of EPO were significantly decreased in wild-type cardiomyocytes treated with L-NAME, which inhibits nitric oxide synthase activity. The results were further confirmed using eNOS(-/-) cardiomyocytes. To investigate the in vivo significance of eNOS in mediating the anti-apoptotic effects of EPO, wild-type and eNOS(-/-) mice were subjected to myocardial ischemia and reperfusion. EPO decreased myocardial apoptosis and infarct size in wild-type mice. However, the protective effects of EPO were significantly diminished in eNOS(-/-) mice. CONCLUSIONS: EPO increases eNOS expression and NO production in cardiomyocytes. The anti-apoptotic effects of EPO in cardiomyocytes are mediated by eNOS-derived NO production.

Animals↗

PubMed2006

Peptide plane can flip in two opposite directions: implication in amyloid formation of transthyretin.

Transthyretin (TTR) is one of the known 20 or so human proteins that form fibrils in vivo, which is a hallmark of amyloid diseases. Recently, molecular dynamics simulations using ENCAD force field have revealed that under low pH conditions, the peptide planes of several amyloidogenic proteins can flip in one direction to form an alpha-pleated structure which may be a common conformational transition in the fibril formation. We performed molecular dynamics simulations with AMBER force fields on a recently engineered double mutant TTR, which was shown experimentally to form amyloid fibrils even under close to physiological conditions. Our simulations have demonstrated that peptide-plane flipping can occur even under neutral pH and room temperature for this amyloidogenic TTR variant. Unlike previously reported peptide-plane flipping of TTR using ENCAD force field, we have found two-way flipping using AMBER force field. We propose a new mechanism of amyloid formation based on the two-way flipping, which gives a better explanation of various experimental and computational results. In principle, the residual dipolar and hydrogen-bond scalar coupling techniques can be applied to the wild-type TTR and the variant to study the peptide-plane flipping of amyloidogenic proteins.

Amyloid↗

PubMed2006

A hydrogel-based implantable micromachined transponder for wireless glucose measurement.

In this paper, we report on the design and characterization of a new hydrogel-based implantable wireless glucose sensor. The basic device structure is a passive [inductor/capacitor (LC)] micromachined resonator coupled to a stimuli-sensitive hydrogel, which is confined between a stiff nanoporous membrane and a thin glass diaphragm. As glucose molecules pass through the nanoporous membrane, the hydrogel swells and deflects the flexible glass diaphragm, which is the movable plate of the variable capacitor in the totally integrated passive LC resonator. The corresponding change in resonant frequency can be remotely detected. A glucose- sensitive phenylboronic acid-based hydrogel was loaded into the microtransponder, and its sensitivity and time response were measured. Prior to hydrogel loading, the sensitivity of the pressure sensor to applied air pressure was measured to be -222 kHz/kPa over the frequency range 51-->42 MHz. The sensor showed a sensitivity of -34.3 kHz/mM over the glucose concentration range 0-20 mM (at pH 7.4), and a response time of 90 min. The dynamic response, although unacceptable at such values, can be easily improved by decreasing the hydrogel thickness and reducing the sensor and porous membrane thicknesses. The transponder's overall dimensions were 5x5x0.8 mm3, small enough for subcutaneous implantation.

Biosensing Techniques↗

PubMed2006

Normal cells, but not cancer cells, survive severe Plk1 depletion.

We previously reported the phenotype of depletion of polo-like kinase 1 (Plk1) using RNA interference (RNAi) and showed that p53 is stabilized in Plk1-depleted cancer cells. In this study, we further analyzed the Plk1 depletion-induced phenotype in both cancer cells and primary cells. The vector-based RNAi approach was used to evaluate the role of the p53 pathway in Plk1 depletion-induced apoptosis in cancer cells with different p53 backgrounds. Although DNA damage and cell death can occur independently of p53, p53-deficient cancer cells were much more sensitive to Plk1 depletion than cancer cells with functional p53. Next, the lentivirus-based RNAi approach was used to generate a series of Plk1 hypomorphs. In HeLa cells, two weak hypomorphs showed only slight G2/M arrest, a medium hypomorph arrested with 4N DNA content, followed later by apoptosis, and a strong Plk1 hypomorph underwent serious mitotic catastrophe. In well-synchronized HeLa cells, a medium level of Plk1 depletion caused a 2-h delay of mitotic progression, and a high degree of Plk1 depletion significantly delayed mitotic entry and completely blocked cells at mitosis. In striking contrast, normal hTERT-RPE1 and MCF10A cells were much less sensitive to Plk1 depletion than HeLa cells; no apparent cell proliferation defect or cell cycle arrest was observed after Plk1 depletion in these cells. Therefore, these data further support suggestions that Plk1 may be a feasible cancer therapy target.

Apoptosis↗

PubMed2006

Optical image processing using the photoinduced anisotropy of pyrrylfulgide.

A synthesized photochromic compound-pyrrylfulgide--is prepared as a thin film doped in a polymethylmethacrylate (PMMA) matrix. Under irradiation by UV light, the film converts from the bleached state into a colored state that has a maximum absorption at 635 nm and is thermally stable at room temperature. When the colored state is irradiated by a linearly polarized 650 nm laser, the film returns to the bleached state; photoinduced anisotropy is produced during this process. Application of optical image processing methods using the photoinduced anisotropy of the pyrrylfulgide/PMMA film is described. Examples in non-Fourier optical image processing, such as contrast reversal and image subtraction and summation, as well as in Fourier optical image processing, such as low-pass filtering and edge enhancement, are presented.

Anisotropy↗

PubMed2006

Diffuse alveolar lesion in BALB/c mice induced with human reovirus BYD1 strain and its potential relation with SARS.

The objective of this study was to investigate the pathogenicity and associated lesions of a new reovirus (ReoV) isolated from patients with Severe Acute Respiratory Syndrome (SARS) in China. Twenty-five four-week-old BALB/c female mice inoculated intranasally with either ReoV (strain BYD1) alone, or ReoV combined with SARS-CoV (strain BJF) displayed ejecting fur and loss of body weight compared with control animals. ReoV and SARS-CoV were isolated from most postmortem tissues. The histopathological features of ReoV infected animals consisted of diffuse alveolar damage, with scattered hemorrhage, hyaline membrane formation and interstitial pneumonia. A typical type II pneumocyte hyperplasia and fibrogranulomatous tissue formation in the alveolar septae were observed both in the animals inoculated simultaneously with these two viruses and in the animals inoculated firstly with SARS-CoV, followed by ReoV. The animals inoculated firstly with ReoV, followed with SARS-CoV displayed scattered hemorrhage in the alveolar septa. Furthermore, other lesions in above two combination groups included depletion of lymphocytes in the germinal center of lymph nodes in the lung hilus and the spleen, hemorrhagic necrosis in white pulp of spleen, hydroid degeneration, and fatty degeneration in the liver and kidney. Mice induced with SARS-CoV alone did not display clinical signs, characteristically hyaline membrane formation, hemorrhage and early pulmonary fibrosis in lung tissue. This study demonstrated that the newly isolated ReoV might be a virulent pathogen for BALB/c mice. Mice infected firstly with SARS-CoV, followed with ReoV developed a typical diffuse alveolar lesion.

Animals↗

PubMed2006

[Nonlinear dynamics characteristics in alpha rhythm of scalp electroencephalogram].

In regard to the controls and schizophrenia EEGs, we have got alpha rhythm from three points of view and verified the nonlinearity of the three kinds of rhythms. The results show that neither normal EEG alpha nor patients EEG alpha have the typical nonlinear characteristics. Therefore, we could not blindly use the theories of nonlinear dynamics to analyze the rhythm of brain wave.

Alpha Rhythm↗

PubMed2005

Polarization holographic high-density optical data storage in bacteriorhodopsin film.

Optical films containing the genetic variant bacteriorhodopsin BR-D96N were experimentally studied in view of their properties as media for holographic storage. Different polarization recording schemes were tested and compared. The influence of the polarization states of the recording and readout waves on the retrieved diffractive image's intensity and its signal-to-noise ratio were analyzed. The experimental results showed that, compared with the other tested polarization relations during holographic recording, the discrimination between the polarization states of diffracted and scattered light is optimized with orthogonal circular polarization of the recording beams, and thus a high signal-to-noise ratio and a high diffraction efficiency are obtained. Using a He-Ne laser (633 nm, 3 mW) for recording and readout, a spatial light modulator as a data input element, and a 2D-CCD sensor for data capture in a Fourier transform holographic setup, a storage density of 2 x 10(8) bits/cm2 was obtained on a 60 x 42 microm2 area in the BR-D96N film. The readout of encoded binary data was possible with a zero-error rate at the tested storage density.

Journal Article↗

PubMed2005

Route to GaN and VN assisted by carbothermal reduction process.

A route to prepare nitrides, such as GaN, VN, and other nitrides, is reported. The reaction pathway involves a two-step process by using the as-synthesized a-C3N3.69 as precursor. The route is so potent that a series of nitrides can be directly synthesized from their oxides at moderate temperatures. A striking feature of this method lies in that a-C3N3.69 is found to play double roles as both carbonizing and nitridizing agent in these reactions. These results will greatly deepen our understandings of the mechanism for solid-state metathesis reactions.

Journal Article↗

PubMed2005

Polarization multiplexed write-once-read-many optical data storage in bacteriorhodopsin films.

In polymeric films of bacteriorhodopsin (BR) a photoconversion product, which was named the F620 state, was observed on excitation of the film with 532 nm nanosecond laser pulses. This photoproduct shows a strong nonlinear absorption. Such BR films can be used for write-once-read-many (WORM) optical data storage. We demonstrate that a photoproduct similar or even identical to that obtained with nanosecond pulses is generated on excitation with 532 nm femtosecond pulses. This photoproduct also shows strong anisotropic absorption, which facilitates polarization storage of data. The product is thermally stable and is irretrievable to the initial B state either by photochemical reaction or through a thermal pathway. The experimental results indicate that the product is formed by a two-photon absorption process. Optical WORM storage is demonstrated by use of two polarization states, but more polarization states may be used. The combination of polarization data multiplexing and extremely short recording time in the femtosecond range enables very high data volumes to be stored within a very short time.

Journal Article↗

PubMed2005

Generation of functional ion-channel tools by E3 targeting.

Here we describe a strategy for generating ion-channel inhibitors. It takes advantage of antibody specificity combined with a pattern recognition approach that targets the third extracellular region (E3) of a channel. To test the concept, we first focused on TRPC5, a member of the transient receptor potential (TRP) calcium channel family, the study of which has been hindered by poor pharmacological tools. Extracellular application of E3-targeted anti-TRPC5 antibody led to a specific TRPC5 inhibitor, enabling TRPC5 to be distinguished from its closest family members, and TRPC5 function to be explored in a relatively intractable physiological system. E3 targeting was further applied to voltage-gated sodium channels, leading to discovery of a subtype-specific inhibitor of Na(V)1.5. These examples illustrate the potential power of E3 targeting as a systematic method for producing gene-type specific ion-channel inhibitors for use in routine assays on cells or tissues from a range of species and having therapeutic potential.

Antibodies, Monoclonal↗

PubMed2005

Genome sequencing in microfabricated high-density picolitre reactors.

The proliferation of large-scale DNA-sequencing projects in recent years has driven a search for alternative methods to reduce time and cost. Here we describe a scalable, highly parallel sequencing system with raw throughput significantly greater than that of state-of-the-art capillary electrophoresis instruments. The apparatus uses a novel fibre-optic slide of individual wells and is able to sequence 25 million bases, at 99% or better accuracy, in one four-hour run. To achieve an approximately 100-fold increase in throughput over current Sanger sequencing technology, we have developed an emulsion method for DNA amplification and an instrument for sequencing by synthesis using a pyrosequencing protocol optimized for solid support and picolitre-scale volumes. Here we show the utility, throughput, accuracy and robustness of this system by shotgun sequencing and de novo assembly of the Mycoplasma genitalium genome with 96% coverage at 99.96% accuracy in one run of the machine.

Electrophoresis, Capillary↗