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Biomedical subjects

K W Li

Publications and source records attributed to K W Li.

At least 19 recordsLinked to original sources

The V-ATPase from etiolated barley (Hordeum vulgare L.) shoots is activated by blue light and interacts with 14-3-3 proteins.

The vacuolar H(+)-ATPase (V-ATPase) is a key enzyme that controls the electrochemical proton potential across endomembranes. Although evidence suggests that V-ATPase is important for photo-morphogenesis, little is known about short-term regulation of V-ATPase upon initiation of the photo-morphogenetic programme by exposure of dark-grown plants to light. In this study, etiolated coleoptiles were given a short blue light treatment and V-ATPase characteristics were determined. The effectiveness of the light treatment was assessed by means of fusicoccin binding to the plasma membrane; this increased 5-fold. The short light treatment also induced a 2-fold to 3-fold increase in the hydrolytic activity of V-ATPase. Members of the 14-3-3 protein family are involved in both blue light perception and the subsequent activation of the P-type ATPase. We provide evidence that 14-3-3 proteins specifically interact with the catalytic A-subunit of the V-ATPase. First, the isolated V1-part of the V-ATPase co-purifies with 14-3-3 on a gel filtration column. Secondly, in an overlay experiment, 14-3-3 interacts with a 68 kDa band that was identified as the V1 A-subunit by mass spectrometry. Thirdly, in 14-3-3 affinity chromatography, both A- and B-subunits of the catalytic moiety of the V-ATPase were identified by matrix-assisted laser desorption ionization tandem time of flight mass spectrometry (MALDI TOF/TOF MS) as 14-3-3-interacting proteins. It was shown that the A-subunit can be phosphorylated in vitro by a tonoplast-bound kinase, whose properties are affected by blue light. Taken together, the data show that besides the P- and F-type H(+)-ATPases, the V-type H(+)-ATPase also interacts with 14-3-3 proteins.

14-3-3 Proteins↗

Peptidomics analysis of neuropeptides involved in copulatory behavior of the mollusk Lymnaea stagnalis.

Male copulation behavior in mollusks is controlled by an array of peptide messengers. In the present study, we have used a peptidomics approach employing liquid chromatography in conjunction with electrospray mass spectrometry to characterize peptides contained in the penial complex of the freshwater snail, Lymnaea stagnalis. In addition to the previously described peptides, we have identified a group of novel peptides that share the carboxyl termini of -FVRIamide. A cDNA cloning study revealed the organization of the precursor, which contains 20 peptide domains with the carboxyl termini of -F(X)RIamide which are flanked by many putative proteolytic sites including the KR and the less commonly occurring (G)K and (G)R sites. In addition, there are several monobasic R and dibasic RR and KK sites that may be used for processing. We then used MALDI-TOF/TOF-MS in a data-dependent mode, which selected all the molecular ion species with the predicted masses of the mature -F(X)RIamide peptides, and performed MS/MS analysis on these peptides. This approach allowed us to identify all the predicted -F(X)RIamide peptides. Immunocytochemistry showed the localization of -FVRIamide immunoreactive neurons in several central ganglia, and immunoreactive axons in the penial complex. Finally, application of synthetic -FVRIamide peptides to an in vitro posterior vas deferens preparation showed inhibitory effect on the spontaneous contraction/relaxation cycle of the vas deferens.

Amino Acid Sequence↗

Auto-inhibitory control of peptidergic molluscan neurons and reproductive senescence.

We recently, characterized a novel peptide of the egg-laying controlling caudodorsal cells (CDC) of Lymnaea stagnalis. Here, we show that the novel peptide has autoinhibitory actions and its expression is significantly up-regulated in reproductively senescent animals. Intracellular recordings show that when bath-applied to the central nervous system in vitro, the peptide reduces the depolarizing after potential (DAP) in CDCs without affecting the action potential-threshold and -amplitude and the resting membrane potential. Moreover, peptide application can terminate an ongoing after discharge in the CDCs or, when electrical stimulation fails to induce an after discharge, can terminate the long-lasting depolarization. Semiquantitative peptide profiling by mass spectrometry demonstrated correct processing and targeting of peptides in the CDC somata and axon terminals of reproductively senescent animals. Interestingly, the level of the autoinhibitory peptide was selectively increased in the CDCs of reproductively senescent animals. Our results indicate that a shift in balance between excitatory and inhibitory auto-transmitter peptides in the CDC system of old non-egg-laying animals, plays a role in after discharge failure in CDCs of reproductively senescent Lymnaea.

Action Potentials↗

LFRFamides: a novel family of parasitation-induced -RFamide neuropeptides that inhibit the activity of neuroendocrine cells in Lymnaea stagnalis.

We report the characterization of a cDNA encoding a novel -RFamide neuropeptide precursor that is up-regulated during parasitation in the snail Lymnaea stagnalis. Processing of this precursor yields five structurally related neuropeptides, all but one ending with the C-terminal sequence -LFRFamide, as was confirmed by direct mass spectrometry of brain tissue. The LFRFamide gene is expressed in a small cluster of neurons in each buccal ganglion, three small clusters in each cerebral ganglion, and one cluster in each lateral lobe of the cerebral ganglia. Application of two of the LFRFamide peptides to neuroendocrine cells that control either growth and metabolism or reproduction induced similar hyperpolarizing K+-currents, and inhibited electrical activity. We conclude that up-regulation of inhibitory LFRFamide neuropeptides during parasitation probably reflects an evolutionary adaptation that allows endoparasites to suppress host metabolism and reproduction in order to fully exploit host energy recourses.

Animals↗

Craniotomies without burr holes using an oscillating saw.

OBJECTIVE: The object of this study is to describe a new method for performing craniotomies which obviates the need for burr holes, improves bony reconstruction, and reduces post-operative cosmetic deformities. Moreover, this technique provides excellent exposure of skull base structures and dural venous sinuses. METHODS: Craniotomies in varied locations are created with the use of a micro-oscillating saw and chisel. No burr holes are used and reconstruction with plates and screws is unnecessary. RESULTS: We initially applied our technique to approaches to the anterior skull base with combined craniofacial tumour resections. We have since performed over 2000 craniotomies of any size and shape in all supratentorial locations using the oscillating saw. CONCLUSIONS: We have found that our method creates better cosmetic results than standard techniques and is safer for craniotomies spanning dural venous sinuses. With experience, operating time was significantly reduced and costs were lowered because reconstruction with fixation devices was not needed.

Brain Neoplasms↗

Spatio-temporal dynamics of the egg-laying-inducing peptides during an egg-laying cycle: a semiquantitative matrix-assisted laser desorption/ionization mass spectrometry approach.

The activity-dependent release of peptides from the neuro-endocrine caudodorsal cell (CDC) system of the freshwater snail Lymnaea stagnalis regulates egg laying and related behaviors. In this study, we optimized a mass spectrometry-based approach to study the spatio-temporal dynamics of peptides that are largely derived from the CDC hormone precursor during an egg-laying cycle and a CDC discharge in vitro. Semi-quantitative peptide mass profiling using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS) indicated a massive depletion of peptides from the neurohemal area in the cerebral commissure (COM) during egg laying and the existence of a reserve pool of peptides in the CDC somata that were transported to the COM to restore peptide levels. The depletion of CDC peptides from the COM was correlated to their release during an induced electrical discharge in vitro. Moreover, MALDI-MS of the releasate revealed extensive truncation of the carboxyl terminal peptide. Finally, two novel peptides of 1788 and 5895 Da, not encoded by the CDC hormone precursor, also exhibited temporal quantitative changes similar to those of CDC peptides. Sequencing of the peptide of 1788 Da by tandem mass spectrometry yielded the novel sequence HF(FH)FYGPYDVFQRDVamide. Together, this implicates a more complex set of CDC peptides for the regulation of egg laying than previously anticipated.

Amino Acid Sequence↗

Tissue engineering of stratified articular cartilage from chondrocyte subpopulations.

OBJECTIVE: To test if subpopulations of chondrocytes from different cartilage zones could be used to engineer cartilage constructs with features of normal stratification. ESIGN: Chondrocytes from the superficial and middle zones of immature bovine cartilage were cultured in alginate, released, and seeded either separately or sequentially to form cartilage constructs. Constructs were cultured for 1 or 2 weeks and were assessed for growth, compressive properties, and deposition, and localization of matrix molecules and superficial zone protein (SZP). RESULTS: The cartilaginous constructs formed from superficial zone chondrocytes exhibited less matrix growth and lower compressive properties than constructs from middle zone chondrocytes, with the stratified superficial-middle constructs exhibiting intermediate properties. Expression of SZP was highest at the construct surfaces, with the localization of SZP in superficial-middle constructs being concentrated at the superficial surface. CONCLUSIONS: Manipulation of subpopulations of chondrocytes can be useful in engineering cartilage tissue with a biomimetic approach, and in fabricating constructs that exhibit stratified features of normal articular cartilage.

Animals↗

Peptidergic modulation of male sexual behavior in Lymnaea stagnalis: structural and functional characterization of -FVamide neuropeptides.

In the simultaneous hermaphrodite snail Lymnaea stagnalis, copulation as a male is controlled by neurons that send axons to the male copulatory organs via a single penis nerve. Using direct mass spectrometry of a penis nerve sample, we show that one of the molecular ions has a mass corresponding to GAPRFVamide, previously identified from the buccal ganglia, and named Lymnaea inhibitory peptide (LIP). The identity of this peptide is confirmed by partial peptide purification from the penis nerve, followed by post source decay mass spectrometry. We cloned the LIP-encoding cDNA, which predicts a prohormone that gives rise to five copies of LIP (now re-named LIP A), two other -FVamide peptides (LIPs B and C), and five structurally unrelated peptides. The LIP gene is expressed in neurons of the right cerebral ventral lobe that send their axons into the penis nerve. We show that the LIP A peptide is present in these neurons and in the penis nerve, and confirmed the presence of LIP B and C in the penis nerve by post source decay mass spectrometry. Finally, we demonstrate that LIP A, B and C inhibit the contractions of the penis retractor muscle, thereby implicating their role in male copulation behavior.

Amino Acid Sequence↗

Adoptive cellular immunotherapy for non-small cell lung cancer: a pilot study.

BACKGROUND: Priming with autologous tumor vaccine followed by ex vivo expansion of activated T cells is a feasible experimental strategy. This paper describes the application of this cellular therapy to treat patients with late-stage non-small-cell lung cancer (NSCLC). METHODS: Twenty-one patients with Stages III and IV NSCLC were treated. Tumor samples were obtained surgically (five patients) or by using aco-axial biopsy needle (16 patients). Each course of vaccination consisted of irradiated tumor cells, mixed with GM-CSF and injected intradermally on Day 1, followed by GM-CSF only on Days 2- 5. The course was repeated 10-14 days later. Lymphocytes were collected 10-14 day after the second course and ex vivo expanded using IL-2 and anti-CD3 Ab. The expansion products were then re-infused into the patients. RESULTS: Twelve out of 16 biopsies resulted in optimal cell numbers for vaccine preparation. Nineteen out of 21 patients achieved a delayed type hypersensitivity (DTH response after two courses of vaccination. In 18/21 patients, the ex vivo expansion products contained > 1.6 x 10(10) cells. Subset analysis showed 77.0-97.2% T cells with a CD4:CD8 ratio of 0.65-4.0; natural killer cells were 2.0-18.6%. There were no significant toxicities. The median survival of all 21 patients was 18.6 months, with a 1-year survival of 51.6%. CONCLUSION: Autologous tumor cell-vaccination may be combined with ex vivo expansion of lymphocytes as adoptive cellular immunotherapy for advanced NSCLC. Overall survival in this cohort of poor prognosis patients compared favorably with results reported in the literature.

Carcinoma, Non-Small-Cell Lung↗

Protein synthesis in synaptosomes: a proteomics analysis.

A proteomics approach was used to identify the translation products of a unique synaptic model system, squid optic lobe synaptosomes. Unlike its vertebrate counterparts, this preparation is largely free of perikaryal cell fragments and consists predominantly of pre-synaptic terminals derived from retinal photoreceptor neurones. We metabolically labelled synaptosomes with [(35)S] methionine and applied two-dimensional gel electrophoresis to resolve newly synthesized proteins at high resolution. Autoradiographs of blotted two-dimensional gels revealed de novo synthesis of about 80 different proteins, 18 of which could be matched to silver-stained gels that were run in parallel. In-gel digestion of the matched spots and mass spectrometric analyses revealed the identities of various cytosolic enzymes, cytoskeletal proteins, molecular chaperones and nuclear-encoded mitochondrial proteins. A number of novel proteins (i.e. not matching with database sequences) were also detected. In situ hybridization was employed to confirm the presence of mRNA and rRNA in synaptosomes. Together, our data show that pre-synaptic endings of squid photoreceptor neurones actively synthesize a wide variety of proteins involved in synaptic functioning, such as transmitter recycling, energy supply and synaptic architecture.

Amino Acid Sequence↗

Functional implications of neurotransmitter expression during axonal regeneration: serotonin, but not peptides, auto-regulate axon growth of an identified central neuron.

We studied the regenerative properties of one of two electrically coupled molluscan neurons, the serotonergic cerebral giant cells (CGCs) of Lymnaea stagnalis, after axotomy. The CGCs play a crucial role in feeding behavior, and when both cells are disconnected from their target neurons, animals no longer feed. When one CGC was permanently disconnected from its targets and the other was reversibly damaged by a nerve crush, the latter one regenerated over a period of 2 weeks to reform functional synapses with specific target neurons. At the same time, recovery of the feeding behavior was observed. After the crush, neuropeptide gene expression in the CGC was downregulated to approximately 50%. Serotonin synthesis, on the other hand, remained unaffected, suggesting that serotonin might have an active role in regeneration. In primary neuron culture, CGCs failed to extend neurites in the presence of serotonin; in cells that extended neurites in the absence of serotonin, focally applied serotonin, but not neuropeptides, induced growth cone collapse. Using serotonin-sensitive sniffer cells, we show that CGC neurites and growth cones release serotonin in culture. Finally, both the spontaneous and stimulation-induced release of serotonin from CGCs in culture resulted in growth cone collapse responses that could be blocked by the serotonin receptor antagonist methysergide. Our data suggest that auto-released serotonin is inhibitory to CGC neurite outgrowth in vitro. During regeneration in vivo, serotonin release might fine-tune axon guidance and branching by inducing local collapse responses in extending neurites.

Animals↗

Structure, localization and potential role of a novel molluscan trypsin inhibitor in Lymnaea.

Eggs and egg masses of the freshwater gastropod mollusc Lymnaea provide a microenvironment for developing embryos. Secretions of the exocrine albumen gland of Lymnaea are packaged in the eggs of an egg mass before the eggs are laid externally. The perivitelline fluid that directly surrounds individual oocytes is the main source of nutrition for developing embryos. During early stages of development, the perivitelline fluid is initially internalized by pinocytosis and degraded by lysosomes; in later stages, the embryo ingests the fluid. We previously found that the albumen gland produces large amounts of Lymnaea epidermal growth factor. The albumen gland also appears to produce significant amounts of a novel Lymnaea trypsin inhibitor (LTI), a second peptide that was purified and characterized from Lymnaea albumen gland extracts. The primary structure was determined by microsequence analysis, mass spectrometry, and C-terminal sequence analysis, and showed that LTI is a 57-residue glycosylated peptide. Comparison of the LTI sequence with other known serine protease inhibitors indicates that LTI is a member of the bovine pancreatic trypsin inhibitor family. Reverse phase-high performance liquid chromatography, microsequence analysis, mass spectrometry, and immunocytochemistry demonstrated that abundant amounts of intact LTI are packaged in egg masses. The presence of a trypsin inhibitor in the perivitelline fluid compartment of the egg mass may minimize digestion of peptides and proteins in the perivitelline fluid that are important for the development of the embryo, for example, Lymnaea epidermal growth factor.

Alkylation↗

Growth responses of cartilage to static and dynamic compression.

During skeletal development, growth, and maturation, gradual changes in the material properties and physical dimensions of cartilage occur under the influence of mechanical loading. The objective of the current study was to compare glycosaminoglyean biosynthesis and cell proliferation in fetal, calf, and adult bovine cartilage explants, isolated from defined depths from the articular surface, in response to controlled compressive loads. Mechanical testing confirmed that for all cartilage samples subjected to load, there was a marked time-averaged (static) compression, whereas the addition of dynamic load at a frequency of 0.01 Hz induced dynamic strain with amplitude and phase shift characteristics typical of stimuli that previously were found to be associated with stimulation of glycosaminoglycan synthesis. In metabolic studies, the application of static loading (84 kPa) for 24 hours inhibited glycosaminoglycan and deoxyribonucleic acid synthesis in all cultured cartilage samples. The superposition of dynamic loading (200 kPa, 0.01 Hz) induced a 20% stimulation of glycosaminoglycan biosynthesis in calf cartilage from the middle-deep zones over statically-loaded samples and an additional approximate 50% suppression of deoxyribonucleic acid synthesis in fetal and calf cartilage from the articular surface. These results indicate that synthesis of glycosaminoglycan and deoxyribonucleic acid, two distinct indices of cartilage growth, are regulated independently by mechanical loading and that cartilage responds differently to static and dynamic loading at different stages of maturation.

Age Factors↗

L-buthionine sulfoximine potentiates the antitumor effect of 4-hydroperoxycyclophosphamide when administered locally in a rat glioma model.

OBJECTIVE: L-buthionine sulfoximine (BSO) inhibits glutathione synthesis and may modulate tumor resistance to some alkylating agents, but it has not been proven effective in the treatment of intracranial neoplasms. To evaluate this drug for the treatment of brain tumors, we studied the use of BSO for potentiating the antineoplastic effect of 4-hydroxyperoxycyclophosphamide (4-HC) in the rat 9L glioma model. METHODS: The survival of male Fischer 344 rats with intracranial 9L gliomas was measured after implantation of controlled-release polymers containing one of the following: no drug, BSO, 4-HC, or both BSO and 4-HC. The efficacy of intracranial 4-HC treatment was assessed with and without serial systemic intraperitoneal BSO injections. Tissue glutathione levels were measured in the brains, tumors, and livers of animals treated with intraperitoneal injections or local delivery of BSO. RESULTS: The median survival of animals treated with intracranial polymers containing 4-HC was 2.3 times greater than that of controls. This survival benefit was doubled by local delivery of BSO. In contrast, systemic BSO therapy did not improve survival time. In animals that were treated systemically, both liver and tumor glutathione levels were significantly lower than they were in control animals. In the locally treated animals, glutathione levels were reduced in the brain tumor but not in the liver. CONCLUSION: These results demonstrate that local but not systemic delivery of BSO enhances the antineoplastic effect of 4-HC in this rat 9L glioma model. In addition, because local delivery of BSO within the brain did not deplete glutathione levels systemically, this method of treatment may be safer than systemic administration of BSO.

Animals↗

Superficial siderosis associated with multiple cavernous malformations: report of three cases.

OBJECTIVE AND IMPORTANCE: Superficial siderosis is a rare but potentially devastating syndrome caused by recurrent subarachnoid hemorrhage. We present three cases of superficial siderosis associated with multiple cavernous malformations, and we review previous reports of superficial siderosis attributable to vascular malformations. CLINICAL PRESENTATION: Patients most commonly present with progressive sensorineural hearing loss, cerebellar ataxia, and pyramidal signs. Magnetic resonance imaging diagnosis may precede symptom development, however. In two of our cases, superficial siderosis was identified on magnetic resonance imaging scans in the absence of clinical symptoms. INTERVENTION: Magnetic resonance imaging studies revealed hemosiderin deposition, characteristic of superficial siderosis, and multiple cavernous malformations in all three cases. Surgical intervention was not pursued. CONCLUSION: We conclude that patients with multiple cavernous malformations and those with perisubarachnoid lesions are at risk for the development of superficial siderosis. Clinicians should recognize the radiographic appearance of superficial siderosis and its clinical presentation in patients with vascular malformations.

Adult↗

Pigment villonodular synovitis of the spine. Case report and review of the literature.

Pigmented villonodular synovitis (PVNS) is a disease of the joints which uncommonly involves the spine. We present a 70-year-old woman with radicular symptoms who was found to have a mass arising from a lumbar zygapophyseal joint with extension into the spinal canal. Following gross-total excision of the mass, histology revealed PVNS. One month after surgery, the patient had no symptoms and there was no evidence of residual or recurrent disease.

Aged↗

Mechanical compression modulates proliferation of transplanted chondrocytes.

The presence of an appropriate number of reparative cells in an articular cartilage defect is probably necessary for consistent and successful repair. Following the transplantation of chondrocytes into a defect, cell proliferation may modulate local defect cellularity. Transplanted cells can be compressed during cartilage repair as a result of joint-loading or press-fitting a graft into a cartilage defect. The objective of this study was to characterize the proliferative response of chondrocytes after attachment to cartilage and application of static compressive stress between cartilaginous surfaces in an ex vivo model. The chondrocytes were isolated from adult bovine cartilage, cultured in high-density monolayer, resuspended, and then transplanted onto the surface of devitalized cartilage at a density of 250,000 cells/cm2. The total DNA content of transplanted cell layers increased steadily to a plateau by 5 days and represented a 4-fold increase in cell number during incubation in medium including serum and ascorbate. Over the culture period, the level of DNA synthesis ([3H]thymidine incorporation), on a per cell basis, decreased steadily (88% between days 0 and 6). The application of 24 hours of static compressive stress (0.06-0.4 MPa) to the adherent cells at 1 and 4 days after transplantation inhibited overall DNA synthesis by 70-approximately 87% compared with unloaded controls. After release from load, cell proliferation generally remained at low levels. The marked proliferation of chondrocytes when attached to cartilage without applied load and the inhibition of this proliferation by relatively low-amplitude static compressive stress may be relevant to the occasional overgrowth of tissue in some chondrocyte transplantation procedures. The dosimetry of these effects suggests that the in vivo mechanical environment may have a marked effect on proliferation of transplanted chondrocytes.

Animals↗

Surgical resection of a cerebral arteriovenous malformation for treatment of superficial siderosis: case report.

BACKGROUND: To our knowledge, there are only two reported cases of cerebral arteriovenous malformation associated with superficial siderosis. In both cases, the patients were asymptomatic and were discovered on retrospective review of magnetic resonance imaging. CASE DESCRIPTION: We describe a case of superficial siderosis in a 47-year-old male with a remote history of closed head injury that presented with progressive hearing loss, cerebellar ataxia, and urinary incontinence. Lumbar puncture was indicative of active subarachnoid bleeding. Cerebral angiography revealed a small vascular malformation that was resected. RESULTS: Pathological examination confirmed the diagnosis of the arteriovenous malformation. Six months after surgery the patient is neurologically stable with no further progression of clinical signs or symptoms. CONCLUSIONS: We report the first case of surgical resection of an intracranial arteriovenous malformation for the treatment of superficial siderosis. We emphasize the necessity of a detailed evaluation when superficial siderosis is suspected to localize and resect potential bleeding sources, because the disease is progressive and often irreversible.

Brain Diseases↗