Controlled dissolution of physically cross-linked locust bean gum - κ-carrageenan hydrogels.

Most hydrogels swell but do not dissolve in water since their chains are tied to each other. Nevertheless, some hydrogels disintegrate under physiological conditions, a property that could be beneficial in emerging applications, including sacrificial materials, 3D bioprinting, and wound dressings. This paper proposes a novel approach to control the dissolution rate of hydrogels based on the integration of kappa carrageenan nanoparticles (KCAR-NPs) into kappa carrageenan (KCAR) and locust bean gum (LBG) hydrogels to obtain a three-component hybrid system. KCAR and LBG are known to have synergistic interactions, where physical interactions and chain entanglements lead to their gelation. We hypothesized that integrating the bulky nanoparticles would disturb the three-dimensional network formed by the polysaccharide chains and enable manipulating the dissolution rate. Compression, water absorption, rheology, and cryo-scanning electron microscopy measurements were performed to characterize the physical properties and structure of the hydrogels. The hybrid hydrogels displayed much faster dissolution rates than a control system without nanoparticles, which did not completely dissolve within 50 days and offered a cutting-edge means to finely adjust hydrogel dissolution through modulation of KCAR and KCAR-NPs concentrations. The new hydrogels also exhibited shear-thinning and self-healing properties resulting from the weak and reversible nature of the physical bonds.

Crosslinking konjac-glucomannan with kappa-carrageenan nanogels: A step toward the design of sacrificial materials.

The challenge in designing sacrificial materials is to obtain materials that are both mechanically stable and easily dissolvable. This research aimed to meet this challenge by fabricating a new polymer-nanogel hydrogel based solely on hydrogen bonds between two polysaccharides. The study focused on hydrogels formed from soluble konjac-glucomannan and nanogels synthesized from kappa-carrageenan. This novel hydrogel exhibited self-healing and shear-thinning properties due to its weak physical interactions. The hydrogel dissolved simultaneously with its swelling. Changes in temperature or nanogel concentration, or the addition of potassium ions, altered the swelling and dissolution rates. Furthermore, adding KCl to the as-prepared hydrogel increased its compression and tensile moduli and its strength. The new formulation opens numerous possibilities as a potential sacrificial material for different applications since it is mechanically stable yet rapidly dissolves in physiological conditions without applying high temperatures or using chelating agents.

Utility and validity of DISC1 mouse models in biological psychiatry.

We have seen an era of explosive progress in translating neurobiology into etiological understanding of mental disorders for the past 10-15 years. The discovery of Disrupted-in-schizophrenia 1 (DISC1) gene was one of the major driving forces that have contributed to the progress. The finding that DISC1 plays crucial roles in neurodevelopment and synapse regulation clearly underscored the utility and validity of DISC1-related biology in advancing our understanding of pathophysiological processes underlying psychiatric conditions. Despite recent genetic studies that failed to identify DISC1 as a risk gene for sporadic cases of schizophrenia, DISC1 mutant mice, coupled with various environmental stressors, have proven successful in satisfying face validity as models of a wide range of human psychiatric conditions. Investigating mental disorders using these models is expected to further contribute to the circuit-level understanding of the pathological mechanisms, as well as to the development of novel therapeutic strategies in the future.

Role for neonatal D-serine signaling: prevention of physiological and behavioral deficits in adult Pick1 knockout mice.

NMDA glutamate receptors have key roles in brain development, function and dysfunction. Regulatory roles of D-serine in NMDA receptor-mediated synaptic plasticity have been reported. Nonetheless, it is unclear whether and how neonatal deficits in NMDA-receptor-mediated neurotransmission affect adult brain functions and behavior. Likewise, the role of D-serine during development remains elusive. Here we report behavioral and electrophysiological deficits associated with the frontal cortex in Pick1 knockout mice, which show D-serine deficits in a neonatal- and forebrain-specific manner. The pathological manifestations observed in adult Pick1 mice are rescued by transient neonatal supplementation of D-serine, but not by a similar treatment in adulthood. These results indicate a role for D-serine in neurodevelopment and provide novel insights on how we interpret data of psychiatric genetics, indicating the involvement of genes associated with D-serine synthesis and degradation, as well as how we consider animal models with neonatal application of NMDA receptor antagonists.

DISC1 regulates trafficking and processing of APP and Aß generation.

We report the novel regulation of proteolytic processing of amyloid precursor protein (APP) by DISC1, a major risk factor for psychiatric illnesses, such as depression and schizophrenia. RNAi knockdown of DISC1 in mature primary cortical neurons led to a significant increase in the levels of intracellular α-C-terminal fragment of APP (APP-CTFα) and the corresponding N-terminal-secreted ectodomain product sAPPα. DISC1 knockdown also elicited a significant decrease in the levels of amyloid beta (Aß)42 and Aß40. These aberrant proteolytic events were successfully rescued by co-expression of wild-type DISC1, but not by mutant DISC1 lacking the amino acids required for the interaction with APP, suggesting that APP-DISC1 protein interactions are crucial for the regulation of the C-terminal proteolysis. In a genetically engineered model in which a major full-length DISC1 isoform is depleted, consistent changes in APP processing were seen: an increase in APP-CTFα and decrease in Aß42 and Aß40 levels. Finally, we found that knockdown of DISC1 increased the expression of APP at the cell surface and decreased its internalization. The presented DISC1 mechanism of APP proteolytic processing and Aß peptide generation, which is central to Alzheimer's disease pathology, suggests a novel interface between neurological and psychiatric conditions.

Unique pharmacological actions of atypical neuroleptic quetiapine: possible role in cell cycle/fate control.

Quetiapine is an atypical neuroleptic with a pharmacological profile distinct from classic neuroleptics that function primarily via blockade of dopamine D2 receptors. In the United States, quetiapine is currently approved for treating patients with schizophrenia, major depression and bipolar I disorder. Despite its widespread use, its cellular effects remain elusive. To address possible mechanisms, we chronically treated mice with quetiapine, haloperidol or vehicle and examined quetiapine-specific gene expression change in the frontal cortex. Through microarray analysis, we observed that several groups of genes were differentially expressed upon exposure to quetiapine compared with haloperidol or vehicle; among them, Cdkn1a, the gene encoding p21, exhibited the greatest fold change relative to haloperidol. The quetiapine-induced downregulation of p21/Cdkn1a was confirmed by real-time polymerase chain reaction and in situ hybridization. Consistent with single gene-level analyses, functional group analyses also indicated that gene sets associated with cell cycle/fate were differentially regulated in the quetiapine-treated group. In cortical cell cultures treated with quetiapine, p21/Cdkn1a was significantly downregulated in oligodendrocyte precursor cells and neurons, but not in astrocytes. We propose that cell cycle-associated intervention by quetiapine in the frontal cortex may underlie a unique efficacy of quetiapine compared with typical neuroleptics.

Enhanced dopamine function in DISC1-L100P mutant mice: implications for schizophrenia.

Significant advances have been made in understanding the role of disrupted-in-schizophrenia-1 (DISC1) in the brain and accumulating findings suggest the possible implication of DISC1 in the regulation of dopamine (DA) function. A mutation in the second exon of DISC1 at L100P leads to the development of schizophrenia-related behavior in mutant mice (DISC1-L100P). We investigated here the role of DA in the expression of schizophrenia-related endophenotypes in the DISC1-L100P genetic mouse model. The mutated DISC1 resulted in facilitation of the psychostimulant effect of amphetamine in DISC1-L100P mutant mice assessed in the open field and prepulse inhibition (PPI) tests. Biochemical studies detected a 2.1-fold increase in the proportion of striatal D receptors without significant changes in DA release in vivo in the striatum of DISC1-L100P mutants in response to the low dose of amphetamine. The D(2) receptor antagonist haloperidol reversed the hyperactivity, PPI and latent inhibition (LI) deficits and blocked the psychostimulant effect of amphetamine in DISC1-L100P mutants. Taken together, our findings show the role of DISC1 in D(2) -related pathophysiological mechanism of schizophrenia, linking DISC1 with well-established DA hypothesis of schizophrenia.

Change of colloidal and surface properties of Mytilus edulis foot protein 1 in the presence of an oxidation (NaIO4) or a complex-binding (Cu2+) agent.

Quartz crystal microbalance with dissipation monitoring (QCM-D) was used to study the viscoelastic properties of the blue mussel, Mytilus edulis, foot protein 1 (Mefp-1) adsorbed on modified hydrophobic gold surfaces. The change in viscoelasticity was studied after addition of Cu2+ and Mn2+, which theoretically could induce metal complex formation with 3,4-dihydroxyphenylalanine (DOPA) moieties. We also used NaIO4, a nonmetal oxidative agent known to induce di-DOPA formation. Reduction in viscoelasticity of adsorbed Mefp-1 followed the order of NaIO4 > Cu2+ > buffer control > Mn2+. We also studied the formation of molecular aggregates of Mefp-1 in solution with the use of dynamic light scattering (DLS). We found that addition of Cu2+, but not Mn2+, induced the formation of larger DLS-detectable aggregates. Minor aggregate formation was found with NaIO4. With the analytical resolution of small angle X-ray scattering (SAXS), we could detect differences in the molecular structure between NaIO4- and Cu2+-treated Mefp-1 aggregates. We concluded from this study that Cu2+ could participate in intermolecular cross-linking of the Mefp-1 molecule via metal complex formation. Metal incorporation in the protein most likely increases the abrasion resistance of the Mefp-1 layer. NaIO4, on the other hand, resulted in mainly intramolecular formation of di-DOPA, but failed to induce larger intermolecular aggregation phenomena. The described methodological combination of surface sensitive methods, like QCM-D, and bulk sensitive methods, like DLS and SAXS, generates high resolution results and is an attractive platform to investigate intra- and intermolecular aspects of assembly and cross-linking of the Mefp proteins.

Ligand accessibility as means to control cell response to bioactive bilayer membranes.

We report a new method to create a biofunctional surface in which the accessibility of a ligand is used as a means to influence the cell behavior. Supported bioactive bilayer membranes were created by Langmuir-Blodgett (LB) deposition of either a pure poly(ethylene glycol) (PEG) lipid, having PEG head groups of various lengths, or 50 mol % binary mixtures of a PEG lipid and a novel collagen-like peptide amphiphile on a hydrophobic surface. The peptide amphiphile contains a peptide synthetically lipidated by covalent linkage to hydrophobic dialkyl tails. The amphiphile head group lengths were determined using neutron reflectivity. Cell adhesion and spreading assays showed that the cell response to the membranes depends on the length difference between head groups of the membrane components. Cells adhere and spread on mixtures of the peptide amphiphile with the PEG lipids having PEG chains of 120 and 750 molecular weight (MW). In contrast, cells adhered but did not spread on the mixture containing the 2000 MW PEG. Cells did not adhere to any of the pure PEG lipid membranes or to the mixture containing the 5000 MW PEG. Selective masking of a ligand on a surface is one method of controlling the surface bioactivity.

Synthetic S-2 and H-5 segments of the Shaker K+ channel: secondary structure, membrane interaction, and assembly within phospholipid membranes.

Current models of voltage-activated K+ channels predict that the channels are formed by the coassembly of four polypeptide monomers, each of which consists of six transmembrane segments (S1-S6) and long terminal domains. The aqueous pores are thought to be composed of the conserved H-5 regions contributed by four monomers. In this study, two putative membrane-embedded segments of the Shaker K+ channel were synthesized. One segment corresponds to the putative, transmembrane helix S-2 (amino acids 275-300), and the other corresponds to the highly conserved 12 amino acid residues within the H-5 region [amino acids 432-443, designated (12)H-5]. Structural and functional characterization at elevated lipid/peptide molar ratios (> 3000:1) was performed on the two segments, as well as on a previously synthesized 21 amino acid long peptide with a sequence resembling the entire H-5 region (designated (21)H-5) (Peled & Shai, 1993). Circular dichroism spectroscopy revealed that S-2 adopts predominantly alpha-helical structure in both trifluoroethanol and 35 mM SDS (78% or 99%, respectively), while (12)H-5 and (21)H-5 adopt low alpha-helical structure only in the presence of 35 mM SDS. Functional characterization demonstrated that S-2 and (12)H-5 segments bind to zwitterionic phospholipids, with partition coefficients on the order of 10(4) M-1. Resonance energy transfer measurements, between donor/acceptor-labeled pairs of peptides, revealed that the peptides self-associate in their membrane-bound state, which may correlate with the existence of functional interactions between the conserved (12)H-5 regions of different subunits of K+ channels (Kirsch et al., 1993).(ABSTRACT TRUNCATED AT 250 WORDS)

The Gulf War: pediatric emergency room function.

PURPOSE: To analyze the effects of war on the civilian population through patterns of medical service consumption in a pediatric emergency room. METHODOLOGY: A survey of variables related to use of emergency room services before, during, and after the Gulf War. RESULTS: There was a dramatic decrease in the number of visits during the war. During the war, there were fewer visits for URI, home accidents and intoxications; there were more visits for complaints such as headaches, restlessness, and tremors. CONCLUSIONS: Visits during the ware were more related to emergency situations with fewer visits of the walk-in clinic type.

Membrane interaction and self-assembly within phospholipid membranes of synthetic segments corresponding to the H-5 region of the shaker K+ channel.

The voltage-activated K+ channels are assumed to be formed by the coassembly of four polypeptide monomers. Each of these monomers is postulated to consist of six transmembrane segments (S1 to S6), and long N- and C-terminal domains. The highly conserved linker, H-5, between the fifth and the sixth transmembrane segments, is hypothesized to line the lumen of the K+ channel formed by the bundle of the transmembrane segments of the monomers. Herein we utilize the spectrofluorometric approach and investigate the interaction with phospholipid membranes of fluorescently-labeled synthetic peptides, whose sequences are derived from the H-5 region. Binding experiments reveal that the peptides can strongly bind to phospholipid membranes with partition coefficients on the order of 10(4) M-1. However, a truncated peptide without four amino acids within the most conserved region (amino acids 432-435) did not bind to the membranes at all. Moreover, the single substitution of a conserved tryptophan at position 435 to serine reduced the partition coefficient of the peptide approximately 5-fold, which may account for a mutated K+ channel with this substitution not producing functional channels (Yool & Schwarz, 1991). Structural characterization using circular dichroism spectroscopy (CD) reveals that H-5 can partially adopt an alpha-helix structure in hydrophobic environments. Resonance energy transfer (RET) experiments reveal that the H-5-derived segments can self-assemble within the membrane but cannot coassemble with other unrelated membrane-bound peptides. The results herein support the hypothesis that H-5 segments are packed in close proximity and might participate in mediating the appropriate assembly of the core region of K+ channel monomers.

Atrial infarction: diagnosis and management.

Atrial infarction has been a relatively understudied entity. Its incidence by autopsy study has been widely variable, from 0.7% to 42%, with the largest series of 182 patients demonstrating an incidence of 17%. The right atrium is involved five times as often as the left, with the auricle the predominant site in either atria. Clinical atrial infarction may present with supraventricular arrhythmias, atrial rupture, hemodynamic compromise from loss of atrial "kick," and thromboembolic phenomena. Diagnosis currently is made in an appropriate clinical setting with characteristic PR interval changes. Other noninvasive techniques have shown only limited diagnostic utility, but esophageal echocardiography may prove to be a useful technique in this setting.

Calcium channel blockers in systemic hypertension.

Alterations in transmembrane flux of calcium ions may be playing a role in the pathophysiology of systemic hypertension. Calcium channel blockers have been shown to be effective antihypertensive drugs with excellent safety profiles. They are efficacious in the long term treatment of systemic hypertension in all population subgroups, and have special applicability for treating patients with hypertensive urgencies and individuals with concomitant diseases such as angina pectoris and arrhythmias.

Prognostic factors in acute pulmonary edema.

Over a six-month period, 106 admissions of 94 patients for acute pulmonary edema were identified and their charts were reviewed. Precipitating factors for acute pulmonary edema included progressively worsening congestive heart failure in 25.5% of cases, coronary insufficiency in 20.8%, subendocardial myocardial infarction in 16.0%, acute transmural myocardial infarction in 10.4%, arrhythmia in 8.5%, medical noncompliance in 6.6%, and other causes in 12.6%. In-hospital mortality was 17.0% (16 patients). Of those patients discharged from the hospital, an additional 27 (39.7%) were dead at one year, giving an overall one-year mortality of 51.2%. We found that patients with progressively worsening congestive heart failure have a better prognosis than patients with other precipitants. Also, patients with an initial systolic blood pressure in the emergency room of 160 mm Hg or higher had an improved survival over patients with an initial systolic blood pressure under 160 mm Hg. No other in-hospital or long-term prognostic factors were identified.

Calcium entry blockers for the treatment of severe hypertension and hypertensive crisis.

Calcium entry blockers (diltiazem, nifedipine, and verapamil) are currently indicated for the treatment of patients with vasospastic and chronic stable angina pectoris. The calcium entry blocking actions of these drugs cause potent peripheral vasodilatory and antihypertensive effects in human subjects. The drugs have proved beneficial in the treatment of patients with severe hypertension and hypertensive emergencies. Single oral, sublingual, and intravenous doses of these drugs have been shown to rapidly and smoothly reduce blood pressure in adults and children, without significant untoward effects. The absolute reduction in blood pressure with treatment appears to be inversely correlated with the pretreatment blood pressure level, and few episodes of hypotension have been reported. Combinations of calcium entry blockers with other antihypertensive regimens have also proved effective. Some patients experience a mild increase in heart rate with nifedipine, an effect that appears to be inversely related to age. Side effects are minimal and not life-threatening. Continuous hemodynamic monitoring of patients does not seem necessary in most cases. The role of calcium entry blockade in the treatment of hypertensive emergencies still needs to be established in relation to other available approved drug regimens for this condition.